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CABANA: Ablation bests drugs for AFib in racial/ethnic minorities
CABANA, which was undertaken to compare catheter ablation and rate-control or rhythm-control drug therapy for AFib, concluded there was no significant difference between the two strategies in improving the trial’s composite primary outcome of death, disabling stroke, serious bleeding, or cardiac arrest.
But a closer look at a subgroup of participants reveals an important difference in outcome among racial and ethnic minorities.
In that group, which made up about 10% of the CABANA study population, catheter ablation was significantly better at treating AFib than was drug therapy, producing roughly a 70% relative reduction in the primary endpoint and all-cause mortality.
The benefit for catheter ablation, which was not seen in the nonminority participants, appeared to be due to worse outcomes with drug therapy, the investigators report in an article published July 5 in the Journal of the American College of Cardiology.
“The study really highlights the importance of trying to secure an inclusive and diverse population in clinical trials,” lead author Kevin L. Thomas, MD, Duke University, Durham, N.C., said in an interview.
“When we focused on the racial and ethnic minorities who were included in CABANA, the findings were different. This was a surprise,” Dr. Thomas said.
“The findings from the secondary analysis of CABANA suggest that racial and ethnic minorities that are treated with drugs compared with ablation do worse,” he said. “If we can validate this in a larger sample of patients and this does in fact turn out to be true, then we would change how we practice medicine. We would have discussions with these populations about the benefits of ablation over drugs, and this would be important information to help guide our practice.”
The investigators analyzed data from 1,280 participants enrolled in the North American arm of CABANA. Of these, 127 (9.9%) were of racial or ethnic minorities, as defined by the National Institutes of Health, and were randomly assigned to receive ablation (n = 62) or drug therapy (n = 65).
Compared with nonminorities, participants of racial and ethnic minorities were younger (median age, 65.5 years, vs. 68.5 years) and were more likely to have NYHA functional class greater than or equal to II symptoms (37.0% vs. 22.0%), hypertension (92.1% vs. 76.8%), and an ejection fraction less than 40% (20.8% vs. 7.1%).
The overall median follow-up was 54.9 months. Among ethnic and minority participants, the median follow-up was 48 months, compared with 55.5 months for the nonminority participants.
Although there was no significant difference in the primary composite endpoint in the main CABANA trial, among racial and ethnic minorities treated with ablation, there was a 68% relative reduction in the trial’s primary endpoint (adjusted hazard ratio, 0.32; 95% confidence interval, 0.13-0.78) and a 72% relative reduction in all-cause mortality (aHR, 0.28; 95% CI, 0.10-0.79).
The 4-year Kaplan-Meier primary event rates were similar in both racial/ethnic minority and nonminority groups that received catheter ablation (12.3% vs. 9.9%).
However, the 4-year event rate was much higher among nonminority participants than among racial and ethnic minorities who received drug therapy (27.4% vs. 9.4%).
The corresponding all-cause 4-year mortality rates were 8.1% and 6.7%, respectively, in the ablation arm and 20.2% and 4.5%, respectively, in the drug arm.
Dr. Thomas and colleagues point out that heart failure in racial and ethnic minorities, particularly Black patients, is typically due to hypertensive heart disease, whereas in non-Hispanic White patients, it is overwhelmingly associated with coronary artery disease. “Our results in CABANA, therefore, raise the possibility that the variations in the prevalence of the heart diseases associated with AFib might account for differences in the benefits observed with ablation therapy.”
Prior data suggest that AFib in the setting of heart failure with either reduced or preserved ejection fraction has substantially better clinical outcomes with ablation versus drug therapy, but most studies either do not report racial/ethnic demographics or enroll very low numbers of minorities, they note.
Andrea M. Russo, MD, a professor of medicine at Rowan University, Camden, New Jersey, asks why drug therapy might result in worse outcomes in racial and ethnic minorities in an accompanying editorial.
“Those who received ablation did better than those who received drugs, and the main reason for that is not that ablation works better in minorities than nonminorities, it’s because drugs are worse in minority patients than they are in nonminority patients. This means that either the way we are using the drugs or the ones that we are using in minority patients are resulting in worse overall outcomes,” Dr. Russo told this news organization.
“The minority patients were younger and yet had more hypertension at baseline. There could be all kinds of factors contributing to their health,” she said.
Dr. Russo agrees with Dr. Thomas on the need to enroll diverse populations in clinical trials.
“Dr. Thomas should be commended. He did a fabulous job of looking at this issue. It’s only 10% of the group, but it is better than what we have had so far, and this is a start,” Dr. Russo said. “It’s bringing recognition to how important it is to make sure that we include underrepresented populations in these trials and also that we offer all appropriate therapies to everyone.”
Dr. Thomas reports financial relationships with Janssen, Pfizer, Biosense Webster. Dr. Russo reports no relevant financial relationships. The study was funded by the National Institutes of Health, St. Jude Medical Foundation and Corporation, Biosense Webster, Medtronic, and Boston Scientific.
A version of this article first appeared on Medscape.com.
CABANA, which was undertaken to compare catheter ablation and rate-control or rhythm-control drug therapy for AFib, concluded there was no significant difference between the two strategies in improving the trial’s composite primary outcome of death, disabling stroke, serious bleeding, or cardiac arrest.
But a closer look at a subgroup of participants reveals an important difference in outcome among racial and ethnic minorities.
In that group, which made up about 10% of the CABANA study population, catheter ablation was significantly better at treating AFib than was drug therapy, producing roughly a 70% relative reduction in the primary endpoint and all-cause mortality.
The benefit for catheter ablation, which was not seen in the nonminority participants, appeared to be due to worse outcomes with drug therapy, the investigators report in an article published July 5 in the Journal of the American College of Cardiology.
“The study really highlights the importance of trying to secure an inclusive and diverse population in clinical trials,” lead author Kevin L. Thomas, MD, Duke University, Durham, N.C., said in an interview.
“When we focused on the racial and ethnic minorities who were included in CABANA, the findings were different. This was a surprise,” Dr. Thomas said.
“The findings from the secondary analysis of CABANA suggest that racial and ethnic minorities that are treated with drugs compared with ablation do worse,” he said. “If we can validate this in a larger sample of patients and this does in fact turn out to be true, then we would change how we practice medicine. We would have discussions with these populations about the benefits of ablation over drugs, and this would be important information to help guide our practice.”
The investigators analyzed data from 1,280 participants enrolled in the North American arm of CABANA. Of these, 127 (9.9%) were of racial or ethnic minorities, as defined by the National Institutes of Health, and were randomly assigned to receive ablation (n = 62) or drug therapy (n = 65).
Compared with nonminorities, participants of racial and ethnic minorities were younger (median age, 65.5 years, vs. 68.5 years) and were more likely to have NYHA functional class greater than or equal to II symptoms (37.0% vs. 22.0%), hypertension (92.1% vs. 76.8%), and an ejection fraction less than 40% (20.8% vs. 7.1%).
The overall median follow-up was 54.9 months. Among ethnic and minority participants, the median follow-up was 48 months, compared with 55.5 months for the nonminority participants.
Although there was no significant difference in the primary composite endpoint in the main CABANA trial, among racial and ethnic minorities treated with ablation, there was a 68% relative reduction in the trial’s primary endpoint (adjusted hazard ratio, 0.32; 95% confidence interval, 0.13-0.78) and a 72% relative reduction in all-cause mortality (aHR, 0.28; 95% CI, 0.10-0.79).
The 4-year Kaplan-Meier primary event rates were similar in both racial/ethnic minority and nonminority groups that received catheter ablation (12.3% vs. 9.9%).
However, the 4-year event rate was much higher among nonminority participants than among racial and ethnic minorities who received drug therapy (27.4% vs. 9.4%).
The corresponding all-cause 4-year mortality rates were 8.1% and 6.7%, respectively, in the ablation arm and 20.2% and 4.5%, respectively, in the drug arm.
Dr. Thomas and colleagues point out that heart failure in racial and ethnic minorities, particularly Black patients, is typically due to hypertensive heart disease, whereas in non-Hispanic White patients, it is overwhelmingly associated with coronary artery disease. “Our results in CABANA, therefore, raise the possibility that the variations in the prevalence of the heart diseases associated with AFib might account for differences in the benefits observed with ablation therapy.”
Prior data suggest that AFib in the setting of heart failure with either reduced or preserved ejection fraction has substantially better clinical outcomes with ablation versus drug therapy, but most studies either do not report racial/ethnic demographics or enroll very low numbers of minorities, they note.
Andrea M. Russo, MD, a professor of medicine at Rowan University, Camden, New Jersey, asks why drug therapy might result in worse outcomes in racial and ethnic minorities in an accompanying editorial.
“Those who received ablation did better than those who received drugs, and the main reason for that is not that ablation works better in minorities than nonminorities, it’s because drugs are worse in minority patients than they are in nonminority patients. This means that either the way we are using the drugs or the ones that we are using in minority patients are resulting in worse overall outcomes,” Dr. Russo told this news organization.
“The minority patients were younger and yet had more hypertension at baseline. There could be all kinds of factors contributing to their health,” she said.
Dr. Russo agrees with Dr. Thomas on the need to enroll diverse populations in clinical trials.
“Dr. Thomas should be commended. He did a fabulous job of looking at this issue. It’s only 10% of the group, but it is better than what we have had so far, and this is a start,” Dr. Russo said. “It’s bringing recognition to how important it is to make sure that we include underrepresented populations in these trials and also that we offer all appropriate therapies to everyone.”
Dr. Thomas reports financial relationships with Janssen, Pfizer, Biosense Webster. Dr. Russo reports no relevant financial relationships. The study was funded by the National Institutes of Health, St. Jude Medical Foundation and Corporation, Biosense Webster, Medtronic, and Boston Scientific.
A version of this article first appeared on Medscape.com.
CABANA, which was undertaken to compare catheter ablation and rate-control or rhythm-control drug therapy for AFib, concluded there was no significant difference between the two strategies in improving the trial’s composite primary outcome of death, disabling stroke, serious bleeding, or cardiac arrest.
But a closer look at a subgroup of participants reveals an important difference in outcome among racial and ethnic minorities.
In that group, which made up about 10% of the CABANA study population, catheter ablation was significantly better at treating AFib than was drug therapy, producing roughly a 70% relative reduction in the primary endpoint and all-cause mortality.
The benefit for catheter ablation, which was not seen in the nonminority participants, appeared to be due to worse outcomes with drug therapy, the investigators report in an article published July 5 in the Journal of the American College of Cardiology.
“The study really highlights the importance of trying to secure an inclusive and diverse population in clinical trials,” lead author Kevin L. Thomas, MD, Duke University, Durham, N.C., said in an interview.
“When we focused on the racial and ethnic minorities who were included in CABANA, the findings were different. This was a surprise,” Dr. Thomas said.
“The findings from the secondary analysis of CABANA suggest that racial and ethnic minorities that are treated with drugs compared with ablation do worse,” he said. “If we can validate this in a larger sample of patients and this does in fact turn out to be true, then we would change how we practice medicine. We would have discussions with these populations about the benefits of ablation over drugs, and this would be important information to help guide our practice.”
The investigators analyzed data from 1,280 participants enrolled in the North American arm of CABANA. Of these, 127 (9.9%) were of racial or ethnic minorities, as defined by the National Institutes of Health, and were randomly assigned to receive ablation (n = 62) or drug therapy (n = 65).
Compared with nonminorities, participants of racial and ethnic minorities were younger (median age, 65.5 years, vs. 68.5 years) and were more likely to have NYHA functional class greater than or equal to II symptoms (37.0% vs. 22.0%), hypertension (92.1% vs. 76.8%), and an ejection fraction less than 40% (20.8% vs. 7.1%).
The overall median follow-up was 54.9 months. Among ethnic and minority participants, the median follow-up was 48 months, compared with 55.5 months for the nonminority participants.
Although there was no significant difference in the primary composite endpoint in the main CABANA trial, among racial and ethnic minorities treated with ablation, there was a 68% relative reduction in the trial’s primary endpoint (adjusted hazard ratio, 0.32; 95% confidence interval, 0.13-0.78) and a 72% relative reduction in all-cause mortality (aHR, 0.28; 95% CI, 0.10-0.79).
The 4-year Kaplan-Meier primary event rates were similar in both racial/ethnic minority and nonminority groups that received catheter ablation (12.3% vs. 9.9%).
However, the 4-year event rate was much higher among nonminority participants than among racial and ethnic minorities who received drug therapy (27.4% vs. 9.4%).
The corresponding all-cause 4-year mortality rates were 8.1% and 6.7%, respectively, in the ablation arm and 20.2% and 4.5%, respectively, in the drug arm.
Dr. Thomas and colleagues point out that heart failure in racial and ethnic minorities, particularly Black patients, is typically due to hypertensive heart disease, whereas in non-Hispanic White patients, it is overwhelmingly associated with coronary artery disease. “Our results in CABANA, therefore, raise the possibility that the variations in the prevalence of the heart diseases associated with AFib might account for differences in the benefits observed with ablation therapy.”
Prior data suggest that AFib in the setting of heart failure with either reduced or preserved ejection fraction has substantially better clinical outcomes with ablation versus drug therapy, but most studies either do not report racial/ethnic demographics or enroll very low numbers of minorities, they note.
Andrea M. Russo, MD, a professor of medicine at Rowan University, Camden, New Jersey, asks why drug therapy might result in worse outcomes in racial and ethnic minorities in an accompanying editorial.
“Those who received ablation did better than those who received drugs, and the main reason for that is not that ablation works better in minorities than nonminorities, it’s because drugs are worse in minority patients than they are in nonminority patients. This means that either the way we are using the drugs or the ones that we are using in minority patients are resulting in worse overall outcomes,” Dr. Russo told this news organization.
“The minority patients were younger and yet had more hypertension at baseline. There could be all kinds of factors contributing to their health,” she said.
Dr. Russo agrees with Dr. Thomas on the need to enroll diverse populations in clinical trials.
“Dr. Thomas should be commended. He did a fabulous job of looking at this issue. It’s only 10% of the group, but it is better than what we have had so far, and this is a start,” Dr. Russo said. “It’s bringing recognition to how important it is to make sure that we include underrepresented populations in these trials and also that we offer all appropriate therapies to everyone.”
Dr. Thomas reports financial relationships with Janssen, Pfizer, Biosense Webster. Dr. Russo reports no relevant financial relationships. The study was funded by the National Institutes of Health, St. Jude Medical Foundation and Corporation, Biosense Webster, Medtronic, and Boston Scientific.
A version of this article first appeared on Medscape.com.
Heart failure med undertreatment because of older age common, flouts evidence
, suggests a large cohort study.
About 80% of patients aged 80 years or older were prescribed renin-angiotensin-system inhibitors (RASi) in a multivariate-adjusted analysis of more than 27,000 patients in the Swedish Heart Failure Registry (SwedeHF). In contrast, such drugs – which included angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin receptor blockers, and ACE inhibitors – were prescribed to 95% of patients younger than 70 years.
Similarly, fewer of the oldest patients were offered meds from the two other drug classes core to HF management at the time: Beta blockers and mineralocorticoid receptor antagonists (MRA).
And among those in the 80-and-older age group who were prescribed RASi or beta blockers, their uptitration more often fell short of even half the target dosage, compared with the youngest patients in the analysis.
Physicians may hold back on full guideline-directed medical therapy in their very elderly patients with HFrEF for many reasons, including a perceived likelihood of drug intolerance due to frailty or multiple comorbidities, including renal dysfunction, Davide Stolfo, MD, Karolinska Institutet, Stockholm, and University of Trieste, Italy, told this news organization.
But the current analysis was adjusted for about 80 variables “that in our interpretation may be main reasons for not introducing drugs and using them in the older patients,” he said. They included care setting (that is, inpatient or outpatient), HF severity by several measures, a range of comorbidities, renal dysfunction, and history of serious illness such as cancer.
Even then, age emerged as a significant, independent predictor of medical therapy underuse in the oldest patients. Some physicians apparently see advanced age, by itself, as an “intrinsic reason” not to abide by HFrEF medical therapy recommendations, said Dr. Stolfo, who presented the analysis at HFA 2021, the annual meeting of the Heart Failure Association of the European Society of Cardiology (ESC-HFA), conducted both virtually and live in Florence, Italy.
Most major HF-drug trials have excluded or admitted few patients aged 80 years or older, but “the guidelines recommend treatment regardless of age, and in the trials there has been no influence from age on the effectiveness of drugs,” Dr. Stolfo observed.
Moreover, in a prior SwedeHF analysis with propensity matching, patients with HFrEF aged 80 or older showed steeper reductions in risk for death or HF hospitalization from treatment with RASi than those in younger age groups.
One of the few randomized trials to focus on the very elderly, called SENIORS, enrolled patients aged 70 years and older – the average age was 76 – and saw a significantly reduced risk of death or cardiovascular hospitalization for those assigned to the beta blocker nebivolol. The benefits in the trial, which was conducted 15 years ago, were independent of left ventricular function.
So in the oldest patients, “we could question the need to achieve full dose of an evidence-based drug, but we shouldn’t question the use of these drugs.”
The findings are consistent with a need to individualize medical therapy in senior patients with HFrEF, especially those of more advanced age, some of whom may be robust enough to be managed similarly to younger patients while others who may be less suitable for full guideline-directed medical therapy, Dr. Stolfo said.
Even for those who are more frail or have major comorbidities, drug therapy of HFrEF continues to be important for symptom control even if competing causes of death make it harder to prolong survival, Dr. Stolfo said.
“We should provide to all patients the best strategy they can tolerate,” he said. “If we cannot greatly impact on the long-term survival for these patients, treatment can be aimed to improve the quality of life and keep the patient out of the hospital.”
The analysis was supported by Boehringer Ingelheim. Dr. Stolfo disclosed personal fees from Novartis, Merck, GlaxoSmithKline, and Acceleron.
A version of this article first appeared on Medscape.com.
, suggests a large cohort study.
About 80% of patients aged 80 years or older were prescribed renin-angiotensin-system inhibitors (RASi) in a multivariate-adjusted analysis of more than 27,000 patients in the Swedish Heart Failure Registry (SwedeHF). In contrast, such drugs – which included angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin receptor blockers, and ACE inhibitors – were prescribed to 95% of patients younger than 70 years.
Similarly, fewer of the oldest patients were offered meds from the two other drug classes core to HF management at the time: Beta blockers and mineralocorticoid receptor antagonists (MRA).
And among those in the 80-and-older age group who were prescribed RASi or beta blockers, their uptitration more often fell short of even half the target dosage, compared with the youngest patients in the analysis.
Physicians may hold back on full guideline-directed medical therapy in their very elderly patients with HFrEF for many reasons, including a perceived likelihood of drug intolerance due to frailty or multiple comorbidities, including renal dysfunction, Davide Stolfo, MD, Karolinska Institutet, Stockholm, and University of Trieste, Italy, told this news organization.
But the current analysis was adjusted for about 80 variables “that in our interpretation may be main reasons for not introducing drugs and using them in the older patients,” he said. They included care setting (that is, inpatient or outpatient), HF severity by several measures, a range of comorbidities, renal dysfunction, and history of serious illness such as cancer.
Even then, age emerged as a significant, independent predictor of medical therapy underuse in the oldest patients. Some physicians apparently see advanced age, by itself, as an “intrinsic reason” not to abide by HFrEF medical therapy recommendations, said Dr. Stolfo, who presented the analysis at HFA 2021, the annual meeting of the Heart Failure Association of the European Society of Cardiology (ESC-HFA), conducted both virtually and live in Florence, Italy.
Most major HF-drug trials have excluded or admitted few patients aged 80 years or older, but “the guidelines recommend treatment regardless of age, and in the trials there has been no influence from age on the effectiveness of drugs,” Dr. Stolfo observed.
Moreover, in a prior SwedeHF analysis with propensity matching, patients with HFrEF aged 80 or older showed steeper reductions in risk for death or HF hospitalization from treatment with RASi than those in younger age groups.
One of the few randomized trials to focus on the very elderly, called SENIORS, enrolled patients aged 70 years and older – the average age was 76 – and saw a significantly reduced risk of death or cardiovascular hospitalization for those assigned to the beta blocker nebivolol. The benefits in the trial, which was conducted 15 years ago, were independent of left ventricular function.
So in the oldest patients, “we could question the need to achieve full dose of an evidence-based drug, but we shouldn’t question the use of these drugs.”
The findings are consistent with a need to individualize medical therapy in senior patients with HFrEF, especially those of more advanced age, some of whom may be robust enough to be managed similarly to younger patients while others who may be less suitable for full guideline-directed medical therapy, Dr. Stolfo said.
Even for those who are more frail or have major comorbidities, drug therapy of HFrEF continues to be important for symptom control even if competing causes of death make it harder to prolong survival, Dr. Stolfo said.
“We should provide to all patients the best strategy they can tolerate,” he said. “If we cannot greatly impact on the long-term survival for these patients, treatment can be aimed to improve the quality of life and keep the patient out of the hospital.”
The analysis was supported by Boehringer Ingelheim. Dr. Stolfo disclosed personal fees from Novartis, Merck, GlaxoSmithKline, and Acceleron.
A version of this article first appeared on Medscape.com.
, suggests a large cohort study.
About 80% of patients aged 80 years or older were prescribed renin-angiotensin-system inhibitors (RASi) in a multivariate-adjusted analysis of more than 27,000 patients in the Swedish Heart Failure Registry (SwedeHF). In contrast, such drugs – which included angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin receptor blockers, and ACE inhibitors – were prescribed to 95% of patients younger than 70 years.
Similarly, fewer of the oldest patients were offered meds from the two other drug classes core to HF management at the time: Beta blockers and mineralocorticoid receptor antagonists (MRA).
And among those in the 80-and-older age group who were prescribed RASi or beta blockers, their uptitration more often fell short of even half the target dosage, compared with the youngest patients in the analysis.
Physicians may hold back on full guideline-directed medical therapy in their very elderly patients with HFrEF for many reasons, including a perceived likelihood of drug intolerance due to frailty or multiple comorbidities, including renal dysfunction, Davide Stolfo, MD, Karolinska Institutet, Stockholm, and University of Trieste, Italy, told this news organization.
But the current analysis was adjusted for about 80 variables “that in our interpretation may be main reasons for not introducing drugs and using them in the older patients,” he said. They included care setting (that is, inpatient or outpatient), HF severity by several measures, a range of comorbidities, renal dysfunction, and history of serious illness such as cancer.
Even then, age emerged as a significant, independent predictor of medical therapy underuse in the oldest patients. Some physicians apparently see advanced age, by itself, as an “intrinsic reason” not to abide by HFrEF medical therapy recommendations, said Dr. Stolfo, who presented the analysis at HFA 2021, the annual meeting of the Heart Failure Association of the European Society of Cardiology (ESC-HFA), conducted both virtually and live in Florence, Italy.
Most major HF-drug trials have excluded or admitted few patients aged 80 years or older, but “the guidelines recommend treatment regardless of age, and in the trials there has been no influence from age on the effectiveness of drugs,” Dr. Stolfo observed.
Moreover, in a prior SwedeHF analysis with propensity matching, patients with HFrEF aged 80 or older showed steeper reductions in risk for death or HF hospitalization from treatment with RASi than those in younger age groups.
One of the few randomized trials to focus on the very elderly, called SENIORS, enrolled patients aged 70 years and older – the average age was 76 – and saw a significantly reduced risk of death or cardiovascular hospitalization for those assigned to the beta blocker nebivolol. The benefits in the trial, which was conducted 15 years ago, were independent of left ventricular function.
So in the oldest patients, “we could question the need to achieve full dose of an evidence-based drug, but we shouldn’t question the use of these drugs.”
The findings are consistent with a need to individualize medical therapy in senior patients with HFrEF, especially those of more advanced age, some of whom may be robust enough to be managed similarly to younger patients while others who may be less suitable for full guideline-directed medical therapy, Dr. Stolfo said.
Even for those who are more frail or have major comorbidities, drug therapy of HFrEF continues to be important for symptom control even if competing causes of death make it harder to prolong survival, Dr. Stolfo said.
“We should provide to all patients the best strategy they can tolerate,” he said. “If we cannot greatly impact on the long-term survival for these patients, treatment can be aimed to improve the quality of life and keep the patient out of the hospital.”
The analysis was supported by Boehringer Ingelheim. Dr. Stolfo disclosed personal fees from Novartis, Merck, GlaxoSmithKline, and Acceleron.
A version of this article first appeared on Medscape.com.
FDA okays 1-month dual antiplatelet therapy for Abbott’s Xience stents
The U.S. Food and Drug Administration, Abbott announced on June 30.
Patients who receive stents are typically on DAPT regimens such as aspirin and P2Y12 inhibitors for 6 to 12 months to prevent blood clots, but high-bleeding risk patients can experience bleeding during prolonged DAPT.
“The new FDA approval for DAPT for the XIENCE family of stents provides interventional cardiologists confidence they are delivering the best care to patients with high bleeding risk. A short DAPT duration minimizes risks for high bleeding risk patients and allows them to return to daily life sooner and with more assurance,” Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York and the global principal investigator for Abbott’s Short DAPT program (XIENCE 28 and XIENCE 90), said in a news release.
The new labeling comes on the heels of European CE Mark approval for the Xience stents with DAPT as short as 28 days, “giving Xience stents the shortest DAPT indication in the world,” the company noted.
Results of the XIENCE 28 trial were used to support the new CE Mark DAPT indication. The trial showed no increase in death of myocardial infarction between 1 and 6 months and a significantly lower risk for severe bleeding with the Xience stent and 1-month DAPT, compared with 6-month DAPT in more than 1,600 high-bleeding risk patients.
The XIENCE 90 trial involving more than 2,000 high-bleeding risk patients reported no difference in death or MI between 3 and 12 months with Xience and 3-month DAPT versus 12-month DAPT.
Abbott scored a second win, also announcing FDA and CE Mark approval of its next-generation Xience Skypoint stent in high-bleeding risk patients with 1-month DAPT.
“XIENCE Skypoint is easier to place and allows physicians to treat larger blood vessels through improved stent expansion that can open clogged vessels more effectively,” the company said.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration, Abbott announced on June 30.
Patients who receive stents are typically on DAPT regimens such as aspirin and P2Y12 inhibitors for 6 to 12 months to prevent blood clots, but high-bleeding risk patients can experience bleeding during prolonged DAPT.
“The new FDA approval for DAPT for the XIENCE family of stents provides interventional cardiologists confidence they are delivering the best care to patients with high bleeding risk. A short DAPT duration minimizes risks for high bleeding risk patients and allows them to return to daily life sooner and with more assurance,” Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York and the global principal investigator for Abbott’s Short DAPT program (XIENCE 28 and XIENCE 90), said in a news release.
The new labeling comes on the heels of European CE Mark approval for the Xience stents with DAPT as short as 28 days, “giving Xience stents the shortest DAPT indication in the world,” the company noted.
Results of the XIENCE 28 trial were used to support the new CE Mark DAPT indication. The trial showed no increase in death of myocardial infarction between 1 and 6 months and a significantly lower risk for severe bleeding with the Xience stent and 1-month DAPT, compared with 6-month DAPT in more than 1,600 high-bleeding risk patients.
The XIENCE 90 trial involving more than 2,000 high-bleeding risk patients reported no difference in death or MI between 3 and 12 months with Xience and 3-month DAPT versus 12-month DAPT.
Abbott scored a second win, also announcing FDA and CE Mark approval of its next-generation Xience Skypoint stent in high-bleeding risk patients with 1-month DAPT.
“XIENCE Skypoint is easier to place and allows physicians to treat larger blood vessels through improved stent expansion that can open clogged vessels more effectively,” the company said.
A version of this article first appeared on Medscape.com.
The U.S. Food and Drug Administration, Abbott announced on June 30.
Patients who receive stents are typically on DAPT regimens such as aspirin and P2Y12 inhibitors for 6 to 12 months to prevent blood clots, but high-bleeding risk patients can experience bleeding during prolonged DAPT.
“The new FDA approval for DAPT for the XIENCE family of stents provides interventional cardiologists confidence they are delivering the best care to patients with high bleeding risk. A short DAPT duration minimizes risks for high bleeding risk patients and allows them to return to daily life sooner and with more assurance,” Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York and the global principal investigator for Abbott’s Short DAPT program (XIENCE 28 and XIENCE 90), said in a news release.
The new labeling comes on the heels of European CE Mark approval for the Xience stents with DAPT as short as 28 days, “giving Xience stents the shortest DAPT indication in the world,” the company noted.
Results of the XIENCE 28 trial were used to support the new CE Mark DAPT indication. The trial showed no increase in death of myocardial infarction between 1 and 6 months and a significantly lower risk for severe bleeding with the Xience stent and 1-month DAPT, compared with 6-month DAPT in more than 1,600 high-bleeding risk patients.
The XIENCE 90 trial involving more than 2,000 high-bleeding risk patients reported no difference in death or MI between 3 and 12 months with Xience and 3-month DAPT versus 12-month DAPT.
Abbott scored a second win, also announcing FDA and CE Mark approval of its next-generation Xience Skypoint stent in high-bleeding risk patients with 1-month DAPT.
“XIENCE Skypoint is easier to place and allows physicians to treat larger blood vessels through improved stent expansion that can open clogged vessels more effectively,” the company said.
A version of this article first appeared on Medscape.com.
Midlife change in wealth may be costly for heart health
It found that upward wealth mobility relative to peers was independently associated with protection against cardiovascular disease after age 65. In contrast, downward wealth mobility during middle age was linked to an increased risk of adverse cardiovascular events.
“A lot of studies have shown an inverse relationship between wealth and health in cross section at a single timepoint. What we really wanted to understand is whether this risk is modifiable and if this relationship changes over time,” senior author Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview.
The results were published online June 15 in JAMA Cardiology.
For the primary analysis, the researchers collected data from 5,579 U.S. adults aged 50 years and older with no known cardiovascular disease at baseline who participated in the RAND Health and Retirement Study, a longitudinal survey that measures changes in health and wealth every 2 years. The participants had been interviewed in at least two of three 5-year age intervals (50-54, 55-59, 60-64 years) and had follow-up data available after age 65. Survey data from Jan. 1, 1992 to Dec. 31, 2016 was used.
Participants were grouped into quintiles based on wealth, defined as total nonhousing assets in 2012 U.S. dollars, and were further stratified by birth cohort (1931-1935, 1936-1940, 1941-1945, 1946-1950). Upward relative wealth mobility involved an increase of one or more wealth quintiles during the observation period, while downward relative wealth mobility was defined as a decrease of one or more wealth quintiles. Participants who remained in the same quintile were described as having stable wealth.
Across the birth cohorts, the bottom wealth quintile ranged from -$581,447 to $7,460 and the top wealth quintile ranged from $327,064 to $22,661,450.
Over a mean 16.9 years of follow-up, the primary outcome of cardiovascular death or a nonfatal cardiovascular event such as a heart attack or stroke occurred in 1,336 participants, including 22.5% whose wealth increased by one quintile versus 28.1% whose wealth decreased by one quintile.
In adjusted analyses, higher initial wealth was associated with lower cardiovascular risk after turning 65 (adjusted hazard ratio per quintile, 0.89; 95% confidence interval, 0.84-0.95; P = .001). Additionally, experiencing relative upward wealth mobility by at least one quintile was independently associated with a lower risk of a nonfatal cardiovascular event or cardiovascular death, compared with stable wealth (aHR, 0.84; 95% CI, 0.73-0.97; P = .02).
Downward wealth mobility was associated with worse cardiovascular outcomes (aHR, 1.15; 95% CI, 1.00-1.32; P = .046). This effect was also observed on the risk of cardiovascular death in a secondary analysis of 3,360 participants who had a previous history of cardiovascular disease (aHR, 1.48; 95% CI, 1.13-1.93; P = .004).
“We estimate that each $100,000 increase in wealth was associated with a roughly 1% lower hazard of cardiovascular outcome in follow-up,” the authors write.
The protective effect of wealth on cardiovascular health may be the result of factors such as “better access to care, having more time to adhere to a healthier diet or exercise regularly, and reduced stress,” Kiarri Kershaw, PhD, a social epidemiologist at Northwestern University, Chicago, said in an interview. Dr. Kershaw, who was not involved in the study, added that “stress can affect health through both biological and behavioral pathways.”
The study did not find a statistical relationship between race, wealth, and health. However, it was observed that the overall risk of cardiovascular events among non-Hispanic Black and Black participants was lower. The authors noted that “these findings are likely a byproduct of collider bias, in which Black and Hispanic participants who experience downward wealth mobility are more likely to experience barriers to care and subsequently less likely to receive a diagnosis of cardiovascular disease.”
Moving forward, the researchers plan to investigate health policy interventions that “best promote and sustain economic opportunity and wealth formed among low-income individuals,” Dr. Vaduganathan said.
The study was funded independently. Dr. Vaduganathan and Dr. Kershaw have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
It found that upward wealth mobility relative to peers was independently associated with protection against cardiovascular disease after age 65. In contrast, downward wealth mobility during middle age was linked to an increased risk of adverse cardiovascular events.
“A lot of studies have shown an inverse relationship between wealth and health in cross section at a single timepoint. What we really wanted to understand is whether this risk is modifiable and if this relationship changes over time,” senior author Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview.
The results were published online June 15 in JAMA Cardiology.
For the primary analysis, the researchers collected data from 5,579 U.S. adults aged 50 years and older with no known cardiovascular disease at baseline who participated in the RAND Health and Retirement Study, a longitudinal survey that measures changes in health and wealth every 2 years. The participants had been interviewed in at least two of three 5-year age intervals (50-54, 55-59, 60-64 years) and had follow-up data available after age 65. Survey data from Jan. 1, 1992 to Dec. 31, 2016 was used.
Participants were grouped into quintiles based on wealth, defined as total nonhousing assets in 2012 U.S. dollars, and were further stratified by birth cohort (1931-1935, 1936-1940, 1941-1945, 1946-1950). Upward relative wealth mobility involved an increase of one or more wealth quintiles during the observation period, while downward relative wealth mobility was defined as a decrease of one or more wealth quintiles. Participants who remained in the same quintile were described as having stable wealth.
Across the birth cohorts, the bottom wealth quintile ranged from -$581,447 to $7,460 and the top wealth quintile ranged from $327,064 to $22,661,450.
Over a mean 16.9 years of follow-up, the primary outcome of cardiovascular death or a nonfatal cardiovascular event such as a heart attack or stroke occurred in 1,336 participants, including 22.5% whose wealth increased by one quintile versus 28.1% whose wealth decreased by one quintile.
In adjusted analyses, higher initial wealth was associated with lower cardiovascular risk after turning 65 (adjusted hazard ratio per quintile, 0.89; 95% confidence interval, 0.84-0.95; P = .001). Additionally, experiencing relative upward wealth mobility by at least one quintile was independently associated with a lower risk of a nonfatal cardiovascular event or cardiovascular death, compared with stable wealth (aHR, 0.84; 95% CI, 0.73-0.97; P = .02).
Downward wealth mobility was associated with worse cardiovascular outcomes (aHR, 1.15; 95% CI, 1.00-1.32; P = .046). This effect was also observed on the risk of cardiovascular death in a secondary analysis of 3,360 participants who had a previous history of cardiovascular disease (aHR, 1.48; 95% CI, 1.13-1.93; P = .004).
“We estimate that each $100,000 increase in wealth was associated with a roughly 1% lower hazard of cardiovascular outcome in follow-up,” the authors write.
The protective effect of wealth on cardiovascular health may be the result of factors such as “better access to care, having more time to adhere to a healthier diet or exercise regularly, and reduced stress,” Kiarri Kershaw, PhD, a social epidemiologist at Northwestern University, Chicago, said in an interview. Dr. Kershaw, who was not involved in the study, added that “stress can affect health through both biological and behavioral pathways.”
The study did not find a statistical relationship between race, wealth, and health. However, it was observed that the overall risk of cardiovascular events among non-Hispanic Black and Black participants was lower. The authors noted that “these findings are likely a byproduct of collider bias, in which Black and Hispanic participants who experience downward wealth mobility are more likely to experience barriers to care and subsequently less likely to receive a diagnosis of cardiovascular disease.”
Moving forward, the researchers plan to investigate health policy interventions that “best promote and sustain economic opportunity and wealth formed among low-income individuals,” Dr. Vaduganathan said.
The study was funded independently. Dr. Vaduganathan and Dr. Kershaw have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
It found that upward wealth mobility relative to peers was independently associated with protection against cardiovascular disease after age 65. In contrast, downward wealth mobility during middle age was linked to an increased risk of adverse cardiovascular events.
“A lot of studies have shown an inverse relationship between wealth and health in cross section at a single timepoint. What we really wanted to understand is whether this risk is modifiable and if this relationship changes over time,” senior author Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview.
The results were published online June 15 in JAMA Cardiology.
For the primary analysis, the researchers collected data from 5,579 U.S. adults aged 50 years and older with no known cardiovascular disease at baseline who participated in the RAND Health and Retirement Study, a longitudinal survey that measures changes in health and wealth every 2 years. The participants had been interviewed in at least two of three 5-year age intervals (50-54, 55-59, 60-64 years) and had follow-up data available after age 65. Survey data from Jan. 1, 1992 to Dec. 31, 2016 was used.
Participants were grouped into quintiles based on wealth, defined as total nonhousing assets in 2012 U.S. dollars, and were further stratified by birth cohort (1931-1935, 1936-1940, 1941-1945, 1946-1950). Upward relative wealth mobility involved an increase of one or more wealth quintiles during the observation period, while downward relative wealth mobility was defined as a decrease of one or more wealth quintiles. Participants who remained in the same quintile were described as having stable wealth.
Across the birth cohorts, the bottom wealth quintile ranged from -$581,447 to $7,460 and the top wealth quintile ranged from $327,064 to $22,661,450.
Over a mean 16.9 years of follow-up, the primary outcome of cardiovascular death or a nonfatal cardiovascular event such as a heart attack or stroke occurred in 1,336 participants, including 22.5% whose wealth increased by one quintile versus 28.1% whose wealth decreased by one quintile.
In adjusted analyses, higher initial wealth was associated with lower cardiovascular risk after turning 65 (adjusted hazard ratio per quintile, 0.89; 95% confidence interval, 0.84-0.95; P = .001). Additionally, experiencing relative upward wealth mobility by at least one quintile was independently associated with a lower risk of a nonfatal cardiovascular event or cardiovascular death, compared with stable wealth (aHR, 0.84; 95% CI, 0.73-0.97; P = .02).
Downward wealth mobility was associated with worse cardiovascular outcomes (aHR, 1.15; 95% CI, 1.00-1.32; P = .046). This effect was also observed on the risk of cardiovascular death in a secondary analysis of 3,360 participants who had a previous history of cardiovascular disease (aHR, 1.48; 95% CI, 1.13-1.93; P = .004).
“We estimate that each $100,000 increase in wealth was associated with a roughly 1% lower hazard of cardiovascular outcome in follow-up,” the authors write.
The protective effect of wealth on cardiovascular health may be the result of factors such as “better access to care, having more time to adhere to a healthier diet or exercise regularly, and reduced stress,” Kiarri Kershaw, PhD, a social epidemiologist at Northwestern University, Chicago, said in an interview. Dr. Kershaw, who was not involved in the study, added that “stress can affect health through both biological and behavioral pathways.”
The study did not find a statistical relationship between race, wealth, and health. However, it was observed that the overall risk of cardiovascular events among non-Hispanic Black and Black participants was lower. The authors noted that “these findings are likely a byproduct of collider bias, in which Black and Hispanic participants who experience downward wealth mobility are more likely to experience barriers to care and subsequently less likely to receive a diagnosis of cardiovascular disease.”
Moving forward, the researchers plan to investigate health policy interventions that “best promote and sustain economic opportunity and wealth formed among low-income individuals,” Dr. Vaduganathan said.
The study was funded independently. Dr. Vaduganathan and Dr. Kershaw have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Infusion centers may best EDs for treating sickle cell crises
At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.
“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”
To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.
The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.
The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs.
Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.
The investigators used propensity score methodology to balance patient characteristics in the study groups.
Quick, effective pain reduction is beneficial
The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write.
Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.
The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note.
“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write.
“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.
Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote.
The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study.
“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
Infusion centers are scarce
“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.
“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.”
The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.
“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”
To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.
The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.
The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs.
Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.
The investigators used propensity score methodology to balance patient characteristics in the study groups.
Quick, effective pain reduction is beneficial
The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write.
Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.
The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note.
“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write.
“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.
Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote.
The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study.
“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
Infusion centers are scarce
“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.
“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.”
The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.
“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”
To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.
The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.
The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs.
Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.
The investigators used propensity score methodology to balance patient characteristics in the study groups.
Quick, effective pain reduction is beneficial
The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write.
Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.
The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note.
“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write.
“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.
Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote.
The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study.
“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
Infusion centers are scarce
“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.
“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.”
The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
New details of myocarditis linked to COVID vaccines
Further details from multiple cases of myocarditis linked to the Pfizer and Moderna mRNA COVID vaccines have been described in recent papers in the medical literature.
The cases appear to occur almost exclusively in males and most often in younger age groups. While symptoms and signs of myocarditis mostly resolved with a few days of supportive care, long-term effects are unknown at present.
The authors of all the reports and of two accompanying editorials in JAMA Cardiology are unanimous in their opinion that the benefits of vaccination still outweigh the risks.
The Centers for Disease Control and Prevention’s but committee members delivered a strong endorsement for continuing to vaccinate young people with the mRNA vaccines.
The current case reports are published in two papers in JAMA Cardiology and in three in Circulation.
U.S. military reports 23 cases
In one report in JAMA Cardiology, authors led by Jay Montgomery, MD, from Walter Reed National Military Medical Center in Bethesda, Md., described 23 cases from the U.S. Military Health System of individuals with acute myocarditis who presented within 4 days after mRNA-based COVID-19 vaccination (7 Pfizer and 16 Moderna).
All patients were male, 22 of 23 were on active duty, and the median age was 25 years (range, 20-51); 20 of the 23 cases occurred after receipt of a second dose of an mRNA COVID-19 vaccine.
The patients all presented with acute onset of marked chest pain. All patients had significantly elevated cardiac troponin levels. Among eight patients who underwent cardiac MRI (cMRI), all had findings consistent with the clinical diagnosis of myocarditis.
Additional testing did not identify other possible causes of myocarditis. All patients received brief supportive care and were recovered or recovering.
The authors reported that the military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period, and while the observed number of myocarditis cases was small, the number was “substantially higher” than expected among male military members after a second vaccine dose.
They noted that, based on historical data, among the 544,000 second doses to military members there may have been 0-10 expected myocarditis cases, but they observed 19 cases.
“All patients in this series reflect substantial similarities in demographic characteristics, proximate vaccine dose, onset interval, and character of vaccine-associated myocarditis. The consistent pattern of clinical presentation, rapid recovery, and absence of evidence of other causes support the diagnosis of hypersensitivity myocarditis,” they stated.
They added that presentation after a second vaccine dose or, in three patients, when vaccination followed SARS-CoV-2 infection, suggests that prior exposure was relevant in the hypersensitivity response.
“The spectrum of clinical presentation and reliance on patients seeking health care and on health care professionals recognizing a rare vaccine-associated adverse event limits determination of the true incidence of this condition,” the authors wrote.
They stressed that recognition of vaccine-associated myocarditis is clinically important because diagnosis impacts management, recommendations for exercise, and monitoring for cardiomyopathy.
But the authors also acknowledged that it is important to frame concerns about potential vaccine-associated myocarditis within the context of the current pandemic.
“Infection with SARS-CoV-2 is a clear cause of serious cardiac injury in many patients. ... Prevalence of cardiac injury may be as high as 60% in seriously ill patients. Notably, nearly 1% of highly fit athletes with mild COVID-19 infection have evidence of myocarditis on cMRI,” they wrote.
“Given that COVID-19 vaccines are remarkably effective at preventing infection, any risk of rare adverse events following immunization must be carefully weighed against the very substantial benefit of vaccination,” they concluded.
Four cases at Duke
In the second paper in JAMA Cardiology, a group led by Han W. Kim, MD, reported four patients with acute myocarditis occurring within days of mRNA COVID-19 vaccination (two Pfizer and two Moderna) in patients treated at Duke University Medical Center, Durham, N.C. The hospital courses of the four patients with myocarditis following COVID-19 vaccination were uneventful, and they were discharged within 2-4 days.
The authors said that, although a causal relationship cannot be established, none of the patients had a viral prodrome or had coincident testing that revealed an alternative explanation.
They stated that these four patients represent the majority of patients with acute myocarditis identified in the past 3 months at their institution, and this led to the highest total number of patients with acute myocarditis, compared with the same 3-month period for the past 5 years.
“Additionally, we identified only those patients with severe unremitting chest pain who sought medical attention. Those with mild or moderate chest pain might not seek medical attention, and it is possible that subclinical myocarditis may occur and could be detected by active surveillance, as has been described with smallpox vaccination,” they wrote.
Further case reports
In one of the papers in Circulation, a group led by Kathryn F. Larson, MD, from the Mayo Clinic in Rochester, Minn., described eight patients hospitalized with chest pain who were diagnosed with myocarditis within 2-4 days of receiving either the Pfizer or Moderna vaccine.
Two of the patients had previously been infected by SARS-CoV-2 without need for hospitalization. All individuals were otherwise healthy males between the ages of 21 and 56 years. All but one patient developed symptoms after their second dose, and the one patient who developed myocarditis after the first vaccine dose had previously been infected with SARS-CoV-2.
Systemic symptoms began within 24 hours after vaccine administration in five of eight patients, with chest pain presenting between 48 and 96 hours later. Troponin values were elevated in all individuals and appeared to peak the day after admission, whereas none had eosinophilia.
Cardiac MRI revealed findings consistent with myocarditis in all patients. All patients had resolution of their chest pain and were discharged from the hospital in stable condition.
“The patients presented here demonstrated typical signs, symptoms, and diagnostic features of acute myocarditis. The temporal association between receiving an mRNA-based COVID-19 vaccine and the development of myocarditis is notable,” the authors said.
They added that they would consider the use of corticosteroids in these patients but cautioned that this could reduce the specific immune response against SARS-COV-2 triggered by the vaccine. “Thus, the duration of corticosteroid administration should be limited to the resolution of the symptoms or ventricular arrhythmias or the recovery of the left ventricular ejection fraction.”
Pending publication of long-term outcome data after SARS-CoV-2 vaccine–related myocarditis, they suggest adherence to the current consensus recommendation to abstain from competitive sports for a period of 3-6 months with reevaluation prior to sports participation.
In another of the Circulation papers, a group led by Carolyn M. Rosner, MSN, presented a case series of seven patients hospitalized for acute myocarditis-like illness following COVID-19 vaccination, from two U.S. medical centers, in Falls Church, Va., and Dallas. All patients were males below the age of 40 years and of White or Hispanic race/ethnicity. Only one patient reported prior history of COVID-19 infection. Six patients received mRNA (Moderna or Pfizer) and one received the adenovirus (Johnson & Johnson) vaccine. All patients presented 3-7 days post vaccination with acute onset chest pain and biochemical evidence of myocardial injury.
Hospital length of stay was 3 days, and all patients’ symptoms resolved by hospital discharge.
And finally, the third paper in Circulation reported a detailed description of one patient – a 52-year-old, previously healthy male who presented with acute myocarditis 3 days after the administration of the second dose of Moderna’s COVID-19 vaccine. The symptoms resolved, and there was a gradual improvement in cMRI findings. Ischemic injury and other potential causes of acute myocardial injury were excluded, as were other potential infectious causes of myocarditis, and there was no evidence of systemic autoimmune disease.
“Clinicians should be aware that myocarditis may be present in patients exhibiting cardiac signs and symptoms 2-4 days after COVID-19 vaccination,” the authors said.
They added that additional surveillance of such adverse events post–COVID-19 vaccination will help identify subgroups at higher risk for this vaccine-related effect, and whether additional precautions are necessary.
‘Benefits outweigh risk’
In an accompanying editorial in JAMA Cardiology, three doctors from the CDC cite several other reports of myocarditis after mRNA COVID vaccination. These include a case report published in Pediatrics of seven male adolescents aged 14-19 years who presented with myocarditis or myopericarditis within 4 days after receipt of a second dose of the Pfizer vaccine.
But the editorialists noted that the most comprehensive data about the risk for myocarditis following immunization with mRNA vaccines comes from Israel.
The Israeli Ministry of Health recently posted data describing 121 myocarditis cases occurring within 30 days of a second dose of mRNA vaccine among 5,049,424 persons, suggesting a crude incidence rate of approximately 24 cases per million.
On the current case reports, the CDC doctors wrote: “The striking clinical similarities in the presentations of these patients, their recent vaccination with an mRNA-based COVID-19 vaccine, and the lack of any alternative etiologies for acute myocarditis suggest an association with immunization.”
They said that acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism.
But SARS-CoV-2 infection also causes cardiac injury which may result in severe outcomes, and based on currently available data, myocarditis following immunization with current mRNA-based vaccines is rare.
“At present, the benefits of immunization in preventing severe morbidity favors continued COVID-19 vaccination, particularly considering the increasing COVID-19 hospitalization rates among adolescents reported during spring 2021,” the editorialists stated.
But they added that many questions remain. These include whether modifications are needed to the vaccine schedule among persons with a history of possible or confirmed myocarditis after COVID vaccine, how should postvaccine myocarditis be managed, how often should follow-up assessments be performed, how might follow-up assessments affect recommendations to avoid vigorous physical activity following the diagnosis of myocarditis, and do all likely cases of acute myocarditis that appear to be uncomplicated require cardiac MRI for more definitive diagnosis?
“While the data needed to answer such questions are being collected, there is an opportunity for researchers with expertise in myocarditis to develop a comprehensive, national assessment of the natural history, pathogenesis, and treatment of acute myocarditis associated with receipt of mRNA-based COVID-19 vaccines,” they concluded.
In a second editorial in JAMA Cardiology, a group of editors from the journal acknowledged that publication of the current case reports may contribute to additional public concern regarding immunization. But they added that clinicians discussing immunization with patients should recognize that these case series suggest that the symptomatic events consistent with myocarditis are still very rare and appear to be self-limiting.
“Given the risks of COVID-19, including the risk of myocarditis from COVID-19 infection, the editors do not believe these case reports are sufficient to interrupt the march toward maximal vaccination against SARS-CoV-2 as expeditiously as possible,” they said.
A version of this article first appeared on Medscape.com.
Further details from multiple cases of myocarditis linked to the Pfizer and Moderna mRNA COVID vaccines have been described in recent papers in the medical literature.
The cases appear to occur almost exclusively in males and most often in younger age groups. While symptoms and signs of myocarditis mostly resolved with a few days of supportive care, long-term effects are unknown at present.
The authors of all the reports and of two accompanying editorials in JAMA Cardiology are unanimous in their opinion that the benefits of vaccination still outweigh the risks.
The Centers for Disease Control and Prevention’s but committee members delivered a strong endorsement for continuing to vaccinate young people with the mRNA vaccines.
The current case reports are published in two papers in JAMA Cardiology and in three in Circulation.
U.S. military reports 23 cases
In one report in JAMA Cardiology, authors led by Jay Montgomery, MD, from Walter Reed National Military Medical Center in Bethesda, Md., described 23 cases from the U.S. Military Health System of individuals with acute myocarditis who presented within 4 days after mRNA-based COVID-19 vaccination (7 Pfizer and 16 Moderna).
All patients were male, 22 of 23 were on active duty, and the median age was 25 years (range, 20-51); 20 of the 23 cases occurred after receipt of a second dose of an mRNA COVID-19 vaccine.
The patients all presented with acute onset of marked chest pain. All patients had significantly elevated cardiac troponin levels. Among eight patients who underwent cardiac MRI (cMRI), all had findings consistent with the clinical diagnosis of myocarditis.
Additional testing did not identify other possible causes of myocarditis. All patients received brief supportive care and were recovered or recovering.
The authors reported that the military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period, and while the observed number of myocarditis cases was small, the number was “substantially higher” than expected among male military members after a second vaccine dose.
They noted that, based on historical data, among the 544,000 second doses to military members there may have been 0-10 expected myocarditis cases, but they observed 19 cases.
“All patients in this series reflect substantial similarities in demographic characteristics, proximate vaccine dose, onset interval, and character of vaccine-associated myocarditis. The consistent pattern of clinical presentation, rapid recovery, and absence of evidence of other causes support the diagnosis of hypersensitivity myocarditis,” they stated.
They added that presentation after a second vaccine dose or, in three patients, when vaccination followed SARS-CoV-2 infection, suggests that prior exposure was relevant in the hypersensitivity response.
“The spectrum of clinical presentation and reliance on patients seeking health care and on health care professionals recognizing a rare vaccine-associated adverse event limits determination of the true incidence of this condition,” the authors wrote.
They stressed that recognition of vaccine-associated myocarditis is clinically important because diagnosis impacts management, recommendations for exercise, and monitoring for cardiomyopathy.
But the authors also acknowledged that it is important to frame concerns about potential vaccine-associated myocarditis within the context of the current pandemic.
“Infection with SARS-CoV-2 is a clear cause of serious cardiac injury in many patients. ... Prevalence of cardiac injury may be as high as 60% in seriously ill patients. Notably, nearly 1% of highly fit athletes with mild COVID-19 infection have evidence of myocarditis on cMRI,” they wrote.
“Given that COVID-19 vaccines are remarkably effective at preventing infection, any risk of rare adverse events following immunization must be carefully weighed against the very substantial benefit of vaccination,” they concluded.
Four cases at Duke
In the second paper in JAMA Cardiology, a group led by Han W. Kim, MD, reported four patients with acute myocarditis occurring within days of mRNA COVID-19 vaccination (two Pfizer and two Moderna) in patients treated at Duke University Medical Center, Durham, N.C. The hospital courses of the four patients with myocarditis following COVID-19 vaccination were uneventful, and they were discharged within 2-4 days.
The authors said that, although a causal relationship cannot be established, none of the patients had a viral prodrome or had coincident testing that revealed an alternative explanation.
They stated that these four patients represent the majority of patients with acute myocarditis identified in the past 3 months at their institution, and this led to the highest total number of patients with acute myocarditis, compared with the same 3-month period for the past 5 years.
“Additionally, we identified only those patients with severe unremitting chest pain who sought medical attention. Those with mild or moderate chest pain might not seek medical attention, and it is possible that subclinical myocarditis may occur and could be detected by active surveillance, as has been described with smallpox vaccination,” they wrote.
Further case reports
In one of the papers in Circulation, a group led by Kathryn F. Larson, MD, from the Mayo Clinic in Rochester, Minn., described eight patients hospitalized with chest pain who were diagnosed with myocarditis within 2-4 days of receiving either the Pfizer or Moderna vaccine.
Two of the patients had previously been infected by SARS-CoV-2 without need for hospitalization. All individuals were otherwise healthy males between the ages of 21 and 56 years. All but one patient developed symptoms after their second dose, and the one patient who developed myocarditis after the first vaccine dose had previously been infected with SARS-CoV-2.
Systemic symptoms began within 24 hours after vaccine administration in five of eight patients, with chest pain presenting between 48 and 96 hours later. Troponin values were elevated in all individuals and appeared to peak the day after admission, whereas none had eosinophilia.
Cardiac MRI revealed findings consistent with myocarditis in all patients. All patients had resolution of their chest pain and were discharged from the hospital in stable condition.
“The patients presented here demonstrated typical signs, symptoms, and diagnostic features of acute myocarditis. The temporal association between receiving an mRNA-based COVID-19 vaccine and the development of myocarditis is notable,” the authors said.
They added that they would consider the use of corticosteroids in these patients but cautioned that this could reduce the specific immune response against SARS-COV-2 triggered by the vaccine. “Thus, the duration of corticosteroid administration should be limited to the resolution of the symptoms or ventricular arrhythmias or the recovery of the left ventricular ejection fraction.”
Pending publication of long-term outcome data after SARS-CoV-2 vaccine–related myocarditis, they suggest adherence to the current consensus recommendation to abstain from competitive sports for a period of 3-6 months with reevaluation prior to sports participation.
In another of the Circulation papers, a group led by Carolyn M. Rosner, MSN, presented a case series of seven patients hospitalized for acute myocarditis-like illness following COVID-19 vaccination, from two U.S. medical centers, in Falls Church, Va., and Dallas. All patients were males below the age of 40 years and of White or Hispanic race/ethnicity. Only one patient reported prior history of COVID-19 infection. Six patients received mRNA (Moderna or Pfizer) and one received the adenovirus (Johnson & Johnson) vaccine. All patients presented 3-7 days post vaccination with acute onset chest pain and biochemical evidence of myocardial injury.
Hospital length of stay was 3 days, and all patients’ symptoms resolved by hospital discharge.
And finally, the third paper in Circulation reported a detailed description of one patient – a 52-year-old, previously healthy male who presented with acute myocarditis 3 days after the administration of the second dose of Moderna’s COVID-19 vaccine. The symptoms resolved, and there was a gradual improvement in cMRI findings. Ischemic injury and other potential causes of acute myocardial injury were excluded, as were other potential infectious causes of myocarditis, and there was no evidence of systemic autoimmune disease.
“Clinicians should be aware that myocarditis may be present in patients exhibiting cardiac signs and symptoms 2-4 days after COVID-19 vaccination,” the authors said.
They added that additional surveillance of such adverse events post–COVID-19 vaccination will help identify subgroups at higher risk for this vaccine-related effect, and whether additional precautions are necessary.
‘Benefits outweigh risk’
In an accompanying editorial in JAMA Cardiology, three doctors from the CDC cite several other reports of myocarditis after mRNA COVID vaccination. These include a case report published in Pediatrics of seven male adolescents aged 14-19 years who presented with myocarditis or myopericarditis within 4 days after receipt of a second dose of the Pfizer vaccine.
But the editorialists noted that the most comprehensive data about the risk for myocarditis following immunization with mRNA vaccines comes from Israel.
The Israeli Ministry of Health recently posted data describing 121 myocarditis cases occurring within 30 days of a second dose of mRNA vaccine among 5,049,424 persons, suggesting a crude incidence rate of approximately 24 cases per million.
On the current case reports, the CDC doctors wrote: “The striking clinical similarities in the presentations of these patients, their recent vaccination with an mRNA-based COVID-19 vaccine, and the lack of any alternative etiologies for acute myocarditis suggest an association with immunization.”
They said that acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism.
But SARS-CoV-2 infection also causes cardiac injury which may result in severe outcomes, and based on currently available data, myocarditis following immunization with current mRNA-based vaccines is rare.
“At present, the benefits of immunization in preventing severe morbidity favors continued COVID-19 vaccination, particularly considering the increasing COVID-19 hospitalization rates among adolescents reported during spring 2021,” the editorialists stated.
But they added that many questions remain. These include whether modifications are needed to the vaccine schedule among persons with a history of possible or confirmed myocarditis after COVID vaccine, how should postvaccine myocarditis be managed, how often should follow-up assessments be performed, how might follow-up assessments affect recommendations to avoid vigorous physical activity following the diagnosis of myocarditis, and do all likely cases of acute myocarditis that appear to be uncomplicated require cardiac MRI for more definitive diagnosis?
“While the data needed to answer such questions are being collected, there is an opportunity for researchers with expertise in myocarditis to develop a comprehensive, national assessment of the natural history, pathogenesis, and treatment of acute myocarditis associated with receipt of mRNA-based COVID-19 vaccines,” they concluded.
In a second editorial in JAMA Cardiology, a group of editors from the journal acknowledged that publication of the current case reports may contribute to additional public concern regarding immunization. But they added that clinicians discussing immunization with patients should recognize that these case series suggest that the symptomatic events consistent with myocarditis are still very rare and appear to be self-limiting.
“Given the risks of COVID-19, including the risk of myocarditis from COVID-19 infection, the editors do not believe these case reports are sufficient to interrupt the march toward maximal vaccination against SARS-CoV-2 as expeditiously as possible,” they said.
A version of this article first appeared on Medscape.com.
Further details from multiple cases of myocarditis linked to the Pfizer and Moderna mRNA COVID vaccines have been described in recent papers in the medical literature.
The cases appear to occur almost exclusively in males and most often in younger age groups. While symptoms and signs of myocarditis mostly resolved with a few days of supportive care, long-term effects are unknown at present.
The authors of all the reports and of two accompanying editorials in JAMA Cardiology are unanimous in their opinion that the benefits of vaccination still outweigh the risks.
The Centers for Disease Control and Prevention’s but committee members delivered a strong endorsement for continuing to vaccinate young people with the mRNA vaccines.
The current case reports are published in two papers in JAMA Cardiology and in three in Circulation.
U.S. military reports 23 cases
In one report in JAMA Cardiology, authors led by Jay Montgomery, MD, from Walter Reed National Military Medical Center in Bethesda, Md., described 23 cases from the U.S. Military Health System of individuals with acute myocarditis who presented within 4 days after mRNA-based COVID-19 vaccination (7 Pfizer and 16 Moderna).
All patients were male, 22 of 23 were on active duty, and the median age was 25 years (range, 20-51); 20 of the 23 cases occurred after receipt of a second dose of an mRNA COVID-19 vaccine.
The patients all presented with acute onset of marked chest pain. All patients had significantly elevated cardiac troponin levels. Among eight patients who underwent cardiac MRI (cMRI), all had findings consistent with the clinical diagnosis of myocarditis.
Additional testing did not identify other possible causes of myocarditis. All patients received brief supportive care and were recovered or recovering.
The authors reported that the military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period, and while the observed number of myocarditis cases was small, the number was “substantially higher” than expected among male military members after a second vaccine dose.
They noted that, based on historical data, among the 544,000 second doses to military members there may have been 0-10 expected myocarditis cases, but they observed 19 cases.
“All patients in this series reflect substantial similarities in demographic characteristics, proximate vaccine dose, onset interval, and character of vaccine-associated myocarditis. The consistent pattern of clinical presentation, rapid recovery, and absence of evidence of other causes support the diagnosis of hypersensitivity myocarditis,” they stated.
They added that presentation after a second vaccine dose or, in three patients, when vaccination followed SARS-CoV-2 infection, suggests that prior exposure was relevant in the hypersensitivity response.
“The spectrum of clinical presentation and reliance on patients seeking health care and on health care professionals recognizing a rare vaccine-associated adverse event limits determination of the true incidence of this condition,” the authors wrote.
They stressed that recognition of vaccine-associated myocarditis is clinically important because diagnosis impacts management, recommendations for exercise, and monitoring for cardiomyopathy.
But the authors also acknowledged that it is important to frame concerns about potential vaccine-associated myocarditis within the context of the current pandemic.
“Infection with SARS-CoV-2 is a clear cause of serious cardiac injury in many patients. ... Prevalence of cardiac injury may be as high as 60% in seriously ill patients. Notably, nearly 1% of highly fit athletes with mild COVID-19 infection have evidence of myocarditis on cMRI,” they wrote.
“Given that COVID-19 vaccines are remarkably effective at preventing infection, any risk of rare adverse events following immunization must be carefully weighed against the very substantial benefit of vaccination,” they concluded.
Four cases at Duke
In the second paper in JAMA Cardiology, a group led by Han W. Kim, MD, reported four patients with acute myocarditis occurring within days of mRNA COVID-19 vaccination (two Pfizer and two Moderna) in patients treated at Duke University Medical Center, Durham, N.C. The hospital courses of the four patients with myocarditis following COVID-19 vaccination were uneventful, and they were discharged within 2-4 days.
The authors said that, although a causal relationship cannot be established, none of the patients had a viral prodrome or had coincident testing that revealed an alternative explanation.
They stated that these four patients represent the majority of patients with acute myocarditis identified in the past 3 months at their institution, and this led to the highest total number of patients with acute myocarditis, compared with the same 3-month period for the past 5 years.
“Additionally, we identified only those patients with severe unremitting chest pain who sought medical attention. Those with mild or moderate chest pain might not seek medical attention, and it is possible that subclinical myocarditis may occur and could be detected by active surveillance, as has been described with smallpox vaccination,” they wrote.
Further case reports
In one of the papers in Circulation, a group led by Kathryn F. Larson, MD, from the Mayo Clinic in Rochester, Minn., described eight patients hospitalized with chest pain who were diagnosed with myocarditis within 2-4 days of receiving either the Pfizer or Moderna vaccine.
Two of the patients had previously been infected by SARS-CoV-2 without need for hospitalization. All individuals were otherwise healthy males between the ages of 21 and 56 years. All but one patient developed symptoms after their second dose, and the one patient who developed myocarditis after the first vaccine dose had previously been infected with SARS-CoV-2.
Systemic symptoms began within 24 hours after vaccine administration in five of eight patients, with chest pain presenting between 48 and 96 hours later. Troponin values were elevated in all individuals and appeared to peak the day after admission, whereas none had eosinophilia.
Cardiac MRI revealed findings consistent with myocarditis in all patients. All patients had resolution of their chest pain and were discharged from the hospital in stable condition.
“The patients presented here demonstrated typical signs, symptoms, and diagnostic features of acute myocarditis. The temporal association between receiving an mRNA-based COVID-19 vaccine and the development of myocarditis is notable,” the authors said.
They added that they would consider the use of corticosteroids in these patients but cautioned that this could reduce the specific immune response against SARS-COV-2 triggered by the vaccine. “Thus, the duration of corticosteroid administration should be limited to the resolution of the symptoms or ventricular arrhythmias or the recovery of the left ventricular ejection fraction.”
Pending publication of long-term outcome data after SARS-CoV-2 vaccine–related myocarditis, they suggest adherence to the current consensus recommendation to abstain from competitive sports for a period of 3-6 months with reevaluation prior to sports participation.
In another of the Circulation papers, a group led by Carolyn M. Rosner, MSN, presented a case series of seven patients hospitalized for acute myocarditis-like illness following COVID-19 vaccination, from two U.S. medical centers, in Falls Church, Va., and Dallas. All patients were males below the age of 40 years and of White or Hispanic race/ethnicity. Only one patient reported prior history of COVID-19 infection. Six patients received mRNA (Moderna or Pfizer) and one received the adenovirus (Johnson & Johnson) vaccine. All patients presented 3-7 days post vaccination with acute onset chest pain and biochemical evidence of myocardial injury.
Hospital length of stay was 3 days, and all patients’ symptoms resolved by hospital discharge.
And finally, the third paper in Circulation reported a detailed description of one patient – a 52-year-old, previously healthy male who presented with acute myocarditis 3 days after the administration of the second dose of Moderna’s COVID-19 vaccine. The symptoms resolved, and there was a gradual improvement in cMRI findings. Ischemic injury and other potential causes of acute myocardial injury were excluded, as were other potential infectious causes of myocarditis, and there was no evidence of systemic autoimmune disease.
“Clinicians should be aware that myocarditis may be present in patients exhibiting cardiac signs and symptoms 2-4 days after COVID-19 vaccination,” the authors said.
They added that additional surveillance of such adverse events post–COVID-19 vaccination will help identify subgroups at higher risk for this vaccine-related effect, and whether additional precautions are necessary.
‘Benefits outweigh risk’
In an accompanying editorial in JAMA Cardiology, three doctors from the CDC cite several other reports of myocarditis after mRNA COVID vaccination. These include a case report published in Pediatrics of seven male adolescents aged 14-19 years who presented with myocarditis or myopericarditis within 4 days after receipt of a second dose of the Pfizer vaccine.
But the editorialists noted that the most comprehensive data about the risk for myocarditis following immunization with mRNA vaccines comes from Israel.
The Israeli Ministry of Health recently posted data describing 121 myocarditis cases occurring within 30 days of a second dose of mRNA vaccine among 5,049,424 persons, suggesting a crude incidence rate of approximately 24 cases per million.
On the current case reports, the CDC doctors wrote: “The striking clinical similarities in the presentations of these patients, their recent vaccination with an mRNA-based COVID-19 vaccine, and the lack of any alternative etiologies for acute myocarditis suggest an association with immunization.”
They said that acute onset of chest pain 3-5 days after vaccine administration, usually after a second dose, is a typical feature of reported cases and suggests an immune-mediated mechanism.
But SARS-CoV-2 infection also causes cardiac injury which may result in severe outcomes, and based on currently available data, myocarditis following immunization with current mRNA-based vaccines is rare.
“At present, the benefits of immunization in preventing severe morbidity favors continued COVID-19 vaccination, particularly considering the increasing COVID-19 hospitalization rates among adolescents reported during spring 2021,” the editorialists stated.
But they added that many questions remain. These include whether modifications are needed to the vaccine schedule among persons with a history of possible or confirmed myocarditis after COVID vaccine, how should postvaccine myocarditis be managed, how often should follow-up assessments be performed, how might follow-up assessments affect recommendations to avoid vigorous physical activity following the diagnosis of myocarditis, and do all likely cases of acute myocarditis that appear to be uncomplicated require cardiac MRI for more definitive diagnosis?
“While the data needed to answer such questions are being collected, there is an opportunity for researchers with expertise in myocarditis to develop a comprehensive, national assessment of the natural history, pathogenesis, and treatment of acute myocarditis associated with receipt of mRNA-based COVID-19 vaccines,” they concluded.
In a second editorial in JAMA Cardiology, a group of editors from the journal acknowledged that publication of the current case reports may contribute to additional public concern regarding immunization. But they added that clinicians discussing immunization with patients should recognize that these case series suggest that the symptomatic events consistent with myocarditis are still very rare and appear to be self-limiting.
“Given the risks of COVID-19, including the risk of myocarditis from COVID-19 infection, the editors do not believe these case reports are sufficient to interrupt the march toward maximal vaccination against SARS-CoV-2 as expeditiously as possible,” they said.
A version of this article first appeared on Medscape.com.
What’s best for diabetes after metformin? GRADE outdated at outset
Liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin for treating patients with type 2 diabetes in a multicenter U.S. trial that randomized just over 5,000 patients.
. Results were reported at the virtual American Diabetes Association (ADA) 81st Scientific Sessions.
The comparison included two oral medications – the sulfonylurea glimepiride and dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin – and two injectable medications – insulin glargine and glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide.
The primary endpoint was change in A1c level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, renal, gastrointestinal, and other complications.
For the primary endpoint – keeping A1c levels below 7% – liraglutide and the basal insulin glargine both did this best and were almost equivalent.
During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were 67% among patients randomized to insulin glargine, 68% maintained on liraglutide, 72% taking the sulfonylurea glimepiride, and 77% taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University, Washington.
Too soon for take-aways, or are the data already obsolete?
“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” noted David M. Nathan, MD, chair of the study and director of the Diabetes Center at Massachusetts General Hospital, in an ADA press release.
Dr. Nathan, as well as several other members of the GRADE trial steering committee who presented results, repeatedly cautioned that the findings were preliminary because they represent 90% of outcomes, with the remaining 10% still to be adjudicated.
“We undertook this study to fill a gap in the guidelines,” said investigator Deborah J. Wexler, MD, clinical director of the Diabetes Center at Massachusetts General Hospital in Boston. “I would like to have all the results in ... before I comment on how the guidelines should change.”
“The metabolic data are solid, but the cardiovascular disease data are preliminary,” warned Dr. Nathan.
But that didn’t stop some from drawing their own conclusions, with Julio Rosenstock, MD, who comoderated the session but was not involved with the study, giving his own opinion.
“A pleasant surprise was the performance of basal insulin,” he said, calling the findings “a vindication” for basal insulin as a treatment for the types of patients with type 2 diabetes that enrolled in the study.
Steven E. Kahn, MB, ChB, another GRADE co-investigator agreed. “Based on the results, guidelines should say that you add insulin early on,” he observed.
A generic basal insulin and a generic sulfonylurea are both reasonable options, after metformin, for patients with limited resources, added Dr. Kahn, an endocrinologist and professor at the University of Washington, Seattle.
Dr. Rosenstock, director of the Dallas Diabetes Research Center, also saw the results as an indictment of agents in the DDP-4 inhibitor class, such as sitagliptin.
The DPP-4 inhibitors generate $9 billion a year, he said, wondering whether it “is justifiable to put them on the same level as other agents?”
Meanwhile the assigned discussant, David R. Matthews, DPhil, a professor of diabetes medicine at the University of Oxford, England – while congratulating the investigators on certain aspects of the study – said it ultimately fell short because it didn’t include an arm with an SGLT2 inhibitor.
“We should kick the authors for missing out on SGLT2 inhibitors,” Dr. Matthews said. “The omission means that the GRADE data are already obsolescent.”
In reply, Dr. Nathan admitted “we feel bad we did not include” an SGLT2 inhibitor, but he vigorously defended the dilemma faced by the trial’s organizers.
Oral SGLT2 inhibitors were not “well-established drugs” for type 2 diabetes when enrollment launched in 2013, and the researchers were wary of including what could turn out to be a problematic agent soon after controversy over the safety of agents in the thiazolidinedione drug class (such as rosiglitazone), he explained.
They also realized that adding a fifth drug to the study would necessitate doubling enrollment size, which would have undercut the funding plans already in place.
Dr. Matthews also derided GRADE as being underpowered to adequately address the impact of the tested agents on major adverse cardiovascular events (MACE) and hospitalizations for heart failure and too U.S.-centric to be generalizable elsewhere.
A study with lots of data
The roughly 5,000 patients enrolled in GRADE were an average age of 57 years old, 64% were men, 66% were White, and 20% were Black. They had had type 2 diabetes, on average, for 4.2 years. Mean body mass index at entry was about 34 kg/m2, average A1c was 7.5%, and average estimated glomerular filtration rate was 95 mL/min/1.73m2. The trial included a 6-12 week run-in period during which background metformin treatment was optimized and led to average A1c levels less than 7%.
Patients were then randomized to one of the four agents as add-on treatment.
Both liraglutide and insulin glargine performed well on many of the numerous metrics in the data-rich trial, largely funded by two branches of the National Institutes of Health, with commercial involvement limited to free supplies of the study drugs.
The secondary metabolic outcome, of disease progressing to a confirmed A1c of 7.5%, was reached by 39% of patients taking insulin glargine, significantly lower than the rate of 46% among patients taking liraglutide, and that rate, in turn, was significantly below the 50% rate among patients taking glimepiride and the 55% rate of those taking sitagliptin.
Mean doses of the second-line agents after 4 years of treatment were 38.3 units/day for glargine, 3.5 mg/day for glimepiride, 1.3 mg/day for subcutaneous liraglutide, and 82.9 mg/day for sitagliptin.
A trio of cardiovascular outcomes showed one significant benefit of liraglutide over the other three drugs for the endpoint of any cardiovascular event, which included not only major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke), but also several other event types, including heart failure requiring hospitalization, unstable angina requiring hospitalization, revascularization or any arterial repairs, stent thrombosis, or transient ischemic attack.
For the endpoint of any cardiovascular event, the rate was 5.8% for patients taking liraglutide, significantly less than the rate of 7.6% of those taking insulin glargine, 8.0% for glimepiride, and 8.6% for sitagliptin, reported John B. Buse, MD, PhD, professor, chief of endocrinology, and director of the Diabetes Center at the University of North Carolina at Chapel Hill.
For each of the other two main cardiovascular endpoints – MACE and hospitalization for heart failure – liraglutide had a numeric advantage over the other three drugs but failed to reach significance.
Patients taking liraglutide also had a smaller but not significantly different point estimate for all-cause death, at 2.1%, compared with 3.1%-3.4% in the other three groups.
And, Dr. Nathan emphasized, the cardiovascular disease data are still considered preliminary.
Liraglutide scored a pair of additional outcome victories. Its use resulted in a significantly lower rate of patients who progressed during follow-up to either needing antihypertensive medications or having their blood pressure rise above 140/90 mm Hg compared with the other three drugs. (At baseline, average blood pressure for all patients was 128/77 mm Hg.)
And after 4 years, patients taking liraglutide lost an average of about 4 kg (8.8 lb) from their baseline weight (which averaged about 100 kg [220 lb]), roughly the same as patients taking sitagliptin but significantly better than with glimepiride or insulin glargine. Patients taking glargine gained a small amount of weight on average during their first couple of years of treatment, roughly 1 kg, but returned to around their baseline weight by the end of 4 years.
Four drugs performed equally well for some outcomes
Finally, the four drugs had similar results for some outcomes. This included their effects on renal function, distal sensory polyneuropathy, and low-density lipoprotein (LDL) cholesterol.
The four agents also had roughly similar safety profiles, with rates of serious adverse events all falling within the tight range of 33%-37%.
But the rate of severe hypoglycemic episodes that required assistance to treat showed significant separation, ranging from 2.3% for glimepiride, 1.4% for glargine, 0.9% for liraglutide, and 0.7% for sitagliptin. Gastrointestinal symptoms occurred in about 50% of patients in three of the treatment groups but were significantly higher in those taking liraglutide, affecting 60%.
GRADE received no commercial funding. Dr. Wexler has reported serving on data monitoring committees for Novo Nordisk. Dr. Buse has reported being a consultant for and holding stock in numerous companies. Dr. Rosenstock has reported being an advisor or consultant to Applied Therapeutics, Boehringer Ingelheim, Hanmi Pharmaceutical, Intarcia Therapeutics, Lilly, Novo Nordisk, Oramed, and Sanofi and has received research support from numerous companies. Dr. Kahn has reported being an advisor to or speaker on behalf of Bayer, Boehringer Ingelheim, Casma Therapeutics, Intarcia Therapeutics, Lilly, Merck, Novo Nordisk, Pfizer, and Third Rock Ventures. Dr. Matthews has reported receiving lecture and advisor fees from Merck, Novartis, Novo Nordisk, Sanofi Aventis, and Servier. Dr. Lachin and Dr. Nathan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin for treating patients with type 2 diabetes in a multicenter U.S. trial that randomized just over 5,000 patients.
. Results were reported at the virtual American Diabetes Association (ADA) 81st Scientific Sessions.
The comparison included two oral medications – the sulfonylurea glimepiride and dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin – and two injectable medications – insulin glargine and glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide.
The primary endpoint was change in A1c level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, renal, gastrointestinal, and other complications.
For the primary endpoint – keeping A1c levels below 7% – liraglutide and the basal insulin glargine both did this best and were almost equivalent.
During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were 67% among patients randomized to insulin glargine, 68% maintained on liraglutide, 72% taking the sulfonylurea glimepiride, and 77% taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University, Washington.
Too soon for take-aways, or are the data already obsolete?
“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” noted David M. Nathan, MD, chair of the study and director of the Diabetes Center at Massachusetts General Hospital, in an ADA press release.
Dr. Nathan, as well as several other members of the GRADE trial steering committee who presented results, repeatedly cautioned that the findings were preliminary because they represent 90% of outcomes, with the remaining 10% still to be adjudicated.
“We undertook this study to fill a gap in the guidelines,” said investigator Deborah J. Wexler, MD, clinical director of the Diabetes Center at Massachusetts General Hospital in Boston. “I would like to have all the results in ... before I comment on how the guidelines should change.”
“The metabolic data are solid, but the cardiovascular disease data are preliminary,” warned Dr. Nathan.
But that didn’t stop some from drawing their own conclusions, with Julio Rosenstock, MD, who comoderated the session but was not involved with the study, giving his own opinion.
“A pleasant surprise was the performance of basal insulin,” he said, calling the findings “a vindication” for basal insulin as a treatment for the types of patients with type 2 diabetes that enrolled in the study.
Steven E. Kahn, MB, ChB, another GRADE co-investigator agreed. “Based on the results, guidelines should say that you add insulin early on,” he observed.
A generic basal insulin and a generic sulfonylurea are both reasonable options, after metformin, for patients with limited resources, added Dr. Kahn, an endocrinologist and professor at the University of Washington, Seattle.
Dr. Rosenstock, director of the Dallas Diabetes Research Center, also saw the results as an indictment of agents in the DDP-4 inhibitor class, such as sitagliptin.
The DPP-4 inhibitors generate $9 billion a year, he said, wondering whether it “is justifiable to put them on the same level as other agents?”
Meanwhile the assigned discussant, David R. Matthews, DPhil, a professor of diabetes medicine at the University of Oxford, England – while congratulating the investigators on certain aspects of the study – said it ultimately fell short because it didn’t include an arm with an SGLT2 inhibitor.
“We should kick the authors for missing out on SGLT2 inhibitors,” Dr. Matthews said. “The omission means that the GRADE data are already obsolescent.”
In reply, Dr. Nathan admitted “we feel bad we did not include” an SGLT2 inhibitor, but he vigorously defended the dilemma faced by the trial’s organizers.
Oral SGLT2 inhibitors were not “well-established drugs” for type 2 diabetes when enrollment launched in 2013, and the researchers were wary of including what could turn out to be a problematic agent soon after controversy over the safety of agents in the thiazolidinedione drug class (such as rosiglitazone), he explained.
They also realized that adding a fifth drug to the study would necessitate doubling enrollment size, which would have undercut the funding plans already in place.
Dr. Matthews also derided GRADE as being underpowered to adequately address the impact of the tested agents on major adverse cardiovascular events (MACE) and hospitalizations for heart failure and too U.S.-centric to be generalizable elsewhere.
A study with lots of data
The roughly 5,000 patients enrolled in GRADE were an average age of 57 years old, 64% were men, 66% were White, and 20% were Black. They had had type 2 diabetes, on average, for 4.2 years. Mean body mass index at entry was about 34 kg/m2, average A1c was 7.5%, and average estimated glomerular filtration rate was 95 mL/min/1.73m2. The trial included a 6-12 week run-in period during which background metformin treatment was optimized and led to average A1c levels less than 7%.
Patients were then randomized to one of the four agents as add-on treatment.
Both liraglutide and insulin glargine performed well on many of the numerous metrics in the data-rich trial, largely funded by two branches of the National Institutes of Health, with commercial involvement limited to free supplies of the study drugs.
The secondary metabolic outcome, of disease progressing to a confirmed A1c of 7.5%, was reached by 39% of patients taking insulin glargine, significantly lower than the rate of 46% among patients taking liraglutide, and that rate, in turn, was significantly below the 50% rate among patients taking glimepiride and the 55% rate of those taking sitagliptin.
Mean doses of the second-line agents after 4 years of treatment were 38.3 units/day for glargine, 3.5 mg/day for glimepiride, 1.3 mg/day for subcutaneous liraglutide, and 82.9 mg/day for sitagliptin.
A trio of cardiovascular outcomes showed one significant benefit of liraglutide over the other three drugs for the endpoint of any cardiovascular event, which included not only major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke), but also several other event types, including heart failure requiring hospitalization, unstable angina requiring hospitalization, revascularization or any arterial repairs, stent thrombosis, or transient ischemic attack.
For the endpoint of any cardiovascular event, the rate was 5.8% for patients taking liraglutide, significantly less than the rate of 7.6% of those taking insulin glargine, 8.0% for glimepiride, and 8.6% for sitagliptin, reported John B. Buse, MD, PhD, professor, chief of endocrinology, and director of the Diabetes Center at the University of North Carolina at Chapel Hill.
For each of the other two main cardiovascular endpoints – MACE and hospitalization for heart failure – liraglutide had a numeric advantage over the other three drugs but failed to reach significance.
Patients taking liraglutide also had a smaller but not significantly different point estimate for all-cause death, at 2.1%, compared with 3.1%-3.4% in the other three groups.
And, Dr. Nathan emphasized, the cardiovascular disease data are still considered preliminary.
Liraglutide scored a pair of additional outcome victories. Its use resulted in a significantly lower rate of patients who progressed during follow-up to either needing antihypertensive medications or having their blood pressure rise above 140/90 mm Hg compared with the other three drugs. (At baseline, average blood pressure for all patients was 128/77 mm Hg.)
And after 4 years, patients taking liraglutide lost an average of about 4 kg (8.8 lb) from their baseline weight (which averaged about 100 kg [220 lb]), roughly the same as patients taking sitagliptin but significantly better than with glimepiride or insulin glargine. Patients taking glargine gained a small amount of weight on average during their first couple of years of treatment, roughly 1 kg, but returned to around their baseline weight by the end of 4 years.
Four drugs performed equally well for some outcomes
Finally, the four drugs had similar results for some outcomes. This included their effects on renal function, distal sensory polyneuropathy, and low-density lipoprotein (LDL) cholesterol.
The four agents also had roughly similar safety profiles, with rates of serious adverse events all falling within the tight range of 33%-37%.
But the rate of severe hypoglycemic episodes that required assistance to treat showed significant separation, ranging from 2.3% for glimepiride, 1.4% for glargine, 0.9% for liraglutide, and 0.7% for sitagliptin. Gastrointestinal symptoms occurred in about 50% of patients in three of the treatment groups but were significantly higher in those taking liraglutide, affecting 60%.
GRADE received no commercial funding. Dr. Wexler has reported serving on data monitoring committees for Novo Nordisk. Dr. Buse has reported being a consultant for and holding stock in numerous companies. Dr. Rosenstock has reported being an advisor or consultant to Applied Therapeutics, Boehringer Ingelheim, Hanmi Pharmaceutical, Intarcia Therapeutics, Lilly, Novo Nordisk, Oramed, and Sanofi and has received research support from numerous companies. Dr. Kahn has reported being an advisor to or speaker on behalf of Bayer, Boehringer Ingelheim, Casma Therapeutics, Intarcia Therapeutics, Lilly, Merck, Novo Nordisk, Pfizer, and Third Rock Ventures. Dr. Matthews has reported receiving lecture and advisor fees from Merck, Novartis, Novo Nordisk, Sanofi Aventis, and Servier. Dr. Lachin and Dr. Nathan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin for treating patients with type 2 diabetes in a multicenter U.S. trial that randomized just over 5,000 patients.
. Results were reported at the virtual American Diabetes Association (ADA) 81st Scientific Sessions.
The comparison included two oral medications – the sulfonylurea glimepiride and dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin – and two injectable medications – insulin glargine and glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide.
The primary endpoint was change in A1c level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, renal, gastrointestinal, and other complications.
For the primary endpoint – keeping A1c levels below 7% – liraglutide and the basal insulin glargine both did this best and were almost equivalent.
During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were 67% among patients randomized to insulin glargine, 68% maintained on liraglutide, 72% taking the sulfonylurea glimepiride, and 77% taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University, Washington.
Too soon for take-aways, or are the data already obsolete?
“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” noted David M. Nathan, MD, chair of the study and director of the Diabetes Center at Massachusetts General Hospital, in an ADA press release.
Dr. Nathan, as well as several other members of the GRADE trial steering committee who presented results, repeatedly cautioned that the findings were preliminary because they represent 90% of outcomes, with the remaining 10% still to be adjudicated.
“We undertook this study to fill a gap in the guidelines,” said investigator Deborah J. Wexler, MD, clinical director of the Diabetes Center at Massachusetts General Hospital in Boston. “I would like to have all the results in ... before I comment on how the guidelines should change.”
“The metabolic data are solid, but the cardiovascular disease data are preliminary,” warned Dr. Nathan.
But that didn’t stop some from drawing their own conclusions, with Julio Rosenstock, MD, who comoderated the session but was not involved with the study, giving his own opinion.
“A pleasant surprise was the performance of basal insulin,” he said, calling the findings “a vindication” for basal insulin as a treatment for the types of patients with type 2 diabetes that enrolled in the study.
Steven E. Kahn, MB, ChB, another GRADE co-investigator agreed. “Based on the results, guidelines should say that you add insulin early on,” he observed.
A generic basal insulin and a generic sulfonylurea are both reasonable options, after metformin, for patients with limited resources, added Dr. Kahn, an endocrinologist and professor at the University of Washington, Seattle.
Dr. Rosenstock, director of the Dallas Diabetes Research Center, also saw the results as an indictment of agents in the DDP-4 inhibitor class, such as sitagliptin.
The DPP-4 inhibitors generate $9 billion a year, he said, wondering whether it “is justifiable to put them on the same level as other agents?”
Meanwhile the assigned discussant, David R. Matthews, DPhil, a professor of diabetes medicine at the University of Oxford, England – while congratulating the investigators on certain aspects of the study – said it ultimately fell short because it didn’t include an arm with an SGLT2 inhibitor.
“We should kick the authors for missing out on SGLT2 inhibitors,” Dr. Matthews said. “The omission means that the GRADE data are already obsolescent.”
In reply, Dr. Nathan admitted “we feel bad we did not include” an SGLT2 inhibitor, but he vigorously defended the dilemma faced by the trial’s organizers.
Oral SGLT2 inhibitors were not “well-established drugs” for type 2 diabetes when enrollment launched in 2013, and the researchers were wary of including what could turn out to be a problematic agent soon after controversy over the safety of agents in the thiazolidinedione drug class (such as rosiglitazone), he explained.
They also realized that adding a fifth drug to the study would necessitate doubling enrollment size, which would have undercut the funding plans already in place.
Dr. Matthews also derided GRADE as being underpowered to adequately address the impact of the tested agents on major adverse cardiovascular events (MACE) and hospitalizations for heart failure and too U.S.-centric to be generalizable elsewhere.
A study with lots of data
The roughly 5,000 patients enrolled in GRADE were an average age of 57 years old, 64% were men, 66% were White, and 20% were Black. They had had type 2 diabetes, on average, for 4.2 years. Mean body mass index at entry was about 34 kg/m2, average A1c was 7.5%, and average estimated glomerular filtration rate was 95 mL/min/1.73m2. The trial included a 6-12 week run-in period during which background metformin treatment was optimized and led to average A1c levels less than 7%.
Patients were then randomized to one of the four agents as add-on treatment.
Both liraglutide and insulin glargine performed well on many of the numerous metrics in the data-rich trial, largely funded by two branches of the National Institutes of Health, with commercial involvement limited to free supplies of the study drugs.
The secondary metabolic outcome, of disease progressing to a confirmed A1c of 7.5%, was reached by 39% of patients taking insulin glargine, significantly lower than the rate of 46% among patients taking liraglutide, and that rate, in turn, was significantly below the 50% rate among patients taking glimepiride and the 55% rate of those taking sitagliptin.
Mean doses of the second-line agents after 4 years of treatment were 38.3 units/day for glargine, 3.5 mg/day for glimepiride, 1.3 mg/day for subcutaneous liraglutide, and 82.9 mg/day for sitagliptin.
A trio of cardiovascular outcomes showed one significant benefit of liraglutide over the other three drugs for the endpoint of any cardiovascular event, which included not only major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke), but also several other event types, including heart failure requiring hospitalization, unstable angina requiring hospitalization, revascularization or any arterial repairs, stent thrombosis, or transient ischemic attack.
For the endpoint of any cardiovascular event, the rate was 5.8% for patients taking liraglutide, significantly less than the rate of 7.6% of those taking insulin glargine, 8.0% for glimepiride, and 8.6% for sitagliptin, reported John B. Buse, MD, PhD, professor, chief of endocrinology, and director of the Diabetes Center at the University of North Carolina at Chapel Hill.
For each of the other two main cardiovascular endpoints – MACE and hospitalization for heart failure – liraglutide had a numeric advantage over the other three drugs but failed to reach significance.
Patients taking liraglutide also had a smaller but not significantly different point estimate for all-cause death, at 2.1%, compared with 3.1%-3.4% in the other three groups.
And, Dr. Nathan emphasized, the cardiovascular disease data are still considered preliminary.
Liraglutide scored a pair of additional outcome victories. Its use resulted in a significantly lower rate of patients who progressed during follow-up to either needing antihypertensive medications or having their blood pressure rise above 140/90 mm Hg compared with the other three drugs. (At baseline, average blood pressure for all patients was 128/77 mm Hg.)
And after 4 years, patients taking liraglutide lost an average of about 4 kg (8.8 lb) from their baseline weight (which averaged about 100 kg [220 lb]), roughly the same as patients taking sitagliptin but significantly better than with glimepiride or insulin glargine. Patients taking glargine gained a small amount of weight on average during their first couple of years of treatment, roughly 1 kg, but returned to around their baseline weight by the end of 4 years.
Four drugs performed equally well for some outcomes
Finally, the four drugs had similar results for some outcomes. This included their effects on renal function, distal sensory polyneuropathy, and low-density lipoprotein (LDL) cholesterol.
The four agents also had roughly similar safety profiles, with rates of serious adverse events all falling within the tight range of 33%-37%.
But the rate of severe hypoglycemic episodes that required assistance to treat showed significant separation, ranging from 2.3% for glimepiride, 1.4% for glargine, 0.9% for liraglutide, and 0.7% for sitagliptin. Gastrointestinal symptoms occurred in about 50% of patients in three of the treatment groups but were significantly higher in those taking liraglutide, affecting 60%.
GRADE received no commercial funding. Dr. Wexler has reported serving on data monitoring committees for Novo Nordisk. Dr. Buse has reported being a consultant for and holding stock in numerous companies. Dr. Rosenstock has reported being an advisor or consultant to Applied Therapeutics, Boehringer Ingelheim, Hanmi Pharmaceutical, Intarcia Therapeutics, Lilly, Novo Nordisk, Oramed, and Sanofi and has received research support from numerous companies. Dr. Kahn has reported being an advisor to or speaker on behalf of Bayer, Boehringer Ingelheim, Casma Therapeutics, Intarcia Therapeutics, Lilly, Merck, Novo Nordisk, Pfizer, and Third Rock Ventures. Dr. Matthews has reported receiving lecture and advisor fees from Merck, Novartis, Novo Nordisk, Sanofi Aventis, and Servier. Dr. Lachin and Dr. Nathan have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
EAS lipid guidance: Start high-risk patients on combo drug
Very-high-risk dyslipidemia patients unlikely to reach goal with a statin should be given combination statin–ezetimibe (Nustendi) therapy upfront, rather than wasting time and resources on trialing a statin alone, suggests a practical guidance document.
The document points out that, even with high-intensity statin therapy, patients achieve a reduction in low-density-lipoprotein (LDL) cholesterol levels of around 50%, which for many is not enough for them to achieve the stringent new guideline targets deemed necessary for risk reduction.
Instead, clinicians should determine at the first visit whether their patient, if they are not already on a statin, is likely to reach their goal with that drug alone, and if not, should immediately start them on the combination.
The guidance, which aims to offer a practical way to implement the 2019 European Society of Cardiology/EAS guidelines for the management of dyslipidemias, was published April 12 in Atherosclerosis .
Lead author Alberico L. Catapano, MD, PhD, discussed the new practical guidance at the recent European Atherosclerosis Society (EAS) 2021 Virtual Congress.
He explained that the motivation for creating the practical guidance was “very simple” and concerns something already embedded in the ESC/EAS guidelines; it’s just that “people didn’t notice” it.
Dr. Catapano, professor of pharmacology at the University of Milan and past president of the EAS, said the guidelines set out the average reduction in LDL-cholesterol levels “you can get by starting with high-intensity therapy and/or starting with a combination therapy.”
The guidelines, he said, suggest steps for achieving lipid control: Begin with a statin, add ezetimibe if the patient is still not at goal, and proceed to a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor if the patient is still not at target levels.
Dr. Catapano added that, “having said that, at the beginning, you can guess by knowing how far you are from the goal as to whether a statin by itself with help you get [there].”
If clinicians follow the new practical guidance of giving upfront combination statin–ezetimibe therapy in very-high-risk patients with high LDL-cholesterol levels, it will “save a lot of time, a lot of clinic visits, and will you get you to goal earlier.”
He gave the example of a patient who has an LDL-cholesterol level of 190 mg/dL, who would be classified as being at very high risk. With the target goal of 55 mg/dL, “you would never be able to get them to goal [with only] a high-intensity statin.”
The addition of ezetimibe to the regimen of this patient would have two advantages, Dr. Catapano said. The first is that “you get to goal more easily,” and the second is that, with the drugs available as a single-pill combination, it “makes it easier for the patient to be compliant.”
Consequently, there will be no “unnecessary back and forth,” he said. “Some of these are young people. They go to work; one less visit is less time lost at work.
“This is a practical issue,” he added. “It doesn’t contradict the guidelines,” it’s about “everyday clinical practice.”
Useful between updates
Responding to the guidance, Donald Lloyd-Jones, MD, president-elect of the American Heart Association (AHA), told this news organization that “this kind of document can be useful in periods between updates of the formal guidelines.”
New evidence comes out in between guidelines, and they “don’t often provide us with all of the practical solutions needed for everyday guidance when we’re dealing with individual patients with real-world problems.”
Dr. Lloyd-Jones, who is chair of the Department of Preventive Medicine at Northwestern University, Chicago, said the 2019 ESC/EAS guidelines set “quite aggressive targets, particularly for LDL cholesterol … but didn’t really provide much practical advice on how clinicians could get there for their patients.”
“While this document doesn’t completely address all patient groups, it does provide some good practical advice,” recognizing that “if you need to get to a certain LDL target, it’s unlikely you’re going to get there with just a statin in certain types of patients,” and “if you need a certain amount of LDL lowering, it’s certainly reasonable to start upfront with a statin and ezetimibe and see how you do.”
Crucially, Dr. Lloyd-Jones believes that the practical guidance does “flesh out some of the details the guidelines didn’t address.”
In terms of the aggressive LDL-cholesterol targets set out in the original guidelines, he said that “everyone agrees that lower is always better … and we’ve not get yet found a level that is too low.”
Further, “we’re certainly pushing patients lower and lower, especially with the use of PCSK9 inhibitors, so I think the general philosophy is consistent and correct,” although “it’s difficult to point to great evidence from clinical trials that specially says that 55 mg/dL or 40 mg/dL is the right target for a given group of patients.”
“There’s really very limited evidence for those specific numbers,” Dr. Lloyd-Jones added, “but I think everyone agrees, especially for patients at higher risk, the lower we can get them the better. What really matters, and what this document starts to address, is how we achieve as low as possible, and I think there are some important considerations that they take into account.”
Aside from how far patients need their LDL cholesterol lowered from baseline, there are issues like cost and patient preference for different types of medication, and these “weren’t particularly well addressed in the guidelines,” he added.
Scott D. Isaacs, MD, Secretary of the American Association of Clinical Endocrinologists (AACE), commented that the ESC/EAS recommendations echo the 2017 AACE/American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.
He said that both guidelines “call for the need to lower LDL cholesterol as much as possible to prevent cardiovascular disease.”
He agreed, however, that high- or very-high-risk patients “have aggressive LDL targets that are often lower than what can be accomplished with high-dose, high-intensity statin monotherapy. Therefore, starting with combination therapy … will get more patients to goal more quickly and will prevent more cardiovascular events.”
Isaacs added: “It just makes sense that if you know a drug will not be strong enough, then you should start with two drugs.”
He noted that this approach is commonly used for conditions such as diabetes and hypertension, “when monotherapy is not expected to achieve the desired results.”
Dr. Isaacs also underlined that the combination of a statin plus ezetimibe “is appealing because of the price and ease of use.”
Although PCSK9 inhibitors are more potent and achieve even lower LDL levels, “the higher price and need to take an injection has limited their use,” he noted.
“One would expect that as the prices of PCSK9 inhibitors come down, their place in care pathways will move up since they are more effective and have proven cardiovascular benefit, but for now, statin plus ezetimibe is a potent and cost-effective way to achieve LDL targets in high- and very-high-risk patients,” Dr. Isaacs concluded.
One issue Dr. Lloyd-Jones raised with the ESC/EAS guidelines is that they seem to have put a lot of weight Mendelian randomization analysis.
“Those are useful in understanding whether having low LDL-cholesterol levels or triglycerides naturally are better for you – of course they are – but they actually provide no evidence about treatment effects, so I think what we need from that is actual data from the clinical trials to understand the treatment effects, both positive and negative.”
He added that that “really then helps us to drive to how and in whom we want to achieve the lowest levels possible.”
Dr. Lloyd-Jones said that Mendelian randomization analyses “continue to crop in a lot of these ESC and EAS documents,” and although they are “elegant and interesting,” they “don’t really inform treatment at all.”
No funding declared. Catapano declares relationships with Pfizer, Sanofi, Regeneron, Merck, Mediolanum, SigmaTau, Menarini, Kowa, Recordati, Eli Lilly, AstraZeneca, Merck, Aegerion and Amgen.
A version of this article first appeared on Medscape.com.
Very-high-risk dyslipidemia patients unlikely to reach goal with a statin should be given combination statin–ezetimibe (Nustendi) therapy upfront, rather than wasting time and resources on trialing a statin alone, suggests a practical guidance document.
The document points out that, even with high-intensity statin therapy, patients achieve a reduction in low-density-lipoprotein (LDL) cholesterol levels of around 50%, which for many is not enough for them to achieve the stringent new guideline targets deemed necessary for risk reduction.
Instead, clinicians should determine at the first visit whether their patient, if they are not already on a statin, is likely to reach their goal with that drug alone, and if not, should immediately start them on the combination.
The guidance, which aims to offer a practical way to implement the 2019 European Society of Cardiology/EAS guidelines for the management of dyslipidemias, was published April 12 in Atherosclerosis .
Lead author Alberico L. Catapano, MD, PhD, discussed the new practical guidance at the recent European Atherosclerosis Society (EAS) 2021 Virtual Congress.
He explained that the motivation for creating the practical guidance was “very simple” and concerns something already embedded in the ESC/EAS guidelines; it’s just that “people didn’t notice” it.
Dr. Catapano, professor of pharmacology at the University of Milan and past president of the EAS, said the guidelines set out the average reduction in LDL-cholesterol levels “you can get by starting with high-intensity therapy and/or starting with a combination therapy.”
The guidelines, he said, suggest steps for achieving lipid control: Begin with a statin, add ezetimibe if the patient is still not at goal, and proceed to a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor if the patient is still not at target levels.
Dr. Catapano added that, “having said that, at the beginning, you can guess by knowing how far you are from the goal as to whether a statin by itself with help you get [there].”
If clinicians follow the new practical guidance of giving upfront combination statin–ezetimibe therapy in very-high-risk patients with high LDL-cholesterol levels, it will “save a lot of time, a lot of clinic visits, and will you get you to goal earlier.”
He gave the example of a patient who has an LDL-cholesterol level of 190 mg/dL, who would be classified as being at very high risk. With the target goal of 55 mg/dL, “you would never be able to get them to goal [with only] a high-intensity statin.”
The addition of ezetimibe to the regimen of this patient would have two advantages, Dr. Catapano said. The first is that “you get to goal more easily,” and the second is that, with the drugs available as a single-pill combination, it “makes it easier for the patient to be compliant.”
Consequently, there will be no “unnecessary back and forth,” he said. “Some of these are young people. They go to work; one less visit is less time lost at work.
“This is a practical issue,” he added. “It doesn’t contradict the guidelines,” it’s about “everyday clinical practice.”
Useful between updates
Responding to the guidance, Donald Lloyd-Jones, MD, president-elect of the American Heart Association (AHA), told this news organization that “this kind of document can be useful in periods between updates of the formal guidelines.”
New evidence comes out in between guidelines, and they “don’t often provide us with all of the practical solutions needed for everyday guidance when we’re dealing with individual patients with real-world problems.”
Dr. Lloyd-Jones, who is chair of the Department of Preventive Medicine at Northwestern University, Chicago, said the 2019 ESC/EAS guidelines set “quite aggressive targets, particularly for LDL cholesterol … but didn’t really provide much practical advice on how clinicians could get there for their patients.”
“While this document doesn’t completely address all patient groups, it does provide some good practical advice,” recognizing that “if you need to get to a certain LDL target, it’s unlikely you’re going to get there with just a statin in certain types of patients,” and “if you need a certain amount of LDL lowering, it’s certainly reasonable to start upfront with a statin and ezetimibe and see how you do.”
Crucially, Dr. Lloyd-Jones believes that the practical guidance does “flesh out some of the details the guidelines didn’t address.”
In terms of the aggressive LDL-cholesterol targets set out in the original guidelines, he said that “everyone agrees that lower is always better … and we’ve not get yet found a level that is too low.”
Further, “we’re certainly pushing patients lower and lower, especially with the use of PCSK9 inhibitors, so I think the general philosophy is consistent and correct,” although “it’s difficult to point to great evidence from clinical trials that specially says that 55 mg/dL or 40 mg/dL is the right target for a given group of patients.”
“There’s really very limited evidence for those specific numbers,” Dr. Lloyd-Jones added, “but I think everyone agrees, especially for patients at higher risk, the lower we can get them the better. What really matters, and what this document starts to address, is how we achieve as low as possible, and I think there are some important considerations that they take into account.”
Aside from how far patients need their LDL cholesterol lowered from baseline, there are issues like cost and patient preference for different types of medication, and these “weren’t particularly well addressed in the guidelines,” he added.
Scott D. Isaacs, MD, Secretary of the American Association of Clinical Endocrinologists (AACE), commented that the ESC/EAS recommendations echo the 2017 AACE/American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.
He said that both guidelines “call for the need to lower LDL cholesterol as much as possible to prevent cardiovascular disease.”
He agreed, however, that high- or very-high-risk patients “have aggressive LDL targets that are often lower than what can be accomplished with high-dose, high-intensity statin monotherapy. Therefore, starting with combination therapy … will get more patients to goal more quickly and will prevent more cardiovascular events.”
Isaacs added: “It just makes sense that if you know a drug will not be strong enough, then you should start with two drugs.”
He noted that this approach is commonly used for conditions such as diabetes and hypertension, “when monotherapy is not expected to achieve the desired results.”
Dr. Isaacs also underlined that the combination of a statin plus ezetimibe “is appealing because of the price and ease of use.”
Although PCSK9 inhibitors are more potent and achieve even lower LDL levels, “the higher price and need to take an injection has limited their use,” he noted.
“One would expect that as the prices of PCSK9 inhibitors come down, their place in care pathways will move up since they are more effective and have proven cardiovascular benefit, but for now, statin plus ezetimibe is a potent and cost-effective way to achieve LDL targets in high- and very-high-risk patients,” Dr. Isaacs concluded.
One issue Dr. Lloyd-Jones raised with the ESC/EAS guidelines is that they seem to have put a lot of weight Mendelian randomization analysis.
“Those are useful in understanding whether having low LDL-cholesterol levels or triglycerides naturally are better for you – of course they are – but they actually provide no evidence about treatment effects, so I think what we need from that is actual data from the clinical trials to understand the treatment effects, both positive and negative.”
He added that that “really then helps us to drive to how and in whom we want to achieve the lowest levels possible.”
Dr. Lloyd-Jones said that Mendelian randomization analyses “continue to crop in a lot of these ESC and EAS documents,” and although they are “elegant and interesting,” they “don’t really inform treatment at all.”
No funding declared. Catapano declares relationships with Pfizer, Sanofi, Regeneron, Merck, Mediolanum, SigmaTau, Menarini, Kowa, Recordati, Eli Lilly, AstraZeneca, Merck, Aegerion and Amgen.
A version of this article first appeared on Medscape.com.
Very-high-risk dyslipidemia patients unlikely to reach goal with a statin should be given combination statin–ezetimibe (Nustendi) therapy upfront, rather than wasting time and resources on trialing a statin alone, suggests a practical guidance document.
The document points out that, even with high-intensity statin therapy, patients achieve a reduction in low-density-lipoprotein (LDL) cholesterol levels of around 50%, which for many is not enough for them to achieve the stringent new guideline targets deemed necessary for risk reduction.
Instead, clinicians should determine at the first visit whether their patient, if they are not already on a statin, is likely to reach their goal with that drug alone, and if not, should immediately start them on the combination.
The guidance, which aims to offer a practical way to implement the 2019 European Society of Cardiology/EAS guidelines for the management of dyslipidemias, was published April 12 in Atherosclerosis .
Lead author Alberico L. Catapano, MD, PhD, discussed the new practical guidance at the recent European Atherosclerosis Society (EAS) 2021 Virtual Congress.
He explained that the motivation for creating the practical guidance was “very simple” and concerns something already embedded in the ESC/EAS guidelines; it’s just that “people didn’t notice” it.
Dr. Catapano, professor of pharmacology at the University of Milan and past president of the EAS, said the guidelines set out the average reduction in LDL-cholesterol levels “you can get by starting with high-intensity therapy and/or starting with a combination therapy.”
The guidelines, he said, suggest steps for achieving lipid control: Begin with a statin, add ezetimibe if the patient is still not at goal, and proceed to a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor if the patient is still not at target levels.
Dr. Catapano added that, “having said that, at the beginning, you can guess by knowing how far you are from the goal as to whether a statin by itself with help you get [there].”
If clinicians follow the new practical guidance of giving upfront combination statin–ezetimibe therapy in very-high-risk patients with high LDL-cholesterol levels, it will “save a lot of time, a lot of clinic visits, and will you get you to goal earlier.”
He gave the example of a patient who has an LDL-cholesterol level of 190 mg/dL, who would be classified as being at very high risk. With the target goal of 55 mg/dL, “you would never be able to get them to goal [with only] a high-intensity statin.”
The addition of ezetimibe to the regimen of this patient would have two advantages, Dr. Catapano said. The first is that “you get to goal more easily,” and the second is that, with the drugs available as a single-pill combination, it “makes it easier for the patient to be compliant.”
Consequently, there will be no “unnecessary back and forth,” he said. “Some of these are young people. They go to work; one less visit is less time lost at work.
“This is a practical issue,” he added. “It doesn’t contradict the guidelines,” it’s about “everyday clinical practice.”
Useful between updates
Responding to the guidance, Donald Lloyd-Jones, MD, president-elect of the American Heart Association (AHA), told this news organization that “this kind of document can be useful in periods between updates of the formal guidelines.”
New evidence comes out in between guidelines, and they “don’t often provide us with all of the practical solutions needed for everyday guidance when we’re dealing with individual patients with real-world problems.”
Dr. Lloyd-Jones, who is chair of the Department of Preventive Medicine at Northwestern University, Chicago, said the 2019 ESC/EAS guidelines set “quite aggressive targets, particularly for LDL cholesterol … but didn’t really provide much practical advice on how clinicians could get there for their patients.”
“While this document doesn’t completely address all patient groups, it does provide some good practical advice,” recognizing that “if you need to get to a certain LDL target, it’s unlikely you’re going to get there with just a statin in certain types of patients,” and “if you need a certain amount of LDL lowering, it’s certainly reasonable to start upfront with a statin and ezetimibe and see how you do.”
Crucially, Dr. Lloyd-Jones believes that the practical guidance does “flesh out some of the details the guidelines didn’t address.”
In terms of the aggressive LDL-cholesterol targets set out in the original guidelines, he said that “everyone agrees that lower is always better … and we’ve not get yet found a level that is too low.”
Further, “we’re certainly pushing patients lower and lower, especially with the use of PCSK9 inhibitors, so I think the general philosophy is consistent and correct,” although “it’s difficult to point to great evidence from clinical trials that specially says that 55 mg/dL or 40 mg/dL is the right target for a given group of patients.”
“There’s really very limited evidence for those specific numbers,” Dr. Lloyd-Jones added, “but I think everyone agrees, especially for patients at higher risk, the lower we can get them the better. What really matters, and what this document starts to address, is how we achieve as low as possible, and I think there are some important considerations that they take into account.”
Aside from how far patients need their LDL cholesterol lowered from baseline, there are issues like cost and patient preference for different types of medication, and these “weren’t particularly well addressed in the guidelines,” he added.
Scott D. Isaacs, MD, Secretary of the American Association of Clinical Endocrinologists (AACE), commented that the ESC/EAS recommendations echo the 2017 AACE/American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.
He said that both guidelines “call for the need to lower LDL cholesterol as much as possible to prevent cardiovascular disease.”
He agreed, however, that high- or very-high-risk patients “have aggressive LDL targets that are often lower than what can be accomplished with high-dose, high-intensity statin monotherapy. Therefore, starting with combination therapy … will get more patients to goal more quickly and will prevent more cardiovascular events.”
Isaacs added: “It just makes sense that if you know a drug will not be strong enough, then you should start with two drugs.”
He noted that this approach is commonly used for conditions such as diabetes and hypertension, “when monotherapy is not expected to achieve the desired results.”
Dr. Isaacs also underlined that the combination of a statin plus ezetimibe “is appealing because of the price and ease of use.”
Although PCSK9 inhibitors are more potent and achieve even lower LDL levels, “the higher price and need to take an injection has limited their use,” he noted.
“One would expect that as the prices of PCSK9 inhibitors come down, their place in care pathways will move up since they are more effective and have proven cardiovascular benefit, but for now, statin plus ezetimibe is a potent and cost-effective way to achieve LDL targets in high- and very-high-risk patients,” Dr. Isaacs concluded.
One issue Dr. Lloyd-Jones raised with the ESC/EAS guidelines is that they seem to have put a lot of weight Mendelian randomization analysis.
“Those are useful in understanding whether having low LDL-cholesterol levels or triglycerides naturally are better for you – of course they are – but they actually provide no evidence about treatment effects, so I think what we need from that is actual data from the clinical trials to understand the treatment effects, both positive and negative.”
He added that that “really then helps us to drive to how and in whom we want to achieve the lowest levels possible.”
Dr. Lloyd-Jones said that Mendelian randomization analyses “continue to crop in a lot of these ESC and EAS documents,” and although they are “elegant and interesting,” they “don’t really inform treatment at all.”
No funding declared. Catapano declares relationships with Pfizer, Sanofi, Regeneron, Merck, Mediolanum, SigmaTau, Menarini, Kowa, Recordati, Eli Lilly, AstraZeneca, Merck, Aegerion and Amgen.
A version of this article first appeared on Medscape.com.
AMPLITUDE-O: Efpeglenatide benefits in high-risk diabetes
The AMPLITUDE-O phase 3 trial showed that investigational drug efpeglenatide (Sanofi/Hanmi Pharmaceutical) – an exendin-based glucagonlike peptide-1 receptor agonist – was safe and reduced the risk of worsening renal and cardiovascular outcomes in patients with type 2 diabetes at high cardiovascular risk.
That is, in patients with type 2 diabetes and a high prevalence of cardiovascular and kidney disease with a high hemoglobin A1c and moderate use of a sodium-glucose cotransporter 2 inhibitor, subcutaneous efpeglenatide (4 or 6 mg/week) significantly and safely reduced cardiovascular and renal outcomes, said study investigator Naveed Sattar, MD.
Dr. Sattar, of the University of Glasgow, summarized the results during a symposium at the annual scientific sessions of the American Diabetes Association. The study was simultaneously published online in the New England Journal of Medicine.
AMPLITUDE-O was a cardiovascular outcome trial (CVOT) in more than 4,000 high-risk patients with type 2 diabetes followed for a mean of 1.8 years.
Compared with patients who received placebo, those who received either dose of efpeglenatide had a 27% lower risk of a major adverse cardiovascular event, defined as nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes; a 21% lower risk of expanded MACE (MACE, coronary revascularization, or hospitalization for unstable angina); a 32% lower risk of a composite renal outcome (decrease in kidney function or macroalbuminuria); and a 27% lower risk of MACE or noncardiovascular death.
And “these effects were independent of baseline SGLT2 inhibitors, estimated glomerular filtration rate (eGFR), or metformin use,” Dr. Sattar pointed out.
New and important findings, but Sanofi no longer developing drug
The trial’s primary investigator, Hertzel C. Gerstein, MD, pointed out several new and important findings of the drug and study, compared with CVOTs of seven other GLP-1 receptor agonists.
The trial included more patients (32%) with renal disease (eGFR, 25-60 mL/min) than the other trials.
There were enough patients taking SGLT2 inhibitors at baseline (15%) to show no difference in the effect of a GLP-1 receptor agonist in the presence/absence of an SGLT2 inhibitor.
So this is the first clearly positive GLP-1 receptor agonist CVOT with an exendin-4–based GLP-1 receptor agonist showing that the GLP-1 receptor agonist class is cardioprotective whether or not it is based on a human or animal GLP-1 structure.
And there was a significant reduction in MACE or noncardiovascular death.
“This would be good for people with type 2 diabetes and either cardiovascular or renal disease at high risk for cardiovascular and/or renal outcomes,” said Dr. Gerstein, professor of medicine at McMaster University, Hamilton, Ont.
However, the trial sponsor, Sanofi, is no longer developing the drug. The company returned the rights back to Hanmi, which had started this line of research. “Hopefully” Hanmi or another company will develop the drug further, said Dr. Gerstein.
Sicker patients than in 7 other GLP-1 agonist CVOTs
Efpeglenatide – like two other drugs in the class, exenatide and lixisenatide – is an exendin-based GLP-1 agonist. (Exendin-4 is a peptide found in the saliva of the Gila monster lizard.) In contrast, liraglutide, dulaglutide, albiglutide, and semaglutide are human-analog GLP-1 agonists.
A meta-analysis of the seven CVOTs of these other drugs in this class reported, among other things, that “overall, GLP-1 agonist treatment reduced MACE by 12%.”
Amanda I. Adler, MD, PhD, professor of diabetic medicine and health policy, University of Oxford, (England), and the assigned independent commenter at the symposium, cited many things “the investigators did well.”
Compared with the CVOTs of the other GLP-1 receptor agonists – ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide) – patients in the AMPLITUDE-O trial were sicker, she noted.
AMPLITUDE-O participants had the longest duration of diabetes (15 years), lowest mean eGFR of 72 ml/min per 1.73 m2, highest A1c (8.9%), and highest percentage of insulin use (62%), she noted.
The study was primarily a safety and noninferiority trial, she pointed out, although a series of superiority analyses were prespecified that would be conducted if the drug was found to be noninferior to placebo for the primary outcome of 3-point MACE.
It was good that patients were stratified according to SGLT2 inhibitor use – into current user, likely future user, and not likely future user – although “likely future user” may have misclassified some patients.
The various stakeholders – patients, regulators, doctors, payers, statisticians, and the marketing department of any company providing the drug – would want to know more, such as quality of life, long-term effects, and cost, she observed.
Meta-analysis of 8 CVOTs shows stronger class benefit
Dr. Sattar presented an eight-trial meta-analysis (an update of the seven-trial meta-analysis that included data from AMPLITUDE-O), which showed patients with type 2 diabetes who received GLP-1 agonists had a decreased rate of the 3-component MACE and decreased individual components (stroke more so than MI) – regardless of the structure of these drugs (exenatide or human analogs).
The updated meta-analysis also showed that, overall, GLP-1 agonists decreased all-cause mortality and possibly reduced the risk of heart failure hospitalization (perhaps linked to atherosclerotic benefits) as well as renal dysfunction.
There was no increase in risk of severe hypoglycemia, retinopathy, or pancreatic adverse effects.
AMPLITUDE-O: Design and findings
AMPLITUDE-O included 4,076 adults with type 2 diabetes from 344 sites in 28 countries who were screened from May 2018 to April 2019. Participants also had cardiovascular disease or kidney disease (eGFR, 25-60 mL/min) plus at least one other cardiovascular risk factor. They were randomized 1:1:1 to receive subcutaneous efpeglenatide (4 or 6 mg/week) or placebo.
Patients were a mean age of 65, most (87%) were White, and 33% were female. They had a mean A1c of 8.9%. Most (90%) had a history of cardiovascular disease and 31% had current kidney disease.
MACE occurred in 189 participants (7.0%) assigned to efpeglenatide and 125 participants (9.2%) assigned to receive placebo (3.9 vs. 5.3 events/100 person-years) (hazard ratio, 0.73; 95% confidence interval, 0.58-0.92; P < .001 for noninferiority; P = .007 for superiority).
The composite renal outcome event (decreased kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (HR, 0.68; 95% CI, 0.57-0.79; P < .001).
Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than placebo.
The study was funded by Sanofi. Dr. Sattar has reported being on advisory panels for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi, and receiving research support from Boehringer Ingelheim. Dr. Gerstein has reported being a member of advisory panels for Novo Nordisk, Pfizer, and Sanofi, and a consultant for Abbott, Covance, Eli Lilly, Kowa, and Sanofi. He reported receiving research support from AstraZeneca, Eli Lilly, Merck, Novo Nordisk, and Sanofi, and having other relationships with Boehringer Ingelheim, DKSH, Eli Lilly, Sanofi, and Zuellig Pharma. Dr. Adler has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The AMPLITUDE-O phase 3 trial showed that investigational drug efpeglenatide (Sanofi/Hanmi Pharmaceutical) – an exendin-based glucagonlike peptide-1 receptor agonist – was safe and reduced the risk of worsening renal and cardiovascular outcomes in patients with type 2 diabetes at high cardiovascular risk.
That is, in patients with type 2 diabetes and a high prevalence of cardiovascular and kidney disease with a high hemoglobin A1c and moderate use of a sodium-glucose cotransporter 2 inhibitor, subcutaneous efpeglenatide (4 or 6 mg/week) significantly and safely reduced cardiovascular and renal outcomes, said study investigator Naveed Sattar, MD.
Dr. Sattar, of the University of Glasgow, summarized the results during a symposium at the annual scientific sessions of the American Diabetes Association. The study was simultaneously published online in the New England Journal of Medicine.
AMPLITUDE-O was a cardiovascular outcome trial (CVOT) in more than 4,000 high-risk patients with type 2 diabetes followed for a mean of 1.8 years.
Compared with patients who received placebo, those who received either dose of efpeglenatide had a 27% lower risk of a major adverse cardiovascular event, defined as nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes; a 21% lower risk of expanded MACE (MACE, coronary revascularization, or hospitalization for unstable angina); a 32% lower risk of a composite renal outcome (decrease in kidney function or macroalbuminuria); and a 27% lower risk of MACE or noncardiovascular death.
And “these effects were independent of baseline SGLT2 inhibitors, estimated glomerular filtration rate (eGFR), or metformin use,” Dr. Sattar pointed out.
New and important findings, but Sanofi no longer developing drug
The trial’s primary investigator, Hertzel C. Gerstein, MD, pointed out several new and important findings of the drug and study, compared with CVOTs of seven other GLP-1 receptor agonists.
The trial included more patients (32%) with renal disease (eGFR, 25-60 mL/min) than the other trials.
There were enough patients taking SGLT2 inhibitors at baseline (15%) to show no difference in the effect of a GLP-1 receptor agonist in the presence/absence of an SGLT2 inhibitor.
So this is the first clearly positive GLP-1 receptor agonist CVOT with an exendin-4–based GLP-1 receptor agonist showing that the GLP-1 receptor agonist class is cardioprotective whether or not it is based on a human or animal GLP-1 structure.
And there was a significant reduction in MACE or noncardiovascular death.
“This would be good for people with type 2 diabetes and either cardiovascular or renal disease at high risk for cardiovascular and/or renal outcomes,” said Dr. Gerstein, professor of medicine at McMaster University, Hamilton, Ont.
However, the trial sponsor, Sanofi, is no longer developing the drug. The company returned the rights back to Hanmi, which had started this line of research. “Hopefully” Hanmi or another company will develop the drug further, said Dr. Gerstein.
Sicker patients than in 7 other GLP-1 agonist CVOTs
Efpeglenatide – like two other drugs in the class, exenatide and lixisenatide – is an exendin-based GLP-1 agonist. (Exendin-4 is a peptide found in the saliva of the Gila monster lizard.) In contrast, liraglutide, dulaglutide, albiglutide, and semaglutide are human-analog GLP-1 agonists.
A meta-analysis of the seven CVOTs of these other drugs in this class reported, among other things, that “overall, GLP-1 agonist treatment reduced MACE by 12%.”
Amanda I. Adler, MD, PhD, professor of diabetic medicine and health policy, University of Oxford, (England), and the assigned independent commenter at the symposium, cited many things “the investigators did well.”
Compared with the CVOTs of the other GLP-1 receptor agonists – ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide) – patients in the AMPLITUDE-O trial were sicker, she noted.
AMPLITUDE-O participants had the longest duration of diabetes (15 years), lowest mean eGFR of 72 ml/min per 1.73 m2, highest A1c (8.9%), and highest percentage of insulin use (62%), she noted.
The study was primarily a safety and noninferiority trial, she pointed out, although a series of superiority analyses were prespecified that would be conducted if the drug was found to be noninferior to placebo for the primary outcome of 3-point MACE.
It was good that patients were stratified according to SGLT2 inhibitor use – into current user, likely future user, and not likely future user – although “likely future user” may have misclassified some patients.
The various stakeholders – patients, regulators, doctors, payers, statisticians, and the marketing department of any company providing the drug – would want to know more, such as quality of life, long-term effects, and cost, she observed.
Meta-analysis of 8 CVOTs shows stronger class benefit
Dr. Sattar presented an eight-trial meta-analysis (an update of the seven-trial meta-analysis that included data from AMPLITUDE-O), which showed patients with type 2 diabetes who received GLP-1 agonists had a decreased rate of the 3-component MACE and decreased individual components (stroke more so than MI) – regardless of the structure of these drugs (exenatide or human analogs).
The updated meta-analysis also showed that, overall, GLP-1 agonists decreased all-cause mortality and possibly reduced the risk of heart failure hospitalization (perhaps linked to atherosclerotic benefits) as well as renal dysfunction.
There was no increase in risk of severe hypoglycemia, retinopathy, or pancreatic adverse effects.
AMPLITUDE-O: Design and findings
AMPLITUDE-O included 4,076 adults with type 2 diabetes from 344 sites in 28 countries who were screened from May 2018 to April 2019. Participants also had cardiovascular disease or kidney disease (eGFR, 25-60 mL/min) plus at least one other cardiovascular risk factor. They were randomized 1:1:1 to receive subcutaneous efpeglenatide (4 or 6 mg/week) or placebo.
Patients were a mean age of 65, most (87%) were White, and 33% were female. They had a mean A1c of 8.9%. Most (90%) had a history of cardiovascular disease and 31% had current kidney disease.
MACE occurred in 189 participants (7.0%) assigned to efpeglenatide and 125 participants (9.2%) assigned to receive placebo (3.9 vs. 5.3 events/100 person-years) (hazard ratio, 0.73; 95% confidence interval, 0.58-0.92; P < .001 for noninferiority; P = .007 for superiority).
The composite renal outcome event (decreased kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (HR, 0.68; 95% CI, 0.57-0.79; P < .001).
Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than placebo.
The study was funded by Sanofi. Dr. Sattar has reported being on advisory panels for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi, and receiving research support from Boehringer Ingelheim. Dr. Gerstein has reported being a member of advisory panels for Novo Nordisk, Pfizer, and Sanofi, and a consultant for Abbott, Covance, Eli Lilly, Kowa, and Sanofi. He reported receiving research support from AstraZeneca, Eli Lilly, Merck, Novo Nordisk, and Sanofi, and having other relationships with Boehringer Ingelheim, DKSH, Eli Lilly, Sanofi, and Zuellig Pharma. Dr. Adler has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The AMPLITUDE-O phase 3 trial showed that investigational drug efpeglenatide (Sanofi/Hanmi Pharmaceutical) – an exendin-based glucagonlike peptide-1 receptor agonist – was safe and reduced the risk of worsening renal and cardiovascular outcomes in patients with type 2 diabetes at high cardiovascular risk.
That is, in patients with type 2 diabetes and a high prevalence of cardiovascular and kidney disease with a high hemoglobin A1c and moderate use of a sodium-glucose cotransporter 2 inhibitor, subcutaneous efpeglenatide (4 or 6 mg/week) significantly and safely reduced cardiovascular and renal outcomes, said study investigator Naveed Sattar, MD.
Dr. Sattar, of the University of Glasgow, summarized the results during a symposium at the annual scientific sessions of the American Diabetes Association. The study was simultaneously published online in the New England Journal of Medicine.
AMPLITUDE-O was a cardiovascular outcome trial (CVOT) in more than 4,000 high-risk patients with type 2 diabetes followed for a mean of 1.8 years.
Compared with patients who received placebo, those who received either dose of efpeglenatide had a 27% lower risk of a major adverse cardiovascular event, defined as nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or undetermined causes; a 21% lower risk of expanded MACE (MACE, coronary revascularization, or hospitalization for unstable angina); a 32% lower risk of a composite renal outcome (decrease in kidney function or macroalbuminuria); and a 27% lower risk of MACE or noncardiovascular death.
And “these effects were independent of baseline SGLT2 inhibitors, estimated glomerular filtration rate (eGFR), or metformin use,” Dr. Sattar pointed out.
New and important findings, but Sanofi no longer developing drug
The trial’s primary investigator, Hertzel C. Gerstein, MD, pointed out several new and important findings of the drug and study, compared with CVOTs of seven other GLP-1 receptor agonists.
The trial included more patients (32%) with renal disease (eGFR, 25-60 mL/min) than the other trials.
There were enough patients taking SGLT2 inhibitors at baseline (15%) to show no difference in the effect of a GLP-1 receptor agonist in the presence/absence of an SGLT2 inhibitor.
So this is the first clearly positive GLP-1 receptor agonist CVOT with an exendin-4–based GLP-1 receptor agonist showing that the GLP-1 receptor agonist class is cardioprotective whether or not it is based on a human or animal GLP-1 structure.
And there was a significant reduction in MACE or noncardiovascular death.
“This would be good for people with type 2 diabetes and either cardiovascular or renal disease at high risk for cardiovascular and/or renal outcomes,” said Dr. Gerstein, professor of medicine at McMaster University, Hamilton, Ont.
However, the trial sponsor, Sanofi, is no longer developing the drug. The company returned the rights back to Hanmi, which had started this line of research. “Hopefully” Hanmi or another company will develop the drug further, said Dr. Gerstein.
Sicker patients than in 7 other GLP-1 agonist CVOTs
Efpeglenatide – like two other drugs in the class, exenatide and lixisenatide – is an exendin-based GLP-1 agonist. (Exendin-4 is a peptide found in the saliva of the Gila monster lizard.) In contrast, liraglutide, dulaglutide, albiglutide, and semaglutide are human-analog GLP-1 agonists.
A meta-analysis of the seven CVOTs of these other drugs in this class reported, among other things, that “overall, GLP-1 agonist treatment reduced MACE by 12%.”
Amanda I. Adler, MD, PhD, professor of diabetic medicine and health policy, University of Oxford, (England), and the assigned independent commenter at the symposium, cited many things “the investigators did well.”
Compared with the CVOTs of the other GLP-1 receptor agonists – ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide) – patients in the AMPLITUDE-O trial were sicker, she noted.
AMPLITUDE-O participants had the longest duration of diabetes (15 years), lowest mean eGFR of 72 ml/min per 1.73 m2, highest A1c (8.9%), and highest percentage of insulin use (62%), she noted.
The study was primarily a safety and noninferiority trial, she pointed out, although a series of superiority analyses were prespecified that would be conducted if the drug was found to be noninferior to placebo for the primary outcome of 3-point MACE.
It was good that patients were stratified according to SGLT2 inhibitor use – into current user, likely future user, and not likely future user – although “likely future user” may have misclassified some patients.
The various stakeholders – patients, regulators, doctors, payers, statisticians, and the marketing department of any company providing the drug – would want to know more, such as quality of life, long-term effects, and cost, she observed.
Meta-analysis of 8 CVOTs shows stronger class benefit
Dr. Sattar presented an eight-trial meta-analysis (an update of the seven-trial meta-analysis that included data from AMPLITUDE-O), which showed patients with type 2 diabetes who received GLP-1 agonists had a decreased rate of the 3-component MACE and decreased individual components (stroke more so than MI) – regardless of the structure of these drugs (exenatide or human analogs).
The updated meta-analysis also showed that, overall, GLP-1 agonists decreased all-cause mortality and possibly reduced the risk of heart failure hospitalization (perhaps linked to atherosclerotic benefits) as well as renal dysfunction.
There was no increase in risk of severe hypoglycemia, retinopathy, or pancreatic adverse effects.
AMPLITUDE-O: Design and findings
AMPLITUDE-O included 4,076 adults with type 2 diabetes from 344 sites in 28 countries who were screened from May 2018 to April 2019. Participants also had cardiovascular disease or kidney disease (eGFR, 25-60 mL/min) plus at least one other cardiovascular risk factor. They were randomized 1:1:1 to receive subcutaneous efpeglenatide (4 or 6 mg/week) or placebo.
Patients were a mean age of 65, most (87%) were White, and 33% were female. They had a mean A1c of 8.9%. Most (90%) had a history of cardiovascular disease and 31% had current kidney disease.
MACE occurred in 189 participants (7.0%) assigned to efpeglenatide and 125 participants (9.2%) assigned to receive placebo (3.9 vs. 5.3 events/100 person-years) (hazard ratio, 0.73; 95% confidence interval, 0.58-0.92; P < .001 for noninferiority; P = .007 for superiority).
The composite renal outcome event (decreased kidney function or macroalbuminuria) occurred in 353 participants (13.0%) assigned to receive efpeglenatide and in 250 participants (18.4%) assigned to receive placebo (HR, 0.68; 95% CI, 0.57-0.79; P < .001).
Diarrhea, constipation, nausea, vomiting, or bloating occurred more frequently with efpeglenatide than placebo.
The study was funded by Sanofi. Dr. Sattar has reported being on advisory panels for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi, and receiving research support from Boehringer Ingelheim. Dr. Gerstein has reported being a member of advisory panels for Novo Nordisk, Pfizer, and Sanofi, and a consultant for Abbott, Covance, Eli Lilly, Kowa, and Sanofi. He reported receiving research support from AstraZeneca, Eli Lilly, Merck, Novo Nordisk, and Sanofi, and having other relationships with Boehringer Ingelheim, DKSH, Eli Lilly, Sanofi, and Zuellig Pharma. Dr. Adler has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Maintain OMT for 5 years after revascularization, boost survival at 10 years: SYNTAXES
When it comes to medical therapy after a coronary revascularization procedure, more is better. Patients started and then maintained indefinitely on more rather than fewer of the drugs identified as optimal medical therapy (OMT) achieve a major survival benefit 10 years later, according to long-term follow-up from an extended analysis of the SYNTAX trial.
For the survival benefit at 10 years, “the present study suggests that at least three types of optimal medical therapy should be maintained for at least 5 years after revascularization,” reported a multinational team of cardiovascular specialists led by Hideyuki Kawashima, MD and Patrick Serruys, MD, who both have affiliations with the department of cardiology of the National University of Ireland, Galway.
The SYNTAX trial was conducted to compare percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) for patients with previously untreated three-vessel and/or left main disease (N Engl J Med 2009;360:961-72). The conclusion from that study, published in 2009 and subsequently reinforced by a 5-year follow-up, was that CABG should remain the standard of care for complex lesions.
Optimal medical therapy defined
In the course of SYNTAX, the impact of OMT on outcome was also evaluated in a subanalysis. At 5 years, there was a mortality advantage for those receiving an antiplatelet drug, a statin, a renin-angiotensin system inhibitor (ACE inhibitor or angiotensin receptor blocker), and a beta-blocker when compared with fewer of these agents.
When an investigator-initiated extension of SYNTAX, called SYNTAXES, was conducted to compare the outcomes of PCI and CABG at 10 years, it also permitted an extended analysis of OMT. Although the primary comparison of SYNTAXES, reported 2 years ago, did not show a significant difference between PCI and CABG for mortality at 10 years, there was a difference for OMT.
When investigators compared treatment with three or more OMT agents with that with two or fewer OMT drugs at 5 years, the result for all-cause death at 10 years translated into a more than 50% relative reduction (hazard ratio, 0.47; P = .002). The absolute difference in mortality was a more than 6% reduction (13.1% vs. 19.9%).
OMT data offer major message
The current study is considered to have a major message for patients as well as physicians.
“OMT even outweighs the survival benefit from revascularization alone, so our patients should convince themselves of the value of rigorous adherence and compliance,” Dr. Serruys said in an interview. According to him, these are compelling data for telling patients that OMT “is the best insurance for extended survival.” We now know from these data “the longer, the better.”
The same message from these data extends to physicians.
“I wish I could understand the apparent blind spot physicians have with respect to prescribing OMT despite the overwhelming benefit from multiple clinical trials,” said William E. Boden, MD, professor of medicine, Boston University.
Dr. Boden was a coauthor of an editorial accompanying the newly published SYNTAXES subanalysis. In the editorial, he noted that OMT following revascularization and in other high-risk patients “has been unacceptably low,” but he was asked to expand on the lessons from the newly released SYNTAXES subanalysis in an interview.
“There has often been a belief that revascularization negates the need for OMT and that’s why the SYNTAXES trial 10-year mortality reduction – which builds upon an earlier 5-year mortality reduction analysis – is so important,” he said.
Patients should take OMT long term
These data “should be both a motivator for physicians to prescribe OMT and for patients to remain adherent to OMT,” he said. “It is the best warranty to blunt the progression of atherosclerosis and to reduce subsequent cardiac events.”
For the 10-year subanalysis of OMT in SYNTAXES, the patients were stratified by the number of OMTs they were taking at 5 years after revascularization and then evaluated for survival at 10 years. Of the 1,472 patients available for analysis at 5 years, only 678 (46%) were on OMT. The other 794 patients were not.
Graphically, the Kaplan-Meier survival curve for those on three types of OMT was consistently beneath that of those on four OMTs, but the gap narrowed over time. At the end of 10 years, the advantage of the four-drug OMT was not statistically significant relative to three or fewer (13.1% vs. 12.7%).
Statins and antiplatelets show largest effect
When analyzed individually and in different combinations, the agents with OMT did not appear to be equal. For example, the biggest survival gap at 10 years was for those who were on an antiplatelet therapy and a statin at 5 years relative to those who were not on either (13.2% vs. 22.6%; P = .006). Even after adjustment, there was nearly 45% survival benefit for these two agents (HR, 0.556; P = .02).
Conversely, the 10-year survival advantage for being on a renin-angiotensin system inhibitor at 5 years versus not being exposed to this therapy was small and nonsignificant (14.7% vs. 13.7%; P = .651).
The precise proportion of patients who were prescribed and adhered to OMT between 5 years and 10 years is unknown, acknowledged the authors, so conclusions are limited about the added benefit of 10- versus 5-year OMT, although the authors presume that a substantial proportion of those adherent for 5 years would likely continue on these therapies.
It can be said with confidence that those adherent for at least 5 years are more likely to be alive at 10 years than those who are not, according to Dr. Boden. He considers these data a call for physicians and all high-risk patients, not just those who have undergone revascularization, to take these standard therapies.
There are plenty of data to “show how poorly we treat patients with OMT,” said Dr. Boden, citing several studies. In one, which looked at OMT in a nationally representative sample in the United States, only a third of patients with angina were taking an antiplatelet, a statin, and a beta-blocker, all of which are indicated.
“Hospitalization for revascularization provides an opportune time to capture the attention of patients and their physicians,” he wrote in his editorial. He called OMT “an imperative to optimize clinical outcomes.”
Many of the investigators involved in the SYNTAXES subanalysis, including Dr. Serruys, have financial relationships with multiple pharmaceutical companies, including Boston Scientific, which provided the initial funding for the SYNTAX trial. Dr. Boden reports no potential conflicts of interest.
When it comes to medical therapy after a coronary revascularization procedure, more is better. Patients started and then maintained indefinitely on more rather than fewer of the drugs identified as optimal medical therapy (OMT) achieve a major survival benefit 10 years later, according to long-term follow-up from an extended analysis of the SYNTAX trial.
For the survival benefit at 10 years, “the present study suggests that at least three types of optimal medical therapy should be maintained for at least 5 years after revascularization,” reported a multinational team of cardiovascular specialists led by Hideyuki Kawashima, MD and Patrick Serruys, MD, who both have affiliations with the department of cardiology of the National University of Ireland, Galway.
The SYNTAX trial was conducted to compare percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) for patients with previously untreated three-vessel and/or left main disease (N Engl J Med 2009;360:961-72). The conclusion from that study, published in 2009 and subsequently reinforced by a 5-year follow-up, was that CABG should remain the standard of care for complex lesions.
Optimal medical therapy defined
In the course of SYNTAX, the impact of OMT on outcome was also evaluated in a subanalysis. At 5 years, there was a mortality advantage for those receiving an antiplatelet drug, a statin, a renin-angiotensin system inhibitor (ACE inhibitor or angiotensin receptor blocker), and a beta-blocker when compared with fewer of these agents.
When an investigator-initiated extension of SYNTAX, called SYNTAXES, was conducted to compare the outcomes of PCI and CABG at 10 years, it also permitted an extended analysis of OMT. Although the primary comparison of SYNTAXES, reported 2 years ago, did not show a significant difference between PCI and CABG for mortality at 10 years, there was a difference for OMT.
When investigators compared treatment with three or more OMT agents with that with two or fewer OMT drugs at 5 years, the result for all-cause death at 10 years translated into a more than 50% relative reduction (hazard ratio, 0.47; P = .002). The absolute difference in mortality was a more than 6% reduction (13.1% vs. 19.9%).
OMT data offer major message
The current study is considered to have a major message for patients as well as physicians.
“OMT even outweighs the survival benefit from revascularization alone, so our patients should convince themselves of the value of rigorous adherence and compliance,” Dr. Serruys said in an interview. According to him, these are compelling data for telling patients that OMT “is the best insurance for extended survival.” We now know from these data “the longer, the better.”
The same message from these data extends to physicians.
“I wish I could understand the apparent blind spot physicians have with respect to prescribing OMT despite the overwhelming benefit from multiple clinical trials,” said William E. Boden, MD, professor of medicine, Boston University.
Dr. Boden was a coauthor of an editorial accompanying the newly published SYNTAXES subanalysis. In the editorial, he noted that OMT following revascularization and in other high-risk patients “has been unacceptably low,” but he was asked to expand on the lessons from the newly released SYNTAXES subanalysis in an interview.
“There has often been a belief that revascularization negates the need for OMT and that’s why the SYNTAXES trial 10-year mortality reduction – which builds upon an earlier 5-year mortality reduction analysis – is so important,” he said.
Patients should take OMT long term
These data “should be both a motivator for physicians to prescribe OMT and for patients to remain adherent to OMT,” he said. “It is the best warranty to blunt the progression of atherosclerosis and to reduce subsequent cardiac events.”
For the 10-year subanalysis of OMT in SYNTAXES, the patients were stratified by the number of OMTs they were taking at 5 years after revascularization and then evaluated for survival at 10 years. Of the 1,472 patients available for analysis at 5 years, only 678 (46%) were on OMT. The other 794 patients were not.
Graphically, the Kaplan-Meier survival curve for those on three types of OMT was consistently beneath that of those on four OMTs, but the gap narrowed over time. At the end of 10 years, the advantage of the four-drug OMT was not statistically significant relative to three or fewer (13.1% vs. 12.7%).
Statins and antiplatelets show largest effect
When analyzed individually and in different combinations, the agents with OMT did not appear to be equal. For example, the biggest survival gap at 10 years was for those who were on an antiplatelet therapy and a statin at 5 years relative to those who were not on either (13.2% vs. 22.6%; P = .006). Even after adjustment, there was nearly 45% survival benefit for these two agents (HR, 0.556; P = .02).
Conversely, the 10-year survival advantage for being on a renin-angiotensin system inhibitor at 5 years versus not being exposed to this therapy was small and nonsignificant (14.7% vs. 13.7%; P = .651).
The precise proportion of patients who were prescribed and adhered to OMT between 5 years and 10 years is unknown, acknowledged the authors, so conclusions are limited about the added benefit of 10- versus 5-year OMT, although the authors presume that a substantial proportion of those adherent for 5 years would likely continue on these therapies.
It can be said with confidence that those adherent for at least 5 years are more likely to be alive at 10 years than those who are not, according to Dr. Boden. He considers these data a call for physicians and all high-risk patients, not just those who have undergone revascularization, to take these standard therapies.
There are plenty of data to “show how poorly we treat patients with OMT,” said Dr. Boden, citing several studies. In one, which looked at OMT in a nationally representative sample in the United States, only a third of patients with angina were taking an antiplatelet, a statin, and a beta-blocker, all of which are indicated.
“Hospitalization for revascularization provides an opportune time to capture the attention of patients and their physicians,” he wrote in his editorial. He called OMT “an imperative to optimize clinical outcomes.”
Many of the investigators involved in the SYNTAXES subanalysis, including Dr. Serruys, have financial relationships with multiple pharmaceutical companies, including Boston Scientific, which provided the initial funding for the SYNTAX trial. Dr. Boden reports no potential conflicts of interest.
When it comes to medical therapy after a coronary revascularization procedure, more is better. Patients started and then maintained indefinitely on more rather than fewer of the drugs identified as optimal medical therapy (OMT) achieve a major survival benefit 10 years later, according to long-term follow-up from an extended analysis of the SYNTAX trial.
For the survival benefit at 10 years, “the present study suggests that at least three types of optimal medical therapy should be maintained for at least 5 years after revascularization,” reported a multinational team of cardiovascular specialists led by Hideyuki Kawashima, MD and Patrick Serruys, MD, who both have affiliations with the department of cardiology of the National University of Ireland, Galway.
The SYNTAX trial was conducted to compare percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) for patients with previously untreated three-vessel and/or left main disease (N Engl J Med 2009;360:961-72). The conclusion from that study, published in 2009 and subsequently reinforced by a 5-year follow-up, was that CABG should remain the standard of care for complex lesions.
Optimal medical therapy defined
In the course of SYNTAX, the impact of OMT on outcome was also evaluated in a subanalysis. At 5 years, there was a mortality advantage for those receiving an antiplatelet drug, a statin, a renin-angiotensin system inhibitor (ACE inhibitor or angiotensin receptor blocker), and a beta-blocker when compared with fewer of these agents.
When an investigator-initiated extension of SYNTAX, called SYNTAXES, was conducted to compare the outcomes of PCI and CABG at 10 years, it also permitted an extended analysis of OMT. Although the primary comparison of SYNTAXES, reported 2 years ago, did not show a significant difference between PCI and CABG for mortality at 10 years, there was a difference for OMT.
When investigators compared treatment with three or more OMT agents with that with two or fewer OMT drugs at 5 years, the result for all-cause death at 10 years translated into a more than 50% relative reduction (hazard ratio, 0.47; P = .002). The absolute difference in mortality was a more than 6% reduction (13.1% vs. 19.9%).
OMT data offer major message
The current study is considered to have a major message for patients as well as physicians.
“OMT even outweighs the survival benefit from revascularization alone, so our patients should convince themselves of the value of rigorous adherence and compliance,” Dr. Serruys said in an interview. According to him, these are compelling data for telling patients that OMT “is the best insurance for extended survival.” We now know from these data “the longer, the better.”
The same message from these data extends to physicians.
“I wish I could understand the apparent blind spot physicians have with respect to prescribing OMT despite the overwhelming benefit from multiple clinical trials,” said William E. Boden, MD, professor of medicine, Boston University.
Dr. Boden was a coauthor of an editorial accompanying the newly published SYNTAXES subanalysis. In the editorial, he noted that OMT following revascularization and in other high-risk patients “has been unacceptably low,” but he was asked to expand on the lessons from the newly released SYNTAXES subanalysis in an interview.
“There has often been a belief that revascularization negates the need for OMT and that’s why the SYNTAXES trial 10-year mortality reduction – which builds upon an earlier 5-year mortality reduction analysis – is so important,” he said.
Patients should take OMT long term
These data “should be both a motivator for physicians to prescribe OMT and for patients to remain adherent to OMT,” he said. “It is the best warranty to blunt the progression of atherosclerosis and to reduce subsequent cardiac events.”
For the 10-year subanalysis of OMT in SYNTAXES, the patients were stratified by the number of OMTs they were taking at 5 years after revascularization and then evaluated for survival at 10 years. Of the 1,472 patients available for analysis at 5 years, only 678 (46%) were on OMT. The other 794 patients were not.
Graphically, the Kaplan-Meier survival curve for those on three types of OMT was consistently beneath that of those on four OMTs, but the gap narrowed over time. At the end of 10 years, the advantage of the four-drug OMT was not statistically significant relative to three or fewer (13.1% vs. 12.7%).
Statins and antiplatelets show largest effect
When analyzed individually and in different combinations, the agents with OMT did not appear to be equal. For example, the biggest survival gap at 10 years was for those who were on an antiplatelet therapy and a statin at 5 years relative to those who were not on either (13.2% vs. 22.6%; P = .006). Even after adjustment, there was nearly 45% survival benefit for these two agents (HR, 0.556; P = .02).
Conversely, the 10-year survival advantage for being on a renin-angiotensin system inhibitor at 5 years versus not being exposed to this therapy was small and nonsignificant (14.7% vs. 13.7%; P = .651).
The precise proportion of patients who were prescribed and adhered to OMT between 5 years and 10 years is unknown, acknowledged the authors, so conclusions are limited about the added benefit of 10- versus 5-year OMT, although the authors presume that a substantial proportion of those adherent for 5 years would likely continue on these therapies.
It can be said with confidence that those adherent for at least 5 years are more likely to be alive at 10 years than those who are not, according to Dr. Boden. He considers these data a call for physicians and all high-risk patients, not just those who have undergone revascularization, to take these standard therapies.
There are plenty of data to “show how poorly we treat patients with OMT,” said Dr. Boden, citing several studies. In one, which looked at OMT in a nationally representative sample in the United States, only a third of patients with angina were taking an antiplatelet, a statin, and a beta-blocker, all of which are indicated.
“Hospitalization for revascularization provides an opportune time to capture the attention of patients and their physicians,” he wrote in his editorial. He called OMT “an imperative to optimize clinical outcomes.”
Many of the investigators involved in the SYNTAXES subanalysis, including Dr. Serruys, have financial relationships with multiple pharmaceutical companies, including Boston Scientific, which provided the initial funding for the SYNTAX trial. Dr. Boden reports no potential conflicts of interest.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY