Cardiology

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Marijuana use was associated with a higher prevalence of recurrent MI and a greater risk of bleeding or stroke after percutaneous coronary intervention (PCI) in separate studies.

Rhushik Bhuva, MD, presented the recurrent-MI results from a national U.S. study, and Sang Gune K. Yoo, MD, presented the PCI study, which used data from a Michigan cohort. The studies were presented at the American Heart Association scientific sessions.

Both studies “add to our accumulating knowledge of the cardiovascular risks of marijuana,” Ersilia M. DeFilippis, MD, a cardiology fellow at Columbia University Irvine Medical Center, New York, who was not involved with this research, said in an interview.

Dr. DeFilippis and the two study authors say clinicians and patients need to be more aware of cardiovascular risks from smoking marijuana, and they call for more patient screening, counseling, and research.
 

Need for screening and counseling

Marijuana is a Schedule 1 controlled substance in the United States, which makes it illegal to conduct rigorous controlled trials of marijuana products. Existing knowledge is therefore based on observational studies, Dr. DeFilippis noted.

She was lead author of a review of marijuana use by patients with cardiovascular disease. The review was published in the Journal of the American College of Cardiology. An AHA scientific statement about marijuana and cardiovascular health was published in Circulation.

Both documents drew attention to risks from marijuana use in patients with cardiovascular disease.

Until more data are available, “I think it is absolutely critical” that cardiologists and general providers screen patients for marijuana use, “either at the time of their MI or ideally prior to that, when they are making a cardiovascular risk assessment,” said Dr. DeFilippis.

That is also the time to “counsel patients, especially those who have had an MI, about risks associated with continuing to use marijuana.”

Importantly, providers and patients need to be aware that “cannabinoids, through the cytochrome P450 system, can interact with well-known cardiovascular medications, which we know provide benefit in the post-MI period,” she added. “For example, marijuana can interfere with beta-blockers, statins, antiarrhythmics, and certain anticoagulants.”

Dr. Bhuva, a cardiology fellow with the Wright Center for Community Health, Scranton, Pa., said that it is “concerning” that “recurrent heart attacks and cardiac interventions [were] higher among cannabis users, even though they were younger and had fewer risk factors for heart disease.

“Spreading awareness regarding the potential risk of recurrent heart attacks in middle-aged, African American, and male cannabis users and screening them at an earlier age for potential risk factors of future heart attacks should be encouraged among clinicians,” he urged in a statement from the AHA.

Dr. Yoo, an internal medicine resident at the University of Michigan, Ann Arbor, pointed out that, in their study of patients who underwent PCI after MI or because they had coronary artery disease, those who smoked or vaped marijuana were younger and were more likely to be male. They were less likely to have traditional cardiovascular risk factors except for smoking tobacco, which was highly prevalent.

After propensity matching, patients who used marijuana had a 1.5-fold increased risk of in-hospital bleeding and an 11-fold higher risk for in-hospital stroke following PCI.

However, the absolute number of strokes in PCI was small, and the confidence interval was wide (indicating a large uncertainty), Dr. Yoo said in an interview.

These risks “should not deter patients from undergoing these [lifesaving] procedures,” he said; however, clinicians should be aware of these risks with marijuana use and should screen and counsel patients about this.
 

Hospitalized patients with prior MI

Dr. Bhuva and colleagues identified patients from the National Inpatient Sample who were hospitalized in the United States from 2007 to 2014 and who had experienced a prior MI and had undergone revascularization with PCI or coronary artery bypass grafting (CABG).

There were about 8 million hospital stays per year. The database did not specify the type of marijuana that patients used.

During the 8-year study period, many states legalized or decriminalized medical and/or recreational marijuana, and marijuana use increased steadily, from 0.2% to 0.7%.

Compared with nonusers, those who used marijuana were younger (median age, 53 vs. 72 years), and there were more men (77% vs. 62%) or Black persons (34% vs. 10%) (all P < .001). Fewer marijuana users had hypertension (72% vs. 75%), diabetes (24% vs. 33%), or dyslipidemia (51% vs. 58%) (all P < .001). More marijuana users underwent a repeat MI (67% vs. 41%).

On the other hand, marijuana users, who were younger and healthier than the other patients, were less likely to die during hospitalization for a recurrent MI (0.8% vs. 2.5%), and their hospital costs were lower.

The researchers acknowledged that study limitations include lack of information about marijuana type (smoked, edible, medicinal, or recreational) or dose, as well as the time from marijuana use to cardiac event.
 

In-Hospital outcomes after PCI

Dr. Yoo and colleagues analyzed data from patients who underwent PCI from Jan. 1, 2013, to Oct. 1, 2016, at Michigan’s 48 nonfederal hospitals, which are part of the Blue Cross Blue Shield Michigan Cardiovascular Consortium PCI registry.

In this cohort, 3,970 patients (3.5%) had smoked or vaped marijuana in the month prior to PCI, and 109,507 patients had not done so. The marijuana users were younger (mean age, 54 vs. 66 years) and were more likely to be male (79% vs. 67%) and to smoke cigarettes (73% vs. 27%).

They were less likely to have hypertension, type 2 diabetes, dyslipidemia, cerebrovascular disease, or prior CABG and were equally likely to have had a prior MI (36%).

Compared with nonusers, marijuana users were more likely to present with non–ST-elevation MI (30% vs. 23%) or ST-elevation MI (27% vs. 16%) and were less likely to present with angina.

Using propensity score matching, the researchers matched 3,803 marijuana users with the same number of nonusers.

In the matched cohort, patients who used marijuana had a greater risk of in-hospital bleeding (adjusted odds ratio, 1.54; 95% confidence interval, 1.20-1.97; P < .001) or stroke (aOR, 11.01; 95% CI, 1.32-91.67; P = .026) following PCI.

Marijuana users had a lower risk for acute kidney injury (2.2% vs. 2.9%; P = .007). Transfusion and mortality rates were similar in both groups.

The researchers acknowledged study limitations, including the fact that it did not include marijuana edibles, that the results may not be generalizable, and that marijuana use is now likely more common in Michigan following legalization of recreational marijuana in 2018.

Dr. Bhuva, Dr. Yoo, and Dr. DeFilippis have disclosed no relevant financial relationships.

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

Greater involvement of the patient and family in decision-making, clarity on the role of genetic testing and parameters for team-oriented care, and use of high-volume specialty centers are cornerstones of the first update in almost a decade of the American Heart Association/American College of Cardiology guideline for patients with hypertrophic cardiomyopathy (HCM).

The update lists 133 recommendations for HCM care in six categories: shared decision-making; role of high-volume HCM centers; diagnosis, initial evaluation, and follow-up; risk assessment and prevention of sudden cardiac death (SCD); management of HCM; and lifestyle considerations for patients.

“The guideline puts the patient front and center in the shared decision-making process and emphasizes the importance of incorporating patient’s lifestyle choices and preferences when making complex, life-altering decisions,” writing committee vice chair Seema Mital, MD, of the University of Toronto and the Hospital for Sick Children, also in Toronto, said in an interview.

The fully updated guideline, authored by a joint committee of the AHA and ACC with input from other specialty societies, has been published online in the Journal of the American College of Cardiology. It replaces the 2011 guideline.

Another key component of the update is the strong recommendation to utilize multidisciplinary care, said Matthew W. Martinez, MD, a writing committee member and sports cardiologists at Morristown (N.J.) Medical Center. “This is not only as a part of shared decision-making, but really in care for the patients,” he said, “that there’s a level of expertise that is provided by centers of excellence who handle HCM, and we did lay out some recommendations with regards to surgery, imaging, interventionists, and management with electrophysiology, and the care of athletes with potential for HCM and pregnant women.”

The update ranks recommendations by class of recommendation (COR), ranging from strong benefit much greater than risk to harm with risk exceeding benefit, and level of evidence (LOE). The recommendation for shared decision making, for example, carries at COR of 1, the highest rating, and a mid-level LOE of B-NR, meaning from nonrandomized studies. Patients who need septal reduction therapy (SRT) should be referred to a comprehensive or primary HCM center – a recommendation with a COR of 1 but an LOE of C-LD, meaning there are limited data.
 

From diagnosis to follow-up

The most extensive list of recommendations falls under the category covering diagnosis, initial evaluation and follow-up. They include a three-generation family history as part of the initial diagnostic assessment (COR, 1; LOE, B-NR), high-level recommendations for use of transthoracic echocardiogram in the initial work-up, every 1 or 2 years or when the patient’s status changes in confirmed cases, as well as parameters for using other imaging and diagnostic tests. Cardiovascular MRI, for example, is indicated when echocardiography is inconclusive (COR, 1; LOE, B-NR) and in other scenarios. When echocardiography is inconclusive but cardiac MRI isn’t available, cardiac CT is an option, albeit at a lower level of evidence (COR, 2b; LOE, C-LD).

Heart rhythm assessment has a high level of recommendation in multiple scenarios, even in first-degree relatives of HCM patients. Invasive hemodynamic assessment is in order for candidates of SRT whose left ventricular (LV) outflow tract obstruction status is unknown. This category also sets parameters for angiography, and exercise stress testing.

The most extensive recommendations for diagnosis and follow-up cover genetic testing; it consists of nine high-level recommendations.

“The guideline highlights not only the importance of genetic testing of an affected patient and genetic screening of family members, but also emphasizes ongoing reassessment of variant classification as this may evolve with time and change how we recommend ongoing family screening,” Dr. Mital noted.

“The guideline proposes initiating screening of family members at the earliest regardless of age given HCM can manifest at any age in affected families,” she added.

The guideline notes that the usefulness of genetic testing to evaluate the risk of sudden cardiac death (SCD) is uncertain. There’s even guidance for implementing those test results. Further testing is recommended for patients who are genotype positive and phenotype negative for HCM (COR, 1; LOE, B-NR). Those same patients may participate in competitive sports (COR, 2a; LOE, C-LD), but a pacemaker isn’t recommended as a primary prevention (COR, 3 [no benefit]; LOE, B-NR).
 

Risk evaluation and prevention

For SCD risk evaluation and prevention, the guideline spells out five components for the initial and follow-up evaluations (COR, 1; LOE, B-NR). That includes maximal LV wall thickness, ejection fraction, and LV apical aneurysm. The section include multiple recommendations for patient selection for placement of an implantable cardioverter-defibrillator (ICD). For example, it’s recommended for patient’s who’ve had a heart attack or sustained ventricular tachycardia (COR, 1; LOE, B-NR), but not so much for patients without risk factors or for participating in sports (COR, 3 [harm]; LOE, B-NR). The guideline even provides recommendations for selecting an ICD.

Management recommendations address when medical therapy is indicated, including which therapies are indicated for specific scenarios, as well as higher level interventions such as SRT for severely symptomatic patients with obstructive HCM (COR, 2b; LOE, C-LD) and surgical myectomy with ablation in patients with HCM and atrial fibrillation (COR, 2a; LOE, B-NR). This section also provides recommendations for managing patients with HCM and ventricular arrhythmias or advanced heart failure.

The guideline also includes a host of lifestyle considerations. Mild to moderate exercise is beneficial (COR, 1; LOE, B-NR), but athletes with HCM should consult with an “expert provider” (COR, 1; LOE, C, meaning based on expert opinion). Truck drivers, pilots and people who do strenuous physical labor with HCM should meet specific standards.

These recommendations again emphasize the role of shared decision-making, said Dr. Martinez. “It’s not a cookie-cutter discussion. It is taking all of the information, incorporating what the patient’s needs are, and then making sure you appropriately tell them what are the risks of exercising and not exercising. I have as many discussions through the day about what the risks of exercise are as I do the risks of not exercising.”
 

Refining nomenclature, pathophysiology

The writing committee addressed the nomenclature for HCM. The use of HCM to describe increased LV wall thickness linked to systemic diseases or secondary to LV hypertrophy “can lead to confusion,” the committee stated, so other cardiac or systemic causes of LV hypertrophy shouldn’t be labeled HCM. Other etiologies can cause secondary LV hypertrophy that can overlap with HCM; clinical markers and testing can help differentiate these mimickers from HCM. When echocardiography is inconclusive, cardiovascular MRI is indicated (COR, 1; LOE, B-NR).

The guideline update also provides clarity on the pathophysiology of HCM: It consists of dynamic LV outflow tract obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, or autonomic dysfunction. “For a given patient with HCM, the clinical outcome may be dominated by one of these components or may be the result of a complex interplay,” the guideline states. The clinical evaluation should consider all these conditions.

This update also provides “clear separation” between care of HCM with and without obstruction, Dr. Martinez said. “The role of advanced therapies and referrals with advanced treatment options such as heart transplantation or CRT therapy in this group is different than before, recognizing that people with obstruction have symptoms that may be similar to those without obstruction, and the individual should be [thoroughly] investigated to make sure that you can discern between those two groups to make appropriate recommendations.”

The guideline was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society for Cardiovascular Magnetic Resonance. It’s also been endorsed by the Pediatric & Congenital Electrophysiology Society.

Dr. Mital and Dr. Martinez have no relevant financial relationships to disclose.

SOURCE: Mital S et al. J Am Coll Cardiol. 2020 Nov 20. doi: 10.1016/j.jacc.2020.08.044.

Greater involvement of the patient and family in decision-making, clarity on the role of genetic testing and parameters for team-oriented care, and use of high-volume specialty centers are cornerstones of the first update in almost a decade of the American Heart Association/American College of Cardiology guideline for patients with hypertrophic cardiomyopathy (HCM).

The update lists 133 recommendations for HCM care in six categories: shared decision-making; role of high-volume HCM centers; diagnosis, initial evaluation, and follow-up; risk assessment and prevention of sudden cardiac death (SCD); management of HCM; and lifestyle considerations for patients.

“The guideline puts the patient front and center in the shared decision-making process and emphasizes the importance of incorporating patient’s lifestyle choices and preferences when making complex, life-altering decisions,” writing committee vice chair Seema Mital, MD, of the University of Toronto and the Hospital for Sick Children, also in Toronto, said in an interview.

The fully updated guideline, authored by a joint committee of the AHA and ACC with input from other specialty societies, has been published online in the Journal of the American College of Cardiology. It replaces the 2011 guideline.

Another key component of the update is the strong recommendation to utilize multidisciplinary care, said Matthew W. Martinez, MD, a writing committee member and sports cardiologists at Morristown (N.J.) Medical Center. “This is not only as a part of shared decision-making, but really in care for the patients,” he said, “that there’s a level of expertise that is provided by centers of excellence who handle HCM, and we did lay out some recommendations with regards to surgery, imaging, interventionists, and management with electrophysiology, and the care of athletes with potential for HCM and pregnant women.”

The update ranks recommendations by class of recommendation (COR), ranging from strong benefit much greater than risk to harm with risk exceeding benefit, and level of evidence (LOE). The recommendation for shared decision making, for example, carries at COR of 1, the highest rating, and a mid-level LOE of B-NR, meaning from nonrandomized studies. Patients who need septal reduction therapy (SRT) should be referred to a comprehensive or primary HCM center – a recommendation with a COR of 1 but an LOE of C-LD, meaning there are limited data.
 

From diagnosis to follow-up

The most extensive list of recommendations falls under the category covering diagnosis, initial evaluation and follow-up. They include a three-generation family history as part of the initial diagnostic assessment (COR, 1; LOE, B-NR), high-level recommendations for use of transthoracic echocardiogram in the initial work-up, every 1 or 2 years or when the patient’s status changes in confirmed cases, as well as parameters for using other imaging and diagnostic tests. Cardiovascular MRI, for example, is indicated when echocardiography is inconclusive (COR, 1; LOE, B-NR) and in other scenarios. When echocardiography is inconclusive but cardiac MRI isn’t available, cardiac CT is an option, albeit at a lower level of evidence (COR, 2b; LOE, C-LD).

Heart rhythm assessment has a high level of recommendation in multiple scenarios, even in first-degree relatives of HCM patients. Invasive hemodynamic assessment is in order for candidates of SRT whose left ventricular (LV) outflow tract obstruction status is unknown. This category also sets parameters for angiography, and exercise stress testing.

The most extensive recommendations for diagnosis and follow-up cover genetic testing; it consists of nine high-level recommendations.

“The guideline highlights not only the importance of genetic testing of an affected patient and genetic screening of family members, but also emphasizes ongoing reassessment of variant classification as this may evolve with time and change how we recommend ongoing family screening,” Dr. Mital noted.

“The guideline proposes initiating screening of family members at the earliest regardless of age given HCM can manifest at any age in affected families,” she added.

The guideline notes that the usefulness of genetic testing to evaluate the risk of sudden cardiac death (SCD) is uncertain. There’s even guidance for implementing those test results. Further testing is recommended for patients who are genotype positive and phenotype negative for HCM (COR, 1; LOE, B-NR). Those same patients may participate in competitive sports (COR, 2a; LOE, C-LD), but a pacemaker isn’t recommended as a primary prevention (COR, 3 [no benefit]; LOE, B-NR).
 

Risk evaluation and prevention

For SCD risk evaluation and prevention, the guideline spells out five components for the initial and follow-up evaluations (COR, 1; LOE, B-NR). That includes maximal LV wall thickness, ejection fraction, and LV apical aneurysm. The section include multiple recommendations for patient selection for placement of an implantable cardioverter-defibrillator (ICD). For example, it’s recommended for patient’s who’ve had a heart attack or sustained ventricular tachycardia (COR, 1; LOE, B-NR), but not so much for patients without risk factors or for participating in sports (COR, 3 [harm]; LOE, B-NR). The guideline even provides recommendations for selecting an ICD.

Management recommendations address when medical therapy is indicated, including which therapies are indicated for specific scenarios, as well as higher level interventions such as SRT for severely symptomatic patients with obstructive HCM (COR, 2b; LOE, C-LD) and surgical myectomy with ablation in patients with HCM and atrial fibrillation (COR, 2a; LOE, B-NR). This section also provides recommendations for managing patients with HCM and ventricular arrhythmias or advanced heart failure.

The guideline also includes a host of lifestyle considerations. Mild to moderate exercise is beneficial (COR, 1; LOE, B-NR), but athletes with HCM should consult with an “expert provider” (COR, 1; LOE, C, meaning based on expert opinion). Truck drivers, pilots and people who do strenuous physical labor with HCM should meet specific standards.

These recommendations again emphasize the role of shared decision-making, said Dr. Martinez. “It’s not a cookie-cutter discussion. It is taking all of the information, incorporating what the patient’s needs are, and then making sure you appropriately tell them what are the risks of exercising and not exercising. I have as many discussions through the day about what the risks of exercise are as I do the risks of not exercising.”
 

Refining nomenclature, pathophysiology

The writing committee addressed the nomenclature for HCM. The use of HCM to describe increased LV wall thickness linked to systemic diseases or secondary to LV hypertrophy “can lead to confusion,” the committee stated, so other cardiac or systemic causes of LV hypertrophy shouldn’t be labeled HCM. Other etiologies can cause secondary LV hypertrophy that can overlap with HCM; clinical markers and testing can help differentiate these mimickers from HCM. When echocardiography is inconclusive, cardiovascular MRI is indicated (COR, 1; LOE, B-NR).

The guideline update also provides clarity on the pathophysiology of HCM: It consists of dynamic LV outflow tract obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, or autonomic dysfunction. “For a given patient with HCM, the clinical outcome may be dominated by one of these components or may be the result of a complex interplay,” the guideline states. The clinical evaluation should consider all these conditions.

This update also provides “clear separation” between care of HCM with and without obstruction, Dr. Martinez said. “The role of advanced therapies and referrals with advanced treatment options such as heart transplantation or CRT therapy in this group is different than before, recognizing that people with obstruction have symptoms that may be similar to those without obstruction, and the individual should be [thoroughly] investigated to make sure that you can discern between those two groups to make appropriate recommendations.”

The guideline was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society for Cardiovascular Magnetic Resonance. It’s also been endorsed by the Pediatric & Congenital Electrophysiology Society.

Dr. Mital and Dr. Martinez have no relevant financial relationships to disclose.

SOURCE: Mital S et al. J Am Coll Cardiol. 2020 Nov 20. doi: 10.1016/j.jacc.2020.08.044.

Greater involvement of the patient and family in decision-making, clarity on the role of genetic testing and parameters for team-oriented care, and use of high-volume specialty centers are cornerstones of the first update in almost a decade of the American Heart Association/American College of Cardiology guideline for patients with hypertrophic cardiomyopathy (HCM).

The update lists 133 recommendations for HCM care in six categories: shared decision-making; role of high-volume HCM centers; diagnosis, initial evaluation, and follow-up; risk assessment and prevention of sudden cardiac death (SCD); management of HCM; and lifestyle considerations for patients.

“The guideline puts the patient front and center in the shared decision-making process and emphasizes the importance of incorporating patient’s lifestyle choices and preferences when making complex, life-altering decisions,” writing committee vice chair Seema Mital, MD, of the University of Toronto and the Hospital for Sick Children, also in Toronto, said in an interview.

The fully updated guideline, authored by a joint committee of the AHA and ACC with input from other specialty societies, has been published online in the Journal of the American College of Cardiology. It replaces the 2011 guideline.

Another key component of the update is the strong recommendation to utilize multidisciplinary care, said Matthew W. Martinez, MD, a writing committee member and sports cardiologists at Morristown (N.J.) Medical Center. “This is not only as a part of shared decision-making, but really in care for the patients,” he said, “that there’s a level of expertise that is provided by centers of excellence who handle HCM, and we did lay out some recommendations with regards to surgery, imaging, interventionists, and management with electrophysiology, and the care of athletes with potential for HCM and pregnant women.”

The update ranks recommendations by class of recommendation (COR), ranging from strong benefit much greater than risk to harm with risk exceeding benefit, and level of evidence (LOE). The recommendation for shared decision making, for example, carries at COR of 1, the highest rating, and a mid-level LOE of B-NR, meaning from nonrandomized studies. Patients who need septal reduction therapy (SRT) should be referred to a comprehensive or primary HCM center – a recommendation with a COR of 1 but an LOE of C-LD, meaning there are limited data.
 

From diagnosis to follow-up

The most extensive list of recommendations falls under the category covering diagnosis, initial evaluation and follow-up. They include a three-generation family history as part of the initial diagnostic assessment (COR, 1; LOE, B-NR), high-level recommendations for use of transthoracic echocardiogram in the initial work-up, every 1 or 2 years or when the patient’s status changes in confirmed cases, as well as parameters for using other imaging and diagnostic tests. Cardiovascular MRI, for example, is indicated when echocardiography is inconclusive (COR, 1; LOE, B-NR) and in other scenarios. When echocardiography is inconclusive but cardiac MRI isn’t available, cardiac CT is an option, albeit at a lower level of evidence (COR, 2b; LOE, C-LD).

Heart rhythm assessment has a high level of recommendation in multiple scenarios, even in first-degree relatives of HCM patients. Invasive hemodynamic assessment is in order for candidates of SRT whose left ventricular (LV) outflow tract obstruction status is unknown. This category also sets parameters for angiography, and exercise stress testing.

The most extensive recommendations for diagnosis and follow-up cover genetic testing; it consists of nine high-level recommendations.

“The guideline highlights not only the importance of genetic testing of an affected patient and genetic screening of family members, but also emphasizes ongoing reassessment of variant classification as this may evolve with time and change how we recommend ongoing family screening,” Dr. Mital noted.

“The guideline proposes initiating screening of family members at the earliest regardless of age given HCM can manifest at any age in affected families,” she added.

The guideline notes that the usefulness of genetic testing to evaluate the risk of sudden cardiac death (SCD) is uncertain. There’s even guidance for implementing those test results. Further testing is recommended for patients who are genotype positive and phenotype negative for HCM (COR, 1; LOE, B-NR). Those same patients may participate in competitive sports (COR, 2a; LOE, C-LD), but a pacemaker isn’t recommended as a primary prevention (COR, 3 [no benefit]; LOE, B-NR).
 

Risk evaluation and prevention

For SCD risk evaluation and prevention, the guideline spells out five components for the initial and follow-up evaluations (COR, 1; LOE, B-NR). That includes maximal LV wall thickness, ejection fraction, and LV apical aneurysm. The section include multiple recommendations for patient selection for placement of an implantable cardioverter-defibrillator (ICD). For example, it’s recommended for patient’s who’ve had a heart attack or sustained ventricular tachycardia (COR, 1; LOE, B-NR), but not so much for patients without risk factors or for participating in sports (COR, 3 [harm]; LOE, B-NR). The guideline even provides recommendations for selecting an ICD.

Management recommendations address when medical therapy is indicated, including which therapies are indicated for specific scenarios, as well as higher level interventions such as SRT for severely symptomatic patients with obstructive HCM (COR, 2b; LOE, C-LD) and surgical myectomy with ablation in patients with HCM and atrial fibrillation (COR, 2a; LOE, B-NR). This section also provides recommendations for managing patients with HCM and ventricular arrhythmias or advanced heart failure.

The guideline also includes a host of lifestyle considerations. Mild to moderate exercise is beneficial (COR, 1; LOE, B-NR), but athletes with HCM should consult with an “expert provider” (COR, 1; LOE, C, meaning based on expert opinion). Truck drivers, pilots and people who do strenuous physical labor with HCM should meet specific standards.

These recommendations again emphasize the role of shared decision-making, said Dr. Martinez. “It’s not a cookie-cutter discussion. It is taking all of the information, incorporating what the patient’s needs are, and then making sure you appropriately tell them what are the risks of exercising and not exercising. I have as many discussions through the day about what the risks of exercise are as I do the risks of not exercising.”
 

Refining nomenclature, pathophysiology

The writing committee addressed the nomenclature for HCM. The use of HCM to describe increased LV wall thickness linked to systemic diseases or secondary to LV hypertrophy “can lead to confusion,” the committee stated, so other cardiac or systemic causes of LV hypertrophy shouldn’t be labeled HCM. Other etiologies can cause secondary LV hypertrophy that can overlap with HCM; clinical markers and testing can help differentiate these mimickers from HCM. When echocardiography is inconclusive, cardiovascular MRI is indicated (COR, 1; LOE, B-NR).

The guideline update also provides clarity on the pathophysiology of HCM: It consists of dynamic LV outflow tract obstruction, mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, or autonomic dysfunction. “For a given patient with HCM, the clinical outcome may be dominated by one of these components or may be the result of a complex interplay,” the guideline states. The clinical evaluation should consider all these conditions.

This update also provides “clear separation” between care of HCM with and without obstruction, Dr. Martinez said. “The role of advanced therapies and referrals with advanced treatment options such as heart transplantation or CRT therapy in this group is different than before, recognizing that people with obstruction have symptoms that may be similar to those without obstruction, and the individual should be [thoroughly] investigated to make sure that you can discern between those two groups to make appropriate recommendations.”

The guideline was developed in collaboration with and endorsed by the American Association for Thoracic Surgery, American Society of Echocardiography, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society for Cardiovascular Magnetic Resonance. It’s also been endorsed by the Pediatric & Congenital Electrophysiology Society.

Dr. Mital and Dr. Martinez have no relevant financial relationships to disclose.

SOURCE: Mital S et al. J Am Coll Cardiol. 2020 Nov 20. doi: 10.1016/j.jacc.2020.08.044.

Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.

For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.

“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”

The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.

“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.

In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.

The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.

Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.

In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.

In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.

It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.

“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.

Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.

“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.

“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
 

SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.

Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.

For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.

“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”

The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.

“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.

In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.

The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.

Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.

In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.

In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.

It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.

“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.

Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.

“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.

“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
 

SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.

Restricting percutaneous interventions (PCI) to only those stenotic lesions that are ischemic by fractional flow reserve (FFR) thresholds is associated with better 5-year outcomes whether or not PCI is deployed, according to a cohort study presented at the American Heart Association scientific sessions.

For those that met the FFR threshold for ischemia, defined as up to 0.80, PCI reduced the risk of a major adverse cardiac event (MACE) at 5 years by 23% (hazard ratio, 0.77) relative to no PCI. Conversely, those not indicated for PCI because of a higher FFR had a 37% higher risk of MACE (HR, 1.37) at 5 years if treated with PCI relative to those who were not.

“The story of overuse of PCI is important,” reported the senior author Dennis Ko, MD, a scientist affiliated with the Schulich Heart Research Program, Sunnybrook Research Institute, University of Toronto, Canada. “We as interventionalists often think that putting in a stent is not harmful, and that turned out not to be the case.”

The FFR threshold for intervening with PCI is evidence based. Several trials, including one published in 2014, have associated PCI with better outcomes relative to medical therapy when FFR is 0.80 or lower. Other evidence suggests no advantage and possible harm for PCI performed if FFR is higher. Multiple guidelines, including those from the AHA, recommend against PCI if FFR is more than 0.80.

“As FRR is gaining in popularity, we were interested in whether physicians follow the thresholds in routine clinical practice and what happens to patient outcomes [if they are or are not followed],” Dr. Ko explained.

In this retrospective study by Dr. Ko’s trainee, Maneesh Sud, MD, and simultaneously published in JAMA, the answer was that there is deviation, and deviation leads to bad outcomes.

The 9,106 coronary artery disease patients included in the study underwent single-vessel FFR assessment within a 5-year period in Canada. The two cohorts evaluated were those with a lesional FFR of 0.80 or less, defined as ischemic, and those with a lesion with higher FFR, defined as nonischemic. The primary MACE outcome comprised death, myocardial infarction, unstable angina, or urgent coronary revascularization.

Of the 2,693 patients who met the FFR threshold of ischemia, 75.3% received PCI, and 24.7% were treated with medical therapy only. Of the 6,413 patients with nonischemic FFR, 87.4% were treated with medical therapy and 12.6% received PCI.

In those with ischemic FFR, event curves for MACE separated rapidly. At 30 days, the risk of MACE was 53% lower (HR, 0.47) in those receiving PCI. By 1 year, the advantage was less (HR, 0.76), but it was steady thereafter and remained about the same at 5 years (HR, 0.77; 95% confidence interval, 0.63-0.94). Relative advantages for each component of MACE went in the same direction. At 5 years, PCI exerted its greatest numerical advantage for the outcome or urgent coronary revascularization (HR, 0.71) and its least numerical advantage for MI (HR, 0.92), but none of these differences reached statistical significance.

In those with nonischemic coronary lesions on FFR, PCI was associated with more than twice the risk for MACE at 30 days (HR, 2.11), but the increase in risk relative to medical management fell at 1 year (HR 1.67) and 5 years (HR, 1.37). All of the individual components of MACE were numerically increased at all time points except for death, which was numerically lower at 30 days (HR, 0.41) and 5 years (HR, 0.94), even though these differences were not significant.

It could not be ascertained from these data why PCI was not performed when there was an indication or why it was performed when there was not. The investigators speculated that some clinicians may decide against PCI for ischemic lesions in the absence of symptoms or when concerned about comorbidities. They might offer PCI in nonischemic lesions because of symptoms, positive tests other than FFR, or FFR values near the threshold.

“I think the main message of our paper is that adherence of the FFR threshold as established by clinical trials is important,” Dr. Ko said in an interview. This not only means performing PCI when it is indicated, but refraining from PCI when it is not.

Basically, this study confirms that the guideline thresholds are valid, according to Jared M. O’Leary, MD, who is experienced with FFR and is Medical Director for Quality at the Vanderbilt Heart and Vascular Institute, Nashville, Tenn.

“It confirms the utility of FFR in the real world,” he said, adding that the results are “totally consistent with our practice.” He called FFR “an important tool in the cardiac cath lab” not only for determining when revascularization will benefit the patient but the opposite.

“The flip side is also true: Stenting should be avoided if a negative FFR is obtained,” he said, calling this technique “particularly useful for lesions that appear borderline by visual estimation alone.”
 

SOURCE: Sud M et al. AHA 2020. JAMA. 2020 Nov 13. doi: 10.1001/jama.2020.22708.

Current evidence is insufficient to assess the balance of benefits and harms of screening for high blood pressure in children and adolescents, the U.S. Preventive Services Task Force reported in JAMA.

©Vishnu Kumar/Thinkstock

However, two experts in this area suggested there is evidence if you know where to look, and pediatric BP testing is crucial now.

In this update to the 2013 statement, the USPSTF’s systematic review focused on evidence surrounding the benefits of screening, test accuracy, treatment effectiveness and harms, and links between hypertension and cardiovascular disease (CVD) markers in childhood and adulthood.

Limited information was available on the accuracy of screening tests. No studies were found that directly evaluated screening for pediatric high BP or reported effectiveness in delayed onset or risk reduction for cardiovascular outcomes related to hypertension. Additionally, no studies were found that addressed screening for secondary hypertension in asymptomatic pediatric patients. No studies were found that evaluated the treatment of primary childhood hypertension and BP reduction or other outcomes in adulthood. The panel also was unable to identify any studies that reported on harms of screening and treatment.

When the adult framework for cardiovascular risk reduction is extended in pediatric patients, there are methodological challenges that make it harder to determine how much of the potential burden can actually be prevented, the panel said. The clinical and epidemiologic significance of percentile thresholds that are used to determine their ties to adult CVD has limited supporting evidence. Inconsistent performance characteristics of current diagnostic methods, of which there are few, tend to yield unfavorable high false-positive rates. Such false positives are potentially harmful, because they lead to “unnecessary secondary evaluations or treatments.” Because pharmacologic management of pediatric hypertension is continued for a much longer period, it is the increased likelihood of adverse events that should be cause for concern.
 

Should the focus for screening be shifted to significant risk factors?

In an accompanying editorial, Joseph T. Flynn, MD, MS, of Seattle Children’s Hospital, said that the outcome of the latest statement is expected, “given how the key questions were framed and the analysis performed.” To begin, he suggested restating the question: “What is the best approach to assess whether childhood BP measurement is associated with adult CVD or whether treatment of high BP in childhood is associated with reducing the burden of adult CVD?” The answer is to tackle these questions with randomized clinical trials that compare screening to no screening and treatment to no treatment. But such studies are likely infeasible, partly because of the required length of follow-up of 5-6 decades.

Perhaps a better question would be: “Does BP measurement in childhood identify children and adolescents who already have markers of CVD or who are at risk of developing them as adults?” Were these youth to be identified, they would become candidates for approaches that seek to prevent disease progression. Reframing the question in this manner better positions physicians to focus on prevention and sidestep “the requirement that the only acceptable outcome is prevention of CVD events in adulthood,” he explained.

The next step would be to identify data already available to address the reframed question. Cross-sectional studies could be used to make the association between BP levels and cardiovascular risk markers already present. For example, several publications from the multicenter Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth (SHIP-AHOY), which enrolled roughly 400 youth, provided data that reinforce prior single-center studies that essentially proved there are adverse consequences for youth with high BP, and they “set the stage for the institution of measures designed to reverse target-organ damage and reduce cardiovascular risk in youth,” said Dr. Flynn.

More specifically, results from SHIP-AHOY “have demonstrated that increased left ventricular mass can be demonstrated at BP levels currently classified as normotensive and that abnormal left ventricular function can be seen at similar BP levels,” Dr. Flynn noted. In addition, “they have established a substantial association between an abnormal metabolic phenotype and several forms of target-organ damage associated with high BP.”
 

One approach is to analyze longitudinal cohort studies

Because there is a paucity of prospective clinical trials, Dr. Flynn suggested that analyzing longitudinal cohort studies would be the most effective approach for evaluating the potential link between current BP levels and future CVD. Such studies already have “data that address an important point raised in the USPSTF statement, namely whether the pediatric percentile-based BP cut points, such as those in the 2017 AAP [American Academy of Pediatrics] guideline, are associated with adult hypertension and CVD,” noted Dr. Flynn. “In the International Childhood Cardiovascular Cohort Consortium study, the specific childhood BP levels that were associated with increased adult carotid intima-medial thickness were remarkably similar to the BP percentile cut points in the AAP guideline for children of similar ages.”

Analysis of data from the Bogalusa Heart Study found looking at children classified as having high BP by the 2017 AAP guideline had “increased relative risks of having hypertension, left ventricular hypertrophy, or metabolic syndrome as adults 36 years later.”

“The conclusions of the USPSTF statement underscore the need for additional research on childhood high BP and its association with adult CVD. The starting points for such research can be deduced from currently available cross-sectional and longitudinal data, which demonstrate the detrimental outcomes associated with high BP in youth. Using these data to reframe and answer the questions raised by the USPSTF should point the way toward effective prevention of adult CVD,” concluded Dr. Flynn.

In a separate interview, Kristen Sexson Tejtel, MD, PhD, MPH, medical director of the preventive cardiology clinic at Texas Children’s Hospital and Baylor College of Medicine, both in Houston, noted that in spite of USPSTF’s findings, there is actually an association between children with high blood pressure and intermediate outcomes in adults.

“Dr. Flynn suggests reframing the question. In fact, evidence exists that children with high blood pressure are at higher risk of left ventricular hypertrophy, increased arterial stiffness, and changes in retinal arteries,” noted Dr. Sexson Tejtel.
 

Evidence of pediatric heart damage has been documented in autopsies

“It is imperative that children have blood pressure evaluation,” she urged. “There is evidence that there are changes similar to those seen in adults with cardiovascular compromise. It has been shown that children dying of other causes [accidents] who have these problems also have more plaque on autopsy, indicating that those with high blood pressure are more likely to have markers of CVD already present in childhood.

“One of the keys of pediatric medicine is prevention and the counseling for prevention of adult diseases. The duration of study necessary to objectively determine whether treatment of hypertension in childhood reduces the risk of adult cardiac problems is extensive. If nothing is done now, we are putting more future generations in danger. We must provide appropriate counseling for children and their families regarding lifestyle improvements, to have a chance to improve cardiovascular risk factors in adults, including hypertension, hyperlipidemia and/or obesity,” urged Dr. Sexson Tejtel.

All members of the USPSTF received travel reimbursement and honoraria. Dr. Barry received grants and personal fees from Healthwise. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF. Dr. Flynn reported receiving grants from the National Institutes of Health and royalties from UpToDate and Springer outside the submitted work. Dr. Sexson Tejtel said she had no relevant financial disclosures or conflicts of interest.

SOURCE: USPSTF. JAMA. 2020 Nov 10. doi: 10.1001/jama.2020.20122.

Current evidence is insufficient to assess the balance of benefits and harms of screening for high blood pressure in children and adolescents, the U.S. Preventive Services Task Force reported in JAMA.

©Vishnu Kumar/Thinkstock

However, two experts in this area suggested there is evidence if you know where to look, and pediatric BP testing is crucial now.

In this update to the 2013 statement, the USPSTF’s systematic review focused on evidence surrounding the benefits of screening, test accuracy, treatment effectiveness and harms, and links between hypertension and cardiovascular disease (CVD) markers in childhood and adulthood.

Limited information was available on the accuracy of screening tests. No studies were found that directly evaluated screening for pediatric high BP or reported effectiveness in delayed onset or risk reduction for cardiovascular outcomes related to hypertension. Additionally, no studies were found that addressed screening for secondary hypertension in asymptomatic pediatric patients. No studies were found that evaluated the treatment of primary childhood hypertension and BP reduction or other outcomes in adulthood. The panel also was unable to identify any studies that reported on harms of screening and treatment.

When the adult framework for cardiovascular risk reduction is extended in pediatric patients, there are methodological challenges that make it harder to determine how much of the potential burden can actually be prevented, the panel said. The clinical and epidemiologic significance of percentile thresholds that are used to determine their ties to adult CVD has limited supporting evidence. Inconsistent performance characteristics of current diagnostic methods, of which there are few, tend to yield unfavorable high false-positive rates. Such false positives are potentially harmful, because they lead to “unnecessary secondary evaluations or treatments.” Because pharmacologic management of pediatric hypertension is continued for a much longer period, it is the increased likelihood of adverse events that should be cause for concern.
 

Should the focus for screening be shifted to significant risk factors?

In an accompanying editorial, Joseph T. Flynn, MD, MS, of Seattle Children’s Hospital, said that the outcome of the latest statement is expected, “given how the key questions were framed and the analysis performed.” To begin, he suggested restating the question: “What is the best approach to assess whether childhood BP measurement is associated with adult CVD or whether treatment of high BP in childhood is associated with reducing the burden of adult CVD?” The answer is to tackle these questions with randomized clinical trials that compare screening to no screening and treatment to no treatment. But such studies are likely infeasible, partly because of the required length of follow-up of 5-6 decades.

Perhaps a better question would be: “Does BP measurement in childhood identify children and adolescents who already have markers of CVD or who are at risk of developing them as adults?” Were these youth to be identified, they would become candidates for approaches that seek to prevent disease progression. Reframing the question in this manner better positions physicians to focus on prevention and sidestep “the requirement that the only acceptable outcome is prevention of CVD events in adulthood,” he explained.

The next step would be to identify data already available to address the reframed question. Cross-sectional studies could be used to make the association between BP levels and cardiovascular risk markers already present. For example, several publications from the multicenter Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth (SHIP-AHOY), which enrolled roughly 400 youth, provided data that reinforce prior single-center studies that essentially proved there are adverse consequences for youth with high BP, and they “set the stage for the institution of measures designed to reverse target-organ damage and reduce cardiovascular risk in youth,” said Dr. Flynn.

More specifically, results from SHIP-AHOY “have demonstrated that increased left ventricular mass can be demonstrated at BP levels currently classified as normotensive and that abnormal left ventricular function can be seen at similar BP levels,” Dr. Flynn noted. In addition, “they have established a substantial association between an abnormal metabolic phenotype and several forms of target-organ damage associated with high BP.”
 

One approach is to analyze longitudinal cohort studies

Because there is a paucity of prospective clinical trials, Dr. Flynn suggested that analyzing longitudinal cohort studies would be the most effective approach for evaluating the potential link between current BP levels and future CVD. Such studies already have “data that address an important point raised in the USPSTF statement, namely whether the pediatric percentile-based BP cut points, such as those in the 2017 AAP [American Academy of Pediatrics] guideline, are associated with adult hypertension and CVD,” noted Dr. Flynn. “In the International Childhood Cardiovascular Cohort Consortium study, the specific childhood BP levels that were associated with increased adult carotid intima-medial thickness were remarkably similar to the BP percentile cut points in the AAP guideline for children of similar ages.”

Analysis of data from the Bogalusa Heart Study found looking at children classified as having high BP by the 2017 AAP guideline had “increased relative risks of having hypertension, left ventricular hypertrophy, or metabolic syndrome as adults 36 years later.”

“The conclusions of the USPSTF statement underscore the need for additional research on childhood high BP and its association with adult CVD. The starting points for such research can be deduced from currently available cross-sectional and longitudinal data, which demonstrate the detrimental outcomes associated with high BP in youth. Using these data to reframe and answer the questions raised by the USPSTF should point the way toward effective prevention of adult CVD,” concluded Dr. Flynn.

In a separate interview, Kristen Sexson Tejtel, MD, PhD, MPH, medical director of the preventive cardiology clinic at Texas Children’s Hospital and Baylor College of Medicine, both in Houston, noted that in spite of USPSTF’s findings, there is actually an association between children with high blood pressure and intermediate outcomes in adults.

“Dr. Flynn suggests reframing the question. In fact, evidence exists that children with high blood pressure are at higher risk of left ventricular hypertrophy, increased arterial stiffness, and changes in retinal arteries,” noted Dr. Sexson Tejtel.
 

Evidence of pediatric heart damage has been documented in autopsies

“It is imperative that children have blood pressure evaluation,” she urged. “There is evidence that there are changes similar to those seen in adults with cardiovascular compromise. It has been shown that children dying of other causes [accidents] who have these problems also have more plaque on autopsy, indicating that those with high blood pressure are more likely to have markers of CVD already present in childhood.

“One of the keys of pediatric medicine is prevention and the counseling for prevention of adult diseases. The duration of study necessary to objectively determine whether treatment of hypertension in childhood reduces the risk of adult cardiac problems is extensive. If nothing is done now, we are putting more future generations in danger. We must provide appropriate counseling for children and their families regarding lifestyle improvements, to have a chance to improve cardiovascular risk factors in adults, including hypertension, hyperlipidemia and/or obesity,” urged Dr. Sexson Tejtel.

All members of the USPSTF received travel reimbursement and honoraria. Dr. Barry received grants and personal fees from Healthwise. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF. Dr. Flynn reported receiving grants from the National Institutes of Health and royalties from UpToDate and Springer outside the submitted work. Dr. Sexson Tejtel said she had no relevant financial disclosures or conflicts of interest.

SOURCE: USPSTF. JAMA. 2020 Nov 10. doi: 10.1001/jama.2020.20122.

Current evidence is insufficient to assess the balance of benefits and harms of screening for high blood pressure in children and adolescents, the U.S. Preventive Services Task Force reported in JAMA.

©Vishnu Kumar/Thinkstock

However, two experts in this area suggested there is evidence if you know where to look, and pediatric BP testing is crucial now.

In this update to the 2013 statement, the USPSTF’s systematic review focused on evidence surrounding the benefits of screening, test accuracy, treatment effectiveness and harms, and links between hypertension and cardiovascular disease (CVD) markers in childhood and adulthood.

Limited information was available on the accuracy of screening tests. No studies were found that directly evaluated screening for pediatric high BP or reported effectiveness in delayed onset or risk reduction for cardiovascular outcomes related to hypertension. Additionally, no studies were found that addressed screening for secondary hypertension in asymptomatic pediatric patients. No studies were found that evaluated the treatment of primary childhood hypertension and BP reduction or other outcomes in adulthood. The panel also was unable to identify any studies that reported on harms of screening and treatment.

When the adult framework for cardiovascular risk reduction is extended in pediatric patients, there are methodological challenges that make it harder to determine how much of the potential burden can actually be prevented, the panel said. The clinical and epidemiologic significance of percentile thresholds that are used to determine their ties to adult CVD has limited supporting evidence. Inconsistent performance characteristics of current diagnostic methods, of which there are few, tend to yield unfavorable high false-positive rates. Such false positives are potentially harmful, because they lead to “unnecessary secondary evaluations or treatments.” Because pharmacologic management of pediatric hypertension is continued for a much longer period, it is the increased likelihood of adverse events that should be cause for concern.
 

Should the focus for screening be shifted to significant risk factors?

In an accompanying editorial, Joseph T. Flynn, MD, MS, of Seattle Children’s Hospital, said that the outcome of the latest statement is expected, “given how the key questions were framed and the analysis performed.” To begin, he suggested restating the question: “What is the best approach to assess whether childhood BP measurement is associated with adult CVD or whether treatment of high BP in childhood is associated with reducing the burden of adult CVD?” The answer is to tackle these questions with randomized clinical trials that compare screening to no screening and treatment to no treatment. But such studies are likely infeasible, partly because of the required length of follow-up of 5-6 decades.

Perhaps a better question would be: “Does BP measurement in childhood identify children and adolescents who already have markers of CVD or who are at risk of developing them as adults?” Were these youth to be identified, they would become candidates for approaches that seek to prevent disease progression. Reframing the question in this manner better positions physicians to focus on prevention and sidestep “the requirement that the only acceptable outcome is prevention of CVD events in adulthood,” he explained.

The next step would be to identify data already available to address the reframed question. Cross-sectional studies could be used to make the association between BP levels and cardiovascular risk markers already present. For example, several publications from the multicenter Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth (SHIP-AHOY), which enrolled roughly 400 youth, provided data that reinforce prior single-center studies that essentially proved there are adverse consequences for youth with high BP, and they “set the stage for the institution of measures designed to reverse target-organ damage and reduce cardiovascular risk in youth,” said Dr. Flynn.

More specifically, results from SHIP-AHOY “have demonstrated that increased left ventricular mass can be demonstrated at BP levels currently classified as normotensive and that abnormal left ventricular function can be seen at similar BP levels,” Dr. Flynn noted. In addition, “they have established a substantial association between an abnormal metabolic phenotype and several forms of target-organ damage associated with high BP.”
 

One approach is to analyze longitudinal cohort studies

Because there is a paucity of prospective clinical trials, Dr. Flynn suggested that analyzing longitudinal cohort studies would be the most effective approach for evaluating the potential link between current BP levels and future CVD. Such studies already have “data that address an important point raised in the USPSTF statement, namely whether the pediatric percentile-based BP cut points, such as those in the 2017 AAP [American Academy of Pediatrics] guideline, are associated with adult hypertension and CVD,” noted Dr. Flynn. “In the International Childhood Cardiovascular Cohort Consortium study, the specific childhood BP levels that were associated with increased adult carotid intima-medial thickness were remarkably similar to the BP percentile cut points in the AAP guideline for children of similar ages.”

Analysis of data from the Bogalusa Heart Study found looking at children classified as having high BP by the 2017 AAP guideline had “increased relative risks of having hypertension, left ventricular hypertrophy, or metabolic syndrome as adults 36 years later.”

“The conclusions of the USPSTF statement underscore the need for additional research on childhood high BP and its association with adult CVD. The starting points for such research can be deduced from currently available cross-sectional and longitudinal data, which demonstrate the detrimental outcomes associated with high BP in youth. Using these data to reframe and answer the questions raised by the USPSTF should point the way toward effective prevention of adult CVD,” concluded Dr. Flynn.

In a separate interview, Kristen Sexson Tejtel, MD, PhD, MPH, medical director of the preventive cardiology clinic at Texas Children’s Hospital and Baylor College of Medicine, both in Houston, noted that in spite of USPSTF’s findings, there is actually an association between children with high blood pressure and intermediate outcomes in adults.

“Dr. Flynn suggests reframing the question. In fact, evidence exists that children with high blood pressure are at higher risk of left ventricular hypertrophy, increased arterial stiffness, and changes in retinal arteries,” noted Dr. Sexson Tejtel.
 

Evidence of pediatric heart damage has been documented in autopsies

“It is imperative that children have blood pressure evaluation,” she urged. “There is evidence that there are changes similar to those seen in adults with cardiovascular compromise. It has been shown that children dying of other causes [accidents] who have these problems also have more plaque on autopsy, indicating that those with high blood pressure are more likely to have markers of CVD already present in childhood.

“One of the keys of pediatric medicine is prevention and the counseling for prevention of adult diseases. The duration of study necessary to objectively determine whether treatment of hypertension in childhood reduces the risk of adult cardiac problems is extensive. If nothing is done now, we are putting more future generations in danger. We must provide appropriate counseling for children and their families regarding lifestyle improvements, to have a chance to improve cardiovascular risk factors in adults, including hypertension, hyperlipidemia and/or obesity,” urged Dr. Sexson Tejtel.

All members of the USPSTF received travel reimbursement and honoraria. Dr. Barry received grants and personal fees from Healthwise. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF. Dr. Flynn reported receiving grants from the National Institutes of Health and royalties from UpToDate and Springer outside the submitted work. Dr. Sexson Tejtel said she had no relevant financial disclosures or conflicts of interest.

SOURCE: USPSTF. JAMA. 2020 Nov 10. doi: 10.1001/jama.2020.20122.

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

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

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

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

An international autopsy study of 21 patients who died from COVID-19 has shown the presence of multifocal lymphocytic myocarditis in three patients (14%). In an additional six patients, focally increased interstitial T-lymphocytes within the myocardium were noted, with only focal or no myocyte injury.

However, increased interstitial macrophage infiltration, possibly related to cytokine infiltration, was seen in 86% of patients.

“One way to think about this is that, if these patients were having biopsies and not autopsies, there would be myocardial injury in the patients with myocarditis, even after they recovered. But with interstitial macrophages, there may or may not be any injury,” said cardiovascular pathologist James R. Stone, MD, PhD, Massachusetts General Hospital, Boston.

Dr. Stone and colleagues from Mass General, two hospitals in Italy, the University of Amsterdam, and the Mayo Clinic in Rochester, Minn., conducted the autopsies in March and April. The results were published in the October 14 issue of the European Heart Journal.

Their technique was rigorous: a median of 20 full-thickness blocks of myocardium were examined histologically (range, 5-29 blocks).

The presence of myocarditis, defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analyzed by immunohistochemistry.

“I think one of the take-homes from this study is that you have to do a thorough sampling of the heart in order to exclude myocardial injury. You cannot exclude myocarditis with just a biopsy or two,” said Dr. Stone in an interview.

“We looked at multiple different sections of tissue preserved in paraffin for every case and found only 14% had myocarditis. The vast majority of autopsies done on patients dying from COVID-19 have short-changed the autopsy and not been done in a way to exclude myocarditis,” he added.

For all patients, COVID-19 was the underlying cause of death, but the mechanisms of death were acute respiratory distress syndrome in 15, viral pneumonia in 4, cardiogenic shock in 1, and cardiac arrest in 1. Seven patients had a history of cardiovascular disease, including atrial fibrillation in four, coronary artery disease in three, left ventricular hypertrophy in one, and previous valve replacement in one. A total of 16 had hypertension, 7 had diabetes mellitus, and 1 had chronic obstructive pulmonary disease. In four cases, mild pericarditis was present. Acute myocyte injury in the right ventricle, most probably from strain or overload, was also present in four cases.

A nonsignificant trend was seen toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. There were no reports of disrupted coronary artery plaques, coronary artery aneurysms, or large pulmonary emboli.

Macrophage infiltration rather than myocarditis, myocardial injury?

The study sheds more light on previous cardiac magnetic resonance (CMR) imaging findings that have suggested that many patients who recover from COVID-19 show signs suggestive of myocarditis. These earlier studies include a recent one in competitive athletes and the earlier Puntmann and colleagues study of relatively young COVID-19 patients, which showed ongoing myocardial involvement in a majority of patients.

“It would not surprise me if some or all of the cardiac MR changes seen in some of these recent imaging studies are due to the macrophages,” said Dr. Stone.

“What we saw was not a routine pathology by any means. It was a huge amount of macrophages, higher that what we saw in SARS and more similar to a study published in 2007 that looked at patients with bacterial sepsis,” said Dr. Stone.

In an older study of SARS patients, 35% had the virus detected in myocardial tissue by polymerase chain reaction. In that subset, the degree of myocardial macrophage infiltrate was comparable to that seen in 86% of the COVID-19 cases described in this series.

Another possibility is that the macrophage infiltration reflects underlying disease rather than COVID-19. All but one of the patients had known underlying medical conditions associated with cardiac remodeling, said Nikolaos G. Frangogiannis, MD, a cardiologist who studies the mechanisms of cardiac injury, repair, and remodeling.

Frangogiannis, from Albert Einstein College of Medicine, New York, wrote an editorial that accompanied the autopsy study.

“The problem with this finding of increased macrophage infiltration is that it’s very hard to interpret because as we age, and especially in a less healthy population, the numbers and the density of macrophages in the heart increase, so it’s impossible to interpret as an effect of the infection itself unless you have an appropriate control population that matches the same characteristics, which is almost impossible to ask for,” he said.

“I’ve observed since the beginning of the pandemic that there seemed to be some people who wanted every single case to be myocarditis and others who had a bias toward not wanting COVID-19 to be a cause of myocarditis. I think what we’re seeing is it’s not either/or for anything with this virus, it’s a bit of everything,” said Dr. Stone.

Dr. Stone and Dr. Frangogiannis reported no conflict of interest.
 

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

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

mzoler@mdedge.com

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

mzoler@mdedge.com

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

mzoler@mdedge.com

In the early weeks of the COVID-19 pandemic in the United States, rates of sustained return of spontaneous circulation after out-of-hospital cardiac arrest were lower throughout the country, compared with a year earlier, in one study.

A second study of that period showed that patients with COVID-19 had rates that were better than previously reported of surviving in-hospital cardiac arrest.

Paul S. Chan, MD, presented the out-of-hospital cardiac arrest research, and Oscar J. Mitchell, MD, presented the in-hospital cardiac arrest findings in a late-breaking resuscitation science session at the American Heart Association scientific sessions. The former study was also simultaneously published online Nov. 14 in JAMA Cardiology.

Importantly, “the survival rates were not zero in either setting,” said Dr. Chan, commenting on the implications of both studies taken together.

“The survival rates – either return of circulation or survival to discharge – were not futile,” Dr. Chan, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said in an interview.

“And I think that’s an overall important message – that we can’t write off patients who have a cardiac arrest at this point,” he stressed. “They deserve a response. Although the outcomes might not be as good as we had seen in years prior, we are seeing patients making it out of the hospital and surviving.”

Dr. Mitchell, from the University of Pennsylvania in Philadelphia, echoed this message in an interview.

“I think that the key finding here is that survival is possible after patients with COVID-19 suffer an in-hospital cardiac arrest,” Dr. Mitchell said. “We hope that the information from our study will be of use to frontline providers who are treating patients with COVID-19.”

“In coming weeks, there will likely be increased hospital strain and enormous challenges to providing COVID-19 care,” added Benjamin S. Abella, MD, the senior author of the in-hospital study. Dr. Abella is also from the University of Pennsylvania and was cochair of the Resuscitation Science symposium during the AHA meeting.

“It is crucial that hospital leaders prepare now for how they will manage COVID-19 resuscitation efforts,” Dr. Abella said. “Emergency medicine and critical care leaders must be mindful that many COVID-19 patients with arrest could survive to return to their families.”

“It is important to note both studies demonstrated variations in outcome and that those differences were associated with the differential COVID prevalence and mortality,” session comoderator Cindy H. Hsu, MD, PhD, University of Michigan, said in an interview.

“Future studies,” she said, “should address knowledge gaps including associated comorbidities and affected resuscitation process variables during the COVID-19 pandemic.”
 

Out-of-hospital cardiac arrest, March 2019 vs. March 2020

Compared with 2019, in 2020, the reported rates of return of spontaneous circulation after out-of-hospital cardiac arrest fell from 25% to 10.6% in New York and from 13.5% to 5.0% in northern Italy – two areas that were severely affected, Dr. Chan noted.

In this study, the researchers aimed to examine whether out-of-hospital cardiac arrest outcomes would be similar throughout the United States, including areas that were less severely affected, in the first weeks of the pandemic.

They linked data from the Cardiac Arrest Registry to Enhance Survival (CARES), which covers an area with about 152 million U.S. residents, with COVID-19 disease mortality data.

There were 9,863 out-of-hospital arrests from March 16 to April 30, 2020, compared with 9,440 cases during this time in 2019.

The patients in both years had a similar age (mean, 62 years) and sex (62% male), but there were more Black patients in 2020 (28% vs. 23%).

Overall, in communities with low to high rates of death from COVID-19, the rate of return of spontaneous circulation was 18% lower in that early pandemic period than in the same time in the previous year (23% vs. 29.8%; adjusted rate ratio, 0.82).

The rates of return of spontaneous circulation were also lower in communities with a low rate of COVID-19 mortality, but to a lesser extent (11%-15% lower in 2020 vs. 2019).

In the subset of emergency medical agencies with complete data on hospital survival, overall rates of survival to discharge were 17% lower during the studied pandemic period versus the same time a year earlier (6.6% vs. 9.8%; adjusted RR, 0.83).

This drop in survival was greater in communities with moderate to high COVID-19 mortality.

These outcomes were not explained by differences in emergency medical services arrival or treatment times, rates of bystander CPR, or initial out-of-hospital cardiac arrest rhythm.

Dr. Chan was a coauthor of an interim guidance issued April 9, 2020, by the AHA and several other medical societies for ways to protect frontline workers from contracting COVID-19 while they were performing CPR.

Communities that were not heavily affected by COVID-19 could have also been following the recommendations, which might have affected outcomes, he speculated.

For example, “when we pause chest compressions it can potentially worsen survival even if it’s for a short period of time. That might explain the lower rates of return of circulation.”

“That guidance was really meant for heavily affected communities,” Dr. Chan added. “Of course, as we speak, the pandemic is pretty much everywhere in the United States. It’s not just in the northeast; it’s not just in Arizona, Florida, California, Texas like it was in the summer. You are seeing surges in 46 of the 50 states.

“If your community is heavily affected by COVID-19 in terms of deaths at this time, paramedics will need to take caution to also help protect themselves, and the guidance may apply at that point,” he said.

In-hospital cardiac arrest, March Through May 2020

The early studies of in-hospital cardiac arrest in patients with COVID-19 showed “concerningly low rates” of return of spontaneous circulation and survival, said Dr. Mitchell.

“The first was a study from Wuhan, which demonstrated a 2.9% 30-day survival and the second was a small cohort from NYC with 0% survival to hospital discharge,” he said. “This raised concerns that offering CPR to patients who had a cardiac arrest from COVID-19 might only hold a low probability of success.”

To investigate this, the researchers formed a COVID study group comprising two hospitals in New York and nine hospitals in the Northeast and West Coast.

They identified 260 hospitalized adult patients with COVID-19 who had in-hospital cardiac arrest between March 1 and May 31, 2020. The patients had a median age of 69 years, and 72% were male. Most had preexisting comorbidities. Most of the cardiac arrests were in the ICU (64%), and almost all were witnessed (91%).

Return of spontaneous circulation occurred in 22% of the patients, and 12% had survived 30 days later. Of the 260 cardiac arrests, most (204) occurred in the New York hospitals.

There was a huge variation in outcomes. The rate of sustained return of spontaneous circulation was much lower in the two hospitals in New York compared with elsewhere (11% vs. 64%), as was 30-day survival (6% vs. 36%).

“Variation in outcomes from [in-hospital cardiac arrest] has been well described prior to the COVID-19 pandemic,” said Dr. Mitchell, “and is felt to be due to a range of factors, including variation in detection and prevention of cardiac arrest, management of patients during the cardiac arrest, and differences in postarrest care – including targeted temperature management and neuroprognostication.”

“We hypothesize that the strains of the COVID-19 pandemic may have amplified these variations (although we were unable to compare hospital performance before and after the pandemic),” he said.

Nevertheless, “in contrast to [earlier] studies, we have found that survival with a good neurological status is possible after in-hospital cardiac arrest in patients with COVID-19, which is certainly reassuring for those of us on the front line.”

Dr. Chan has received research support from the American Heart Association (which helps fund CARES); the National Heart, Lung, and Blood Institute; and Optum Rx. Dr. Abella has received honoraria from NeuroproteXeon, Becton Dickinson, and Physio-Control, and research grants from Medtronic, PCORI, Physio-Control, Stryker, and TerSera. Dr. Mitchell has disclosed no relevant financial relationships.
 

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

In the early weeks of the COVID-19 pandemic in the United States, rates of sustained return of spontaneous circulation after out-of-hospital cardiac arrest were lower throughout the country, compared with a year earlier, in one study.

A second study of that period showed that patients with COVID-19 had rates that were better than previously reported of surviving in-hospital cardiac arrest.

Paul S. Chan, MD, presented the out-of-hospital cardiac arrest research, and Oscar J. Mitchell, MD, presented the in-hospital cardiac arrest findings in a late-breaking resuscitation science session at the American Heart Association scientific sessions. The former study was also simultaneously published online Nov. 14 in JAMA Cardiology.

Importantly, “the survival rates were not zero in either setting,” said Dr. Chan, commenting on the implications of both studies taken together.

“The survival rates – either return of circulation or survival to discharge – were not futile,” Dr. Chan, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said in an interview.

“And I think that’s an overall important message – that we can’t write off patients who have a cardiac arrest at this point,” he stressed. “They deserve a response. Although the outcomes might not be as good as we had seen in years prior, we are seeing patients making it out of the hospital and surviving.”

Dr. Mitchell, from the University of Pennsylvania in Philadelphia, echoed this message in an interview.

“I think that the key finding here is that survival is possible after patients with COVID-19 suffer an in-hospital cardiac arrest,” Dr. Mitchell said. “We hope that the information from our study will be of use to frontline providers who are treating patients with COVID-19.”

“In coming weeks, there will likely be increased hospital strain and enormous challenges to providing COVID-19 care,” added Benjamin S. Abella, MD, the senior author of the in-hospital study. Dr. Abella is also from the University of Pennsylvania and was cochair of the Resuscitation Science symposium during the AHA meeting.

“It is crucial that hospital leaders prepare now for how they will manage COVID-19 resuscitation efforts,” Dr. Abella said. “Emergency medicine and critical care leaders must be mindful that many COVID-19 patients with arrest could survive to return to their families.”

“It is important to note both studies demonstrated variations in outcome and that those differences were associated with the differential COVID prevalence and mortality,” session comoderator Cindy H. Hsu, MD, PhD, University of Michigan, said in an interview.

“Future studies,” she said, “should address knowledge gaps including associated comorbidities and affected resuscitation process variables during the COVID-19 pandemic.”
 

Out-of-hospital cardiac arrest, March 2019 vs. March 2020

Compared with 2019, in 2020, the reported rates of return of spontaneous circulation after out-of-hospital cardiac arrest fell from 25% to 10.6% in New York and from 13.5% to 5.0% in northern Italy – two areas that were severely affected, Dr. Chan noted.

In this study, the researchers aimed to examine whether out-of-hospital cardiac arrest outcomes would be similar throughout the United States, including areas that were less severely affected, in the first weeks of the pandemic.

They linked data from the Cardiac Arrest Registry to Enhance Survival (CARES), which covers an area with about 152 million U.S. residents, with COVID-19 disease mortality data.

There were 9,863 out-of-hospital arrests from March 16 to April 30, 2020, compared with 9,440 cases during this time in 2019.

The patients in both years had a similar age (mean, 62 years) and sex (62% male), but there were more Black patients in 2020 (28% vs. 23%).

Overall, in communities with low to high rates of death from COVID-19, the rate of return of spontaneous circulation was 18% lower in that early pandemic period than in the same time in the previous year (23% vs. 29.8%; adjusted rate ratio, 0.82).

The rates of return of spontaneous circulation were also lower in communities with a low rate of COVID-19 mortality, but to a lesser extent (11%-15% lower in 2020 vs. 2019).

In the subset of emergency medical agencies with complete data on hospital survival, overall rates of survival to discharge were 17% lower during the studied pandemic period versus the same time a year earlier (6.6% vs. 9.8%; adjusted RR, 0.83).

This drop in survival was greater in communities with moderate to high COVID-19 mortality.

These outcomes were not explained by differences in emergency medical services arrival or treatment times, rates of bystander CPR, or initial out-of-hospital cardiac arrest rhythm.

Dr. Chan was a coauthor of an interim guidance issued April 9, 2020, by the AHA and several other medical societies for ways to protect frontline workers from contracting COVID-19 while they were performing CPR.

Communities that were not heavily affected by COVID-19 could have also been following the recommendations, which might have affected outcomes, he speculated.

For example, “when we pause chest compressions it can potentially worsen survival even if it’s for a short period of time. That might explain the lower rates of return of circulation.”

“That guidance was really meant for heavily affected communities,” Dr. Chan added. “Of course, as we speak, the pandemic is pretty much everywhere in the United States. It’s not just in the northeast; it’s not just in Arizona, Florida, California, Texas like it was in the summer. You are seeing surges in 46 of the 50 states.

“If your community is heavily affected by COVID-19 in terms of deaths at this time, paramedics will need to take caution to also help protect themselves, and the guidance may apply at that point,” he said.

In-hospital cardiac arrest, March Through May 2020

The early studies of in-hospital cardiac arrest in patients with COVID-19 showed “concerningly low rates” of return of spontaneous circulation and survival, said Dr. Mitchell.

“The first was a study from Wuhan, which demonstrated a 2.9% 30-day survival and the second was a small cohort from NYC with 0% survival to hospital discharge,” he said. “This raised concerns that offering CPR to patients who had a cardiac arrest from COVID-19 might only hold a low probability of success.”

To investigate this, the researchers formed a COVID study group comprising two hospitals in New York and nine hospitals in the Northeast and West Coast.

They identified 260 hospitalized adult patients with COVID-19 who had in-hospital cardiac arrest between March 1 and May 31, 2020. The patients had a median age of 69 years, and 72% were male. Most had preexisting comorbidities. Most of the cardiac arrests were in the ICU (64%), and almost all were witnessed (91%).

Return of spontaneous circulation occurred in 22% of the patients, and 12% had survived 30 days later. Of the 260 cardiac arrests, most (204) occurred in the New York hospitals.

There was a huge variation in outcomes. The rate of sustained return of spontaneous circulation was much lower in the two hospitals in New York compared with elsewhere (11% vs. 64%), as was 30-day survival (6% vs. 36%).

“Variation in outcomes from [in-hospital cardiac arrest] has been well described prior to the COVID-19 pandemic,” said Dr. Mitchell, “and is felt to be due to a range of factors, including variation in detection and prevention of cardiac arrest, management of patients during the cardiac arrest, and differences in postarrest care – including targeted temperature management and neuroprognostication.”

“We hypothesize that the strains of the COVID-19 pandemic may have amplified these variations (although we were unable to compare hospital performance before and after the pandemic),” he said.

Nevertheless, “in contrast to [earlier] studies, we have found that survival with a good neurological status is possible after in-hospital cardiac arrest in patients with COVID-19, which is certainly reassuring for those of us on the front line.”

Dr. Chan has received research support from the American Heart Association (which helps fund CARES); the National Heart, Lung, and Blood Institute; and Optum Rx. Dr. Abella has received honoraria from NeuroproteXeon, Becton Dickinson, and Physio-Control, and research grants from Medtronic, PCORI, Physio-Control, Stryker, and TerSera. Dr. Mitchell has disclosed no relevant financial relationships.
 

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

In the early weeks of the COVID-19 pandemic in the United States, rates of sustained return of spontaneous circulation after out-of-hospital cardiac arrest were lower throughout the country, compared with a year earlier, in one study.

A second study of that period showed that patients with COVID-19 had rates that were better than previously reported of surviving in-hospital cardiac arrest.

Paul S. Chan, MD, presented the out-of-hospital cardiac arrest research, and Oscar J. Mitchell, MD, presented the in-hospital cardiac arrest findings in a late-breaking resuscitation science session at the American Heart Association scientific sessions. The former study was also simultaneously published online Nov. 14 in JAMA Cardiology.

Importantly, “the survival rates were not zero in either setting,” said Dr. Chan, commenting on the implications of both studies taken together.

“The survival rates – either return of circulation or survival to discharge – were not futile,” Dr. Chan, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said in an interview.

“And I think that’s an overall important message – that we can’t write off patients who have a cardiac arrest at this point,” he stressed. “They deserve a response. Although the outcomes might not be as good as we had seen in years prior, we are seeing patients making it out of the hospital and surviving.”

Dr. Mitchell, from the University of Pennsylvania in Philadelphia, echoed this message in an interview.

“I think that the key finding here is that survival is possible after patients with COVID-19 suffer an in-hospital cardiac arrest,” Dr. Mitchell said. “We hope that the information from our study will be of use to frontline providers who are treating patients with COVID-19.”

“In coming weeks, there will likely be increased hospital strain and enormous challenges to providing COVID-19 care,” added Benjamin S. Abella, MD, the senior author of the in-hospital study. Dr. Abella is also from the University of Pennsylvania and was cochair of the Resuscitation Science symposium during the AHA meeting.

“It is crucial that hospital leaders prepare now for how they will manage COVID-19 resuscitation efforts,” Dr. Abella said. “Emergency medicine and critical care leaders must be mindful that many COVID-19 patients with arrest could survive to return to their families.”

“It is important to note both studies demonstrated variations in outcome and that those differences were associated with the differential COVID prevalence and mortality,” session comoderator Cindy H. Hsu, MD, PhD, University of Michigan, said in an interview.

“Future studies,” she said, “should address knowledge gaps including associated comorbidities and affected resuscitation process variables during the COVID-19 pandemic.”
 

Out-of-hospital cardiac arrest, March 2019 vs. March 2020

Compared with 2019, in 2020, the reported rates of return of spontaneous circulation after out-of-hospital cardiac arrest fell from 25% to 10.6% in New York and from 13.5% to 5.0% in northern Italy – two areas that were severely affected, Dr. Chan noted.

In this study, the researchers aimed to examine whether out-of-hospital cardiac arrest outcomes would be similar throughout the United States, including areas that were less severely affected, in the first weeks of the pandemic.

They linked data from the Cardiac Arrest Registry to Enhance Survival (CARES), which covers an area with about 152 million U.S. residents, with COVID-19 disease mortality data.

There were 9,863 out-of-hospital arrests from March 16 to April 30, 2020, compared with 9,440 cases during this time in 2019.

The patients in both years had a similar age (mean, 62 years) and sex (62% male), but there were more Black patients in 2020 (28% vs. 23%).

Overall, in communities with low to high rates of death from COVID-19, the rate of return of spontaneous circulation was 18% lower in that early pandemic period than in the same time in the previous year (23% vs. 29.8%; adjusted rate ratio, 0.82).

The rates of return of spontaneous circulation were also lower in communities with a low rate of COVID-19 mortality, but to a lesser extent (11%-15% lower in 2020 vs. 2019).

In the subset of emergency medical agencies with complete data on hospital survival, overall rates of survival to discharge were 17% lower during the studied pandemic period versus the same time a year earlier (6.6% vs. 9.8%; adjusted RR, 0.83).

This drop in survival was greater in communities with moderate to high COVID-19 mortality.

These outcomes were not explained by differences in emergency medical services arrival or treatment times, rates of bystander CPR, or initial out-of-hospital cardiac arrest rhythm.

Dr. Chan was a coauthor of an interim guidance issued April 9, 2020, by the AHA and several other medical societies for ways to protect frontline workers from contracting COVID-19 while they were performing CPR.

Communities that were not heavily affected by COVID-19 could have also been following the recommendations, which might have affected outcomes, he speculated.

For example, “when we pause chest compressions it can potentially worsen survival even if it’s for a short period of time. That might explain the lower rates of return of circulation.”

“That guidance was really meant for heavily affected communities,” Dr. Chan added. “Of course, as we speak, the pandemic is pretty much everywhere in the United States. It’s not just in the northeast; it’s not just in Arizona, Florida, California, Texas like it was in the summer. You are seeing surges in 46 of the 50 states.

“If your community is heavily affected by COVID-19 in terms of deaths at this time, paramedics will need to take caution to also help protect themselves, and the guidance may apply at that point,” he said.

In-hospital cardiac arrest, March Through May 2020

The early studies of in-hospital cardiac arrest in patients with COVID-19 showed “concerningly low rates” of return of spontaneous circulation and survival, said Dr. Mitchell.

“The first was a study from Wuhan, which demonstrated a 2.9% 30-day survival and the second was a small cohort from NYC with 0% survival to hospital discharge,” he said. “This raised concerns that offering CPR to patients who had a cardiac arrest from COVID-19 might only hold a low probability of success.”

To investigate this, the researchers formed a COVID study group comprising two hospitals in New York and nine hospitals in the Northeast and West Coast.

They identified 260 hospitalized adult patients with COVID-19 who had in-hospital cardiac arrest between March 1 and May 31, 2020. The patients had a median age of 69 years, and 72% were male. Most had preexisting comorbidities. Most of the cardiac arrests were in the ICU (64%), and almost all were witnessed (91%).

Return of spontaneous circulation occurred in 22% of the patients, and 12% had survived 30 days later. Of the 260 cardiac arrests, most (204) occurred in the New York hospitals.

There was a huge variation in outcomes. The rate of sustained return of spontaneous circulation was much lower in the two hospitals in New York compared with elsewhere (11% vs. 64%), as was 30-day survival (6% vs. 36%).

“Variation in outcomes from [in-hospital cardiac arrest] has been well described prior to the COVID-19 pandemic,” said Dr. Mitchell, “and is felt to be due to a range of factors, including variation in detection and prevention of cardiac arrest, management of patients during the cardiac arrest, and differences in postarrest care – including targeted temperature management and neuroprognostication.”

“We hypothesize that the strains of the COVID-19 pandemic may have amplified these variations (although we were unable to compare hospital performance before and after the pandemic),” he said.

Nevertheless, “in contrast to [earlier] studies, we have found that survival with a good neurological status is possible after in-hospital cardiac arrest in patients with COVID-19, which is certainly reassuring for those of us on the front line.”

Dr. Chan has received research support from the American Heart Association (which helps fund CARES); the National Heart, Lung, and Blood Institute; and Optum Rx. Dr. Abella has received honoraria from NeuroproteXeon, Becton Dickinson, and Physio-Control, and research grants from Medtronic, PCORI, Physio-Control, Stryker, and TerSera. Dr. Mitchell has disclosed no relevant financial relationships.
 

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

One in five patients at elevated stroke risk who underwent cardiac surgery with no history of atrial fibrillation preoperatively or at discharge developed postoperative AFib documented on a continuous cardiac rhythm monitoring device within the first 30 days after leaving the hospital in the randomized SEARCH-AF trial.

“Postoperative atrial fibrillation after cardiac surgery is not confined to the hospitalization period per se. We believe that these data should help inform on clinical practice guidelines on monitoring for postoperative atrial fibrillation in such patients,” said Subodh Verma, MD, PhD, reporting the results at the virtual American Heart Association scientific sessions.

“Guidelines provide little or no direction on optimal monitoring post cardiac surgery, particularly if patients are in sinus rhythm at discharge,” the surgeon noted.

SEARCH-AF was an open-label, multicenter study that included 336 patients at elevated stroke risk with an average CHA₂DS₂-VASc score of 4, no history of preoperative AFib, and none more than briefly with resolution during hospitalization. They were randomized to 30 days of postdischarge continuous cardiac rhythm monitoring with Medtronic’s SEEQ device, to Icentia’s CardioSTAT device, or to usual care, with Holter monitoring at the discretion of the treating physicians.

The primary result was a cumulative duration of AFib or atrial flutter of 6 minutes or longer during that 30-day period. This outcome occurred in 19.6% of the enhanced cardiac monitoring group and 1.7% of usual-care controls. Thus, there is an ongoing persistent occult risk of AFib that typically goes unrecognized. This 10-fold difference in the incidence of postoperative AFib translated into an absolute 17.9% between-group difference and a number-needed-to-treat of 6.

The secondary outcome of a cumulative atrial fib/flutter burden of 6 hours or more during 30 days occurred in 8.6% of the continuously monitored group and none of the controls. A cumulative AFib/flutter burden of 24 hours or greater occurred in 3.1% of the enhanced cardiac monitoring group and zero controls. These are AFib burdens that in other studies have been linked to increased risks of stroke and death, said Dr. Verma, professor of cardiovascular surgery at the University of Toronto.

“From a clinical standpoint, what this trial tells me is for my patients being discharged home tomorrow from the hospital, where they haven’t had AFib and I haven’t initiated anticoagulation, I have a low threshold to monitor these patients and to watch for periods of sustained unrecognized atrial fibrillation,” the surgeon added.
 

Experts: Results won’t change guidelines

Discussant Ben Freedman, MBBS, PhD, noted that the U.S. Preventive Services Task Force has stated that there are insufficient data available to recommend ECG screening for AFib to prevent stroke. Before the task force can be convinced to recommend it and for payers to cover it, a number of key questions need to be answered. And the SEARCH-AF trial doesn’t provide those answers, said Dr. Freedman, professor of cardiology and deputy director of the Heart Research Institute at the University of Sydney.

First off, it’ll be necessary to know if the risk posed by screen-detected AFib, including postoperative AFib, is similar to that of clinical AFib. Next, it must be shown that this screen-detected postoperative AFib is actionable; that is, that a screening strategy to detect postoperative AFib arising after discharge and then treat with oral anticoagulants will actually prevent more strokes than with usual care. There are large studies underway addressing that question, including HEARTLINE, STROKESTOP, and SAFERGUARD-AF, he observed.

In an interview, Rod S. Passman, MD, who gave a state-of-the-art talk on AFib detection at the meeting and wasn’t involved in SEARCH-AF, said he doesn’t consider the results practice-changing.

“It’s not guideline-changing because you’ve only shown that more intensive monitoring finds more AFib. Guideline-changing would be that finding that AFib and doing something about it impacts hard outcomes, and we don’t have that data yet,” said Dr. Passman, an electrophysiologist who is director of the Center for Arrhythmia Research and professor of medicine and preventive medicine at Northwestern University, Chicago.

The SEARCH-AF trial was funded by the Heart and Stroke Foundation of Canada, Bristol Myers Squibb, Pfizer, and Boehringer Ingelheim. Dr. Verma reported having received speaker’s fees and/or research support from those and other pharmaceutical companies. Dr. Freedman disclosed having no financial conflicts.

bjancin@mdedge.com

One in five patients at elevated stroke risk who underwent cardiac surgery with no history of atrial fibrillation preoperatively or at discharge developed postoperative AFib documented on a continuous cardiac rhythm monitoring device within the first 30 days after leaving the hospital in the randomized SEARCH-AF trial.

“Postoperative atrial fibrillation after cardiac surgery is not confined to the hospitalization period per se. We believe that these data should help inform on clinical practice guidelines on monitoring for postoperative atrial fibrillation in such patients,” said Subodh Verma, MD, PhD, reporting the results at the virtual American Heart Association scientific sessions.

“Guidelines provide little or no direction on optimal monitoring post cardiac surgery, particularly if patients are in sinus rhythm at discharge,” the surgeon noted.

SEARCH-AF was an open-label, multicenter study that included 336 patients at elevated stroke risk with an average CHA₂DS₂-VASc score of 4, no history of preoperative AFib, and none more than briefly with resolution during hospitalization. They were randomized to 30 days of postdischarge continuous cardiac rhythm monitoring with Medtronic’s SEEQ device, to Icentia’s CardioSTAT device, or to usual care, with Holter monitoring at the discretion of the treating physicians.

The primary result was a cumulative duration of AFib or atrial flutter of 6 minutes or longer during that 30-day period. This outcome occurred in 19.6% of the enhanced cardiac monitoring group and 1.7% of usual-care controls. Thus, there is an ongoing persistent occult risk of AFib that typically goes unrecognized. This 10-fold difference in the incidence of postoperative AFib translated into an absolute 17.9% between-group difference and a number-needed-to-treat of 6.

The secondary outcome of a cumulative atrial fib/flutter burden of 6 hours or more during 30 days occurred in 8.6% of the continuously monitored group and none of the controls. A cumulative AFib/flutter burden of 24 hours or greater occurred in 3.1% of the enhanced cardiac monitoring group and zero controls. These are AFib burdens that in other studies have been linked to increased risks of stroke and death, said Dr. Verma, professor of cardiovascular surgery at the University of Toronto.

“From a clinical standpoint, what this trial tells me is for my patients being discharged home tomorrow from the hospital, where they haven’t had AFib and I haven’t initiated anticoagulation, I have a low threshold to monitor these patients and to watch for periods of sustained unrecognized atrial fibrillation,” the surgeon added.
 

Experts: Results won’t change guidelines

Discussant Ben Freedman, MBBS, PhD, noted that the U.S. Preventive Services Task Force has stated that there are insufficient data available to recommend ECG screening for AFib to prevent stroke. Before the task force can be convinced to recommend it and for payers to cover it, a number of key questions need to be answered. And the SEARCH-AF trial doesn’t provide those answers, said Dr. Freedman, professor of cardiology and deputy director of the Heart Research Institute at the University of Sydney.

First off, it’ll be necessary to know if the risk posed by screen-detected AFib, including postoperative AFib, is similar to that of clinical AFib. Next, it must be shown that this screen-detected postoperative AFib is actionable; that is, that a screening strategy to detect postoperative AFib arising after discharge and then treat with oral anticoagulants will actually prevent more strokes than with usual care. There are large studies underway addressing that question, including HEARTLINE, STROKESTOP, and SAFERGUARD-AF, he observed.

In an interview, Rod S. Passman, MD, who gave a state-of-the-art talk on AFib detection at the meeting and wasn’t involved in SEARCH-AF, said he doesn’t consider the results practice-changing.

“It’s not guideline-changing because you’ve only shown that more intensive monitoring finds more AFib. Guideline-changing would be that finding that AFib and doing something about it impacts hard outcomes, and we don’t have that data yet,” said Dr. Passman, an electrophysiologist who is director of the Center for Arrhythmia Research and professor of medicine and preventive medicine at Northwestern University, Chicago.

The SEARCH-AF trial was funded by the Heart and Stroke Foundation of Canada, Bristol Myers Squibb, Pfizer, and Boehringer Ingelheim. Dr. Verma reported having received speaker’s fees and/or research support from those and other pharmaceutical companies. Dr. Freedman disclosed having no financial conflicts.

bjancin@mdedge.com

One in five patients at elevated stroke risk who underwent cardiac surgery with no history of atrial fibrillation preoperatively or at discharge developed postoperative AFib documented on a continuous cardiac rhythm monitoring device within the first 30 days after leaving the hospital in the randomized SEARCH-AF trial.

“Postoperative atrial fibrillation after cardiac surgery is not confined to the hospitalization period per se. We believe that these data should help inform on clinical practice guidelines on monitoring for postoperative atrial fibrillation in such patients,” said Subodh Verma, MD, PhD, reporting the results at the virtual American Heart Association scientific sessions.

“Guidelines provide little or no direction on optimal monitoring post cardiac surgery, particularly if patients are in sinus rhythm at discharge,” the surgeon noted.

SEARCH-AF was an open-label, multicenter study that included 336 patients at elevated stroke risk with an average CHA₂DS₂-VASc score of 4, no history of preoperative AFib, and none more than briefly with resolution during hospitalization. They were randomized to 30 days of postdischarge continuous cardiac rhythm monitoring with Medtronic’s SEEQ device, to Icentia’s CardioSTAT device, or to usual care, with Holter monitoring at the discretion of the treating physicians.

The primary result was a cumulative duration of AFib or atrial flutter of 6 minutes or longer during that 30-day period. This outcome occurred in 19.6% of the enhanced cardiac monitoring group and 1.7% of usual-care controls. Thus, there is an ongoing persistent occult risk of AFib that typically goes unrecognized. This 10-fold difference in the incidence of postoperative AFib translated into an absolute 17.9% between-group difference and a number-needed-to-treat of 6.

The secondary outcome of a cumulative atrial fib/flutter burden of 6 hours or more during 30 days occurred in 8.6% of the continuously monitored group and none of the controls. A cumulative AFib/flutter burden of 24 hours or greater occurred in 3.1% of the enhanced cardiac monitoring group and zero controls. These are AFib burdens that in other studies have been linked to increased risks of stroke and death, said Dr. Verma, professor of cardiovascular surgery at the University of Toronto.

“From a clinical standpoint, what this trial tells me is for my patients being discharged home tomorrow from the hospital, where they haven’t had AFib and I haven’t initiated anticoagulation, I have a low threshold to monitor these patients and to watch for periods of sustained unrecognized atrial fibrillation,” the surgeon added.
 

Experts: Results won’t change guidelines

Discussant Ben Freedman, MBBS, PhD, noted that the U.S. Preventive Services Task Force has stated that there are insufficient data available to recommend ECG screening for AFib to prevent stroke. Before the task force can be convinced to recommend it and for payers to cover it, a number of key questions need to be answered. And the SEARCH-AF trial doesn’t provide those answers, said Dr. Freedman, professor of cardiology and deputy director of the Heart Research Institute at the University of Sydney.

First off, it’ll be necessary to know if the risk posed by screen-detected AFib, including postoperative AFib, is similar to that of clinical AFib. Next, it must be shown that this screen-detected postoperative AFib is actionable; that is, that a screening strategy to detect postoperative AFib arising after discharge and then treat with oral anticoagulants will actually prevent more strokes than with usual care. There are large studies underway addressing that question, including HEARTLINE, STROKESTOP, and SAFERGUARD-AF, he observed.

In an interview, Rod S. Passman, MD, who gave a state-of-the-art talk on AFib detection at the meeting and wasn’t involved in SEARCH-AF, said he doesn’t consider the results practice-changing.

“It’s not guideline-changing because you’ve only shown that more intensive monitoring finds more AFib. Guideline-changing would be that finding that AFib and doing something about it impacts hard outcomes, and we don’t have that data yet,” said Dr. Passman, an electrophysiologist who is director of the Center for Arrhythmia Research and professor of medicine and preventive medicine at Northwestern University, Chicago.

The SEARCH-AF trial was funded by the Heart and Stroke Foundation of Canada, Bristol Myers Squibb, Pfizer, and Boehringer Ingelheim. Dr. Verma reported having received speaker’s fees and/or research support from those and other pharmaceutical companies. Dr. Freedman disclosed having no financial conflicts.

bjancin@mdedge.com

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

mzoler@mdedge.com

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

mzoler@mdedge.com

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

mzoler@mdedge.com

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

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

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

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

A novel randomized trial taking on a vexing issue around one of the world’s most commonly prescribed medications has concluded that frequently intolerable statin side effects, such as muscle weakness or pain, are almost entirely a nocebo effect, the placebo effect’s darker cousin.

The many patients who report such symptoms while taking statins are indeed probably feeling them, but they are a result of taking the pills rather than any pharmacologic effects, concluded researchers based on their 60-patient study, Self-Assessment Method for Statin Side-effects or Nocebo (SAMSON).

“SAMSON leaves no doubt that patients really do get side effects from statin tablets, but what it shows us is that 90% of this symptomatic burden is elicited by placebo tablets too,” said James P. Howard, MB, PhD, Imperial College London, when presenting the results Nov. 15 at the American Heart Association scientific sessions. They were published simultaneously in the New England Journal of Medicine.

Studies have shown that in practice “more than half of patients abandon statins completely within 2 years. And yet, in placebo-controlled trials, no more people stop statins than placebo,” Dr. Howard said.

“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them.”
Patients in the trial, all of whom had a history of dropping statins because of side effects, each took atorvastatin 20 mg/day, a placebo, or neither pill for 1 month, alternating the regimens in randomized order over 1 year so that each was followed a total of 4 months. They used a smartphone app to record the severity of any side effects, not necessarily just pain, on a scale of 0-100.

Symptom intensity scores averaged 16.3 for atorvastatin and 15.4 for placebo, for a nonsignificant difference, but only 8.0 for no-pill months (P < .001 compared with the statin or placebo).
Because such symptoms seem to be based on patient expectations from statin therapy, positive communication about what the drugs can achieve and how the next treatment steps are described can play a big role in their continued use.

For example, “changing them to another statin is a very reasonable thing to do, but as soon as you start trying people on lower doses and working up, you’re sort of telling them that you’re expecting at some dose that they are going to get side effects,” cautioned Dr. Howard at a media briefing on SAMSON.

“The most important thing is to explain the evidence, and what our expectations are, maybe be a bit more optimistic about statins, and tell them they’re very unlikely to suffer from side effects,” he explained, “because the nocebo effect can only really rear its head if the patients are expecting to feel worse – just like the placebo effect will only work if people are expecting to feel better.”
Amit Khera, MD, who moderated the media briefing, said he always tells such patients: “Yes, 1 in 10 patients report having muscle ache. But first and foremost, 9 in 10 don’t. The vast majority of patients don’t get muscle aches. I think that’s really an important part of the communication.”

Now, after SAMSON, “I have an additional point that I’m going to tell them: out of the patients that get muscle aches, probably 90% of that is the anticipation of getting the statin, the nocebo effect,” said Dr. Khera, who directs the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

In practice, however, many patients who report adverse statin effects do so later than 2 weeks after starting therapy, “so these findings cannot be generalized to them,” proposed Francine K. Welty, MD, PhD, Beth Israel Deaconess Medical Center, Boston, as the invited discussant after Dr. Howard’s presentation.

All 60 patients recruited for SAMSON had previously stopped taking a statin because of side effects that arose within 2 weeks of their first dose. That requirement was intended to boost chances that any further symptoms during the trial would arise within a month of starting each new round of pills, Dr. Howard said.

So the trial’s results, Dr. Welty said, “are limited to those subjects who develop symptoms within 2 weeks of starting a statin.”

Including only such patients may have created bias toward a nocebo effect, she said, because “non–drug-related side effects of medications are often greatest during the initial weeks of treatment and tend to abate over time.” For example, “metformin causes diarrhea and beta-blockers cause fatigue, but subjects do adapt and generally tolerate them very well.”

The patients, 25 women and 35 men, 90% of whom were white, received four pill bottles, each with a month’s supply of atorvastatin, four bottles each with 1 month of placebo, and four empty bottles each, to be used double blind for a month in randomized order.

Patients used the smartphone app to document their symptom scores, which ranged from 0 for no symptoms to 100 for symptoms that were the “worst imaginable,” the published report noted. Patients who experienced symptoms so severe as to be intolerable could stop the 1-month regimen they were then following, with instructions to resume the regimens in order starting the next month.

Eleven patients were unable to complete all 12 1-month segments of the trial.

The study’s overall “nocebo ratio” of 0.90 was calculated as the difference between symptom intensity scores on placebo and on no treatment divided by the difference between symptom intensity on the statin and on no treatment. The interpretation: 90% of the symptom burden felt by patients receiving atorvastatin was also felt during placebo use.

A total of 30 patients, contacted 6 months after the trial concluded, had resumed taking a statin, while “4 planned to do so and one could not be contacted,” the report noted. The 25 other patients weren’t receiving a statin and had no plans to take one.

In an important part of the trial, Dr. Howard said, at its conclusion the patients were shown their pattern of symptoms in relation to whether they were taking the statin, placebo, or neither. “Participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect. And this led to half of our patients happily restarting statins.”

The implications of SAMSON, Dr. Welty said, “are very important, in that those developing symptoms within 2 weeks of starting a statin should be reassured that approximately half will be able to successful restart the statin.”

SAMSON was funded by the British Heart Foundation. Howard had no disclosures. Dr. Welty disclosed chairing the data safety monitoring committee for Empagliflozin International Clinical Trials, supported by Boehringer Ingelheim.

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