Friday, July 16, 2021, marked the end of a week on duty in the hospital, and it was time to celebrate with a nice dinner out with my wife, since COVID-19 masking requirements had been lifted in our part of California for people like us who were fully vaccinated.

We always loved a nice dinner out and missed it so much during the pandemic. Unlike 6 months earlier, when I was administering dexamethasone, remdesivir, and high-flow oxygen to half of the patients on my panel, not a single patient was diagnosed with COVID-19, much less treated for it, during the previous week. We were doing so well in Sacramento that the hospital visitation rules had been relaxed and vaccinated patients were not required to have a negative COVID-19 test prior to hospital admission.

Saturday was game 5 of the NBA finals, so we had two couples join us for the game at our house; no masks because we were all vaccinated. On Sunday, we visited our neighbors who had just had a new baby boy and made them the gift of some baby books. The new mom had struggled with the decision of whether to get vaccinated during her pregnancy, but eventually decided to complete the vaccination cycle prior to delivery. She was fully immune at the time of the baby’s birth, wisely wanting the baby to have passive immunity through her. We kept an appropriate distance, and never touched baby or mom, but since masking guidelines had been lifted for the vaccinated,we didn’t bother with them.

On Monday, I felt a little something in my nose but still pursued my usual workout. Interestingly, my performance wasn’t up to my usual standards. There was a meeting that evening that I had to prepare for, when all of a sudden I felt very fatigued. I lay down and slept for a good hour, which disrupted my preparation. I warned the participants that I was feeling a little under the weather, but they wanted to proceed. At this point, I decided it was time to start wearing a mask again.

More meetings on Tuesday morning, but I made sure that I was fully masked. That little thing in my nose had blown up into a full-scale rhinitis, requiring Kleenex and decongestants. Plus, the fatigue was hitting me very hard. “Dang!” I thought. “I haven’t had a cold since 2019. All those COVID-19 precautions not only worked against COVID-19 (which I never got) but also worked against the common cold, which I had now.”

I finished up my meetings and laid down for a good hour and a half. As the father of two, I had plenty of experience with the common cold, and I knew that plenty of rest and hydration was the key to kicking this thing. Besides, my 55th birthday was coming up, and I wanted to make sure I was fully recovered for the festivities my wife was planning for me. Nonetheless, I scheduled myself for a COVID-19 test. I knew this couldn’t be COVID-19 because I was fully vaccinated, but it was hitting me so hard. It had to be a virus that my body had never seen before; maybe the human metapneumovirus. That was my line of reasoning, anyway.

Wednesday was another day on the couch because of continued severe fatigue and myalgias. I figured another good day of rest would help me kick this cold in time for my birthday celebration. Then the COVID-19 results came back positive. “How could this be? I was vaccinated?!” Admittedly I had been more relaxed with masking, per the CDC and county guidelines, but I always wore a mask when I was seeing patients in the hospital. Yeah, I wasn’t wearing an N95 anymore, and I had given up my goggles months ago, but we just weren’t seeing much COVID-19 anymore, so a plain surgical mask was all that was required and seemed sufficient. I had been reading articles about the new Delta variant that was becoming dominant across the country, and reports were that the vaccine was still effective against the Delta variant. However, I was experiencing the COVID-19 vaccine breakthrough infection because of the remarkable talent the Delta variant has for replicating and producing high levels of viremia.

My first thoughts were for my family, of course. As my illness unfolded, I had kept checking in with them to see if they had any of these “cold” symptoms I had; none of them did. When my test came back positive, we all went into quarantine immediately and they went to get tested; all of them were negative. Next, I contacted the people I had been meeting with that week and warned them that I had tested positive. Despite my mask, and their fully vaccinated status, they needed to get tested. They did, and they were negative. I realized that I was probably contagious, though asymptomatic, on Saturday night when we had friends over to watch the NBA finals. Yeah, everyone was vaccinated, but if I could get sick from this new Delta variant, they could too. The public health department sent me a survey when they found out about my positive test, and they pinpointed Saturday as the day I started to be contagious. I told my friends that I was probably contagious when they were over for the game, and that they should get tested. They did, and everyone came back negative for COVID-19.

Wait a minute; what about Sunday night? The newborn baby and the sleep-deprived mom. Oh no! I was contagious then as well. We kept our distance, and were only there for about 10 minutes, but if I felt bad from COVID-19, I felt worse for exposing them to the virus.

I am no Anthony Fauci, and I am grateful that we have had levelheaded scientists like him to lead us through this terrible experience. I am sure there will be many papers written about COVID-19 breakthrough infections in the future, but I have many thoughts from this experience. First, my practice of wearing an N95 and goggles for all patients, not just COVID-19 patients, during the height of the pandemic was effective. Prior to getting vaccinated, my antibody tests were negative, so I never contracted the illness when I stuck to this regimen. Second, we all want to get back to something that looks like “normal,” but because there are large unvaccinated populations in the community the virus will continue to propagate and evolve, and hence everyone is at risk. While the guidelines said it was okay to ease up on our restrictions, because so many people are not vaccinated, we all must continue to keep our guard up. Third, would a booster shot have saved me from this fate? Because I was on the front lines of the pandemic as a hospitalist, I was also among the first members of my community to get vaccinated, receiving my second shot on Jan. 14, 2021. My wife was not in any risk group, was not on any vaccine priority list, and didn’t complete the series until early April. If I was going to give the infection to anyone, it would have been her. Not only did she never develop symptoms, but she also repeatedly tested negative, as did everyone else that I was in contact with when I was most contagious. The thing that was different about me from everyone else was that I had gotten the vaccine well ahead of them. Had my immunity waned over the months?

The good news is that, while I wouldn’t characterize what I had as “mild,” it certainly wasn’t protracted. Yes, I was a good boy, and did the basics: stay hydrated and get plenty of sleep. I was really bad off for about 3 days, and I hate to think what it would have been like if I had coexisting conditions such as asthma or diabetes. We all know what a bad case of COVID-19 looks like in the unvaccinated, with months in the hospital, intravenous infusions, and high-flow oxygen for the lucky ones. I had nothing remotely like that. The dominant symptom I had was incapacitating fatigue and significant body aches. The second night I had some major chills, sweats, and wild dreams. From a respiratory standpoint, I had bad rhinitis and a wicked cough for a while that tapered off. My oxygen saturations dropped into the mid 90’s, but never below 94%. But if I had been ten times sicker, I doubt I would have survived. I was on quarantine for 10 days but I highly doubt I was at all contagious by day 5, based on my symptoms and the fact that nobody around me turned COVID positive with repeat testing.

I was so relieved that none of my contacts when I was most contagious turned positive for COVID-19. Though not scientific, I find that illustrative. While I should have canceled my meetings on Monday and Tuesday, everybody knew I had a “cold” and nobody wanted to cancel. Nobody thought it possible that I had COVID-19, especially me. The Delta variant is notorious for generating high levels of viremia, yet I didn’t get anybody sick, not even my wife. That suggests to me that, while the vaccine doesn’t eliminate the risk of infection – which we already knew – it probably significantly reduced my infectivity. For that I am very grateful. Now that I can say that I had the COVID-19 experience, I can tell you it feels terrible. But I would have felt much worse if I had gotten others ill. My personal belief is that while the vaccine didn’t save me from disease, it dramatically truncated my illness, and significantly reduced my risk of passing the virus on to my friends and family.

So where did I contract the virus? We were unmasked at dinner on Friday night, which was acceptable in Yolo County at that time. By the way, I actually live in Yolo County, not YOLO (you only live once) county. You can imagine the latter would be a bit more loosey-goosey with the masking requirements. That notwithstanding, I don’t think the dinner was where I picked it up because it was too short of an incubation period. My wife and I obviously reacted differently, as I discussed, but we were both at the restaurant. She didn’t get COVID-19 and I did. I think that I probably picked it up at the hospital, because, while I was wearing a mask there, I was only wearing a surgical mask, not an N95. And I wasn’t wearing goggles anymore. While none of my patients were officially diagnosed with COVID-19, I was encountering a lot of people, getting in relatively close contact, and guidelines were being relaxed, including preadmission COVID-19 testing.

I was an outlier, as I have pointed out; none of my other close contacts contracted COVID-19. A lot of politics and public opinion is driven by outlier cases, and even pure fabrications these days; we certainly can’t create public health policy based on an outlier. I am not suggesting that my experience is any basis for rewriting the rules of COVID-19. The experience has given me pause to think through many facets of this horrible illness we have had to deal with in so many ways, however. And I have also reexamined my own practice for protecting myself in the hospital. Clearly what I was doing in the height of the pandemic was effective, and my more relaxed recent practices were not. Now that I am fully recovered after a relatively unique encounter with the condition, I look forward to seeing what the scientists and public policy makers do with COVID-19 vaccine breakthrough cases. So, between us hospitalist friends and colleagues, regardless of the policy guidelines, I say we keep on masking.

Dr. McIlraith is the founding chairman of the hospital medicine department at Mercy Medical Group in Sacramento. He received the SHM Award for Outstanding Service in Hospital Medicine in 2016.

Friday, July 16, 2021, marked the end of a week on duty in the hospital, and it was time to celebrate with a nice dinner out with my wife, since COVID-19 masking requirements had been lifted in our part of California for people like us who were fully vaccinated.

We always loved a nice dinner out and missed it so much during the pandemic. Unlike 6 months earlier, when I was administering dexamethasone, remdesivir, and high-flow oxygen to half of the patients on my panel, not a single patient was diagnosed with COVID-19, much less treated for it, during the previous week. We were doing so well in Sacramento that the hospital visitation rules had been relaxed and vaccinated patients were not required to have a negative COVID-19 test prior to hospital admission.

Saturday was game 5 of the NBA finals, so we had two couples join us for the game at our house; no masks because we were all vaccinated. On Sunday, we visited our neighbors who had just had a new baby boy and made them the gift of some baby books. The new mom had struggled with the decision of whether to get vaccinated during her pregnancy, but eventually decided to complete the vaccination cycle prior to delivery. She was fully immune at the time of the baby’s birth, wisely wanting the baby to have passive immunity through her. We kept an appropriate distance, and never touched baby or mom, but since masking guidelines had been lifted for the vaccinated,we didn’t bother with them.

On Monday, I felt a little something in my nose but still pursued my usual workout. Interestingly, my performance wasn’t up to my usual standards. There was a meeting that evening that I had to prepare for, when all of a sudden I felt very fatigued. I lay down and slept for a good hour, which disrupted my preparation. I warned the participants that I was feeling a little under the weather, but they wanted to proceed. At this point, I decided it was time to start wearing a mask again.

More meetings on Tuesday morning, but I made sure that I was fully masked. That little thing in my nose had blown up into a full-scale rhinitis, requiring Kleenex and decongestants. Plus, the fatigue was hitting me very hard. “Dang!” I thought. “I haven’t had a cold since 2019. All those COVID-19 precautions not only worked against COVID-19 (which I never got) but also worked against the common cold, which I had now.”

I finished up my meetings and laid down for a good hour and a half. As the father of two, I had plenty of experience with the common cold, and I knew that plenty of rest and hydration was the key to kicking this thing. Besides, my 55th birthday was coming up, and I wanted to make sure I was fully recovered for the festivities my wife was planning for me. Nonetheless, I scheduled myself for a COVID-19 test. I knew this couldn’t be COVID-19 because I was fully vaccinated, but it was hitting me so hard. It had to be a virus that my body had never seen before; maybe the human metapneumovirus. That was my line of reasoning, anyway.

Wednesday was another day on the couch because of continued severe fatigue and myalgias. I figured another good day of rest would help me kick this cold in time for my birthday celebration. Then the COVID-19 results came back positive. “How could this be? I was vaccinated?!” Admittedly I had been more relaxed with masking, per the CDC and county guidelines, but I always wore a mask when I was seeing patients in the hospital. Yeah, I wasn’t wearing an N95 anymore, and I had given up my goggles months ago, but we just weren’t seeing much COVID-19 anymore, so a plain surgical mask was all that was required and seemed sufficient. I had been reading articles about the new Delta variant that was becoming dominant across the country, and reports were that the vaccine was still effective against the Delta variant. However, I was experiencing the COVID-19 vaccine breakthrough infection because of the remarkable talent the Delta variant has for replicating and producing high levels of viremia.

My first thoughts were for my family, of course. As my illness unfolded, I had kept checking in with them to see if they had any of these “cold” symptoms I had; none of them did. When my test came back positive, we all went into quarantine immediately and they went to get tested; all of them were negative. Next, I contacted the people I had been meeting with that week and warned them that I had tested positive. Despite my mask, and their fully vaccinated status, they needed to get tested. They did, and they were negative. I realized that I was probably contagious, though asymptomatic, on Saturday night when we had friends over to watch the NBA finals. Yeah, everyone was vaccinated, but if I could get sick from this new Delta variant, they could too. The public health department sent me a survey when they found out about my positive test, and they pinpointed Saturday as the day I started to be contagious. I told my friends that I was probably contagious when they were over for the game, and that they should get tested. They did, and everyone came back negative for COVID-19.

Wait a minute; what about Sunday night? The newborn baby and the sleep-deprived mom. Oh no! I was contagious then as well. We kept our distance, and were only there for about 10 minutes, but if I felt bad from COVID-19, I felt worse for exposing them to the virus.

I am no Anthony Fauci, and I am grateful that we have had levelheaded scientists like him to lead us through this terrible experience. I am sure there will be many papers written about COVID-19 breakthrough infections in the future, but I have many thoughts from this experience. First, my practice of wearing an N95 and goggles for all patients, not just COVID-19 patients, during the height of the pandemic was effective. Prior to getting vaccinated, my antibody tests were negative, so I never contracted the illness when I stuck to this regimen. Second, we all want to get back to something that looks like “normal,” but because there are large unvaccinated populations in the community the virus will continue to propagate and evolve, and hence everyone is at risk. While the guidelines said it was okay to ease up on our restrictions, because so many people are not vaccinated, we all must continue to keep our guard up. Third, would a booster shot have saved me from this fate? Because I was on the front lines of the pandemic as a hospitalist, I was also among the first members of my community to get vaccinated, receiving my second shot on Jan. 14, 2021. My wife was not in any risk group, was not on any vaccine priority list, and didn’t complete the series until early April. If I was going to give the infection to anyone, it would have been her. Not only did she never develop symptoms, but she also repeatedly tested negative, as did everyone else that I was in contact with when I was most contagious. The thing that was different about me from everyone else was that I had gotten the vaccine well ahead of them. Had my immunity waned over the months?

The good news is that, while I wouldn’t characterize what I had as “mild,” it certainly wasn’t protracted. Yes, I was a good boy, and did the basics: stay hydrated and get plenty of sleep. I was really bad off for about 3 days, and I hate to think what it would have been like if I had coexisting conditions such as asthma or diabetes. We all know what a bad case of COVID-19 looks like in the unvaccinated, with months in the hospital, intravenous infusions, and high-flow oxygen for the lucky ones. I had nothing remotely like that. The dominant symptom I had was incapacitating fatigue and significant body aches. The second night I had some major chills, sweats, and wild dreams. From a respiratory standpoint, I had bad rhinitis and a wicked cough for a while that tapered off. My oxygen saturations dropped into the mid 90’s, but never below 94%. But if I had been ten times sicker, I doubt I would have survived. I was on quarantine for 10 days but I highly doubt I was at all contagious by day 5, based on my symptoms and the fact that nobody around me turned COVID positive with repeat testing.

I was so relieved that none of my contacts when I was most contagious turned positive for COVID-19. Though not scientific, I find that illustrative. While I should have canceled my meetings on Monday and Tuesday, everybody knew I had a “cold” and nobody wanted to cancel. Nobody thought it possible that I had COVID-19, especially me. The Delta variant is notorious for generating high levels of viremia, yet I didn’t get anybody sick, not even my wife. That suggests to me that, while the vaccine doesn’t eliminate the risk of infection – which we already knew – it probably significantly reduced my infectivity. For that I am very grateful. Now that I can say that I had the COVID-19 experience, I can tell you it feels terrible. But I would have felt much worse if I had gotten others ill. My personal belief is that while the vaccine didn’t save me from disease, it dramatically truncated my illness, and significantly reduced my risk of passing the virus on to my friends and family.

So where did I contract the virus? We were unmasked at dinner on Friday night, which was acceptable in Yolo County at that time. By the way, I actually live in Yolo County, not YOLO (you only live once) county. You can imagine the latter would be a bit more loosey-goosey with the masking requirements. That notwithstanding, I don’t think the dinner was where I picked it up because it was too short of an incubation period. My wife and I obviously reacted differently, as I discussed, but we were both at the restaurant. She didn’t get COVID-19 and I did. I think that I probably picked it up at the hospital, because, while I was wearing a mask there, I was only wearing a surgical mask, not an N95. And I wasn’t wearing goggles anymore. While none of my patients were officially diagnosed with COVID-19, I was encountering a lot of people, getting in relatively close contact, and guidelines were being relaxed, including preadmission COVID-19 testing.

I was an outlier, as I have pointed out; none of my other close contacts contracted COVID-19. A lot of politics and public opinion is driven by outlier cases, and even pure fabrications these days; we certainly can’t create public health policy based on an outlier. I am not suggesting that my experience is any basis for rewriting the rules of COVID-19. The experience has given me pause to think through many facets of this horrible illness we have had to deal with in so many ways, however. And I have also reexamined my own practice for protecting myself in the hospital. Clearly what I was doing in the height of the pandemic was effective, and my more relaxed recent practices were not. Now that I am fully recovered after a relatively unique encounter with the condition, I look forward to seeing what the scientists and public policy makers do with COVID-19 vaccine breakthrough cases. So, between us hospitalist friends and colleagues, regardless of the policy guidelines, I say we keep on masking.

Dr. McIlraith is the founding chairman of the hospital medicine department at Mercy Medical Group in Sacramento. He received the SHM Award for Outstanding Service in Hospital Medicine in 2016.

Friday, July 16, 2021, marked the end of a week on duty in the hospital, and it was time to celebrate with a nice dinner out with my wife, since COVID-19 masking requirements had been lifted in our part of California for people like us who were fully vaccinated.

We always loved a nice dinner out and missed it so much during the pandemic. Unlike 6 months earlier, when I was administering dexamethasone, remdesivir, and high-flow oxygen to half of the patients on my panel, not a single patient was diagnosed with COVID-19, much less treated for it, during the previous week. We were doing so well in Sacramento that the hospital visitation rules had been relaxed and vaccinated patients were not required to have a negative COVID-19 test prior to hospital admission.

Saturday was game 5 of the NBA finals, so we had two couples join us for the game at our house; no masks because we were all vaccinated. On Sunday, we visited our neighbors who had just had a new baby boy and made them the gift of some baby books. The new mom had struggled with the decision of whether to get vaccinated during her pregnancy, but eventually decided to complete the vaccination cycle prior to delivery. She was fully immune at the time of the baby’s birth, wisely wanting the baby to have passive immunity through her. We kept an appropriate distance, and never touched baby or mom, but since masking guidelines had been lifted for the vaccinated,we didn’t bother with them.

On Monday, I felt a little something in my nose but still pursued my usual workout. Interestingly, my performance wasn’t up to my usual standards. There was a meeting that evening that I had to prepare for, when all of a sudden I felt very fatigued. I lay down and slept for a good hour, which disrupted my preparation. I warned the participants that I was feeling a little under the weather, but they wanted to proceed. At this point, I decided it was time to start wearing a mask again.

More meetings on Tuesday morning, but I made sure that I was fully masked. That little thing in my nose had blown up into a full-scale rhinitis, requiring Kleenex and decongestants. Plus, the fatigue was hitting me very hard. “Dang!” I thought. “I haven’t had a cold since 2019. All those COVID-19 precautions not only worked against COVID-19 (which I never got) but also worked against the common cold, which I had now.”

I finished up my meetings and laid down for a good hour and a half. As the father of two, I had plenty of experience with the common cold, and I knew that plenty of rest and hydration was the key to kicking this thing. Besides, my 55th birthday was coming up, and I wanted to make sure I was fully recovered for the festivities my wife was planning for me. Nonetheless, I scheduled myself for a COVID-19 test. I knew this couldn’t be COVID-19 because I was fully vaccinated, but it was hitting me so hard. It had to be a virus that my body had never seen before; maybe the human metapneumovirus. That was my line of reasoning, anyway.

Wednesday was another day on the couch because of continued severe fatigue and myalgias. I figured another good day of rest would help me kick this cold in time for my birthday celebration. Then the COVID-19 results came back positive. “How could this be? I was vaccinated?!” Admittedly I had been more relaxed with masking, per the CDC and county guidelines, but I always wore a mask when I was seeing patients in the hospital. Yeah, I wasn’t wearing an N95 anymore, and I had given up my goggles months ago, but we just weren’t seeing much COVID-19 anymore, so a plain surgical mask was all that was required and seemed sufficient. I had been reading articles about the new Delta variant that was becoming dominant across the country, and reports were that the vaccine was still effective against the Delta variant. However, I was experiencing the COVID-19 vaccine breakthrough infection because of the remarkable talent the Delta variant has for replicating and producing high levels of viremia.

My first thoughts were for my family, of course. As my illness unfolded, I had kept checking in with them to see if they had any of these “cold” symptoms I had; none of them did. When my test came back positive, we all went into quarantine immediately and they went to get tested; all of them were negative. Next, I contacted the people I had been meeting with that week and warned them that I had tested positive. Despite my mask, and their fully vaccinated status, they needed to get tested. They did, and they were negative. I realized that I was probably contagious, though asymptomatic, on Saturday night when we had friends over to watch the NBA finals. Yeah, everyone was vaccinated, but if I could get sick from this new Delta variant, they could too. The public health department sent me a survey when they found out about my positive test, and they pinpointed Saturday as the day I started to be contagious. I told my friends that I was probably contagious when they were over for the game, and that they should get tested. They did, and everyone came back negative for COVID-19.

Wait a minute; what about Sunday night? The newborn baby and the sleep-deprived mom. Oh no! I was contagious then as well. We kept our distance, and were only there for about 10 minutes, but if I felt bad from COVID-19, I felt worse for exposing them to the virus.

I am no Anthony Fauci, and I am grateful that we have had levelheaded scientists like him to lead us through this terrible experience. I am sure there will be many papers written about COVID-19 breakthrough infections in the future, but I have many thoughts from this experience. First, my practice of wearing an N95 and goggles for all patients, not just COVID-19 patients, during the height of the pandemic was effective. Prior to getting vaccinated, my antibody tests were negative, so I never contracted the illness when I stuck to this regimen. Second, we all want to get back to something that looks like “normal,” but because there are large unvaccinated populations in the community the virus will continue to propagate and evolve, and hence everyone is at risk. While the guidelines said it was okay to ease up on our restrictions, because so many people are not vaccinated, we all must continue to keep our guard up. Third, would a booster shot have saved me from this fate? Because I was on the front lines of the pandemic as a hospitalist, I was also among the first members of my community to get vaccinated, receiving my second shot on Jan. 14, 2021. My wife was not in any risk group, was not on any vaccine priority list, and didn’t complete the series until early April. If I was going to give the infection to anyone, it would have been her. Not only did she never develop symptoms, but she also repeatedly tested negative, as did everyone else that I was in contact with when I was most contagious. The thing that was different about me from everyone else was that I had gotten the vaccine well ahead of them. Had my immunity waned over the months?

The good news is that, while I wouldn’t characterize what I had as “mild,” it certainly wasn’t protracted. Yes, I was a good boy, and did the basics: stay hydrated and get plenty of sleep. I was really bad off for about 3 days, and I hate to think what it would have been like if I had coexisting conditions such as asthma or diabetes. We all know what a bad case of COVID-19 looks like in the unvaccinated, with months in the hospital, intravenous infusions, and high-flow oxygen for the lucky ones. I had nothing remotely like that. The dominant symptom I had was incapacitating fatigue and significant body aches. The second night I had some major chills, sweats, and wild dreams. From a respiratory standpoint, I had bad rhinitis and a wicked cough for a while that tapered off. My oxygen saturations dropped into the mid 90’s, but never below 94%. But if I had been ten times sicker, I doubt I would have survived. I was on quarantine for 10 days but I highly doubt I was at all contagious by day 5, based on my symptoms and the fact that nobody around me turned COVID positive with repeat testing.

I was so relieved that none of my contacts when I was most contagious turned positive for COVID-19. Though not scientific, I find that illustrative. While I should have canceled my meetings on Monday and Tuesday, everybody knew I had a “cold” and nobody wanted to cancel. Nobody thought it possible that I had COVID-19, especially me. The Delta variant is notorious for generating high levels of viremia, yet I didn’t get anybody sick, not even my wife. That suggests to me that, while the vaccine doesn’t eliminate the risk of infection – which we already knew – it probably significantly reduced my infectivity. For that I am very grateful. Now that I can say that I had the COVID-19 experience, I can tell you it feels terrible. But I would have felt much worse if I had gotten others ill. My personal belief is that while the vaccine didn’t save me from disease, it dramatically truncated my illness, and significantly reduced my risk of passing the virus on to my friends and family.

So where did I contract the virus? We were unmasked at dinner on Friday night, which was acceptable in Yolo County at that time. By the way, I actually live in Yolo County, not YOLO (you only live once) county. You can imagine the latter would be a bit more loosey-goosey with the masking requirements. That notwithstanding, I don’t think the dinner was where I picked it up because it was too short of an incubation period. My wife and I obviously reacted differently, as I discussed, but we were both at the restaurant. She didn’t get COVID-19 and I did. I think that I probably picked it up at the hospital, because, while I was wearing a mask there, I was only wearing a surgical mask, not an N95. And I wasn’t wearing goggles anymore. While none of my patients were officially diagnosed with COVID-19, I was encountering a lot of people, getting in relatively close contact, and guidelines were being relaxed, including preadmission COVID-19 testing.

I was an outlier, as I have pointed out; none of my other close contacts contracted COVID-19. A lot of politics and public opinion is driven by outlier cases, and even pure fabrications these days; we certainly can’t create public health policy based on an outlier. I am not suggesting that my experience is any basis for rewriting the rules of COVID-19. The experience has given me pause to think through many facets of this horrible illness we have had to deal with in so many ways, however. And I have also reexamined my own practice for protecting myself in the hospital. Clearly what I was doing in the height of the pandemic was effective, and my more relaxed recent practices were not. Now that I am fully recovered after a relatively unique encounter with the condition, I look forward to seeing what the scientists and public policy makers do with COVID-19 vaccine breakthrough cases. So, between us hospitalist friends and colleagues, regardless of the policy guidelines, I say we keep on masking.

Dr. McIlraith is the founding chairman of the hospital medicine department at Mercy Medical Group in Sacramento. He received the SHM Award for Outstanding Service in Hospital Medicine in 2016.

After Russell Jordan sent a stool sample through the mail to the microbiome company Viome, his idea of what he should eat shifted. The gym owner in Sacramento, had always consumed large quantities of leafy greens. But the results from the test – which sequenced and analyzed the microbes in a pea-sized stool sample – recommended he steer clear of spinach, kale, and broccoli.

“Things I’ve been eating for the better part of 30 years,” said Mr. Jordan, 31. “And it worked.” Soon, his mild indigestion subsided. He recommended the product to his girlfriend.

She took the test in late February, when the company – which sells its “Gut Intelligence” test for $129 and a more extensive “Health Intelligence” test, which requires a blood sample, for $199 – began experiencing hiccups. Viome had promised results within 4 weeks once the sample arrived at a testing facility, but Mr. Jordan said his girlfriend has been waiting more than 5 months and has submitted fresh blood and stool samples – twice.

Other Viome customers have flocked to social media to complain about similar problems: stool samples lost in the mail, months-long waits with no communication from the company, samples being rejected because of shipping or lab-processing snafus. (I, too, have a stool sample lost in transit, which I mailed after a first vial was rejected because it “leaked.”) The company’s CEO, Naveen Jain, took to Facebook to apologize in late July.

Viome’s troubles provide a cautionary tale for consumers in the wild west of microbiome startups, which have been alternately hailed for health breakthroughs and indicted for fraud.

The nascent industry offers individualized diet regimens based on analyzing gut bacteria – collectively known as the gut microbiome. Consumers pay hundreds of dollars for tests not covered by insurance, hoping to get answers to health problems ranging from irritable bowel syndrome to obesity.

Venture capitalists pumped $1 billion into these kinds of startups from 2015 to 2020, according to Crunchbase, buoyed by promising research and consumers’ embrace of at-home testing. PitchBook has identified more than a dozen direct-to-consumer gut health providers.

But not all the startups are equal. Some are supported by peer-reviewed studies. Others are peddling murky science – and not just because poop samples are getting lost in the mail.

“A lot of companies are interested in the space, but they don’t have the research to show that it’s actually working,” said Christopher Lynch, acting director of the National Institutes of Health Office of Nutrition Research. “And the research is really expensive.”

With nearly $160 million in government funding, the NIH Common Fund’s Nutrition for Precision Health research program, expected to launch by early 2022, seeks to enroll 1 million people to study the interactions among diet, the microbiome, genes, metabolism and other factors.

The gut microbiome is a complex community of trillions of bacteria. Research over the past 15 years has determined that these microbes, both good and bad, are an integral part of human biology, and that altering a person’s gut microbes can fundamentally change their metabolism, immune function – and, potentially, cure diseases, explained Justin Sonnenburg, PhD, a microbiology and immunology associate professor at Stanford (Calif.) University.

Metagenomic sequencing, which identifies the unique set of bugs in someone’s gut (similar to what 23andMe does with its saliva test), has also improved dramatically, making the process cheaper for companies to reproduce.

“It’s seen as one of the exciting areas of precision health,” said Dr. Sonnenburg, who recently coauthored a study that found a fermented food diet increases microbiome diversity – which is considered positive – and reduces markers of inflammation. That includes foods like yogurt, kefir, and kimchi.

“The difficulty for the consumer is to differentiate which of these companies is based on solid science versus overreaching the current limits of the field,” he added via email. “And for those companies based on solid science, what are the limits of what they should be recommending?”

San Francisco–based uBiome, founded in 2012, was one of the first to offer fecal sample testing.

But as uBiome began marketing its tests as “clinical” – and seeking reimbursement from insurers for up to nearly $3,000 – its business tactics came under scrutiny. The company was raided by the FBI and later filed for bankruptcy. Earlier this year, its cofounders were indicted for defrauding insurers into paying for tests that “were not validated and not medically necessary” in order to please investors, the Department of Justice alleges.

But for Tim Spector, a professor of genetic epidemiology at King’s College London and cofounder of the startup Zoe, being associated with uBiome is insulting.

Zoe has spent more than 2 years conducting trials, which have included dietary assessments, standardized meals, testing glycemic responses and gut microbiome profiling on thousands of participants. In January, the findings were published in Nature Medicine.

The company offers a $354 test that requires a stool sample, a completed questionnaire, and then a blood sample after eating muffins designed to test blood fat and sugar levels. Customers can also opt in to a 2-week, continuous glucose monitoring test.

The results are run through the company’s algorithm to create a customized library of foods and meals – and how customers are likely to respond to those foods.

DayTwo, a Walnut Creek, Calif., company that recently raised $37 million to expand its precision nutrition program, focuses on people with prediabetes or diabetes. It sells to large employers – and, soon, to health insurance plans – rather than directly to consumers, charging “a few thousand dollars” per person, said Jan Berger, MD, chief clinical strategist.

Based on a decade of research, DayTwo has worked with nearly 75,000 people. It sends participants a testing kit and survey, and arranges for them to chat with a dietitian while their stool sample is processing. Then, when the results come in, it makes recommendations, Dr. Berger said.

“I can still eat two scoops of ice cream, but I need to add walnuts in it to regulate my blood sugar,” she offered as an example.

Viome says it has tested more than 200,000 customers and has published its methodology for analyzing stool samples, which is different from other gut health companies. But the paper does not address Viome’s larger claims of connecting the microbiome to dietary advice, and researcher Elisabeth Bik called the claims “far fetched” in a 2019 review of the preprint version.

Viome makes additional money by selling supplements, probiotics and prebiotics based on consumers’ test results. It has also rebranded as Viome Life Sciences, expanding into precision diagnostics and therapeutics, such as saliva tests to detect throat cancer. Meanwhile, its gut health program has been mired in logistical missteps.

One customer who posted on Facebook tracked her sample through the U.S. Postal Service as it boomeranged between Los Alamos, N.M., and Bothell, Wash., where it was supposed to be picked up. Another fought for a refund after waiting 6 weeks to hear her sample was not viable and learning a second attempt had expired after spending too long in transit. The company’s expected lab processing time jumped from 4 weeks in February, when Mr. Jordan said his girlfriend took her first test, to 6 in summer. (Three weeks after I mailed my second sample in July, it still hadn’t made it to the lab, so I called it quits and asked for a refund.)

In Mr. Jain’s July apology posted to the private Facebook group for Viome users, he said the company recently moved its lab from New Mexico to Washington state, close to its headquarters, which prompted a mail-forwarding fiasco. It bought new robotics that “refused to cooperate,” he wrote. “Many things didn’t go as planned during the move.”

Spokesperson Kendall Donohue said Viome has been working on the problems but laid much of the blame on the Postal Service.

She also said Viome has been notifying customers – even though many (including myself) had not been contacted.

It is Viome’s “top priority right now to ensure complete customer satisfaction, but unfortunately USPS needs to sort the issue internally for further action to be taken,” she said.

She also offered me a free “Health Intelligence” test. I declined.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

After Russell Jordan sent a stool sample through the mail to the microbiome company Viome, his idea of what he should eat shifted. The gym owner in Sacramento, had always consumed large quantities of leafy greens. But the results from the test – which sequenced and analyzed the microbes in a pea-sized stool sample – recommended he steer clear of spinach, kale, and broccoli.

“Things I’ve been eating for the better part of 30 years,” said Mr. Jordan, 31. “And it worked.” Soon, his mild indigestion subsided. He recommended the product to his girlfriend.

She took the test in late February, when the company – which sells its “Gut Intelligence” test for $129 and a more extensive “Health Intelligence” test, which requires a blood sample, for $199 – began experiencing hiccups. Viome had promised results within 4 weeks once the sample arrived at a testing facility, but Mr. Jordan said his girlfriend has been waiting more than 5 months and has submitted fresh blood and stool samples – twice.

Other Viome customers have flocked to social media to complain about similar problems: stool samples lost in the mail, months-long waits with no communication from the company, samples being rejected because of shipping or lab-processing snafus. (I, too, have a stool sample lost in transit, which I mailed after a first vial was rejected because it “leaked.”) The company’s CEO, Naveen Jain, took to Facebook to apologize in late July.

Viome’s troubles provide a cautionary tale for consumers in the wild west of microbiome startups, which have been alternately hailed for health breakthroughs and indicted for fraud.

The nascent industry offers individualized diet regimens based on analyzing gut bacteria – collectively known as the gut microbiome. Consumers pay hundreds of dollars for tests not covered by insurance, hoping to get answers to health problems ranging from irritable bowel syndrome to obesity.

Venture capitalists pumped $1 billion into these kinds of startups from 2015 to 2020, according to Crunchbase, buoyed by promising research and consumers’ embrace of at-home testing. PitchBook has identified more than a dozen direct-to-consumer gut health providers.

But not all the startups are equal. Some are supported by peer-reviewed studies. Others are peddling murky science – and not just because poop samples are getting lost in the mail.

“A lot of companies are interested in the space, but they don’t have the research to show that it’s actually working,” said Christopher Lynch, acting director of the National Institutes of Health Office of Nutrition Research. “And the research is really expensive.”

With nearly $160 million in government funding, the NIH Common Fund’s Nutrition for Precision Health research program, expected to launch by early 2022, seeks to enroll 1 million people to study the interactions among diet, the microbiome, genes, metabolism and other factors.

The gut microbiome is a complex community of trillions of bacteria. Research over the past 15 years has determined that these microbes, both good and bad, are an integral part of human biology, and that altering a person’s gut microbes can fundamentally change their metabolism, immune function – and, potentially, cure diseases, explained Justin Sonnenburg, PhD, a microbiology and immunology associate professor at Stanford (Calif.) University.

Metagenomic sequencing, which identifies the unique set of bugs in someone’s gut (similar to what 23andMe does with its saliva test), has also improved dramatically, making the process cheaper for companies to reproduce.

“It’s seen as one of the exciting areas of precision health,” said Dr. Sonnenburg, who recently coauthored a study that found a fermented food diet increases microbiome diversity – which is considered positive – and reduces markers of inflammation. That includes foods like yogurt, kefir, and kimchi.

“The difficulty for the consumer is to differentiate which of these companies is based on solid science versus overreaching the current limits of the field,” he added via email. “And for those companies based on solid science, what are the limits of what they should be recommending?”

San Francisco–based uBiome, founded in 2012, was one of the first to offer fecal sample testing.

But as uBiome began marketing its tests as “clinical” – and seeking reimbursement from insurers for up to nearly $3,000 – its business tactics came under scrutiny. The company was raided by the FBI and later filed for bankruptcy. Earlier this year, its cofounders were indicted for defrauding insurers into paying for tests that “were not validated and not medically necessary” in order to please investors, the Department of Justice alleges.

But for Tim Spector, a professor of genetic epidemiology at King’s College London and cofounder of the startup Zoe, being associated with uBiome is insulting.

Zoe has spent more than 2 years conducting trials, which have included dietary assessments, standardized meals, testing glycemic responses and gut microbiome profiling on thousands of participants. In January, the findings were published in Nature Medicine.

The company offers a $354 test that requires a stool sample, a completed questionnaire, and then a blood sample after eating muffins designed to test blood fat and sugar levels. Customers can also opt in to a 2-week, continuous glucose monitoring test.

The results are run through the company’s algorithm to create a customized library of foods and meals – and how customers are likely to respond to those foods.

DayTwo, a Walnut Creek, Calif., company that recently raised $37 million to expand its precision nutrition program, focuses on people with prediabetes or diabetes. It sells to large employers – and, soon, to health insurance plans – rather than directly to consumers, charging “a few thousand dollars” per person, said Jan Berger, MD, chief clinical strategist.

Based on a decade of research, DayTwo has worked with nearly 75,000 people. It sends participants a testing kit and survey, and arranges for them to chat with a dietitian while their stool sample is processing. Then, when the results come in, it makes recommendations, Dr. Berger said.

“I can still eat two scoops of ice cream, but I need to add walnuts in it to regulate my blood sugar,” she offered as an example.

Viome says it has tested more than 200,000 customers and has published its methodology for analyzing stool samples, which is different from other gut health companies. But the paper does not address Viome’s larger claims of connecting the microbiome to dietary advice, and researcher Elisabeth Bik called the claims “far fetched” in a 2019 review of the preprint version.

Viome makes additional money by selling supplements, probiotics and prebiotics based on consumers’ test results. It has also rebranded as Viome Life Sciences, expanding into precision diagnostics and therapeutics, such as saliva tests to detect throat cancer. Meanwhile, its gut health program has been mired in logistical missteps.

One customer who posted on Facebook tracked her sample through the U.S. Postal Service as it boomeranged between Los Alamos, N.M., and Bothell, Wash., where it was supposed to be picked up. Another fought for a refund after waiting 6 weeks to hear her sample was not viable and learning a second attempt had expired after spending too long in transit. The company’s expected lab processing time jumped from 4 weeks in February, when Mr. Jordan said his girlfriend took her first test, to 6 in summer. (Three weeks after I mailed my second sample in July, it still hadn’t made it to the lab, so I called it quits and asked for a refund.)

In Mr. Jain’s July apology posted to the private Facebook group for Viome users, he said the company recently moved its lab from New Mexico to Washington state, close to its headquarters, which prompted a mail-forwarding fiasco. It bought new robotics that “refused to cooperate,” he wrote. “Many things didn’t go as planned during the move.”

Spokesperson Kendall Donohue said Viome has been working on the problems but laid much of the blame on the Postal Service.

She also said Viome has been notifying customers – even though many (including myself) had not been contacted.

It is Viome’s “top priority right now to ensure complete customer satisfaction, but unfortunately USPS needs to sort the issue internally for further action to be taken,” she said.

She also offered me a free “Health Intelligence” test. I declined.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

After Russell Jordan sent a stool sample through the mail to the microbiome company Viome, his idea of what he should eat shifted. The gym owner in Sacramento, had always consumed large quantities of leafy greens. But the results from the test – which sequenced and analyzed the microbes in a pea-sized stool sample – recommended he steer clear of spinach, kale, and broccoli.

“Things I’ve been eating for the better part of 30 years,” said Mr. Jordan, 31. “And it worked.” Soon, his mild indigestion subsided. He recommended the product to his girlfriend.

She took the test in late February, when the company – which sells its “Gut Intelligence” test for $129 and a more extensive “Health Intelligence” test, which requires a blood sample, for $199 – began experiencing hiccups. Viome had promised results within 4 weeks once the sample arrived at a testing facility, but Mr. Jordan said his girlfriend has been waiting more than 5 months and has submitted fresh blood and stool samples – twice.

Other Viome customers have flocked to social media to complain about similar problems: stool samples lost in the mail, months-long waits with no communication from the company, samples being rejected because of shipping or lab-processing snafus. (I, too, have a stool sample lost in transit, which I mailed after a first vial was rejected because it “leaked.”) The company’s CEO, Naveen Jain, took to Facebook to apologize in late July.

Viome’s troubles provide a cautionary tale for consumers in the wild west of microbiome startups, which have been alternately hailed for health breakthroughs and indicted for fraud.

The nascent industry offers individualized diet regimens based on analyzing gut bacteria – collectively known as the gut microbiome. Consumers pay hundreds of dollars for tests not covered by insurance, hoping to get answers to health problems ranging from irritable bowel syndrome to obesity.

Venture capitalists pumped $1 billion into these kinds of startups from 2015 to 2020, according to Crunchbase, buoyed by promising research and consumers’ embrace of at-home testing. PitchBook has identified more than a dozen direct-to-consumer gut health providers.

But not all the startups are equal. Some are supported by peer-reviewed studies. Others are peddling murky science – and not just because poop samples are getting lost in the mail.

“A lot of companies are interested in the space, but they don’t have the research to show that it’s actually working,” said Christopher Lynch, acting director of the National Institutes of Health Office of Nutrition Research. “And the research is really expensive.”

With nearly $160 million in government funding, the NIH Common Fund’s Nutrition for Precision Health research program, expected to launch by early 2022, seeks to enroll 1 million people to study the interactions among diet, the microbiome, genes, metabolism and other factors.

The gut microbiome is a complex community of trillions of bacteria. Research over the past 15 years has determined that these microbes, both good and bad, are an integral part of human biology, and that altering a person’s gut microbes can fundamentally change their metabolism, immune function – and, potentially, cure diseases, explained Justin Sonnenburg, PhD, a microbiology and immunology associate professor at Stanford (Calif.) University.

Metagenomic sequencing, which identifies the unique set of bugs in someone’s gut (similar to what 23andMe does with its saliva test), has also improved dramatically, making the process cheaper for companies to reproduce.

“It’s seen as one of the exciting areas of precision health,” said Dr. Sonnenburg, who recently coauthored a study that found a fermented food diet increases microbiome diversity – which is considered positive – and reduces markers of inflammation. That includes foods like yogurt, kefir, and kimchi.

“The difficulty for the consumer is to differentiate which of these companies is based on solid science versus overreaching the current limits of the field,” he added via email. “And for those companies based on solid science, what are the limits of what they should be recommending?”

San Francisco–based uBiome, founded in 2012, was one of the first to offer fecal sample testing.

But as uBiome began marketing its tests as “clinical” – and seeking reimbursement from insurers for up to nearly $3,000 – its business tactics came under scrutiny. The company was raided by the FBI and later filed for bankruptcy. Earlier this year, its cofounders were indicted for defrauding insurers into paying for tests that “were not validated and not medically necessary” in order to please investors, the Department of Justice alleges.

But for Tim Spector, a professor of genetic epidemiology at King’s College London and cofounder of the startup Zoe, being associated with uBiome is insulting.

Zoe has spent more than 2 years conducting trials, which have included dietary assessments, standardized meals, testing glycemic responses and gut microbiome profiling on thousands of participants. In January, the findings were published in Nature Medicine.

The company offers a $354 test that requires a stool sample, a completed questionnaire, and then a blood sample after eating muffins designed to test blood fat and sugar levels. Customers can also opt in to a 2-week, continuous glucose monitoring test.

The results are run through the company’s algorithm to create a customized library of foods and meals – and how customers are likely to respond to those foods.

DayTwo, a Walnut Creek, Calif., company that recently raised $37 million to expand its precision nutrition program, focuses on people with prediabetes or diabetes. It sells to large employers – and, soon, to health insurance plans – rather than directly to consumers, charging “a few thousand dollars” per person, said Jan Berger, MD, chief clinical strategist.

Based on a decade of research, DayTwo has worked with nearly 75,000 people. It sends participants a testing kit and survey, and arranges for them to chat with a dietitian while their stool sample is processing. Then, when the results come in, it makes recommendations, Dr. Berger said.

“I can still eat two scoops of ice cream, but I need to add walnuts in it to regulate my blood sugar,” she offered as an example.

Viome says it has tested more than 200,000 customers and has published its methodology for analyzing stool samples, which is different from other gut health companies. But the paper does not address Viome’s larger claims of connecting the microbiome to dietary advice, and researcher Elisabeth Bik called the claims “far fetched” in a 2019 review of the preprint version.

Viome makes additional money by selling supplements, probiotics and prebiotics based on consumers’ test results. It has also rebranded as Viome Life Sciences, expanding into precision diagnostics and therapeutics, such as saliva tests to detect throat cancer. Meanwhile, its gut health program has been mired in logistical missteps.

One customer who posted on Facebook tracked her sample through the U.S. Postal Service as it boomeranged between Los Alamos, N.M., and Bothell, Wash., where it was supposed to be picked up. Another fought for a refund after waiting 6 weeks to hear her sample was not viable and learning a second attempt had expired after spending too long in transit. The company’s expected lab processing time jumped from 4 weeks in February, when Mr. Jordan said his girlfriend took her first test, to 6 in summer. (Three weeks after I mailed my second sample in July, it still hadn’t made it to the lab, so I called it quits and asked for a refund.)

In Mr. Jain’s July apology posted to the private Facebook group for Viome users, he said the company recently moved its lab from New Mexico to Washington state, close to its headquarters, which prompted a mail-forwarding fiasco. It bought new robotics that “refused to cooperate,” he wrote. “Many things didn’t go as planned during the move.”

Spokesperson Kendall Donohue said Viome has been working on the problems but laid much of the blame on the Postal Service.

She also said Viome has been notifying customers – even though many (including myself) had not been contacted.

It is Viome’s “top priority right now to ensure complete customer satisfaction, but unfortunately USPS needs to sort the issue internally for further action to be taken,” she said.

She also offered me a free “Health Intelligence” test. I declined.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Although breakthrough COVID-19 infections appear to be infrequent in people with inflammatory rheumatic and musculoskeletal diseases (iRMDs), these patients’ comparatively low antibodies after their initial vaccine series validate the recommendation that booster doses could reinforce their immune responses. These findings were highlighted in three letters recently published in Annals of the Rheumatic Diseases.

In the first letter, the researchers assessed breakthrough COVID-19 infections among vaccinated patients with iRMDs who were treated within the Mass General Brigham health care system in the Boston area. Of the 340 COVID-19 infections in patients with iRMDs after vaccinations were approved by the Food and Drug Administration for emergency use, 16 (4.7%) were breakthrough infections. All but one of the breakthrough infections were symptomatic, and six of the patients were hospitalized.

Patients who had breakthrough infections took disease-modifying antirheumatic drugs (DMARDs) that included rituximab and glucocorticoids (five patients each), mycophenolate mofetil or mycophenolic acid (four patients), and methotrexate (three patients). Two of the patients died, both of whom were on rituximab and had interstitial lung disease.

“Some DMARD users may require alternative risk-mitigation strategies, including passive immunity or booster vaccines, and may need to continue shielding practices,” the authors wrote.

“Honestly, it’s hard to know what to make of that rate of breakthrough infections,” Camille Kotton, MD, clinical director of transplant and immunocompromised host infectious diseases in the infectious diseases division at Massachusetts General Hospital in Boston, said in an interview. “People who are immunocompromised were strongly advised to change behavior so as to avoid infection, which probably greatly alters their risk of breakthrough infection. It’s thus hard to evaluate vaccine efficacy.

“Also, 93% were symptomatic, which is fairly high,” she added. “I’m not sure if these patients were more likely to be symptomatic or if there was some bias in testing based on symptoms.”

In the second letter, the researchers assessed postvaccination COVID-19 infections in European patients with iRMDs. Two COVID-19 registries with thousands of patients were reviewed, with less than 1% of patients in each deemed eligible for this study. Of the 34 patients who were ultimately analyzed with available COVID-19 outcomes – 10 were fully vaccinated and 24 were partially vaccinated – 28 fully recovered, 3 recovered with ongoing sequelae, and 3 patients died. The three patients who died were all over 70 years old and had been treated with glucocorticoids and mycophenolate mofetil, glucocorticoids, and rituximab, respectively.

The medications most frequently used by the iRMDs patients with breakthrough cases included glucocorticoids (32%), methotrexate (26%), and tumor necrosis factor inhibitors (26%).

“Overall, the low numbers of SARS-CoV-2 infection post vaccination in both registries are encouraging,” the authors wrote, adding that “all three deceased patients were treated with medications that are potential negative influences on postvaccination SARS-CoV-2 immunogenicity in the RMD population.”
 

Patients with RMDs: Consider COVID-19 booster shots

In the third letter, the researchers investigated booster doses of COVID-19 vaccine in patients with autoimmune diseases. Of the 18 participants who received a booster dose, 14 were on antimetabolite therapy and 8 of those were on mycophenolate. At a median of 29 days after completion of their initial vaccine series, antispike antibodies were negative in 10 of the participants and low positive in 6 others, with a median antispike antibody level of less than 0.4 U/mL (interquartile range, <0.4-222 U/mL).

Booster doses were administered at a median of 77 days after completion of the initial series. At a median of 30 days after booster dose, 89% of the participants had an augmented humoral response, with a median antispike antibody level of 2,500 (IQR, 885-2,500 U/mL). Of the 10 participants who had negative anti-spike antibodies after the initial series, 80% were positive after the booster.

“I think this study supports the wealth of evidence that contributed to the [Centers for Disease Control and Prevention]’s and the FDA’s recommendation to get the third dose of the COVID vaccination,” coauthor Julie J. Paik, MD, of Johns Hopkins University, Baltimore, said in an interview. “Our patients are a very vulnerable group, including lupus patients or myositis patients, both of whom can get severe COVID if they were to contract it. They think they’re protected after a two-dose series, but in reality they’re not.

“We were just happy that they had a response,” she added. “Most of them had absolutely no response whatsoever after the first series.”

One other recently published case report in Arthritis & Rheumatology describes booster vaccination with the viral vector Johnson & Johnson vaccine in a man with seropositive RA who had previously received both doses of the Moderna mRNA-1273 vaccine. The 74-year-old man, who had low disease activity over the past 5 years on hydroxychloroquine, etanercept, and leflunomide, received the booster dose of his own accord after undergoing testing that showed a semiquantitative spike protein receptor binding domain (RBD) antibody level of 53.9 U/mL (reference range, 0-2,500 U/mL) and a negative SARS-CoV-2 antispike (S1/RBD) IgG test, as well as less than 10% blocking activity on an assay designed to detect blocking of the interaction between the SARS-CoV-2 spike protein RBD and the human ACE2 receptor and a negative interferon-gamma release assay detecting SARS-CoV-2–specific T cells. Several weeks after the booster dose, a repeat semiquantitative spike protein RBD antibody level was 2,455.0 U/mL and the S1/RBD IgG level was positive. An ACE2 blocking assay demonstrated 90%-100% blocking activity, but the interferon-gamma release assay remained negative.

“I would recommend abiding by the CDC guidelines regarding boosters for immunocompromised patients,” Dr. Kotton stated. “Patients with rheumatologic disease generally fit into the last category on that list. We don’t have an antibody titer that ensures protection, and as per CDC guidance, we don’t recommend checking antibody titers. Furthermore, boosters were given for this study before the CDC recommendation came out.”

Dr. Paik and coauthors acknowledged their study’s limitations, including a small, inhomogeneous sample and a lack of data on memory B-cell and T-cell response. They also echoed Dr. Kotton’s thoughts by noting that, although this subset of patients had notably limited antibody responses, “no antibody titer has been defined to correlate with protection.”

“Of course, the humoral response isn’t the whole story,” Dr. Paik said. “Some studies are showing that some vaccine recipients may not have the antibodies but their T-cell response may still be intact; it just takes time, and we’re not picking it up. Even if the antibody test is coming up negative, there may be some immunogenicity to the vaccine that we’re not detecting.

“Hopefully at some point, we’ll have more T-cell immunophenotyping to provide better insight into the full vaccine response.”

The Boston-area breakthrough study and the booster shot study were both funded primarily by grants from various institutes within the National Institutes of Health. The European study was financially supported by the European Alliance of Associations for Rheumatology.

Although breakthrough COVID-19 infections appear to be infrequent in people with inflammatory rheumatic and musculoskeletal diseases (iRMDs), these patients’ comparatively low antibodies after their initial vaccine series validate the recommendation that booster doses could reinforce their immune responses. These findings were highlighted in three letters recently published in Annals of the Rheumatic Diseases.

In the first letter, the researchers assessed breakthrough COVID-19 infections among vaccinated patients with iRMDs who were treated within the Mass General Brigham health care system in the Boston area. Of the 340 COVID-19 infections in patients with iRMDs after vaccinations were approved by the Food and Drug Administration for emergency use, 16 (4.7%) were breakthrough infections. All but one of the breakthrough infections were symptomatic, and six of the patients were hospitalized.

Patients who had breakthrough infections took disease-modifying antirheumatic drugs (DMARDs) that included rituximab and glucocorticoids (five patients each), mycophenolate mofetil or mycophenolic acid (four patients), and methotrexate (three patients). Two of the patients died, both of whom were on rituximab and had interstitial lung disease.

“Some DMARD users may require alternative risk-mitigation strategies, including passive immunity or booster vaccines, and may need to continue shielding practices,” the authors wrote.

“Honestly, it’s hard to know what to make of that rate of breakthrough infections,” Camille Kotton, MD, clinical director of transplant and immunocompromised host infectious diseases in the infectious diseases division at Massachusetts General Hospital in Boston, said in an interview. “People who are immunocompromised were strongly advised to change behavior so as to avoid infection, which probably greatly alters their risk of breakthrough infection. It’s thus hard to evaluate vaccine efficacy.

“Also, 93% were symptomatic, which is fairly high,” she added. “I’m not sure if these patients were more likely to be symptomatic or if there was some bias in testing based on symptoms.”

In the second letter, the researchers assessed postvaccination COVID-19 infections in European patients with iRMDs. Two COVID-19 registries with thousands of patients were reviewed, with less than 1% of patients in each deemed eligible for this study. Of the 34 patients who were ultimately analyzed with available COVID-19 outcomes – 10 were fully vaccinated and 24 were partially vaccinated – 28 fully recovered, 3 recovered with ongoing sequelae, and 3 patients died. The three patients who died were all over 70 years old and had been treated with glucocorticoids and mycophenolate mofetil, glucocorticoids, and rituximab, respectively.

The medications most frequently used by the iRMDs patients with breakthrough cases included glucocorticoids (32%), methotrexate (26%), and tumor necrosis factor inhibitors (26%).

“Overall, the low numbers of SARS-CoV-2 infection post vaccination in both registries are encouraging,” the authors wrote, adding that “all three deceased patients were treated with medications that are potential negative influences on postvaccination SARS-CoV-2 immunogenicity in the RMD population.”
 

Patients with RMDs: Consider COVID-19 booster shots

In the third letter, the researchers investigated booster doses of COVID-19 vaccine in patients with autoimmune diseases. Of the 18 participants who received a booster dose, 14 were on antimetabolite therapy and 8 of those were on mycophenolate. At a median of 29 days after completion of their initial vaccine series, antispike antibodies were negative in 10 of the participants and low positive in 6 others, with a median antispike antibody level of less than 0.4 U/mL (interquartile range, <0.4-222 U/mL).

Booster doses were administered at a median of 77 days after completion of the initial series. At a median of 30 days after booster dose, 89% of the participants had an augmented humoral response, with a median antispike antibody level of 2,500 (IQR, 885-2,500 U/mL). Of the 10 participants who had negative anti-spike antibodies after the initial series, 80% were positive after the booster.

“I think this study supports the wealth of evidence that contributed to the [Centers for Disease Control and Prevention]’s and the FDA’s recommendation to get the third dose of the COVID vaccination,” coauthor Julie J. Paik, MD, of Johns Hopkins University, Baltimore, said in an interview. “Our patients are a very vulnerable group, including lupus patients or myositis patients, both of whom can get severe COVID if they were to contract it. They think they’re protected after a two-dose series, but in reality they’re not.

“We were just happy that they had a response,” she added. “Most of them had absolutely no response whatsoever after the first series.”

One other recently published case report in Arthritis & Rheumatology describes booster vaccination with the viral vector Johnson & Johnson vaccine in a man with seropositive RA who had previously received both doses of the Moderna mRNA-1273 vaccine. The 74-year-old man, who had low disease activity over the past 5 years on hydroxychloroquine, etanercept, and leflunomide, received the booster dose of his own accord after undergoing testing that showed a semiquantitative spike protein receptor binding domain (RBD) antibody level of 53.9 U/mL (reference range, 0-2,500 U/mL) and a negative SARS-CoV-2 antispike (S1/RBD) IgG test, as well as less than 10% blocking activity on an assay designed to detect blocking of the interaction between the SARS-CoV-2 spike protein RBD and the human ACE2 receptor and a negative interferon-gamma release assay detecting SARS-CoV-2–specific T cells. Several weeks after the booster dose, a repeat semiquantitative spike protein RBD antibody level was 2,455.0 U/mL and the S1/RBD IgG level was positive. An ACE2 blocking assay demonstrated 90%-100% blocking activity, but the interferon-gamma release assay remained negative.

“I would recommend abiding by the CDC guidelines regarding boosters for immunocompromised patients,” Dr. Kotton stated. “Patients with rheumatologic disease generally fit into the last category on that list. We don’t have an antibody titer that ensures protection, and as per CDC guidance, we don’t recommend checking antibody titers. Furthermore, boosters were given for this study before the CDC recommendation came out.”

Dr. Paik and coauthors acknowledged their study’s limitations, including a small, inhomogeneous sample and a lack of data on memory B-cell and T-cell response. They also echoed Dr. Kotton’s thoughts by noting that, although this subset of patients had notably limited antibody responses, “no antibody titer has been defined to correlate with protection.”

“Of course, the humoral response isn’t the whole story,” Dr. Paik said. “Some studies are showing that some vaccine recipients may not have the antibodies but their T-cell response may still be intact; it just takes time, and we’re not picking it up. Even if the antibody test is coming up negative, there may be some immunogenicity to the vaccine that we’re not detecting.

“Hopefully at some point, we’ll have more T-cell immunophenotyping to provide better insight into the full vaccine response.”

The Boston-area breakthrough study and the booster shot study were both funded primarily by grants from various institutes within the National Institutes of Health. The European study was financially supported by the European Alliance of Associations for Rheumatology.

Although breakthrough COVID-19 infections appear to be infrequent in people with inflammatory rheumatic and musculoskeletal diseases (iRMDs), these patients’ comparatively low antibodies after their initial vaccine series validate the recommendation that booster doses could reinforce their immune responses. These findings were highlighted in three letters recently published in Annals of the Rheumatic Diseases.

In the first letter, the researchers assessed breakthrough COVID-19 infections among vaccinated patients with iRMDs who were treated within the Mass General Brigham health care system in the Boston area. Of the 340 COVID-19 infections in patients with iRMDs after vaccinations were approved by the Food and Drug Administration for emergency use, 16 (4.7%) were breakthrough infections. All but one of the breakthrough infections were symptomatic, and six of the patients were hospitalized.

Patients who had breakthrough infections took disease-modifying antirheumatic drugs (DMARDs) that included rituximab and glucocorticoids (five patients each), mycophenolate mofetil or mycophenolic acid (four patients), and methotrexate (three patients). Two of the patients died, both of whom were on rituximab and had interstitial lung disease.

“Some DMARD users may require alternative risk-mitigation strategies, including passive immunity or booster vaccines, and may need to continue shielding practices,” the authors wrote.

“Honestly, it’s hard to know what to make of that rate of breakthrough infections,” Camille Kotton, MD, clinical director of transplant and immunocompromised host infectious diseases in the infectious diseases division at Massachusetts General Hospital in Boston, said in an interview. “People who are immunocompromised were strongly advised to change behavior so as to avoid infection, which probably greatly alters their risk of breakthrough infection. It’s thus hard to evaluate vaccine efficacy.

“Also, 93% were symptomatic, which is fairly high,” she added. “I’m not sure if these patients were more likely to be symptomatic or if there was some bias in testing based on symptoms.”

In the second letter, the researchers assessed postvaccination COVID-19 infections in European patients with iRMDs. Two COVID-19 registries with thousands of patients were reviewed, with less than 1% of patients in each deemed eligible for this study. Of the 34 patients who were ultimately analyzed with available COVID-19 outcomes – 10 were fully vaccinated and 24 were partially vaccinated – 28 fully recovered, 3 recovered with ongoing sequelae, and 3 patients died. The three patients who died were all over 70 years old and had been treated with glucocorticoids and mycophenolate mofetil, glucocorticoids, and rituximab, respectively.

The medications most frequently used by the iRMDs patients with breakthrough cases included glucocorticoids (32%), methotrexate (26%), and tumor necrosis factor inhibitors (26%).

“Overall, the low numbers of SARS-CoV-2 infection post vaccination in both registries are encouraging,” the authors wrote, adding that “all three deceased patients were treated with medications that are potential negative influences on postvaccination SARS-CoV-2 immunogenicity in the RMD population.”
 

Patients with RMDs: Consider COVID-19 booster shots

In the third letter, the researchers investigated booster doses of COVID-19 vaccine in patients with autoimmune diseases. Of the 18 participants who received a booster dose, 14 were on antimetabolite therapy and 8 of those were on mycophenolate. At a median of 29 days after completion of their initial vaccine series, antispike antibodies were negative in 10 of the participants and low positive in 6 others, with a median antispike antibody level of less than 0.4 U/mL (interquartile range, <0.4-222 U/mL).

Booster doses were administered at a median of 77 days after completion of the initial series. At a median of 30 days after booster dose, 89% of the participants had an augmented humoral response, with a median antispike antibody level of 2,500 (IQR, 885-2,500 U/mL). Of the 10 participants who had negative anti-spike antibodies after the initial series, 80% were positive after the booster.

“I think this study supports the wealth of evidence that contributed to the [Centers for Disease Control and Prevention]’s and the FDA’s recommendation to get the third dose of the COVID vaccination,” coauthor Julie J. Paik, MD, of Johns Hopkins University, Baltimore, said in an interview. “Our patients are a very vulnerable group, including lupus patients or myositis patients, both of whom can get severe COVID if they were to contract it. They think they’re protected after a two-dose series, but in reality they’re not.

“We were just happy that they had a response,” she added. “Most of them had absolutely no response whatsoever after the first series.”

One other recently published case report in Arthritis & Rheumatology describes booster vaccination with the viral vector Johnson & Johnson vaccine in a man with seropositive RA who had previously received both doses of the Moderna mRNA-1273 vaccine. The 74-year-old man, who had low disease activity over the past 5 years on hydroxychloroquine, etanercept, and leflunomide, received the booster dose of his own accord after undergoing testing that showed a semiquantitative spike protein receptor binding domain (RBD) antibody level of 53.9 U/mL (reference range, 0-2,500 U/mL) and a negative SARS-CoV-2 antispike (S1/RBD) IgG test, as well as less than 10% blocking activity on an assay designed to detect blocking of the interaction between the SARS-CoV-2 spike protein RBD and the human ACE2 receptor and a negative interferon-gamma release assay detecting SARS-CoV-2–specific T cells. Several weeks after the booster dose, a repeat semiquantitative spike protein RBD antibody level was 2,455.0 U/mL and the S1/RBD IgG level was positive. An ACE2 blocking assay demonstrated 90%-100% blocking activity, but the interferon-gamma release assay remained negative.

“I would recommend abiding by the CDC guidelines regarding boosters for immunocompromised patients,” Dr. Kotton stated. “Patients with rheumatologic disease generally fit into the last category on that list. We don’t have an antibody titer that ensures protection, and as per CDC guidance, we don’t recommend checking antibody titers. Furthermore, boosters were given for this study before the CDC recommendation came out.”

Dr. Paik and coauthors acknowledged their study’s limitations, including a small, inhomogeneous sample and a lack of data on memory B-cell and T-cell response. They also echoed Dr. Kotton’s thoughts by noting that, although this subset of patients had notably limited antibody responses, “no antibody titer has been defined to correlate with protection.”

“Of course, the humoral response isn’t the whole story,” Dr. Paik said. “Some studies are showing that some vaccine recipients may not have the antibodies but their T-cell response may still be intact; it just takes time, and we’re not picking it up. Even if the antibody test is coming up negative, there may be some immunogenicity to the vaccine that we’re not detecting.

“Hopefully at some point, we’ll have more T-cell immunophenotyping to provide better insight into the full vaccine response.”

The Boston-area breakthrough study and the booster shot study were both funded primarily by grants from various institutes within the National Institutes of Health. The European study was financially supported by the European Alliance of Associations for Rheumatology.

Telehealth can be effective for delivering cognitive-behavioral therapy for insomnia (CBT-I) – and is not inferior to in-person treatment, new research suggests.

Results from a study of 60 adults with insomnia disorder showed no significant between-group difference at 3-month follow-up between those assigned to receive in-person CBT-I and those assigned to telehealth CBT-I in regard to change in score on the Insomnia Severity Index (ISI).

In addition, both groups showed significant change compared with a wait-list group, indicating that telehealth was not inferior to the in-person mode of delivery, the investigators note.

Telehealth ‘explosion’

Although CBT-I is the recommended intervention for insomnia, “widespread implementation of CBT-I is limited by the lack of clinicians who are trained in this treatment,” the investigators note. There is a “need for strategies to increase access, particularly for patients in areas with few health care providers.”

Telehealth is a promising technology for providing treatment, without the necessity of having the patient and the practitioner in the same place. There has been an “explosion” in its use because of restrictions necessitated by the COVID-19 pandemic. However, the “rapid deployment of telehealth interventions did not allow time to assess this approach in a controlled manner,” so it is possible that this type of communication might reduce treatment efficacy, the investigators note.

Previous research suggests that telehealth psychotherapeutic treatments in general are not inferior to in-person treatments. One study showed that CBT-I delivered via telehealth was noninferior to in-person delivery. However, that study did not include a control group.

“I have been doing telehealth clinical work for about 10 years – so way before the pandemic pushed everything virtual,” Dr. Gehrman said. “But when I would talk about my telehealth work to other providers, I would frequently get asked whether the advantages of telehealth (greater access to care, reduced travel costs) came at a price of lower efficacy.”

Dr. Gehrman said he suspected that telehealth treatment was just as effective and wanted to formally test this impression to see whether he was correct.

The investigators randomly assigned 60 adults (mean age, 32.72 years; mean ISI score, 17.0; 65% women) with insomnia disorder to in-person CBT-I (n = 20), telehealth-delivered CBT-I (n = 21), or to a wait-list control group (n = 19). For the study, insomnia disorder was determined on the basis of DSM-5 criteria.

Most participants had completed college or postgraduate school (43% and 37%, respectively) and did not have many comorbidities.

The primary outcome was change on the ISI. Other assessments included measures of depression, anxiety, work and social adjustment, fatigue, and medical outcomes. Participants also completed a home unattended sleep study using a portable monitor to screen participants for obstructive sleep apnea.

Both types of CBT-I were delivered over 6 to 8 weekly sessions, with 2-week and 3-month post-treatment follow-ups.

An a priori margin of -3.0 points was used in the noninferiority analysis, and all analyses were conducted using mixed-effects models, the authors explain.
 

Necessary evil?

In the primary noninferiority analyses, the mean change in ISI score from baseline to 3-month follow-up was -7.8 points for in-person CBT-I, -7.5 points for telehealth, and -1.6 for wait list.

The difference between the CBT-I groups was not statistically significant (t 28 = -0.98, P = .33).

“The lower confidence limit of this between-group difference in the mean ISI changes was greater than the a priori margin of -3.0 points, indicating that telehealth treatment was not inferior to in-person treatment,” the investigators write.

Although there were significant improvements on most secondary outcome measures related to mood/anxiety and daytime functioning, the investigators found no group differences.

The findings suggest that the benefits of telehealth, including increased access and reduced travel time, “do not come with a cost of reduced efficacy,” the researchers write.

The study was conducted prior to the COVID-19 pandemic, the investigators note. However, the results “underscore that the use of telehealth during the pandemic is not a ‘necessary evil,’ but rather a means of providing high quality care while reducing risks of exposure,” they write.
 

Benefits, fidelity maintained

Commenting on the study, J. Todd Arnedt, PhD, professor of psychiatry and neurology and co-director of the Sleep and Circadian Research Laboratory, Michigan Medicine, University of Michigan, Ann Arbor, said it is “one of the first studies to clearly demonstrate that the benefits and fidelity of CBT for insomnia, which is most commonly delivered in-person, can be maintained with telehealth delivery.”

Dr. Arnedt is also director of the Behavioral Sleep Medicine Program and was not involved in the study. He said the findings “support the use of this modality by providers to expand access to this highly effective but underutilized insomnia treatment.”

Additionally, telehealth delivery of CBT-I “offers a safe and effective alternative to in-person care for improving insomnia and associated daytime consequences and has the potential to reduce health care disparities by increasing availability to underserved communities,” Dr. Arnedt said.

However, the investigators point out that the utility of this approach for underserved communities needs further investigation. A study limitation was that the participants were “generally healthy and well educated.”

In addition, further research is needed to see whether the findings can be generalized to individuals who have “more complicated health or socioeconomic difficulties,” they write.

The study was funded by a grant from the American Sleep Medicine Foundation and the Doris Duke Charitable Foundation Clinical Scientist Development Award. Dr. Gehrman has received research funding from Merck, is a consultant to WW, and serves on the scientific advisory board of Eight Sleep. The other authors’ disclosures are listed in the original article. Dr. Arnedt reports no relevant financial relationships but notes that he was the principal investigator of a similar study run in parallel to this one that was also funded by the American Academy of Sleep Medicine Foundation at the same time.

A version of this article first appeared on Medscape.com.

Telehealth can be effective for delivering cognitive-behavioral therapy for insomnia (CBT-I) – and is not inferior to in-person treatment, new research suggests.

Results from a study of 60 adults with insomnia disorder showed no significant between-group difference at 3-month follow-up between those assigned to receive in-person CBT-I and those assigned to telehealth CBT-I in regard to change in score on the Insomnia Severity Index (ISI).

In addition, both groups showed significant change compared with a wait-list group, indicating that telehealth was not inferior to the in-person mode of delivery, the investigators note.

Telehealth ‘explosion’

Although CBT-I is the recommended intervention for insomnia, “widespread implementation of CBT-I is limited by the lack of clinicians who are trained in this treatment,” the investigators note. There is a “need for strategies to increase access, particularly for patients in areas with few health care providers.”

Telehealth is a promising technology for providing treatment, without the necessity of having the patient and the practitioner in the same place. There has been an “explosion” in its use because of restrictions necessitated by the COVID-19 pandemic. However, the “rapid deployment of telehealth interventions did not allow time to assess this approach in a controlled manner,” so it is possible that this type of communication might reduce treatment efficacy, the investigators note.

Previous research suggests that telehealth psychotherapeutic treatments in general are not inferior to in-person treatments. One study showed that CBT-I delivered via telehealth was noninferior to in-person delivery. However, that study did not include a control group.

“I have been doing telehealth clinical work for about 10 years – so way before the pandemic pushed everything virtual,” Dr. Gehrman said. “But when I would talk about my telehealth work to other providers, I would frequently get asked whether the advantages of telehealth (greater access to care, reduced travel costs) came at a price of lower efficacy.”

Dr. Gehrman said he suspected that telehealth treatment was just as effective and wanted to formally test this impression to see whether he was correct.

The investigators randomly assigned 60 adults (mean age, 32.72 years; mean ISI score, 17.0; 65% women) with insomnia disorder to in-person CBT-I (n = 20), telehealth-delivered CBT-I (n = 21), or to a wait-list control group (n = 19). For the study, insomnia disorder was determined on the basis of DSM-5 criteria.

Most participants had completed college or postgraduate school (43% and 37%, respectively) and did not have many comorbidities.

The primary outcome was change on the ISI. Other assessments included measures of depression, anxiety, work and social adjustment, fatigue, and medical outcomes. Participants also completed a home unattended sleep study using a portable monitor to screen participants for obstructive sleep apnea.

Both types of CBT-I were delivered over 6 to 8 weekly sessions, with 2-week and 3-month post-treatment follow-ups.

An a priori margin of -3.0 points was used in the noninferiority analysis, and all analyses were conducted using mixed-effects models, the authors explain.
 

Necessary evil?

In the primary noninferiority analyses, the mean change in ISI score from baseline to 3-month follow-up was -7.8 points for in-person CBT-I, -7.5 points for telehealth, and -1.6 for wait list.

The difference between the CBT-I groups was not statistically significant (t 28 = -0.98, P = .33).

“The lower confidence limit of this between-group difference in the mean ISI changes was greater than the a priori margin of -3.0 points, indicating that telehealth treatment was not inferior to in-person treatment,” the investigators write.

Although there were significant improvements on most secondary outcome measures related to mood/anxiety and daytime functioning, the investigators found no group differences.

The findings suggest that the benefits of telehealth, including increased access and reduced travel time, “do not come with a cost of reduced efficacy,” the researchers write.

The study was conducted prior to the COVID-19 pandemic, the investigators note. However, the results “underscore that the use of telehealth during the pandemic is not a ‘necessary evil,’ but rather a means of providing high quality care while reducing risks of exposure,” they write.
 

Benefits, fidelity maintained

Commenting on the study, J. Todd Arnedt, PhD, professor of psychiatry and neurology and co-director of the Sleep and Circadian Research Laboratory, Michigan Medicine, University of Michigan, Ann Arbor, said it is “one of the first studies to clearly demonstrate that the benefits and fidelity of CBT for insomnia, which is most commonly delivered in-person, can be maintained with telehealth delivery.”

Dr. Arnedt is also director of the Behavioral Sleep Medicine Program and was not involved in the study. He said the findings “support the use of this modality by providers to expand access to this highly effective but underutilized insomnia treatment.”

Additionally, telehealth delivery of CBT-I “offers a safe and effective alternative to in-person care for improving insomnia and associated daytime consequences and has the potential to reduce health care disparities by increasing availability to underserved communities,” Dr. Arnedt said.

However, the investigators point out that the utility of this approach for underserved communities needs further investigation. A study limitation was that the participants were “generally healthy and well educated.”

In addition, further research is needed to see whether the findings can be generalized to individuals who have “more complicated health or socioeconomic difficulties,” they write.

The study was funded by a grant from the American Sleep Medicine Foundation and the Doris Duke Charitable Foundation Clinical Scientist Development Award. Dr. Gehrman has received research funding from Merck, is a consultant to WW, and serves on the scientific advisory board of Eight Sleep. The other authors’ disclosures are listed in the original article. Dr. Arnedt reports no relevant financial relationships but notes that he was the principal investigator of a similar study run in parallel to this one that was also funded by the American Academy of Sleep Medicine Foundation at the same time.

A version of this article first appeared on Medscape.com.

Telehealth can be effective for delivering cognitive-behavioral therapy for insomnia (CBT-I) – and is not inferior to in-person treatment, new research suggests.

Results from a study of 60 adults with insomnia disorder showed no significant between-group difference at 3-month follow-up between those assigned to receive in-person CBT-I and those assigned to telehealth CBT-I in regard to change in score on the Insomnia Severity Index (ISI).

In addition, both groups showed significant change compared with a wait-list group, indicating that telehealth was not inferior to the in-person mode of delivery, the investigators note.

Telehealth ‘explosion’

Although CBT-I is the recommended intervention for insomnia, “widespread implementation of CBT-I is limited by the lack of clinicians who are trained in this treatment,” the investigators note. There is a “need for strategies to increase access, particularly for patients in areas with few health care providers.”

Telehealth is a promising technology for providing treatment, without the necessity of having the patient and the practitioner in the same place. There has been an “explosion” in its use because of restrictions necessitated by the COVID-19 pandemic. However, the “rapid deployment of telehealth interventions did not allow time to assess this approach in a controlled manner,” so it is possible that this type of communication might reduce treatment efficacy, the investigators note.

Previous research suggests that telehealth psychotherapeutic treatments in general are not inferior to in-person treatments. One study showed that CBT-I delivered via telehealth was noninferior to in-person delivery. However, that study did not include a control group.

“I have been doing telehealth clinical work for about 10 years – so way before the pandemic pushed everything virtual,” Dr. Gehrman said. “But when I would talk about my telehealth work to other providers, I would frequently get asked whether the advantages of telehealth (greater access to care, reduced travel costs) came at a price of lower efficacy.”

Dr. Gehrman said he suspected that telehealth treatment was just as effective and wanted to formally test this impression to see whether he was correct.

The investigators randomly assigned 60 adults (mean age, 32.72 years; mean ISI score, 17.0; 65% women) with insomnia disorder to in-person CBT-I (n = 20), telehealth-delivered CBT-I (n = 21), or to a wait-list control group (n = 19). For the study, insomnia disorder was determined on the basis of DSM-5 criteria.

Most participants had completed college or postgraduate school (43% and 37%, respectively) and did not have many comorbidities.

The primary outcome was change on the ISI. Other assessments included measures of depression, anxiety, work and social adjustment, fatigue, and medical outcomes. Participants also completed a home unattended sleep study using a portable monitor to screen participants for obstructive sleep apnea.

Both types of CBT-I were delivered over 6 to 8 weekly sessions, with 2-week and 3-month post-treatment follow-ups.

An a priori margin of -3.0 points was used in the noninferiority analysis, and all analyses were conducted using mixed-effects models, the authors explain.
 

Necessary evil?

In the primary noninferiority analyses, the mean change in ISI score from baseline to 3-month follow-up was -7.8 points for in-person CBT-I, -7.5 points for telehealth, and -1.6 for wait list.

The difference between the CBT-I groups was not statistically significant (t 28 = -0.98, P = .33).

“The lower confidence limit of this between-group difference in the mean ISI changes was greater than the a priori margin of -3.0 points, indicating that telehealth treatment was not inferior to in-person treatment,” the investigators write.

Although there were significant improvements on most secondary outcome measures related to mood/anxiety and daytime functioning, the investigators found no group differences.

The findings suggest that the benefits of telehealth, including increased access and reduced travel time, “do not come with a cost of reduced efficacy,” the researchers write.

The study was conducted prior to the COVID-19 pandemic, the investigators note. However, the results “underscore that the use of telehealth during the pandemic is not a ‘necessary evil,’ but rather a means of providing high quality care while reducing risks of exposure,” they write.
 

Benefits, fidelity maintained

Commenting on the study, J. Todd Arnedt, PhD, professor of psychiatry and neurology and co-director of the Sleep and Circadian Research Laboratory, Michigan Medicine, University of Michigan, Ann Arbor, said it is “one of the first studies to clearly demonstrate that the benefits and fidelity of CBT for insomnia, which is most commonly delivered in-person, can be maintained with telehealth delivery.”

Dr. Arnedt is also director of the Behavioral Sleep Medicine Program and was not involved in the study. He said the findings “support the use of this modality by providers to expand access to this highly effective but underutilized insomnia treatment.”

Additionally, telehealth delivery of CBT-I “offers a safe and effective alternative to in-person care for improving insomnia and associated daytime consequences and has the potential to reduce health care disparities by increasing availability to underserved communities,” Dr. Arnedt said.

However, the investigators point out that the utility of this approach for underserved communities needs further investigation. A study limitation was that the participants were “generally healthy and well educated.”

In addition, further research is needed to see whether the findings can be generalized to individuals who have “more complicated health or socioeconomic difficulties,” they write.

The study was funded by a grant from the American Sleep Medicine Foundation and the Doris Duke Charitable Foundation Clinical Scientist Development Award. Dr. Gehrman has received research funding from Merck, is a consultant to WW, and serves on the scientific advisory board of Eight Sleep. The other authors’ disclosures are listed in the original article. Dr. Arnedt reports no relevant financial relationships but notes that he was the principal investigator of a similar study run in parallel to this one that was also funded by the American Academy of Sleep Medicine Foundation at the same time.

A version of this article first appeared on Medscape.com.

Lung function in early infancy may be influenced by the mother’s level of physical activity during pregnancy, results of a study from Sweden suggest.

Low-lung function at 3 months of age, as measured by the ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE), was more frequent among children whose mothers were physically inactive during the first half of pregnancy compared with those who exercised either moderately or strenuously, reported Hrefna Katrin Gudmundsdottir, MD, a pediatrician and PhD candidate at the University of Oslo, Norway. The results were based on a prospective observational study of 841 mother-child pairs.

“The potential link between maternal inactivity and low lung function in infancy adds to the importance of advising pregnant women and women of childbearing age on physical activity,” she said in an oral abstract presented during the virtual European Respiratory Society (ERS) International Congress.

Jonathan Grigg, MD, professor of pediatric respiratory and environmental medicine at Queen Mary University of London, who was not involved in the study, commented that it “offers a fascinating hint that increased physical activity of mothers is associated with better lung function in their babies and, therefore, possibly their health in later life. More research is needed to confirm this link, but it is important that women feel supported by their health care providers to be active in a way that is comfortable and accessible to them.”

Impaired lung function in infancy is associated with wheezing and asthma in childhood, and lower lung function later in life, Dr. Gudmundsdottir said. She also noted that impaired lung function begins in utero and is related to fetal and infant size, family history of asthma, and/or maternal smoking.

Physical activity during pregnancy has been demonstrated to reduce the risk of preterm birth and cesarean birth and of children being born either abnormally small or abnormally large for their gestational age, she explained.

To see where physical inactivity in the first half of pregnancy is associated with lower lung function in otherwise healthy 3-month old infants, Dr. Gudmundsdottir and colleagues looked at data on a mother-child cohort from the prospective population-based PreventADALL study, which was designed to study prevention of atopic dermatitis and allergies in children in Norway and Sweden.

A total of 814 infants (49% female) had available measures of tidal flow volume in the awake state at 3 months, as well as mother-reported data on physical activity at 18 weeks of pregnancy.

The investigators categorized the mothers as inactive, with either no or only low-intensity physical activity, “fairly” active, or “very” active based on self reporting.

The average tPTEF/tE value among all infants in the study was 0.391. The average value for 290 infants born to inactive mothers was 0.387, compared with 0.394 for 299 infants born to very active mothers, a difference that was not statistically significant.

Maternal physical activity level was not significantly associated with continuous tPTEF/tE, but the investigators did find that the offspring of inactive mothers were significantly more likely than the children of fairly or very active mothers to have a tPTEF/tE below 0.25 in both univariate analysis (odds ratio, 2.15; P = .011), and in multivariate analysis controlling for maternal age, education, parity, prepregnancy body-mass index, parental atopy, and in-utero exposure to nicotine (OR, 2.18; P = .013).

In univariate but not multivariate analysis, children of inactive mothers were significantly more likely than infants of more active mothers to have tPTEF/tE values below the 50th percentile (OR, 1.35; P = .042).

“We observed a trend that adds to the importance of advising women of childbearing age and pregnant women about physical activity. However, there may be factors that affect both maternal physical activity and lung function in offspring that we have not accounted for and could affect the results, so more research is needed,” Dr. Gudmundsdottir said in a statement.

Dr. Grigg pointed out that “it’s also worth keeping in mind that the single most important thing that mothers can do for their own health and that of their baby is to ensure that they do not smoke or use other tobacco products before, during, and after pregnancy. A smoke-free home has the biggest impact on lung function and health in childhood and later life.”

The study was supported by the University of Oslo. Dr. Gudmundsdottir and Dr. Grigg have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Lung function in early infancy may be influenced by the mother’s level of physical activity during pregnancy, results of a study from Sweden suggest.

Low-lung function at 3 months of age, as measured by the ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE), was more frequent among children whose mothers were physically inactive during the first half of pregnancy compared with those who exercised either moderately or strenuously, reported Hrefna Katrin Gudmundsdottir, MD, a pediatrician and PhD candidate at the University of Oslo, Norway. The results were based on a prospective observational study of 841 mother-child pairs.

“The potential link between maternal inactivity and low lung function in infancy adds to the importance of advising pregnant women and women of childbearing age on physical activity,” she said in an oral abstract presented during the virtual European Respiratory Society (ERS) International Congress.

Jonathan Grigg, MD, professor of pediatric respiratory and environmental medicine at Queen Mary University of London, who was not involved in the study, commented that it “offers a fascinating hint that increased physical activity of mothers is associated with better lung function in their babies and, therefore, possibly their health in later life. More research is needed to confirm this link, but it is important that women feel supported by their health care providers to be active in a way that is comfortable and accessible to them.”

Impaired lung function in infancy is associated with wheezing and asthma in childhood, and lower lung function later in life, Dr. Gudmundsdottir said. She also noted that impaired lung function begins in utero and is related to fetal and infant size, family history of asthma, and/or maternal smoking.

Physical activity during pregnancy has been demonstrated to reduce the risk of preterm birth and cesarean birth and of children being born either abnormally small or abnormally large for their gestational age, she explained.

To see where physical inactivity in the first half of pregnancy is associated with lower lung function in otherwise healthy 3-month old infants, Dr. Gudmundsdottir and colleagues looked at data on a mother-child cohort from the prospective population-based PreventADALL study, which was designed to study prevention of atopic dermatitis and allergies in children in Norway and Sweden.

A total of 814 infants (49% female) had available measures of tidal flow volume in the awake state at 3 months, as well as mother-reported data on physical activity at 18 weeks of pregnancy.

The investigators categorized the mothers as inactive, with either no or only low-intensity physical activity, “fairly” active, or “very” active based on self reporting.

The average tPTEF/tE value among all infants in the study was 0.391. The average value for 290 infants born to inactive mothers was 0.387, compared with 0.394 for 299 infants born to very active mothers, a difference that was not statistically significant.

Maternal physical activity level was not significantly associated with continuous tPTEF/tE, but the investigators did find that the offspring of inactive mothers were significantly more likely than the children of fairly or very active mothers to have a tPTEF/tE below 0.25 in both univariate analysis (odds ratio, 2.15; P = .011), and in multivariate analysis controlling for maternal age, education, parity, prepregnancy body-mass index, parental atopy, and in-utero exposure to nicotine (OR, 2.18; P = .013).

In univariate but not multivariate analysis, children of inactive mothers were significantly more likely than infants of more active mothers to have tPTEF/tE values below the 50th percentile (OR, 1.35; P = .042).

“We observed a trend that adds to the importance of advising women of childbearing age and pregnant women about physical activity. However, there may be factors that affect both maternal physical activity and lung function in offspring that we have not accounted for and could affect the results, so more research is needed,” Dr. Gudmundsdottir said in a statement.

Dr. Grigg pointed out that “it’s also worth keeping in mind that the single most important thing that mothers can do for their own health and that of their baby is to ensure that they do not smoke or use other tobacco products before, during, and after pregnancy. A smoke-free home has the biggest impact on lung function and health in childhood and later life.”

The study was supported by the University of Oslo. Dr. Gudmundsdottir and Dr. Grigg have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Lung function in early infancy may be influenced by the mother’s level of physical activity during pregnancy, results of a study from Sweden suggest.

Low-lung function at 3 months of age, as measured by the ratio of time to peak tidal expiratory flow to expiratory time (tPTEF/tE), was more frequent among children whose mothers were physically inactive during the first half of pregnancy compared with those who exercised either moderately or strenuously, reported Hrefna Katrin Gudmundsdottir, MD, a pediatrician and PhD candidate at the University of Oslo, Norway. The results were based on a prospective observational study of 841 mother-child pairs.

“The potential link between maternal inactivity and low lung function in infancy adds to the importance of advising pregnant women and women of childbearing age on physical activity,” she said in an oral abstract presented during the virtual European Respiratory Society (ERS) International Congress.

Jonathan Grigg, MD, professor of pediatric respiratory and environmental medicine at Queen Mary University of London, who was not involved in the study, commented that it “offers a fascinating hint that increased physical activity of mothers is associated with better lung function in their babies and, therefore, possibly their health in later life. More research is needed to confirm this link, but it is important that women feel supported by their health care providers to be active in a way that is comfortable and accessible to them.”

Impaired lung function in infancy is associated with wheezing and asthma in childhood, and lower lung function later in life, Dr. Gudmundsdottir said. She also noted that impaired lung function begins in utero and is related to fetal and infant size, family history of asthma, and/or maternal smoking.

Physical activity during pregnancy has been demonstrated to reduce the risk of preterm birth and cesarean birth and of children being born either abnormally small or abnormally large for their gestational age, she explained.

To see where physical inactivity in the first half of pregnancy is associated with lower lung function in otherwise healthy 3-month old infants, Dr. Gudmundsdottir and colleagues looked at data on a mother-child cohort from the prospective population-based PreventADALL study, which was designed to study prevention of atopic dermatitis and allergies in children in Norway and Sweden.

A total of 814 infants (49% female) had available measures of tidal flow volume in the awake state at 3 months, as well as mother-reported data on physical activity at 18 weeks of pregnancy.

The investigators categorized the mothers as inactive, with either no or only low-intensity physical activity, “fairly” active, or “very” active based on self reporting.

The average tPTEF/tE value among all infants in the study was 0.391. The average value for 290 infants born to inactive mothers was 0.387, compared with 0.394 for 299 infants born to very active mothers, a difference that was not statistically significant.

Maternal physical activity level was not significantly associated with continuous tPTEF/tE, but the investigators did find that the offspring of inactive mothers were significantly more likely than the children of fairly or very active mothers to have a tPTEF/tE below 0.25 in both univariate analysis (odds ratio, 2.15; P = .011), and in multivariate analysis controlling for maternal age, education, parity, prepregnancy body-mass index, parental atopy, and in-utero exposure to nicotine (OR, 2.18; P = .013).

In univariate but not multivariate analysis, children of inactive mothers were significantly more likely than infants of more active mothers to have tPTEF/tE values below the 50th percentile (OR, 1.35; P = .042).

“We observed a trend that adds to the importance of advising women of childbearing age and pregnant women about physical activity. However, there may be factors that affect both maternal physical activity and lung function in offspring that we have not accounted for and could affect the results, so more research is needed,” Dr. Gudmundsdottir said in a statement.

Dr. Grigg pointed out that “it’s also worth keeping in mind that the single most important thing that mothers can do for their own health and that of their baby is to ensure that they do not smoke or use other tobacco products before, during, and after pregnancy. A smoke-free home has the biggest impact on lung function and health in childhood and later life.”

The study was supported by the University of Oslo. Dr. Gudmundsdottir and Dr. Grigg have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A middle-of-the-road dose of an antipsychotic appears to be optimal for relapse prevention in stable schizophrenia, new research suggests.

Results of a meta-analysis show a 5-mg/day equivalent risperidone dose worked best. Higher doses were associated with more adverse events without showing substantial gains in relapse prevention, and lower doses were associated with greater relapse risk.

“The safest approach is to just to carry on with 5 mg,” which in many cases represents a full dose, lead author Stefan Leucht, MD, professor, department of psychiatry and psychotherapy, Technical University of Munich School of Medicine, Germany, told this news organization.

However, he added, patient preferences and other factors should be considered in dosage decision-making.

The findings were published online August 18 in JAMA Psychiatry.
 

Unique meta-analysis

Antipsychotic drugs are effective for short-term treatment of schizophrenia and prevention of relapse but are associated with movement disorders, weight gain, and other metabolic changes. They are also associated with even more severe adverse events, including tardive dyskinesia and increased cardiovascular risk.

For years, researchers have tried to find the optimal dose of antipsychotic drugs to prevent relapse in patients with stable schizophrenia while mitigating adverse event risk.

For the meta-analysis, researchers searched for fixed-dose, randomized, blinded, or open trials that lasted longer than 3 months and compared two first-generation antipsychotics – haloperidol or fluphenazine – or a second-generation antipsychotic with placebo or a different dose of the same drug.

The analysis included 26 studies with 72 individual dose arms and 4,776 participants with stable schizophrenia.  

Researchers used a dose-response meta-analysis. Unlike a simple meta-analysis that provides an “arbitrary” cut-off of superiority of one drug over placebo or another drug, a dose-response meta-analysis gives a plot or curve “that shows how this evolves with different doses,” Dr. Leucht noted.

The investigators estimated dose-response curves for each antipsychotic drug compared with placebo separately and as a group.

They did not have enough data for most of the single antipsychotics, so they converted doses to risperidone equivalents for a pooled analysis across drugs. They chose risperidone because its equivalents “are pretty well-defined,” said Dr. Leucht.
 

Go slow to go low

For the primary outcome of relapse, the dose-response curve showed a hyperbolic shape with a clear plateau. Initially, the plot decreased sharply but then flattened at about 5-mg/day risperidone equivalent (odds ratio, 0.20; 95% confidence interval, 0.13-0.31; relative risk, 0.43; 95% CI, 0.31-0.57).

“We were a little disappointed because we hoped that a dose lower than 5 mg would be most efficacious in terms of relapse rate because this would have reduced the side-effect burden,” Dr. Leucht said.

Nevertheless, he emphasized that doses lower than 5 mg/day risperidone equivalent are not completely ineffective. For example, the 2.5-mg dose reduced risk to relapse in relative terms by about 40% (RR, 0.63).

Dr. Leucht also pointed out there is “huge interindividual variability.” Therefore, 2.5 mg or even 1 mg may be sufficient for some patients. “It just means for the average patient it’s safest, let’s say, to keep her or him on 5 mg,” he said.  

When lowering the dose, Dr. Leucht noted clinicians should “be very careful and to do it very slowly. It should be very small reductions every 3 to 6 months.”

For the secondary endpoint of rehospitalizations, the shape of the curve was similar to the one for relapse but with lower rates.

“If patients need to be rehospitalized, it usually means that the relapse was major and not only a minor increase in symptoms,” said Dr. Leucht.

The curves for all-cause discontinuation and reduction in overall symptoms were also similar to that of relapse.

However, the curve for dropouts because of adverse events showed that higher doses led to more adverse events. For example, with 5-mg/day dose, the OR was 1.4 (95% CI, 0.87-2.25) and the RR was 1.38 (95% CI, 0.87-2.15), but for the 15-mg/day dose, the OR was 2.88 (95% CI, 1.52-5.45) and the RR was 2.68 (95% CI, 1.49-4.62).
 

Patient preference key

The data were insufficient to assess differences between men and women or between older and younger patients, Dr. Leucht noted.

However, post-hoc subgroup analyses turned up some interesting findings, he added. For example, patients who take high-potency first-generation antipsychotics such as haloperidol might do well on a lower dose, said Dr. Leucht.

“They may need a dose even lower than 5 mg, perhaps something like 2.5 mg, because these drugs bind so strongly to dopamine receptors,” he said.

He reiterated that patient preferences should always be considered when deciding on antipsychotic dosage.

“Many patients will say they don’t want to relapse anymore, but others will say these drugs have horrible side effects, and they want to go on a lower dose,” said Dr. Leucht.

Clinicians should also factor in patient characteristics, such as comorbidities or substance abuse, as well as severity of past relapses and properties of individual drugs, he added.
 

Reflects real-world experience

Commenting on the findings, Thomas Sedlak, MD, PhD, director, Schizophrenia and Psychosis Consult Clinic and assistant professor of psychiatry and behavioral sciences, Johns Hopkins School of Medicine, Baltimore, said the research “is a fine addition” to a previous analysis that explored dose-response relationships of antipsychotic drugs in the acute phase.

Crunching all the data from studies that have different types of patients and extracting a single dosage that provides maximum benefit is “a great challenge,” said Dr. Sedlak, who was not involved with the research.

The fact that most patients won’t get additional benefit above 5 mg, at which point they start getting more adverse events, and that 2.5 mg is sufficient for certain subgroups “agrees well with the experience of many who use these medications regularly,” Dr. Sedlak said.

However, he cautioned that psychiatrists “don’t always intuitively know which patients fall into which dose category or who might require clozapine.”

“Clinicians need to be mindful that it’s easy to overshoot an optimal dose and elicit side effects,” said Dr. Sedlak.

He also noted that severely ill patients are often underrepresented in clinical trials because they are too impaired to participate, “so they may have a different optimal dosage,” he concluded.

Dr. Leucht has reported receiving personal fees for consulting, advising, and/or speaking outside the submitted work from Angelini, Boehringer Ingelheim, Geodon & Richter, Janssen, Johnson & Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, Sanofi Aventis, Sandoz, Sunovion, Teva, Eisai, Rovi, and Amiabel. Dr. Sedlak has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A middle-of-the-road dose of an antipsychotic appears to be optimal for relapse prevention in stable schizophrenia, new research suggests.

Results of a meta-analysis show a 5-mg/day equivalent risperidone dose worked best. Higher doses were associated with more adverse events without showing substantial gains in relapse prevention, and lower doses were associated with greater relapse risk.

“The safest approach is to just to carry on with 5 mg,” which in many cases represents a full dose, lead author Stefan Leucht, MD, professor, department of psychiatry and psychotherapy, Technical University of Munich School of Medicine, Germany, told this news organization.

However, he added, patient preferences and other factors should be considered in dosage decision-making.

The findings were published online August 18 in JAMA Psychiatry.
 

Unique meta-analysis

Antipsychotic drugs are effective for short-term treatment of schizophrenia and prevention of relapse but are associated with movement disorders, weight gain, and other metabolic changes. They are also associated with even more severe adverse events, including tardive dyskinesia and increased cardiovascular risk.

For years, researchers have tried to find the optimal dose of antipsychotic drugs to prevent relapse in patients with stable schizophrenia while mitigating adverse event risk.

For the meta-analysis, researchers searched for fixed-dose, randomized, blinded, or open trials that lasted longer than 3 months and compared two first-generation antipsychotics – haloperidol or fluphenazine – or a second-generation antipsychotic with placebo or a different dose of the same drug.

The analysis included 26 studies with 72 individual dose arms and 4,776 participants with stable schizophrenia.  

Researchers used a dose-response meta-analysis. Unlike a simple meta-analysis that provides an “arbitrary” cut-off of superiority of one drug over placebo or another drug, a dose-response meta-analysis gives a plot or curve “that shows how this evolves with different doses,” Dr. Leucht noted.

The investigators estimated dose-response curves for each antipsychotic drug compared with placebo separately and as a group.

They did not have enough data for most of the single antipsychotics, so they converted doses to risperidone equivalents for a pooled analysis across drugs. They chose risperidone because its equivalents “are pretty well-defined,” said Dr. Leucht.
 

Go slow to go low

For the primary outcome of relapse, the dose-response curve showed a hyperbolic shape with a clear plateau. Initially, the plot decreased sharply but then flattened at about 5-mg/day risperidone equivalent (odds ratio, 0.20; 95% confidence interval, 0.13-0.31; relative risk, 0.43; 95% CI, 0.31-0.57).

“We were a little disappointed because we hoped that a dose lower than 5 mg would be most efficacious in terms of relapse rate because this would have reduced the side-effect burden,” Dr. Leucht said.

Nevertheless, he emphasized that doses lower than 5 mg/day risperidone equivalent are not completely ineffective. For example, the 2.5-mg dose reduced risk to relapse in relative terms by about 40% (RR, 0.63).

Dr. Leucht also pointed out there is “huge interindividual variability.” Therefore, 2.5 mg or even 1 mg may be sufficient for some patients. “It just means for the average patient it’s safest, let’s say, to keep her or him on 5 mg,” he said.  

When lowering the dose, Dr. Leucht noted clinicians should “be very careful and to do it very slowly. It should be very small reductions every 3 to 6 months.”

For the secondary endpoint of rehospitalizations, the shape of the curve was similar to the one for relapse but with lower rates.

“If patients need to be rehospitalized, it usually means that the relapse was major and not only a minor increase in symptoms,” said Dr. Leucht.

The curves for all-cause discontinuation and reduction in overall symptoms were also similar to that of relapse.

However, the curve for dropouts because of adverse events showed that higher doses led to more adverse events. For example, with 5-mg/day dose, the OR was 1.4 (95% CI, 0.87-2.25) and the RR was 1.38 (95% CI, 0.87-2.15), but for the 15-mg/day dose, the OR was 2.88 (95% CI, 1.52-5.45) and the RR was 2.68 (95% CI, 1.49-4.62).
 

Patient preference key

The data were insufficient to assess differences between men and women or between older and younger patients, Dr. Leucht noted.

However, post-hoc subgroup analyses turned up some interesting findings, he added. For example, patients who take high-potency first-generation antipsychotics such as haloperidol might do well on a lower dose, said Dr. Leucht.

“They may need a dose even lower than 5 mg, perhaps something like 2.5 mg, because these drugs bind so strongly to dopamine receptors,” he said.

He reiterated that patient preferences should always be considered when deciding on antipsychotic dosage.

“Many patients will say they don’t want to relapse anymore, but others will say these drugs have horrible side effects, and they want to go on a lower dose,” said Dr. Leucht.

Clinicians should also factor in patient characteristics, such as comorbidities or substance abuse, as well as severity of past relapses and properties of individual drugs, he added.
 

Reflects real-world experience

Commenting on the findings, Thomas Sedlak, MD, PhD, director, Schizophrenia and Psychosis Consult Clinic and assistant professor of psychiatry and behavioral sciences, Johns Hopkins School of Medicine, Baltimore, said the research “is a fine addition” to a previous analysis that explored dose-response relationships of antipsychotic drugs in the acute phase.

Crunching all the data from studies that have different types of patients and extracting a single dosage that provides maximum benefit is “a great challenge,” said Dr. Sedlak, who was not involved with the research.

The fact that most patients won’t get additional benefit above 5 mg, at which point they start getting more adverse events, and that 2.5 mg is sufficient for certain subgroups “agrees well with the experience of many who use these medications regularly,” Dr. Sedlak said.

However, he cautioned that psychiatrists “don’t always intuitively know which patients fall into which dose category or who might require clozapine.”

“Clinicians need to be mindful that it’s easy to overshoot an optimal dose and elicit side effects,” said Dr. Sedlak.

He also noted that severely ill patients are often underrepresented in clinical trials because they are too impaired to participate, “so they may have a different optimal dosage,” he concluded.

Dr. Leucht has reported receiving personal fees for consulting, advising, and/or speaking outside the submitted work from Angelini, Boehringer Ingelheim, Geodon & Richter, Janssen, Johnson & Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, Sanofi Aventis, Sandoz, Sunovion, Teva, Eisai, Rovi, and Amiabel. Dr. Sedlak has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A middle-of-the-road dose of an antipsychotic appears to be optimal for relapse prevention in stable schizophrenia, new research suggests.

Results of a meta-analysis show a 5-mg/day equivalent risperidone dose worked best. Higher doses were associated with more adverse events without showing substantial gains in relapse prevention, and lower doses were associated with greater relapse risk.

“The safest approach is to just to carry on with 5 mg,” which in many cases represents a full dose, lead author Stefan Leucht, MD, professor, department of psychiatry and psychotherapy, Technical University of Munich School of Medicine, Germany, told this news organization.

However, he added, patient preferences and other factors should be considered in dosage decision-making.

The findings were published online August 18 in JAMA Psychiatry.
 

Unique meta-analysis

Antipsychotic drugs are effective for short-term treatment of schizophrenia and prevention of relapse but are associated with movement disorders, weight gain, and other metabolic changes. They are also associated with even more severe adverse events, including tardive dyskinesia and increased cardiovascular risk.

For years, researchers have tried to find the optimal dose of antipsychotic drugs to prevent relapse in patients with stable schizophrenia while mitigating adverse event risk.

For the meta-analysis, researchers searched for fixed-dose, randomized, blinded, or open trials that lasted longer than 3 months and compared two first-generation antipsychotics – haloperidol or fluphenazine – or a second-generation antipsychotic with placebo or a different dose of the same drug.

The analysis included 26 studies with 72 individual dose arms and 4,776 participants with stable schizophrenia.  

Researchers used a dose-response meta-analysis. Unlike a simple meta-analysis that provides an “arbitrary” cut-off of superiority of one drug over placebo or another drug, a dose-response meta-analysis gives a plot or curve “that shows how this evolves with different doses,” Dr. Leucht noted.

The investigators estimated dose-response curves for each antipsychotic drug compared with placebo separately and as a group.

They did not have enough data for most of the single antipsychotics, so they converted doses to risperidone equivalents for a pooled analysis across drugs. They chose risperidone because its equivalents “are pretty well-defined,” said Dr. Leucht.
 

Go slow to go low

For the primary outcome of relapse, the dose-response curve showed a hyperbolic shape with a clear plateau. Initially, the plot decreased sharply but then flattened at about 5-mg/day risperidone equivalent (odds ratio, 0.20; 95% confidence interval, 0.13-0.31; relative risk, 0.43; 95% CI, 0.31-0.57).

“We were a little disappointed because we hoped that a dose lower than 5 mg would be most efficacious in terms of relapse rate because this would have reduced the side-effect burden,” Dr. Leucht said.

Nevertheless, he emphasized that doses lower than 5 mg/day risperidone equivalent are not completely ineffective. For example, the 2.5-mg dose reduced risk to relapse in relative terms by about 40% (RR, 0.63).

Dr. Leucht also pointed out there is “huge interindividual variability.” Therefore, 2.5 mg or even 1 mg may be sufficient for some patients. “It just means for the average patient it’s safest, let’s say, to keep her or him on 5 mg,” he said.  

When lowering the dose, Dr. Leucht noted clinicians should “be very careful and to do it very slowly. It should be very small reductions every 3 to 6 months.”

For the secondary endpoint of rehospitalizations, the shape of the curve was similar to the one for relapse but with lower rates.

“If patients need to be rehospitalized, it usually means that the relapse was major and not only a minor increase in symptoms,” said Dr. Leucht.

The curves for all-cause discontinuation and reduction in overall symptoms were also similar to that of relapse.

However, the curve for dropouts because of adverse events showed that higher doses led to more adverse events. For example, with 5-mg/day dose, the OR was 1.4 (95% CI, 0.87-2.25) and the RR was 1.38 (95% CI, 0.87-2.15), but for the 15-mg/day dose, the OR was 2.88 (95% CI, 1.52-5.45) and the RR was 2.68 (95% CI, 1.49-4.62).
 

Patient preference key

The data were insufficient to assess differences between men and women or between older and younger patients, Dr. Leucht noted.

However, post-hoc subgroup analyses turned up some interesting findings, he added. For example, patients who take high-potency first-generation antipsychotics such as haloperidol might do well on a lower dose, said Dr. Leucht.

“They may need a dose even lower than 5 mg, perhaps something like 2.5 mg, because these drugs bind so strongly to dopamine receptors,” he said.

He reiterated that patient preferences should always be considered when deciding on antipsychotic dosage.

“Many patients will say they don’t want to relapse anymore, but others will say these drugs have horrible side effects, and they want to go on a lower dose,” said Dr. Leucht.

Clinicians should also factor in patient characteristics, such as comorbidities or substance abuse, as well as severity of past relapses and properties of individual drugs, he added.
 

Reflects real-world experience

Commenting on the findings, Thomas Sedlak, MD, PhD, director, Schizophrenia and Psychosis Consult Clinic and assistant professor of psychiatry and behavioral sciences, Johns Hopkins School of Medicine, Baltimore, said the research “is a fine addition” to a previous analysis that explored dose-response relationships of antipsychotic drugs in the acute phase.

Crunching all the data from studies that have different types of patients and extracting a single dosage that provides maximum benefit is “a great challenge,” said Dr. Sedlak, who was not involved with the research.

The fact that most patients won’t get additional benefit above 5 mg, at which point they start getting more adverse events, and that 2.5 mg is sufficient for certain subgroups “agrees well with the experience of many who use these medications regularly,” Dr. Sedlak said.

However, he cautioned that psychiatrists “don’t always intuitively know which patients fall into which dose category or who might require clozapine.”

“Clinicians need to be mindful that it’s easy to overshoot an optimal dose and elicit side effects,” said Dr. Sedlak.

He also noted that severely ill patients are often underrepresented in clinical trials because they are too impaired to participate, “so they may have a different optimal dosage,” he concluded.

Dr. Leucht has reported receiving personal fees for consulting, advising, and/or speaking outside the submitted work from Angelini, Boehringer Ingelheim, Geodon & Richter, Janssen, Johnson & Johnson, Lundbeck, LTS Lohmann, MSD, Otsuka, Recordati, Sanofi Aventis, Sandoz, Sunovion, Teva, Eisai, Rovi, and Amiabel. Dr. Sedlak has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Climate change is a global threat, and it presents a dual problem to health care: The system must address health threats that may be caused or exacerbated by climate change, while at the same time minimizing its environmental impact, according to the authors of a paper in Techniques and Innovations in Gastrointestinal Endoscopy.

Because of how often it is performed, endoscopy may have one of the highest environmental impacts of any health care procedure. Waste produced by endoscopy is the third largest source in a typical hospital, equivalent yearly to burning 39 million pounds of coal or 13,500 tons of plastic. That makes endoscopy a key target in reducing the environmental footprint of health care, according to the authors, who were led by Rosemary Haddock, MBChB, MRCP, of Ninewells Hospital in Dundee, Scotland.

Climate change has direct impacts on health, ranging from the effects of wildfire smoke and pollution on respiratory and cardiac health to food insecurity, heat stroke, and alterations to the geographic ranges of vector-borne diseases. It also raises the risk of future pandemics like COVID-19. “Climate change is a major threat to health and threatens to undermine the last 50 years of public health gains,” the authors wrote.

Although the effects of climate change on gastrointestinal diseases has not been studied as extensively as other organ systems, there are known impacts. These include more gastrointestinal infections at higher temperatures, the risk of enteric pathogens and viral hepatitis as a result of flooding and higher water temperatures, and malnutrition caused by the disruption of food crops and distribution. “It seems a little unlikely that the organs which we are interested in as gastroenterologists and hepatologists are largely exempt from the direct effects of hotter temperatures, when every other human organ system appears to be affected almost without exception,” the authors wrote.

Those issues put an onus on health care to address climate change, not only in health care delivery but also to find ways to reduce emissions as an industry. Hospitals and other large facilities can act as “anchor institutions” that set an example within the community and influence others since they procure goods and services and own assets and land. To date, few institutions have adopted this stance.

A key question is how health care institutions can reduce resource use while maintaining quality of care. One approach is to identify areas of medical overuse, where wasteful practices have no patient benefit. The authors believe that a reduction in endoscopic procedures could have one of the largest impacts on carbon emissions. They emphasized that reduced numbers of procedures would likely have greater effect than making procedures “greener.”

Some endoscopic procedures offer little value to the patient. The approach of screening to combat disease, introduced in 1968, should be challenged in some patient groups because it can lead to unnecessary procedures.

The American Gastroenterological Association has identified some procedures as commonly overused, including screening colonoscopy in average-risk individuals, surveillance colonoscopy for low-risk polyps, and surveillance esophagogastroduodenoscopy in Barrett’s esophagus. The authors note that performing fewer endoscopies will require shifts in behavior, referral patterns, education, and culture, all of which will take time.

In the meantime, endoscopists can take some steps to reduce the footprint of existing procedures: source supplies through sustainable means, which is important because supply chain emissions account for more than half of health care emissions; seek out sources of renewable energy; use their institution’s status as an “anchor institution” to pressure suppliers into using sustainable practices; evaluate less invasive procedures, such as Cytosponge or fecal immunochemical test; employ reusable or recyclable equipment; minimize the use of nitrous oxide, which is a key greenhouse gas; segregate infectious waste; and develop multiple recycling streams.

The authors have no relevant financial disclosures.

Climate change is a global threat, and it presents a dual problem to health care: The system must address health threats that may be caused or exacerbated by climate change, while at the same time minimizing its environmental impact, according to the authors of a paper in Techniques and Innovations in Gastrointestinal Endoscopy.

Because of how often it is performed, endoscopy may have one of the highest environmental impacts of any health care procedure. Waste produced by endoscopy is the third largest source in a typical hospital, equivalent yearly to burning 39 million pounds of coal or 13,500 tons of plastic. That makes endoscopy a key target in reducing the environmental footprint of health care, according to the authors, who were led by Rosemary Haddock, MBChB, MRCP, of Ninewells Hospital in Dundee, Scotland.

Climate change has direct impacts on health, ranging from the effects of wildfire smoke and pollution on respiratory and cardiac health to food insecurity, heat stroke, and alterations to the geographic ranges of vector-borne diseases. It also raises the risk of future pandemics like COVID-19. “Climate change is a major threat to health and threatens to undermine the last 50 years of public health gains,” the authors wrote.

Although the effects of climate change on gastrointestinal diseases has not been studied as extensively as other organ systems, there are known impacts. These include more gastrointestinal infections at higher temperatures, the risk of enteric pathogens and viral hepatitis as a result of flooding and higher water temperatures, and malnutrition caused by the disruption of food crops and distribution. “It seems a little unlikely that the organs which we are interested in as gastroenterologists and hepatologists are largely exempt from the direct effects of hotter temperatures, when every other human organ system appears to be affected almost without exception,” the authors wrote.

Those issues put an onus on health care to address climate change, not only in health care delivery but also to find ways to reduce emissions as an industry. Hospitals and other large facilities can act as “anchor institutions” that set an example within the community and influence others since they procure goods and services and own assets and land. To date, few institutions have adopted this stance.

A key question is how health care institutions can reduce resource use while maintaining quality of care. One approach is to identify areas of medical overuse, where wasteful practices have no patient benefit. The authors believe that a reduction in endoscopic procedures could have one of the largest impacts on carbon emissions. They emphasized that reduced numbers of procedures would likely have greater effect than making procedures “greener.”

Some endoscopic procedures offer little value to the patient. The approach of screening to combat disease, introduced in 1968, should be challenged in some patient groups because it can lead to unnecessary procedures.

The American Gastroenterological Association has identified some procedures as commonly overused, including screening colonoscopy in average-risk individuals, surveillance colonoscopy for low-risk polyps, and surveillance esophagogastroduodenoscopy in Barrett’s esophagus. The authors note that performing fewer endoscopies will require shifts in behavior, referral patterns, education, and culture, all of which will take time.

In the meantime, endoscopists can take some steps to reduce the footprint of existing procedures: source supplies through sustainable means, which is important because supply chain emissions account for more than half of health care emissions; seek out sources of renewable energy; use their institution’s status as an “anchor institution” to pressure suppliers into using sustainable practices; evaluate less invasive procedures, such as Cytosponge or fecal immunochemical test; employ reusable or recyclable equipment; minimize the use of nitrous oxide, which is a key greenhouse gas; segregate infectious waste; and develop multiple recycling streams.

The authors have no relevant financial disclosures.

Climate change is a global threat, and it presents a dual problem to health care: The system must address health threats that may be caused or exacerbated by climate change, while at the same time minimizing its environmental impact, according to the authors of a paper in Techniques and Innovations in Gastrointestinal Endoscopy.

Because of how often it is performed, endoscopy may have one of the highest environmental impacts of any health care procedure. Waste produced by endoscopy is the third largest source in a typical hospital, equivalent yearly to burning 39 million pounds of coal or 13,500 tons of plastic. That makes endoscopy a key target in reducing the environmental footprint of health care, according to the authors, who were led by Rosemary Haddock, MBChB, MRCP, of Ninewells Hospital in Dundee, Scotland.

Climate change has direct impacts on health, ranging from the effects of wildfire smoke and pollution on respiratory and cardiac health to food insecurity, heat stroke, and alterations to the geographic ranges of vector-borne diseases. It also raises the risk of future pandemics like COVID-19. “Climate change is a major threat to health and threatens to undermine the last 50 years of public health gains,” the authors wrote.

Although the effects of climate change on gastrointestinal diseases has not been studied as extensively as other organ systems, there are known impacts. These include more gastrointestinal infections at higher temperatures, the risk of enteric pathogens and viral hepatitis as a result of flooding and higher water temperatures, and malnutrition caused by the disruption of food crops and distribution. “It seems a little unlikely that the organs which we are interested in as gastroenterologists and hepatologists are largely exempt from the direct effects of hotter temperatures, when every other human organ system appears to be affected almost without exception,” the authors wrote.

Those issues put an onus on health care to address climate change, not only in health care delivery but also to find ways to reduce emissions as an industry. Hospitals and other large facilities can act as “anchor institutions” that set an example within the community and influence others since they procure goods and services and own assets and land. To date, few institutions have adopted this stance.

A key question is how health care institutions can reduce resource use while maintaining quality of care. One approach is to identify areas of medical overuse, where wasteful practices have no patient benefit. The authors believe that a reduction in endoscopic procedures could have one of the largest impacts on carbon emissions. They emphasized that reduced numbers of procedures would likely have greater effect than making procedures “greener.”

Some endoscopic procedures offer little value to the patient. The approach of screening to combat disease, introduced in 1968, should be challenged in some patient groups because it can lead to unnecessary procedures.

The American Gastroenterological Association has identified some procedures as commonly overused, including screening colonoscopy in average-risk individuals, surveillance colonoscopy for low-risk polyps, and surveillance esophagogastroduodenoscopy in Barrett’s esophagus. The authors note that performing fewer endoscopies will require shifts in behavior, referral patterns, education, and culture, all of which will take time.

In the meantime, endoscopists can take some steps to reduce the footprint of existing procedures: source supplies through sustainable means, which is important because supply chain emissions account for more than half of health care emissions; seek out sources of renewable energy; use their institution’s status as an “anchor institution” to pressure suppliers into using sustainable practices; evaluate less invasive procedures, such as Cytosponge or fecal immunochemical test; employ reusable or recyclable equipment; minimize the use of nitrous oxide, which is a key greenhouse gas; segregate infectious waste; and develop multiple recycling streams.

The authors have no relevant financial disclosures.

A 66-year-old woman is discharged from the hospital after an MI. Her discharge medications include atorvastatin 40 mg, lisinopril 20 mg, acetylsalicylic acid 81 mg, and clopidogrel 75 mg. At this patient’s follow-up appointment, she mentions that she has muscle pain and stiffness in both legs and her back. Her labs include thyroid-stimulating hormone of 2.0 and vitamin D of 40. She stops the atorvastatin for 2 weeks with resolution of her symptoms.

Which treatment recommendation would you make for this patient?

A. Restart atorvastatin

B. Start rosuvastatin twice a week

C. Start ezetimibe

D. Start a PCSK9 inhibitor

We often see high-risk cardiovascular disease patients who are concerned about muscle side effects brought on by statins. I think we all can agree that this patient needs aggressive medical therapy for prevention of secondary cardiovascular events. I would restart her atorvastatin.

Neilsen and Nordestgaard found that early statin discontinuation rates increased from 6% in 1995 to 18% in 2010.¹

Early statin discontinuation correlated with negative statin-related news stories, their paper states. This suggests either an increased awareness of side effects or a possible nocebo effect.
 

Statin rechallenge results

Joy and colleagues reported the results on eight patients who had developed myalgias within 3 weeks of starting a statin. These patients, who received placebo or statin, completed an N-of-1 trial with three double-blind, crossover comparisons separated by 3-week washout periods.

Patients were evaluated pain on a visual analog scale (VAS). For each N-of-1 trial there was no statistically significant difference in pain or myalgia score between those who took statin and placebo. Five of the eight patients chose to continue on statins at the end of the trial.

Herrett and colleagues performed a more extensive series of N-of-1 trials involving 200 patients who had stopped or were considering stopping statins because of muscle symptoms.³ Participants either received 2 months of atorvastatin 20 mg or placebo for 2-month blocks six times. They rated their muscle symptoms on a VAS at the end of each block. There was no difference in muscle symptom scores between the statin and placebo periods.

Wood and colleagues took it a step further, when they studied an N-of-1 trial that included statin, placebo, and no treatment.⁴ Each participant received four bottles of atorvastatin 20 mg, four bottles of placebo, and four empty bottles. Each month they used treatment from the bottles based on random sequence and reported daily symptom scores. The mean symptom intensity was 8.0 during no-tablet months, 15.4 during placebo months (P < .001, compared with no-tablet months), and 16.3 during statin months (P < .001, compared with no-tablet months; P = .39, compared with placebo).

Taylor and colleagues studied 120 patients who had prior statin-associated muscle complaints.⁵ Each patient received either simvastatin 20 mg or placebo for 4 weeks, and then were switched for an additional 4 weeks. A total of 43 patients (36%) had pain on simvastatin but not placebo, 21 (17%) had no pain with either treatment, 21 (17%) reported pain with both treatments, and 35 (29%) had pain with placebo but not simvastatin. These studies support the concept of nocebo effect in patients who have muscle symptoms on statins.

So what should be done? Brennan and Roy did a retrospective study of 118 patients referred to a lipid clinic as being statin intolerant to two or more statins.⁶ Most of the patients were able to tolerate a statin: 71% tolerated same statin rechallenge, 53% tolerated statin switch, and 57% tolerated a nonstatin therapy.

In the Prosisa study, only 27% of patients who reported statin-associated muscle symptoms had reappearance of muscle symptoms after rechallenge with a statin.7
 

Research implications

Rechallenge with the same statin seems to be a reasonable first step, followed by switching to a different statin. I also share the concept of nocebo effect with my patients, and tell them I believe they have an excellent chance of tolerating the statin.

Pearl: The majority of patients with muscle symptoms while taking a statin likely have a nocebo effect, and are likely to tolerate rechallenge with the same statin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Nielsen SF and Nordestgaard BG. Eur Heart J. 2016;37:908-16.

2. Joy TR et al. Ann Intern Med. 2014;160:301-10.

3. Herrett E et al. BMJ. 2021 Feb 24;372:n135.

4. Wood FA et al. N Engl J Med 2020;383:2182-4.

5. Taylor BA et al. Atherosclerosis. 2017;256:100-4.

6. Brennen ET and Roy TR. Can J Card. 2017;33(5):666-73.

7. Bonaiti Fet al. Atherosclerosis. 2020;315:E13-4.

A 66-year-old woman is discharged from the hospital after an MI. Her discharge medications include atorvastatin 40 mg, lisinopril 20 mg, acetylsalicylic acid 81 mg, and clopidogrel 75 mg. At this patient’s follow-up appointment, she mentions that she has muscle pain and stiffness in both legs and her back. Her labs include thyroid-stimulating hormone of 2.0 and vitamin D of 40. She stops the atorvastatin for 2 weeks with resolution of her symptoms.

Which treatment recommendation would you make for this patient?

A. Restart atorvastatin

B. Start rosuvastatin twice a week

C. Start ezetimibe

D. Start a PCSK9 inhibitor

We often see high-risk cardiovascular disease patients who are concerned about muscle side effects brought on by statins. I think we all can agree that this patient needs aggressive medical therapy for prevention of secondary cardiovascular events. I would restart her atorvastatin.

Neilsen and Nordestgaard found that early statin discontinuation rates increased from 6% in 1995 to 18% in 2010.¹

Early statin discontinuation correlated with negative statin-related news stories, their paper states. This suggests either an increased awareness of side effects or a possible nocebo effect.
 

Statin rechallenge results

Joy and colleagues reported the results on eight patients who had developed myalgias within 3 weeks of starting a statin. These patients, who received placebo or statin, completed an N-of-1 trial with three double-blind, crossover comparisons separated by 3-week washout periods.

Patients were evaluated pain on a visual analog scale (VAS). For each N-of-1 trial there was no statistically significant difference in pain or myalgia score between those who took statin and placebo. Five of the eight patients chose to continue on statins at the end of the trial.

Herrett and colleagues performed a more extensive series of N-of-1 trials involving 200 patients who had stopped or were considering stopping statins because of muscle symptoms.³ Participants either received 2 months of atorvastatin 20 mg or placebo for 2-month blocks six times. They rated their muscle symptoms on a VAS at the end of each block. There was no difference in muscle symptom scores between the statin and placebo periods.

Wood and colleagues took it a step further, when they studied an N-of-1 trial that included statin, placebo, and no treatment.⁴ Each participant received four bottles of atorvastatin 20 mg, four bottles of placebo, and four empty bottles. Each month they used treatment from the bottles based on random sequence and reported daily symptom scores. The mean symptom intensity was 8.0 during no-tablet months, 15.4 during placebo months (P < .001, compared with no-tablet months), and 16.3 during statin months (P < .001, compared with no-tablet months; P = .39, compared with placebo).

Taylor and colleagues studied 120 patients who had prior statin-associated muscle complaints.⁵ Each patient received either simvastatin 20 mg or placebo for 4 weeks, and then were switched for an additional 4 weeks. A total of 43 patients (36%) had pain on simvastatin but not placebo, 21 (17%) had no pain with either treatment, 21 (17%) reported pain with both treatments, and 35 (29%) had pain with placebo but not simvastatin. These studies support the concept of nocebo effect in patients who have muscle symptoms on statins.

So what should be done? Brennan and Roy did a retrospective study of 118 patients referred to a lipid clinic as being statin intolerant to two or more statins.⁶ Most of the patients were able to tolerate a statin: 71% tolerated same statin rechallenge, 53% tolerated statin switch, and 57% tolerated a nonstatin therapy.

In the Prosisa study, only 27% of patients who reported statin-associated muscle symptoms had reappearance of muscle symptoms after rechallenge with a statin.7
 

Research implications

Rechallenge with the same statin seems to be a reasonable first step, followed by switching to a different statin. I also share the concept of nocebo effect with my patients, and tell them I believe they have an excellent chance of tolerating the statin.

Pearl: The majority of patients with muscle symptoms while taking a statin likely have a nocebo effect, and are likely to tolerate rechallenge with the same statin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Nielsen SF and Nordestgaard BG. Eur Heart J. 2016;37:908-16.

2. Joy TR et al. Ann Intern Med. 2014;160:301-10.

3. Herrett E et al. BMJ. 2021 Feb 24;372:n135.

4. Wood FA et al. N Engl J Med 2020;383:2182-4.

5. Taylor BA et al. Atherosclerosis. 2017;256:100-4.

6. Brennen ET and Roy TR. Can J Card. 2017;33(5):666-73.

7. Bonaiti Fet al. Atherosclerosis. 2020;315:E13-4.

A 66-year-old woman is discharged from the hospital after an MI. Her discharge medications include atorvastatin 40 mg, lisinopril 20 mg, acetylsalicylic acid 81 mg, and clopidogrel 75 mg. At this patient’s follow-up appointment, she mentions that she has muscle pain and stiffness in both legs and her back. Her labs include thyroid-stimulating hormone of 2.0 and vitamin D of 40. She stops the atorvastatin for 2 weeks with resolution of her symptoms.

Which treatment recommendation would you make for this patient?

A. Restart atorvastatin

B. Start rosuvastatin twice a week

C. Start ezetimibe

D. Start a PCSK9 inhibitor

We often see high-risk cardiovascular disease patients who are concerned about muscle side effects brought on by statins. I think we all can agree that this patient needs aggressive medical therapy for prevention of secondary cardiovascular events. I would restart her atorvastatin.

Neilsen and Nordestgaard found that early statin discontinuation rates increased from 6% in 1995 to 18% in 2010.¹

Early statin discontinuation correlated with negative statin-related news stories, their paper states. This suggests either an increased awareness of side effects or a possible nocebo effect.
 

Statin rechallenge results

Joy and colleagues reported the results on eight patients who had developed myalgias within 3 weeks of starting a statin. These patients, who received placebo or statin, completed an N-of-1 trial with three double-blind, crossover comparisons separated by 3-week washout periods.

Patients were evaluated pain on a visual analog scale (VAS). For each N-of-1 trial there was no statistically significant difference in pain or myalgia score between those who took statin and placebo. Five of the eight patients chose to continue on statins at the end of the trial.

Herrett and colleagues performed a more extensive series of N-of-1 trials involving 200 patients who had stopped or were considering stopping statins because of muscle symptoms.³ Participants either received 2 months of atorvastatin 20 mg or placebo for 2-month blocks six times. They rated their muscle symptoms on a VAS at the end of each block. There was no difference in muscle symptom scores between the statin and placebo periods.

Wood and colleagues took it a step further, when they studied an N-of-1 trial that included statin, placebo, and no treatment.⁴ Each participant received four bottles of atorvastatin 20 mg, four bottles of placebo, and four empty bottles. Each month they used treatment from the bottles based on random sequence and reported daily symptom scores. The mean symptom intensity was 8.0 during no-tablet months, 15.4 during placebo months (P < .001, compared with no-tablet months), and 16.3 during statin months (P < .001, compared with no-tablet months; P = .39, compared with placebo).

Taylor and colleagues studied 120 patients who had prior statin-associated muscle complaints.⁵ Each patient received either simvastatin 20 mg or placebo for 4 weeks, and then were switched for an additional 4 weeks. A total of 43 patients (36%) had pain on simvastatin but not placebo, 21 (17%) had no pain with either treatment, 21 (17%) reported pain with both treatments, and 35 (29%) had pain with placebo but not simvastatin. These studies support the concept of nocebo effect in patients who have muscle symptoms on statins.

So what should be done? Brennan and Roy did a retrospective study of 118 patients referred to a lipid clinic as being statin intolerant to two or more statins.⁶ Most of the patients were able to tolerate a statin: 71% tolerated same statin rechallenge, 53% tolerated statin switch, and 57% tolerated a nonstatin therapy.

In the Prosisa study, only 27% of patients who reported statin-associated muscle symptoms had reappearance of muscle symptoms after rechallenge with a statin.7
 

Research implications

Rechallenge with the same statin seems to be a reasonable first step, followed by switching to a different statin. I also share the concept of nocebo effect with my patients, and tell them I believe they have an excellent chance of tolerating the statin.

Pearl: The majority of patients with muscle symptoms while taking a statin likely have a nocebo effect, and are likely to tolerate rechallenge with the same statin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.

References

1. Nielsen SF and Nordestgaard BG. Eur Heart J. 2016;37:908-16.

2. Joy TR et al. Ann Intern Med. 2014;160:301-10.

3. Herrett E et al. BMJ. 2021 Feb 24;372:n135.

4. Wood FA et al. N Engl J Med 2020;383:2182-4.

5. Taylor BA et al. Atherosclerosis. 2017;256:100-4.

6. Brennen ET and Roy TR. Can J Card. 2017;33(5):666-73.

7. Bonaiti Fet al. Atherosclerosis. 2020;315:E13-4.

A “quadpill” containing quarter doses of four blood pressure (BP)–lowering medications was more effective than monotherapy for initial treatment of hypertension, with similar tolerability, in the 1-year, phase 3 QUARTET randomized, active-control trial.

ClaudioVentrella/Thinkstock

Clara Chow, MD, PhD, academic director of the Westmead Applied Research Centre, University of Sydney, presented the findings in a late-breaking trial session at the annual congress of the European Society of Cardiology. The study was simultaneously published in The Lancet.

The primary outcome, mean unattended office BP at 12 weeks, dropped from 142/86 mm Hg to 120/71 mm Hg in patients who received the daily quadpill – a capsule containing irbesartan, amlodipine, indapamide, and bisoprolol – and fell from 140/83 mm Hg to 127/79 mm Hg in patients who received a daily full dose of irbesartan.

This 6.9 mm Hg greater drop in systolic BP at 12 months is clinically meaningful, Dr. Chow told this news organization. “If maintained, it would be expected to confer about a 15%-20% reduction” in heart disease, stroke, and heart failure.

In the SPRINT study, she noted, the final systolic BP was 120 mm Hg in the intervention group and 134 mm Hg in the control group, and the difference was associated with a 27% reduction in the composite cardiovascular (CV) outcome.

The results of QUARTET suggest that, “even in those with stage 1 hypertension, we can safely reduce BP to a significant degree by this simple approach, compared to usual care,” Salim Yusuf, MD, DPhil, a long-time advocate of a polypill approach, said in an email.

Importantly, Dr. Chow pointed out, at 12 months, 81% of patients treated with the quadpill versus 62% of patients treated with monotherapy had BP control (<140/90 mm Hg). Patients who received monotherapy did not “catch up,” even though a higher percentage received stepped-up therapy.

The quadpill dosing strategy aligns with the latest 2018 ESC/European Society of Hypertension guidelines, which recommend starting antihypertensive treatment with more than one drug, session cochair Thomas Kahan, MD, PhD, Karolinska Institute, Danderyd Hospital, department of clinical sciences, Stockholm, commented.

“How many drugs should be in the initial step?” he asked. “Is four better than three or two, or should we have even more drugs at low doses?”

The trial was not designed to answer these questions, Dr. Chow replied. “We were really comparing [the quadpill] against what the majority of people around the planet are still doing, which is starting on one drug and slowly but surely stepping it up,” she said.

The quadpill was actually a capsule, she clarified, that contained four generic BP medications available in half doses in Australia. The half doses were cut in half and the medications were encapsulated. The control drug was prepared in an identical-looking capsule.  

It is important to note that “the time to BP control was shorter in patients who received the quadpill versus monotherapy,” session cochair Felix Mahfoud, MD, internal medicine and cardiology, Saarland University Hospital, Hamburg, Germany, pointed out, because “in clinical practice we aim to get patients to BP control as quickly as possible.”

“What is new here is the use of four drugs, each given at quarter doses,” Dr. Yusuf, director of the Population Health Research Institute, McMaster University, Hamilton, Ont., said. Although a few questions remain, “this study emphasizes the importance and potential benefits and simplicity of using combination BP-lowering drugs at low doses.”

For guidelines to be changed, he observed, the findings would have to be replicated in independent studies, and the quadpill would likely have to be shown to be superior to the dual pill.

“It took about 20 years [to change guidelines] after the first evidence that combinations of two pills were preferable to single-drug combinations,” he noted.

“I hope that in most people with elevated BP, at least a two-drug combination plus a statin plus aspirin will be prescribed,” Dr. Yusuf said. “This can reduce the risk of CVD events by 50% or more – a big impact both for the individual and for populations. The quad pill may have a role in this approach.”
 

Four-in-one pill

Worldwide, hypertension control is poor, Dr. Chow said, because of the need for multiple medications, treatment inertia, and concerns about adverse events.

The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.

QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia from June 2017 through August 2020.  

Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP greater than 135/95 mm Hg, or they were on BP-lowering monotherapy and had a BP of 130/85 to 179/109 mm Hg or daytime ambulatory BP greater than 125/80 mm Hg. Patients who were taking antihypertensive therapy entered a washout period before the trial.

The researchers randomized 291 participants to receive 150 mg irbesartan daily (usual care or control group).

The other 300 participants received a daily quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The first three drugs are the most commonly prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazidelike diuretic in Australia, and the last drug, a beta-blocker, has a long duration of action, the study protocol explains.

Patients in both groups had similar baseline characteristics. They were a mean age of 58 years, 40% were women, and 82% were White. They also had a mean body mass index of 31 kg/m². About 8% were current smokers, and about 54% were not taking a BP-lowering drug.

Participants had clinic visits at baseline, 6 weeks, and 12 weeks, and if they continued the study, at 26 weeks and 52 weeks.

If a patient’s blood pressure was higher than 140/90 mm Hg, clinicians could add another medication, starting with amlodipine 5 mg.

At 12 weeks, 15% of patients in the intervention group and 40% in the control group had stepped up treatment.

Despite greater up-titration in the usual care group, BP control remained higher in the quadpill group, Dr. Chow pointed out. That is, patients in the quadpill group were more likely than patients in the usual care group to have a BP less than 140/90 mm Hg (76% vs. 58% respectively; P < .0001).

Patients in the quadpill group also had lower daytime and nighttime ambulatory systolic BP.

At 12 months, among the 417 patients who continued treatment, patients in the quadpill group had a 7.7 mm Hg greater drop in systolic BP, compared with patients in the control group, (P < .001).  

There were no significant differences in adverse events, which were most commonly dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.

At 12 weeks, there were seven serious adverse events in the intervention group versus three in the control group. There were 12 treatment withdrawals in the intervention group versus seven in the control group (P = .27).

Remaining questions, upcoming phase 3 U.S. study

“While the [QUARTET] results are impressive, we are left with a number of questions,” Dr. Yusuf said.

Would the results be the same with a three-drug combo or even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses provided similar results to the current study, over a much longer mean follow-up of 5.6 years, he noted.

Also, is the quadpill associated with higher rates of diabetes or higher creatinine levels in the long term? “Given that we do not have any data on long-term clinical outcomes from a four-drug combination,” Dr. Yusuf said, “caution should be utilized.”

Would the reduced risk of CVD be greater with a combination of low doses of two BP-lowering drugs plus a statin plus aspirin? That may be superior, he said, “based on recent information published on the polypill indicating a 50% relative risk reduction in CVD events.”

The related phase 2 QUARTET US trial should shed further light on a quadpill strategy. Patients with hypertension are being randomized to a daily quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to usual care, 8 mg candesartan daily.

Investigators plan to enroll 87 participants in the Chicago area, with estimated study completion by March 31, 2023.

The study was supported by an Australian National Health and Medical Research Council grant. The George Institute for Global Health has submitted patent applications for low–fixed-dose combination products to treat CV or cardiometabolic disease. Dr. Chow and coauthor Kris Rogers, PhD, senior biostatistician at The George Institute for Global Health, Newtown, Australia, are listed as inventors, but they do not have direct financial interests in these patent applications.

A version of this article first appeared on Medscape.com.

A “quadpill” containing quarter doses of four blood pressure (BP)–lowering medications was more effective than monotherapy for initial treatment of hypertension, with similar tolerability, in the 1-year, phase 3 QUARTET randomized, active-control trial.

ClaudioVentrella/Thinkstock

Clara Chow, MD, PhD, academic director of the Westmead Applied Research Centre, University of Sydney, presented the findings in a late-breaking trial session at the annual congress of the European Society of Cardiology. The study was simultaneously published in The Lancet.

The primary outcome, mean unattended office BP at 12 weeks, dropped from 142/86 mm Hg to 120/71 mm Hg in patients who received the daily quadpill – a capsule containing irbesartan, amlodipine, indapamide, and bisoprolol – and fell from 140/83 mm Hg to 127/79 mm Hg in patients who received a daily full dose of irbesartan.

This 6.9 mm Hg greater drop in systolic BP at 12 months is clinically meaningful, Dr. Chow told this news organization. “If maintained, it would be expected to confer about a 15%-20% reduction” in heart disease, stroke, and heart failure.

In the SPRINT study, she noted, the final systolic BP was 120 mm Hg in the intervention group and 134 mm Hg in the control group, and the difference was associated with a 27% reduction in the composite cardiovascular (CV) outcome.

The results of QUARTET suggest that, “even in those with stage 1 hypertension, we can safely reduce BP to a significant degree by this simple approach, compared to usual care,” Salim Yusuf, MD, DPhil, a long-time advocate of a polypill approach, said in an email.

Importantly, Dr. Chow pointed out, at 12 months, 81% of patients treated with the quadpill versus 62% of patients treated with monotherapy had BP control (<140/90 mm Hg). Patients who received monotherapy did not “catch up,” even though a higher percentage received stepped-up therapy.

The quadpill dosing strategy aligns with the latest 2018 ESC/European Society of Hypertension guidelines, which recommend starting antihypertensive treatment with more than one drug, session cochair Thomas Kahan, MD, PhD, Karolinska Institute, Danderyd Hospital, department of clinical sciences, Stockholm, commented.

“How many drugs should be in the initial step?” he asked. “Is four better than three or two, or should we have even more drugs at low doses?”

The trial was not designed to answer these questions, Dr. Chow replied. “We were really comparing [the quadpill] against what the majority of people around the planet are still doing, which is starting on one drug and slowly but surely stepping it up,” she said.

The quadpill was actually a capsule, she clarified, that contained four generic BP medications available in half doses in Australia. The half doses were cut in half and the medications were encapsulated. The control drug was prepared in an identical-looking capsule.  

It is important to note that “the time to BP control was shorter in patients who received the quadpill versus monotherapy,” session cochair Felix Mahfoud, MD, internal medicine and cardiology, Saarland University Hospital, Hamburg, Germany, pointed out, because “in clinical practice we aim to get patients to BP control as quickly as possible.”

“What is new here is the use of four drugs, each given at quarter doses,” Dr. Yusuf, director of the Population Health Research Institute, McMaster University, Hamilton, Ont., said. Although a few questions remain, “this study emphasizes the importance and potential benefits and simplicity of using combination BP-lowering drugs at low doses.”

For guidelines to be changed, he observed, the findings would have to be replicated in independent studies, and the quadpill would likely have to be shown to be superior to the dual pill.

“It took about 20 years [to change guidelines] after the first evidence that combinations of two pills were preferable to single-drug combinations,” he noted.

“I hope that in most people with elevated BP, at least a two-drug combination plus a statin plus aspirin will be prescribed,” Dr. Yusuf said. “This can reduce the risk of CVD events by 50% or more – a big impact both for the individual and for populations. The quad pill may have a role in this approach.”
 

Four-in-one pill

Worldwide, hypertension control is poor, Dr. Chow said, because of the need for multiple medications, treatment inertia, and concerns about adverse events.

The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.

QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia from June 2017 through August 2020.  

Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP greater than 135/95 mm Hg, or they were on BP-lowering monotherapy and had a BP of 130/85 to 179/109 mm Hg or daytime ambulatory BP greater than 125/80 mm Hg. Patients who were taking antihypertensive therapy entered a washout period before the trial.

The researchers randomized 291 participants to receive 150 mg irbesartan daily (usual care or control group).

The other 300 participants received a daily quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The first three drugs are the most commonly prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazidelike diuretic in Australia, and the last drug, a beta-blocker, has a long duration of action, the study protocol explains.

Patients in both groups had similar baseline characteristics. They were a mean age of 58 years, 40% were women, and 82% were White. They also had a mean body mass index of 31 kg/m². About 8% were current smokers, and about 54% were not taking a BP-lowering drug.

Participants had clinic visits at baseline, 6 weeks, and 12 weeks, and if they continued the study, at 26 weeks and 52 weeks.

If a patient’s blood pressure was higher than 140/90 mm Hg, clinicians could add another medication, starting with amlodipine 5 mg.

At 12 weeks, 15% of patients in the intervention group and 40% in the control group had stepped up treatment.

Despite greater up-titration in the usual care group, BP control remained higher in the quadpill group, Dr. Chow pointed out. That is, patients in the quadpill group were more likely than patients in the usual care group to have a BP less than 140/90 mm Hg (76% vs. 58% respectively; P < .0001).

Patients in the quadpill group also had lower daytime and nighttime ambulatory systolic BP.

At 12 months, among the 417 patients who continued treatment, patients in the quadpill group had a 7.7 mm Hg greater drop in systolic BP, compared with patients in the control group, (P < .001).  

There were no significant differences in adverse events, which were most commonly dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.

At 12 weeks, there were seven serious adverse events in the intervention group versus three in the control group. There were 12 treatment withdrawals in the intervention group versus seven in the control group (P = .27).

Remaining questions, upcoming phase 3 U.S. study

“While the [QUARTET] results are impressive, we are left with a number of questions,” Dr. Yusuf said.

Would the results be the same with a three-drug combo or even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses provided similar results to the current study, over a much longer mean follow-up of 5.6 years, he noted.

Also, is the quadpill associated with higher rates of diabetes or higher creatinine levels in the long term? “Given that we do not have any data on long-term clinical outcomes from a four-drug combination,” Dr. Yusuf said, “caution should be utilized.”

Would the reduced risk of CVD be greater with a combination of low doses of two BP-lowering drugs plus a statin plus aspirin? That may be superior, he said, “based on recent information published on the polypill indicating a 50% relative risk reduction in CVD events.”

The related phase 2 QUARTET US trial should shed further light on a quadpill strategy. Patients with hypertension are being randomized to a daily quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to usual care, 8 mg candesartan daily.

Investigators plan to enroll 87 participants in the Chicago area, with estimated study completion by March 31, 2023.

The study was supported by an Australian National Health and Medical Research Council grant. The George Institute for Global Health has submitted patent applications for low–fixed-dose combination products to treat CV or cardiometabolic disease. Dr. Chow and coauthor Kris Rogers, PhD, senior biostatistician at The George Institute for Global Health, Newtown, Australia, are listed as inventors, but they do not have direct financial interests in these patent applications.

A version of this article first appeared on Medscape.com.

A “quadpill” containing quarter doses of four blood pressure (BP)–lowering medications was more effective than monotherapy for initial treatment of hypertension, with similar tolerability, in the 1-year, phase 3 QUARTET randomized, active-control trial.

ClaudioVentrella/Thinkstock

Clara Chow, MD, PhD, academic director of the Westmead Applied Research Centre, University of Sydney, presented the findings in a late-breaking trial session at the annual congress of the European Society of Cardiology. The study was simultaneously published in The Lancet.

The primary outcome, mean unattended office BP at 12 weeks, dropped from 142/86 mm Hg to 120/71 mm Hg in patients who received the daily quadpill – a capsule containing irbesartan, amlodipine, indapamide, and bisoprolol – and fell from 140/83 mm Hg to 127/79 mm Hg in patients who received a daily full dose of irbesartan.

This 6.9 mm Hg greater drop in systolic BP at 12 months is clinically meaningful, Dr. Chow told this news organization. “If maintained, it would be expected to confer about a 15%-20% reduction” in heart disease, stroke, and heart failure.

In the SPRINT study, she noted, the final systolic BP was 120 mm Hg in the intervention group and 134 mm Hg in the control group, and the difference was associated with a 27% reduction in the composite cardiovascular (CV) outcome.

The results of QUARTET suggest that, “even in those with stage 1 hypertension, we can safely reduce BP to a significant degree by this simple approach, compared to usual care,” Salim Yusuf, MD, DPhil, a long-time advocate of a polypill approach, said in an email.

Importantly, Dr. Chow pointed out, at 12 months, 81% of patients treated with the quadpill versus 62% of patients treated with monotherapy had BP control (<140/90 mm Hg). Patients who received monotherapy did not “catch up,” even though a higher percentage received stepped-up therapy.

The quadpill dosing strategy aligns with the latest 2018 ESC/European Society of Hypertension guidelines, which recommend starting antihypertensive treatment with more than one drug, session cochair Thomas Kahan, MD, PhD, Karolinska Institute, Danderyd Hospital, department of clinical sciences, Stockholm, commented.

“How many drugs should be in the initial step?” he asked. “Is four better than three or two, or should we have even more drugs at low doses?”

The trial was not designed to answer these questions, Dr. Chow replied. “We were really comparing [the quadpill] against what the majority of people around the planet are still doing, which is starting on one drug and slowly but surely stepping it up,” she said.

The quadpill was actually a capsule, she clarified, that contained four generic BP medications available in half doses in Australia. The half doses were cut in half and the medications were encapsulated. The control drug was prepared in an identical-looking capsule.  

It is important to note that “the time to BP control was shorter in patients who received the quadpill versus monotherapy,” session cochair Felix Mahfoud, MD, internal medicine and cardiology, Saarland University Hospital, Hamburg, Germany, pointed out, because “in clinical practice we aim to get patients to BP control as quickly as possible.”

“What is new here is the use of four drugs, each given at quarter doses,” Dr. Yusuf, director of the Population Health Research Institute, McMaster University, Hamilton, Ont., said. Although a few questions remain, “this study emphasizes the importance and potential benefits and simplicity of using combination BP-lowering drugs at low doses.”

For guidelines to be changed, he observed, the findings would have to be replicated in independent studies, and the quadpill would likely have to be shown to be superior to the dual pill.

“It took about 20 years [to change guidelines] after the first evidence that combinations of two pills were preferable to single-drug combinations,” he noted.

“I hope that in most people with elevated BP, at least a two-drug combination plus a statin plus aspirin will be prescribed,” Dr. Yusuf said. “This can reduce the risk of CVD events by 50% or more – a big impact both for the individual and for populations. The quad pill may have a role in this approach.”
 

Four-in-one pill

Worldwide, hypertension control is poor, Dr. Chow said, because of the need for multiple medications, treatment inertia, and concerns about adverse events.

The researchers hypothesized that initial antihypertensive treatment with a four-in-one pill with quarter doses of each medication would minimize side effects, maximize BP lowering, and overcome these treatment barriers and concerns. A pilot study of this strategy published by the group in 2017 showed promise.

QUARTET randomized 591 adults with hypertension, seen at clinics in four states in Australia from June 2017 through August 2020.  

Patients were either receiving no antihypertensive medication and had an unattended standard office BP of 140/90 to 179/109 mm Hg or daytime ambulatory BP greater than 135/95 mm Hg, or they were on BP-lowering monotherapy and had a BP of 130/85 to 179/109 mm Hg or daytime ambulatory BP greater than 125/80 mm Hg. Patients who were taking antihypertensive therapy entered a washout period before the trial.

The researchers randomized 291 participants to receive 150 mg irbesartan daily (usual care or control group).

The other 300 participants received a daily quadpill containing 37.5 mg irbesartan, 1.25 mg amlodipine, 0.625 mg indapamide, and 2.5 mg bisoprolol. The first three drugs are the most commonly prescribed angiotensin II receptor blocker, calcium channel blocker, and thiazide or thiazidelike diuretic in Australia, and the last drug, a beta-blocker, has a long duration of action, the study protocol explains.

Patients in both groups had similar baseline characteristics. They were a mean age of 58 years, 40% were women, and 82% were White. They also had a mean body mass index of 31 kg/m². About 8% were current smokers, and about 54% were not taking a BP-lowering drug.

Participants had clinic visits at baseline, 6 weeks, and 12 weeks, and if they continued the study, at 26 weeks and 52 weeks.

If a patient’s blood pressure was higher than 140/90 mm Hg, clinicians could add another medication, starting with amlodipine 5 mg.

At 12 weeks, 15% of patients in the intervention group and 40% in the control group had stepped up treatment.

Despite greater up-titration in the usual care group, BP control remained higher in the quadpill group, Dr. Chow pointed out. That is, patients in the quadpill group were more likely than patients in the usual care group to have a BP less than 140/90 mm Hg (76% vs. 58% respectively; P < .0001).

Patients in the quadpill group also had lower daytime and nighttime ambulatory systolic BP.

At 12 months, among the 417 patients who continued treatment, patients in the quadpill group had a 7.7 mm Hg greater drop in systolic BP, compared with patients in the control group, (P < .001).  

There were no significant differences in adverse events, which were most commonly dizziness (31% and 25%) or muscle cramps, gastrointestinal complaints, headache, or musculoskeletal complaints.

At 12 weeks, there were seven serious adverse events in the intervention group versus three in the control group. There were 12 treatment withdrawals in the intervention group versus seven in the control group (P = .27).

Remaining questions, upcoming phase 3 U.S. study

“While the [QUARTET] results are impressive, we are left with a number of questions,” Dr. Yusuf said.

Would the results be the same with a three-drug combo or even a two-drug combo at half doses? In the HOPE 3 trial, a two-drug combo at half doses provided similar results to the current study, over a much longer mean follow-up of 5.6 years, he noted.

Also, is the quadpill associated with higher rates of diabetes or higher creatinine levels in the long term? “Given that we do not have any data on long-term clinical outcomes from a four-drug combination,” Dr. Yusuf said, “caution should be utilized.”

Would the reduced risk of CVD be greater with a combination of low doses of two BP-lowering drugs plus a statin plus aspirin? That may be superior, he said, “based on recent information published on the polypill indicating a 50% relative risk reduction in CVD events.”

The related phase 2 QUARTET US trial should shed further light on a quadpill strategy. Patients with hypertension are being randomized to a daily quadpill containing 2 mg candesartan, 1.25 mg amlodipine besylate, 0.625 mg indapamide, and 2.5 mg bisoprolol, or to usual care, 8 mg candesartan daily.

Investigators plan to enroll 87 participants in the Chicago area, with estimated study completion by March 31, 2023.

The study was supported by an Australian National Health and Medical Research Council grant. The George Institute for Global Health has submitted patent applications for low–fixed-dose combination products to treat CV or cardiometabolic disease. Dr. Chow and coauthor Kris Rogers, PhD, senior biostatistician at The George Institute for Global Health, Newtown, Australia, are listed as inventors, but they do not have direct financial interests in these patent applications.

A version of this article first appeared on Medscape.com.

On July 9, Philip Morris International Inc. (PMI) issued a statement of intent to purchase Vectura Group plc (Vectura), a provider of inhaled drug delivery solutions. According to the statement, the acquisition contributes to the PMI goal to move “beyond nicotine” by leveraging Vectura’s expertise in inhalation and aerosolization into adjacent areas.

Given PMI’s strong ties to tobacco, the acquisition raises concerns across the medical field. D. Robert McCaffree, MD, Master FCCP, shares his thoughts on the prospective acquisition in the following guest feature.

August 2021: D. Robert McCaffree, MD, Master FCCP

In 2018, Dr. Neeraj Desai and I published an editorial in the journal CHEST®. The title was, in part, “Is Big Tobacco Still Trying to Deceive the Public? ... ”¹ Before I give an opinion about the answer, I should give some background on events eliciting the editorial.

In 1999, the U.S. Department of Justice (DOJ) sued major tobacco companies (Philip Morris, USA; Altria; RJ Reynolds; and Lorillard) for being in violation of the Racketeer Influenced Corrupt Organization Act (RICO) in that they colluded for decades to mislead the public about the risks of smoking and risks of secondhand smoke, downplayed the addictiveness of nicotine, manipulated nicotine levels, marketed cigarettes as “low tar” or “light” when they knew these were no less hazardous than full-flavored cigarettes, purposefully targeted youth, and failed to produce a safer cigarette.

In 2006, Judge Gladys Kessler of the D.C. District Court issued a1 700-page opinion finding the defendants had violated RICO. In her words,

• “[This case] is about an industry, and in particular these defendants, that survives, and profits, from selling a highly addictive product which causes diseases that lead to ... [an] immeasurable amount of human suffering ... they have consistently, repeatedly and with enormous skill and sophistication, denied these facts to the public, the Government, and to the public health community.”

“Defendants have marketed and sold their lethal products with zeal, with deception, with a single-minded focus on their financial success, and without regard for the human tragedy ... exacted.”

• “Over the course of more than 50 years, defendants lied, misrepresented, and deceived the American public, including ... the young people they avidly sought as ‘replacement’ smokers.”

• “The evidence in this case clearly establishes that defendants have not ceased engaging in unlawful activity ... ”

Since, under RICO, the government could not recover monetary damages but only require corrective actions going forward, the court ordered them to publish “corrective statements” (five different ones in total) in major publications and on television during prime time over the course of several months, as well as at the point of sale. (They are still appealing the point-of-sale display.)

Of course, the defendants appealed, but those appeals were largely thwarted until the (almost) final order in 2017, which then led to our editorial in 2018.

While this is a rather long introduction, I thought it necessary to depict the long-standing nature and behavioral patterns of deception, distortion, and destructive behavior of this industry – all designed to maintain their incredible profits - before trying to answer the question posed in our editorial.

Since all of the above, is there evidence the industry’s behaviors have changed? On the negative side, there is a recent study published on the Tobacco Free Kids website documenting the past and continued marketing to women and girls, with all the adverse consequences to women’s health.² The industry continues to produce and market cigarettes to everyone, including youths and focused markets such as Blacks and LGBTQ populations. However, they are quite aware that the future of combustible tobacco, the major source of their incredible profits, is threatened.

Currently, most of the profits from Philip Morris International (PMI), as well as the other major players, come from combustible products. But, the CEO of PMI has stated that he thinks combustible tobacco products will be gone in 10 to 15 years and PMI will be selling only smoke-free products by 2025. So, to preserve similar profits as their combustible products diminish, they have made major investments in vaping products, such as Juul, and development of other noncombustible tobacco products. But these are still addictive, and any reduction in health consequences is still being evaluated. A prime example of trying to change their image is Philip Morris’ Beyond Nicotine campaign. However, currently all the companies continue to produce combustible products in large amounts, both locally and internationally.

One way of assessing the vision of any company is to see where it is putting its money. Currently, all major tobacco companies are investing in marijuana companies. For example, Philip Morris has invested $2.4 billion into Cosmos, a Canadian marijuana company.

They also recently purchased Vectura, Fertin, and Kraft Foods. I know, it’s hard to see where Kraft Foods fits in here, but Vectura, an inhalational device manufacturer, and Fertin, which makes nicotine gum, as well as vehicles such as powders, pouches that dissolve in the mouth, and lozenges, certainly do fit in.

My take on these recent acquisitions is that tobacco companies realize combustibles are dying. However, they continue to develop and market nicotine in noncombustible forms. They are likely looking to move into marijuana, at least as an investment. It’s not a huge leap to consider the possibility that the purchase of Vectura will help develop delivery systems for nicotine, marijuana, and possibly medications. It’s unclear whether PMI intends to get further into inhaled pharmaceuticals.

Bottom line is that, as pulmonary physicians, we need to be aware of all developments in inhaled substances and delivery methods. On the upside, everything the industry is currently doing is apparently more transparent than they have been in the past. They are not yet, however, ceasing production and marketing of cigarettes.

It’s also important that we remind ourselves of their past actions because, personally, that past still bothers me, and I’m not quite ready to trust them. When it comes to “Big Tobacco,” it is appropriate that we always keep in mind the immortal words, often repeated in various forms, of Edgar Allen Poe, master teller of horror stories, “Believe nothing you hear and only half that you see.”³

References

1. McCaffree DR and Desai NR. Is big tobacco still trying to deceive the public? This is no time to rest on our laurels. Chest. 2018 May;153(5):1085-6. doi: 10.1016/j.chest.2018.01.012.

2. A lifetime of damage: How Big Tobacco’s predatory marketing practices harms the health of women and girls. Tobacco-Free Kids. May 2021.

3. Quote Investigator. 2017 Jun 23. “The system of Dr. Tarr and Prof. Fether,” from Graham’s Magazine, November 1845.

On July 9, Philip Morris International Inc. (PMI) issued a statement of intent to purchase Vectura Group plc (Vectura), a provider of inhaled drug delivery solutions. According to the statement, the acquisition contributes to the PMI goal to move “beyond nicotine” by leveraging Vectura’s expertise in inhalation and aerosolization into adjacent areas.

Given PMI’s strong ties to tobacco, the acquisition raises concerns across the medical field. D. Robert McCaffree, MD, Master FCCP, shares his thoughts on the prospective acquisition in the following guest feature.

August 2021: D. Robert McCaffree, MD, Master FCCP

In 2018, Dr. Neeraj Desai and I published an editorial in the journal CHEST®. The title was, in part, “Is Big Tobacco Still Trying to Deceive the Public? ... ”¹ Before I give an opinion about the answer, I should give some background on events eliciting the editorial.

In 1999, the U.S. Department of Justice (DOJ) sued major tobacco companies (Philip Morris, USA; Altria; RJ Reynolds; and Lorillard) for being in violation of the Racketeer Influenced Corrupt Organization Act (RICO) in that they colluded for decades to mislead the public about the risks of smoking and risks of secondhand smoke, downplayed the addictiveness of nicotine, manipulated nicotine levels, marketed cigarettes as “low tar” or “light” when they knew these were no less hazardous than full-flavored cigarettes, purposefully targeted youth, and failed to produce a safer cigarette.

In 2006, Judge Gladys Kessler of the D.C. District Court issued a1 700-page opinion finding the defendants had violated RICO. In her words,

• “[This case] is about an industry, and in particular these defendants, that survives, and profits, from selling a highly addictive product which causes diseases that lead to ... [an] immeasurable amount of human suffering ... they have consistently, repeatedly and with enormous skill and sophistication, denied these facts to the public, the Government, and to the public health community.”

“Defendants have marketed and sold their lethal products with zeal, with deception, with a single-minded focus on their financial success, and without regard for the human tragedy ... exacted.”

• “Over the course of more than 50 years, defendants lied, misrepresented, and deceived the American public, including ... the young people they avidly sought as ‘replacement’ smokers.”

• “The evidence in this case clearly establishes that defendants have not ceased engaging in unlawful activity ... ”

Since, under RICO, the government could not recover monetary damages but only require corrective actions going forward, the court ordered them to publish “corrective statements” (five different ones in total) in major publications and on television during prime time over the course of several months, as well as at the point of sale. (They are still appealing the point-of-sale display.)

Of course, the defendants appealed, but those appeals were largely thwarted until the (almost) final order in 2017, which then led to our editorial in 2018.

While this is a rather long introduction, I thought it necessary to depict the long-standing nature and behavioral patterns of deception, distortion, and destructive behavior of this industry – all designed to maintain their incredible profits - before trying to answer the question posed in our editorial.

Since all of the above, is there evidence the industry’s behaviors have changed? On the negative side, there is a recent study published on the Tobacco Free Kids website documenting the past and continued marketing to women and girls, with all the adverse consequences to women’s health.² The industry continues to produce and market cigarettes to everyone, including youths and focused markets such as Blacks and LGBTQ populations. However, they are quite aware that the future of combustible tobacco, the major source of their incredible profits, is threatened.

Currently, most of the profits from Philip Morris International (PMI), as well as the other major players, come from combustible products. But, the CEO of PMI has stated that he thinks combustible tobacco products will be gone in 10 to 15 years and PMI will be selling only smoke-free products by 2025. So, to preserve similar profits as their combustible products diminish, they have made major investments in vaping products, such as Juul, and development of other noncombustible tobacco products. But these are still addictive, and any reduction in health consequences is still being evaluated. A prime example of trying to change their image is Philip Morris’ Beyond Nicotine campaign. However, currently all the companies continue to produce combustible products in large amounts, both locally and internationally.

One way of assessing the vision of any company is to see where it is putting its money. Currently, all major tobacco companies are investing in marijuana companies. For example, Philip Morris has invested $2.4 billion into Cosmos, a Canadian marijuana company.

They also recently purchased Vectura, Fertin, and Kraft Foods. I know, it’s hard to see where Kraft Foods fits in here, but Vectura, an inhalational device manufacturer, and Fertin, which makes nicotine gum, as well as vehicles such as powders, pouches that dissolve in the mouth, and lozenges, certainly do fit in.

My take on these recent acquisitions is that tobacco companies realize combustibles are dying. However, they continue to develop and market nicotine in noncombustible forms. They are likely looking to move into marijuana, at least as an investment. It’s not a huge leap to consider the possibility that the purchase of Vectura will help develop delivery systems for nicotine, marijuana, and possibly medications. It’s unclear whether PMI intends to get further into inhaled pharmaceuticals.

Bottom line is that, as pulmonary physicians, we need to be aware of all developments in inhaled substances and delivery methods. On the upside, everything the industry is currently doing is apparently more transparent than they have been in the past. They are not yet, however, ceasing production and marketing of cigarettes.

It’s also important that we remind ourselves of their past actions because, personally, that past still bothers me, and I’m not quite ready to trust them. When it comes to “Big Tobacco,” it is appropriate that we always keep in mind the immortal words, often repeated in various forms, of Edgar Allen Poe, master teller of horror stories, “Believe nothing you hear and only half that you see.”³

References

1. McCaffree DR and Desai NR. Is big tobacco still trying to deceive the public? This is no time to rest on our laurels. Chest. 2018 May;153(5):1085-6. doi: 10.1016/j.chest.2018.01.012.

2. A lifetime of damage: How Big Tobacco’s predatory marketing practices harms the health of women and girls. Tobacco-Free Kids. May 2021.

3. Quote Investigator. 2017 Jun 23. “The system of Dr. Tarr and Prof. Fether,” from Graham’s Magazine, November 1845.

On July 9, Philip Morris International Inc. (PMI) issued a statement of intent to purchase Vectura Group plc (Vectura), a provider of inhaled drug delivery solutions. According to the statement, the acquisition contributes to the PMI goal to move “beyond nicotine” by leveraging Vectura’s expertise in inhalation and aerosolization into adjacent areas.

Given PMI’s strong ties to tobacco, the acquisition raises concerns across the medical field. D. Robert McCaffree, MD, Master FCCP, shares his thoughts on the prospective acquisition in the following guest feature.

August 2021: D. Robert McCaffree, MD, Master FCCP

In 2018, Dr. Neeraj Desai and I published an editorial in the journal CHEST®. The title was, in part, “Is Big Tobacco Still Trying to Deceive the Public? ... ”¹ Before I give an opinion about the answer, I should give some background on events eliciting the editorial.

In 1999, the U.S. Department of Justice (DOJ) sued major tobacco companies (Philip Morris, USA; Altria; RJ Reynolds; and Lorillard) for being in violation of the Racketeer Influenced Corrupt Organization Act (RICO) in that they colluded for decades to mislead the public about the risks of smoking and risks of secondhand smoke, downplayed the addictiveness of nicotine, manipulated nicotine levels, marketed cigarettes as “low tar” or “light” when they knew these were no less hazardous than full-flavored cigarettes, purposefully targeted youth, and failed to produce a safer cigarette.

In 2006, Judge Gladys Kessler of the D.C. District Court issued a1 700-page opinion finding the defendants had violated RICO. In her words,

• “[This case] is about an industry, and in particular these defendants, that survives, and profits, from selling a highly addictive product which causes diseases that lead to ... [an] immeasurable amount of human suffering ... they have consistently, repeatedly and with enormous skill and sophistication, denied these facts to the public, the Government, and to the public health community.”

“Defendants have marketed and sold their lethal products with zeal, with deception, with a single-minded focus on their financial success, and without regard for the human tragedy ... exacted.”

• “Over the course of more than 50 years, defendants lied, misrepresented, and deceived the American public, including ... the young people they avidly sought as ‘replacement’ smokers.”

• “The evidence in this case clearly establishes that defendants have not ceased engaging in unlawful activity ... ”

Since, under RICO, the government could not recover monetary damages but only require corrective actions going forward, the court ordered them to publish “corrective statements” (five different ones in total) in major publications and on television during prime time over the course of several months, as well as at the point of sale. (They are still appealing the point-of-sale display.)

Of course, the defendants appealed, but those appeals were largely thwarted until the (almost) final order in 2017, which then led to our editorial in 2018.

While this is a rather long introduction, I thought it necessary to depict the long-standing nature and behavioral patterns of deception, distortion, and destructive behavior of this industry – all designed to maintain their incredible profits - before trying to answer the question posed in our editorial.

Since all of the above, is there evidence the industry’s behaviors have changed? On the negative side, there is a recent study published on the Tobacco Free Kids website documenting the past and continued marketing to women and girls, with all the adverse consequences to women’s health.² The industry continues to produce and market cigarettes to everyone, including youths and focused markets such as Blacks and LGBTQ populations. However, they are quite aware that the future of combustible tobacco, the major source of their incredible profits, is threatened.

Currently, most of the profits from Philip Morris International (PMI), as well as the other major players, come from combustible products. But, the CEO of PMI has stated that he thinks combustible tobacco products will be gone in 10 to 15 years and PMI will be selling only smoke-free products by 2025. So, to preserve similar profits as their combustible products diminish, they have made major investments in vaping products, such as Juul, and development of other noncombustible tobacco products. But these are still addictive, and any reduction in health consequences is still being evaluated. A prime example of trying to change their image is Philip Morris’ Beyond Nicotine campaign. However, currently all the companies continue to produce combustible products in large amounts, both locally and internationally.

One way of assessing the vision of any company is to see where it is putting its money. Currently, all major tobacco companies are investing in marijuana companies. For example, Philip Morris has invested $2.4 billion into Cosmos, a Canadian marijuana company.

They also recently purchased Vectura, Fertin, and Kraft Foods. I know, it’s hard to see where Kraft Foods fits in here, but Vectura, an inhalational device manufacturer, and Fertin, which makes nicotine gum, as well as vehicles such as powders, pouches that dissolve in the mouth, and lozenges, certainly do fit in.

My take on these recent acquisitions is that tobacco companies realize combustibles are dying. However, they continue to develop and market nicotine in noncombustible forms. They are likely looking to move into marijuana, at least as an investment. It’s not a huge leap to consider the possibility that the purchase of Vectura will help develop delivery systems for nicotine, marijuana, and possibly medications. It’s unclear whether PMI intends to get further into inhaled pharmaceuticals.

Bottom line is that, as pulmonary physicians, we need to be aware of all developments in inhaled substances and delivery methods. On the upside, everything the industry is currently doing is apparently more transparent than they have been in the past. They are not yet, however, ceasing production and marketing of cigarettes.

It’s also important that we remind ourselves of their past actions because, personally, that past still bothers me, and I’m not quite ready to trust them. When it comes to “Big Tobacco,” it is appropriate that we always keep in mind the immortal words, often repeated in various forms, of Edgar Allen Poe, master teller of horror stories, “Believe nothing you hear and only half that you see.”³

References

1. McCaffree DR and Desai NR. Is big tobacco still trying to deceive the public? This is no time to rest on our laurels. Chest. 2018 May;153(5):1085-6. doi: 10.1016/j.chest.2018.01.012.

2. A lifetime of damage: How Big Tobacco’s predatory marketing practices harms the health of women and girls. Tobacco-Free Kids. May 2021.

3. Quote Investigator. 2017 Jun 23. “The system of Dr. Tarr and Prof. Fether,” from Graham’s Magazine, November 1845.