Acute Coronary Syndromes

Coronary angiography and percutaneous coronary interventions (PCI) can be performed successfully after transcatheter aortic valve replacement in most cases, according to data drawn from an international registry that has collected more than 400 such cases.

Overall, reaccess coronary angiography was successful in about 99% of cases with type of prosthesis identified as the most important variable in predicting success, according to a multicenter investigating team led by Won-Keun Kim, MD, director of structural heart disease, Kerckhoff Heart Center, Bad Nauheim, Germany.

By type of prosthesis, Dr. Kim was referring to long versus short stent-frame prostheses (SFP). In the case of angiography of the right coronary artery, for example, success was achieved in 99.6% of those with a short SFP and 95.9% of those with a long SFP (P = .005).

The study was published online in JACC: Cardiovascular Interventions.

Based on these and previous data, “prosthetic choice will be the main decisive factor that affects coronary reaccess, and this decision is in the hands of the TAVR operator,” said Dr. Kim in an interview.

This does not preclude use of a long SFP in TAVR. For patients with increased likelihood of eventually requiring a coronary intervention after TAVR, such as those undergoing the procedure at a relatively young age, a short device appears to be preferable, but Dr. Kim emphasized that it is not the only consideration.

When performing TAVR, “the highest priority is to accomplish a safe procedure with a good immediate outcome,” he said, pointing out that angiographic reaccess and PCI are successfully achieved in most patients whether fitted with a short or long SFP.

“If for any reason I assume that the immediate outcome [after TAVR] might be better using a long SFP, I would not hesitate to use a long SFP,” said Dr. Kim, giving such examples as a need for resheathing or precise positioning.
 

Coronary reaccess has low relative priority

“Coronary reaccess is an important issue and there is an increasing awareness of this, but it has a lower priority” than optimizing TAVR success,” Dr. Kim explained.

The analysis of coronary angiographic reaccess was based on 449 TAVR patients from 25 sites who required reaccess angiography. The indication in most cases was an acute coronary syndrome, mostly non–ST-elevation myocardial infarction (STEMI, 79%). Of the remaining patients, about half had STEMIs and half had other acute cardiovascular situations. The median time interval from TAVR to need for coronary angiography was 311 days.

In all but 2.7%, diagnostic catheterization was performed initially. It was successful in 98.3% of the procedures in the right coronary artery, 99.3% of the left coronary artery, and 97.3% overall.

Of the 60% who underwent PCI, 9% were considered unsuccessful. The reasons included lack of reflow in eight cases and coronary access issues in six cases. A variety of other issues accounted for the remaining seven cases.

Technical success was achieved in 91.4% of native arteries. In the six cases in which engagement of the culprit vessel with a guiding catheter failed, three were converted to urgent coronary bypass grafting and three died in the hospital. Neither selective versus unselective guiding-catheter engagement nor long versus short SFP related to PCI success, but PCI was performed less commonly in the native coronary arteries of TAVR patients with a long rather than short SFP (49% vs. 57%).

The 30-day all-cause mortality in this series was 12.2%. The independent predictors were a history of diabetes and the occurrence of cardiogenic shock. In the PCI subgroup, these factors plus PCI success predicted 30-day mortality.
 

Strategies to improve reaccess not resolved

When performing TAVR, other factors that might influence subsequent PCI success includes commissural alignment and positioning, according to Dr. Kim. But he cautioned that there are a number of potential controversies when weighing how to improve chances of post-TAVR angiographic reaccess without compromising the success of valve replacement.

“Lower positioning facilitates coronary access, but unfortunately will increase rates of conduction disturbances,” he noted.

Overall, one of the main messages from this analysis is that “the fear of impaired coronary access [after TAVR] may well be disproportionate to the reality,” according to Neal S. Kleiman, MD, an interventional cardiologist at Houston Methodist DeBakey Heart and Vascular Center. Dr. Kleiman wrote an editorial on the registry findings in the same issue of JACC: Cardiovascular Interventions).

Yet, he agreed that the issue of angiographic reaccess after TAVR cannot be ignored. Although reaccess after TAVR has so far been “surprisingly rare,” Dr. Kleiman expects cases to increase as more younger patients undergo TAVR. He suggested that interventionalists will need consider this issue when performing TAVR, a point he reemphasized in an interview.

“It is still a concern when recommending TAVR to a patient and still poses challenges to device manufacturers,” said Dr. Kleiman, suggesting that “a new set of skills” will be required to perform TAVR that will optimize subsequent angiographic access and PCI.

Dr. Kim agreed. Ultimately, other challenges, such as PCI performed after TAVR-in-TAVR placement, are likely to further complicate this issue, but he, too, is looking to new devices to minimize the problems.

“It would be desirable to modify the design, especially of long SFPs, to improve access for PCI, and there are ongoing efforts of the manufacturers to achieve this,” Dr. Kim said.

Dr. Kim reported financial relationships with Abbot, Boston Scientific, Edwards Lifesciences, Medtronic, and Meril Lifesciences. Dr. Kleiman reported financial relationships with Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic.

Coronary angiography and percutaneous coronary interventions (PCI) can be performed successfully after transcatheter aortic valve replacement in most cases, according to data drawn from an international registry that has collected more than 400 such cases.

Overall, reaccess coronary angiography was successful in about 99% of cases with type of prosthesis identified as the most important variable in predicting success, according to a multicenter investigating team led by Won-Keun Kim, MD, director of structural heart disease, Kerckhoff Heart Center, Bad Nauheim, Germany.

By type of prosthesis, Dr. Kim was referring to long versus short stent-frame prostheses (SFP). In the case of angiography of the right coronary artery, for example, success was achieved in 99.6% of those with a short SFP and 95.9% of those with a long SFP (P = .005).

The study was published online in JACC: Cardiovascular Interventions.

Based on these and previous data, “prosthetic choice will be the main decisive factor that affects coronary reaccess, and this decision is in the hands of the TAVR operator,” said Dr. Kim in an interview.

This does not preclude use of a long SFP in TAVR. For patients with increased likelihood of eventually requiring a coronary intervention after TAVR, such as those undergoing the procedure at a relatively young age, a short device appears to be preferable, but Dr. Kim emphasized that it is not the only consideration.

When performing TAVR, “the highest priority is to accomplish a safe procedure with a good immediate outcome,” he said, pointing out that angiographic reaccess and PCI are successfully achieved in most patients whether fitted with a short or long SFP.

“If for any reason I assume that the immediate outcome [after TAVR] might be better using a long SFP, I would not hesitate to use a long SFP,” said Dr. Kim, giving such examples as a need for resheathing or precise positioning.
 

Coronary reaccess has low relative priority

“Coronary reaccess is an important issue and there is an increasing awareness of this, but it has a lower priority” than optimizing TAVR success,” Dr. Kim explained.

The analysis of coronary angiographic reaccess was based on 449 TAVR patients from 25 sites who required reaccess angiography. The indication in most cases was an acute coronary syndrome, mostly non–ST-elevation myocardial infarction (STEMI, 79%). Of the remaining patients, about half had STEMIs and half had other acute cardiovascular situations. The median time interval from TAVR to need for coronary angiography was 311 days.

In all but 2.7%, diagnostic catheterization was performed initially. It was successful in 98.3% of the procedures in the right coronary artery, 99.3% of the left coronary artery, and 97.3% overall.

Of the 60% who underwent PCI, 9% were considered unsuccessful. The reasons included lack of reflow in eight cases and coronary access issues in six cases. A variety of other issues accounted for the remaining seven cases.

Technical success was achieved in 91.4% of native arteries. In the six cases in which engagement of the culprit vessel with a guiding catheter failed, three were converted to urgent coronary bypass grafting and three died in the hospital. Neither selective versus unselective guiding-catheter engagement nor long versus short SFP related to PCI success, but PCI was performed less commonly in the native coronary arteries of TAVR patients with a long rather than short SFP (49% vs. 57%).

The 30-day all-cause mortality in this series was 12.2%. The independent predictors were a history of diabetes and the occurrence of cardiogenic shock. In the PCI subgroup, these factors plus PCI success predicted 30-day mortality.
 

Strategies to improve reaccess not resolved

When performing TAVR, other factors that might influence subsequent PCI success includes commissural alignment and positioning, according to Dr. Kim. But he cautioned that there are a number of potential controversies when weighing how to improve chances of post-TAVR angiographic reaccess without compromising the success of valve replacement.

“Lower positioning facilitates coronary access, but unfortunately will increase rates of conduction disturbances,” he noted.

Overall, one of the main messages from this analysis is that “the fear of impaired coronary access [after TAVR] may well be disproportionate to the reality,” according to Neal S. Kleiman, MD, an interventional cardiologist at Houston Methodist DeBakey Heart and Vascular Center. Dr. Kleiman wrote an editorial on the registry findings in the same issue of JACC: Cardiovascular Interventions).

Yet, he agreed that the issue of angiographic reaccess after TAVR cannot be ignored. Although reaccess after TAVR has so far been “surprisingly rare,” Dr. Kleiman expects cases to increase as more younger patients undergo TAVR. He suggested that interventionalists will need consider this issue when performing TAVR, a point he reemphasized in an interview.

“It is still a concern when recommending TAVR to a patient and still poses challenges to device manufacturers,” said Dr. Kleiman, suggesting that “a new set of skills” will be required to perform TAVR that will optimize subsequent angiographic access and PCI.

Dr. Kim agreed. Ultimately, other challenges, such as PCI performed after TAVR-in-TAVR placement, are likely to further complicate this issue, but he, too, is looking to new devices to minimize the problems.

“It would be desirable to modify the design, especially of long SFPs, to improve access for PCI, and there are ongoing efforts of the manufacturers to achieve this,” Dr. Kim said.

Dr. Kim reported financial relationships with Abbot, Boston Scientific, Edwards Lifesciences, Medtronic, and Meril Lifesciences. Dr. Kleiman reported financial relationships with Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic.

Coronary angiography and percutaneous coronary interventions (PCI) can be performed successfully after transcatheter aortic valve replacement in most cases, according to data drawn from an international registry that has collected more than 400 such cases.

Overall, reaccess coronary angiography was successful in about 99% of cases with type of prosthesis identified as the most important variable in predicting success, according to a multicenter investigating team led by Won-Keun Kim, MD, director of structural heart disease, Kerckhoff Heart Center, Bad Nauheim, Germany.

By type of prosthesis, Dr. Kim was referring to long versus short stent-frame prostheses (SFP). In the case of angiography of the right coronary artery, for example, success was achieved in 99.6% of those with a short SFP and 95.9% of those with a long SFP (P = .005).

The study was published online in JACC: Cardiovascular Interventions.

Based on these and previous data, “prosthetic choice will be the main decisive factor that affects coronary reaccess, and this decision is in the hands of the TAVR operator,” said Dr. Kim in an interview.

This does not preclude use of a long SFP in TAVR. For patients with increased likelihood of eventually requiring a coronary intervention after TAVR, such as those undergoing the procedure at a relatively young age, a short device appears to be preferable, but Dr. Kim emphasized that it is not the only consideration.

When performing TAVR, “the highest priority is to accomplish a safe procedure with a good immediate outcome,” he said, pointing out that angiographic reaccess and PCI are successfully achieved in most patients whether fitted with a short or long SFP.

“If for any reason I assume that the immediate outcome [after TAVR] might be better using a long SFP, I would not hesitate to use a long SFP,” said Dr. Kim, giving such examples as a need for resheathing or precise positioning.
 

Coronary reaccess has low relative priority

“Coronary reaccess is an important issue and there is an increasing awareness of this, but it has a lower priority” than optimizing TAVR success,” Dr. Kim explained.

The analysis of coronary angiographic reaccess was based on 449 TAVR patients from 25 sites who required reaccess angiography. The indication in most cases was an acute coronary syndrome, mostly non–ST-elevation myocardial infarction (STEMI, 79%). Of the remaining patients, about half had STEMIs and half had other acute cardiovascular situations. The median time interval from TAVR to need for coronary angiography was 311 days.

In all but 2.7%, diagnostic catheterization was performed initially. It was successful in 98.3% of the procedures in the right coronary artery, 99.3% of the left coronary artery, and 97.3% overall.

Of the 60% who underwent PCI, 9% were considered unsuccessful. The reasons included lack of reflow in eight cases and coronary access issues in six cases. A variety of other issues accounted for the remaining seven cases.

Technical success was achieved in 91.4% of native arteries. In the six cases in which engagement of the culprit vessel with a guiding catheter failed, three were converted to urgent coronary bypass grafting and three died in the hospital. Neither selective versus unselective guiding-catheter engagement nor long versus short SFP related to PCI success, but PCI was performed less commonly in the native coronary arteries of TAVR patients with a long rather than short SFP (49% vs. 57%).

The 30-day all-cause mortality in this series was 12.2%. The independent predictors were a history of diabetes and the occurrence of cardiogenic shock. In the PCI subgroup, these factors plus PCI success predicted 30-day mortality.
 

Strategies to improve reaccess not resolved

When performing TAVR, other factors that might influence subsequent PCI success includes commissural alignment and positioning, according to Dr. Kim. But he cautioned that there are a number of potential controversies when weighing how to improve chances of post-TAVR angiographic reaccess without compromising the success of valve replacement.

“Lower positioning facilitates coronary access, but unfortunately will increase rates of conduction disturbances,” he noted.

Overall, one of the main messages from this analysis is that “the fear of impaired coronary access [after TAVR] may well be disproportionate to the reality,” according to Neal S. Kleiman, MD, an interventional cardiologist at Houston Methodist DeBakey Heart and Vascular Center. Dr. Kleiman wrote an editorial on the registry findings in the same issue of JACC: Cardiovascular Interventions).

Yet, he agreed that the issue of angiographic reaccess after TAVR cannot be ignored. Although reaccess after TAVR has so far been “surprisingly rare,” Dr. Kleiman expects cases to increase as more younger patients undergo TAVR. He suggested that interventionalists will need consider this issue when performing TAVR, a point he reemphasized in an interview.

“It is still a concern when recommending TAVR to a patient and still poses challenges to device manufacturers,” said Dr. Kleiman, suggesting that “a new set of skills” will be required to perform TAVR that will optimize subsequent angiographic access and PCI.

Dr. Kim agreed. Ultimately, other challenges, such as PCI performed after TAVR-in-TAVR placement, are likely to further complicate this issue, but he, too, is looking to new devices to minimize the problems.

“It would be desirable to modify the design, especially of long SFPs, to improve access for PCI, and there are ongoing efforts of the manufacturers to achieve this,” Dr. Kim said.

Dr. Kim reported financial relationships with Abbot, Boston Scientific, Edwards Lifesciences, Medtronic, and Meril Lifesciences. Dr. Kleiman reported financial relationships with Abbott, Boston Scientific, Edwards Lifesciences, and Medtronic.

Bicycle riding may help people with diabetes live longer, new research suggests.

NicolasMcComber/E+/Getty Images

Among more than 7,000 adults with diabetes in 10 Western European countries followed for about 15 years, those who cycled regularly were significantly less likely to die of any cause or of cardiovascular causes, even after accounting for differences in factors such as sex, age, educational level, diet, comorbidities, and other physical activities.

“The association between cycling and all-cause and CVD [cardiovascular disease] mortality in this study of person[s] with diabetes was of the same magnitude and direction as observed in the healthy population,” wrote Mathias Ried-Larsen, PhD, of the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and colleagues. The findings were published online July 19, 2021, in JAMA Internal Medicine.

In an accompanying Editor’s Note, JAMA Internal Medicine editor Rita F. Redberg, MD, and two deputy editors said that the new data add to previous studies showing benefits of cycling, compared with other physical activities. “The analysis from Ried-Larsen and colleagues strengthens the epidemiologic data on cycling and strongly suggests that it may contribute directly to longer and healthier lives,” they wrote.

Dr. Redberg, of the University of California, San Francisco, told this news organization: “I think the number of cyclists grew greatly during pandemic, when there was little auto traffic, and people did not want to take public transportation. Cities that add bike lanes, especially protected bike lanes, see an increase in cyclists. I think Americans can cycle more, would enjoy cycling more, and would live longer [by] cycling, to work and for pleasure.”

Dr. Redberg disclosed that she is “an avid cyclist and am currently on a bike ride in Glacier National Park. ... This group [Climate Ride] raises money for more bike lanes, promotes climate change awareness, has paid for solar panels at Glacier, and more.”

However, Dr. Redberg and colleagues also “recognize that cycling requires fitness, a good sense of balance, and the means to purchase a bicycle. We also understand that regular cycling requires living in an area where it is reasonably safe, and we celebrate the installation of more bike lanes, particularly protected lanes, in many cities around the world.”

But, despite the limitations of an observational study and possible selection bias of people who are able to cycle, “it is important to share this evidence for the potentially large health benefits of cycling, which almost surely generalize to persons without diabetes.”
 

Cycling tied to lower all-cause and CVD mortality

The prospective cohort study included 7,459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition. All were assessed during 1992-1998 and again in 1996-2011, with a mean follow-up of roughly 15 years. During that time, there were 1,673 deaths from all causes, with 811 attributed to CVD.

Compared with no cycling, those who reported any cycling had a 24% lower risk of death from any cause over a 5-year period, after adjustment for confounders and for other physical activity. The greatest risk reduction was seen in those who reported cycling between 150-299 minutes per week, particularly in CVD mortality.

In a subanalysis of 5,423 individuals with 10.7 years of follow-up, there were 975 all-cause deaths and 429 from CVD. Individuals who began or continued cycling during follow-up experienced reductions of about 35% for both all-cause and CVD mortality, compared with those who never cycled.

Dr. Redberg and colleagues added that “there are environmental benefits to increasing the use of cycling for commuting and other transport because cycling helps to decrease the adverse environmental and health effects of automobile exhaust.”

They concluded: “As avid and/or aspiring cyclists ourselves, we are sold on the mental and physical benefits of getting to work and seeing the world on two wheels, self-propelled, and think it is well worth a try.”

The study work was supported by the Health Research Fund of Instituto de Salud Carlos III; the Spanish regional governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra; and the Catalan Institute of Oncology. The Centre for Physical Activity Research is supported by a grant from TrygFonden. Dr. Ried-Larsen reported personal fees from Novo Nordisk. Dr. Redberg reported receiving grants from Arnold Ventures; the Greenwall Foundation; and the National Heart, Lung, and Blood Institute.

Bicycle riding may help people with diabetes live longer, new research suggests.

NicolasMcComber/E+/Getty Images

Among more than 7,000 adults with diabetes in 10 Western European countries followed for about 15 years, those who cycled regularly were significantly less likely to die of any cause or of cardiovascular causes, even after accounting for differences in factors such as sex, age, educational level, diet, comorbidities, and other physical activities.

“The association between cycling and all-cause and CVD [cardiovascular disease] mortality in this study of person[s] with diabetes was of the same magnitude and direction as observed in the healthy population,” wrote Mathias Ried-Larsen, PhD, of the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and colleagues. The findings were published online July 19, 2021, in JAMA Internal Medicine.

In an accompanying Editor’s Note, JAMA Internal Medicine editor Rita F. Redberg, MD, and two deputy editors said that the new data add to previous studies showing benefits of cycling, compared with other physical activities. “The analysis from Ried-Larsen and colleagues strengthens the epidemiologic data on cycling and strongly suggests that it may contribute directly to longer and healthier lives,” they wrote.

Dr. Redberg, of the University of California, San Francisco, told this news organization: “I think the number of cyclists grew greatly during pandemic, when there was little auto traffic, and people did not want to take public transportation. Cities that add bike lanes, especially protected bike lanes, see an increase in cyclists. I think Americans can cycle more, would enjoy cycling more, and would live longer [by] cycling, to work and for pleasure.”

Dr. Redberg disclosed that she is “an avid cyclist and am currently on a bike ride in Glacier National Park. ... This group [Climate Ride] raises money for more bike lanes, promotes climate change awareness, has paid for solar panels at Glacier, and more.”

However, Dr. Redberg and colleagues also “recognize that cycling requires fitness, a good sense of balance, and the means to purchase a bicycle. We also understand that regular cycling requires living in an area where it is reasonably safe, and we celebrate the installation of more bike lanes, particularly protected lanes, in many cities around the world.”

But, despite the limitations of an observational study and possible selection bias of people who are able to cycle, “it is important to share this evidence for the potentially large health benefits of cycling, which almost surely generalize to persons without diabetes.”
 

Cycling tied to lower all-cause and CVD mortality

The prospective cohort study included 7,459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition. All were assessed during 1992-1998 and again in 1996-2011, with a mean follow-up of roughly 15 years. During that time, there were 1,673 deaths from all causes, with 811 attributed to CVD.

Compared with no cycling, those who reported any cycling had a 24% lower risk of death from any cause over a 5-year period, after adjustment for confounders and for other physical activity. The greatest risk reduction was seen in those who reported cycling between 150-299 minutes per week, particularly in CVD mortality.

In a subanalysis of 5,423 individuals with 10.7 years of follow-up, there were 975 all-cause deaths and 429 from CVD. Individuals who began or continued cycling during follow-up experienced reductions of about 35% for both all-cause and CVD mortality, compared with those who never cycled.

Dr. Redberg and colleagues added that “there are environmental benefits to increasing the use of cycling for commuting and other transport because cycling helps to decrease the adverse environmental and health effects of automobile exhaust.”

They concluded: “As avid and/or aspiring cyclists ourselves, we are sold on the mental and physical benefits of getting to work and seeing the world on two wheels, self-propelled, and think it is well worth a try.”

The study work was supported by the Health Research Fund of Instituto de Salud Carlos III; the Spanish regional governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra; and the Catalan Institute of Oncology. The Centre for Physical Activity Research is supported by a grant from TrygFonden. Dr. Ried-Larsen reported personal fees from Novo Nordisk. Dr. Redberg reported receiving grants from Arnold Ventures; the Greenwall Foundation; and the National Heart, Lung, and Blood Institute.

Bicycle riding may help people with diabetes live longer, new research suggests.

NicolasMcComber/E+/Getty Images

Among more than 7,000 adults with diabetes in 10 Western European countries followed for about 15 years, those who cycled regularly were significantly less likely to die of any cause or of cardiovascular causes, even after accounting for differences in factors such as sex, age, educational level, diet, comorbidities, and other physical activities.

“The association between cycling and all-cause and CVD [cardiovascular disease] mortality in this study of person[s] with diabetes was of the same magnitude and direction as observed in the healthy population,” wrote Mathias Ried-Larsen, PhD, of the Centre for Physical Activity Research, Rigshospitalet, Copenhagen, and colleagues. The findings were published online July 19, 2021, in JAMA Internal Medicine.

In an accompanying Editor’s Note, JAMA Internal Medicine editor Rita F. Redberg, MD, and two deputy editors said that the new data add to previous studies showing benefits of cycling, compared with other physical activities. “The analysis from Ried-Larsen and colleagues strengthens the epidemiologic data on cycling and strongly suggests that it may contribute directly to longer and healthier lives,” they wrote.

Dr. Redberg, of the University of California, San Francisco, told this news organization: “I think the number of cyclists grew greatly during pandemic, when there was little auto traffic, and people did not want to take public transportation. Cities that add bike lanes, especially protected bike lanes, see an increase in cyclists. I think Americans can cycle more, would enjoy cycling more, and would live longer [by] cycling, to work and for pleasure.”

Dr. Redberg disclosed that she is “an avid cyclist and am currently on a bike ride in Glacier National Park. ... This group [Climate Ride] raises money for more bike lanes, promotes climate change awareness, has paid for solar panels at Glacier, and more.”

However, Dr. Redberg and colleagues also “recognize that cycling requires fitness, a good sense of balance, and the means to purchase a bicycle. We also understand that regular cycling requires living in an area where it is reasonably safe, and we celebrate the installation of more bike lanes, particularly protected lanes, in many cities around the world.”

But, despite the limitations of an observational study and possible selection bias of people who are able to cycle, “it is important to share this evidence for the potentially large health benefits of cycling, which almost surely generalize to persons without diabetes.”
 

Cycling tied to lower all-cause and CVD mortality

The prospective cohort study included 7,459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition. All were assessed during 1992-1998 and again in 1996-2011, with a mean follow-up of roughly 15 years. During that time, there were 1,673 deaths from all causes, with 811 attributed to CVD.

Compared with no cycling, those who reported any cycling had a 24% lower risk of death from any cause over a 5-year period, after adjustment for confounders and for other physical activity. The greatest risk reduction was seen in those who reported cycling between 150-299 minutes per week, particularly in CVD mortality.

In a subanalysis of 5,423 individuals with 10.7 years of follow-up, there were 975 all-cause deaths and 429 from CVD. Individuals who began or continued cycling during follow-up experienced reductions of about 35% for both all-cause and CVD mortality, compared with those who never cycled.

Dr. Redberg and colleagues added that “there are environmental benefits to increasing the use of cycling for commuting and other transport because cycling helps to decrease the adverse environmental and health effects of automobile exhaust.”

They concluded: “As avid and/or aspiring cyclists ourselves, we are sold on the mental and physical benefits of getting to work and seeing the world on two wheels, self-propelled, and think it is well worth a try.”

The study work was supported by the Health Research Fund of Instituto de Salud Carlos III; the Spanish regional governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra; and the Catalan Institute of Oncology. The Centre for Physical Activity Research is supported by a grant from TrygFonden. Dr. Ried-Larsen reported personal fees from Novo Nordisk. Dr. Redberg reported receiving grants from Arnold Ventures; the Greenwall Foundation; and the National Heart, Lung, and Blood Institute.

Following a transcatheter aortic valve replacement (TAVR), direct oral anticoagulants (DOACs) are preferable to vitamin K antagonists (VKAs) in patients who are candidates for oral anticoagulants, according to data drawn from a large multicenter French TAVR registry.

When oral anticoagulation is appropriate following TAVR, such as in patients with atrial fibrillation, “DOACs are associated with improved survival and lower incidence of bleeding, compared to VKA,” reported a team of investigators led by Martine Gilard, MD, PhD, director of interventional cardiology, Brest (France) University Hospital Center.

The comparison, using propensity score matching, is not definitive, but it might be the best data currently available to support DOACs over VKA until a randomized trial is completed, according to Dr. Gilard, senior author of the newly published study.

Asked in an interview if DOACs should now be used preferentially after TAVR when patients are indicated for oral anticoagulation, Dr. Gilard replied, “My answer is yes.”

Of more than 24,000 TAVR patients in the French TAVI and FRANCE2 multicenter registries, which are linked to the French single-payer claims database (SNDS), 8,962 (36.4%) received an oral anticoagulant following their procedure. Of these, 2,180 (24.3%) received a DOAC and the remaining received VKA.

By linking data from the registries to the SNDS, outcomes were tracked. Propensity matching was employed to control for differences in baseline characteristics, including age, body mass index, functional class, diabetes, comorbidities, and past medical history.

On the primary endpoint of mortality at the end of 3 years, the rates were 35.6% and 31.2% for VKA and DOACs, respectively. This translated in a 37% greater hazard ratio for death among those treated with VKA (P < .005).

The rate of major bleeding, a secondary endpoint, was also higher (12.3% vs. 8.4%) and significantly different (HR, 1.65; P < .005) for VKA versus DOACs. The rates of ischemic stroke, acute coronary syndrome, and hemorrhagic stroke were all numerically higher in patients treated with VKA than DOACs, although none of these differences reached statistical significance.
 

Residual confounding cannot be discounted

“The large number of events allowed for taking into account a higher number of potential confounders with appropriate statistical power,” according to the authors. However, they acknowledged that residual confounding cannot be eliminated by propensity matching and conceded that prospective data are needed for a definitive comparison.

In an accompanying editorial, Daniele Giacoppo, MD, a cardiologist at Alto Vicentino Hospital, Santorso, Italy, enlarged on this point . In addition to the inherent limitations of retrospective data, he also noted that data from other studies addressing the same question have been inconsistent.

Of these studies, he pointed to the ATLANTIS trial, presented 2 months ago at the annual meeting of the American College of Cardiology. This study failed to show an advantage for the DOAC apixaban over VKA in TAVR patients for the primary composite outcome of time to death, myocardial infarction, systemic emboli, valve thrombosis, or major bleeding. Although this study was not limited to patients with an indication for oral anticoagulants, Dr. Giacoppo pointed out that there was no advantage, even among the subgroup of patients who did have an indication.
 

Data are supportive in absence of trial results

In general, Dr. Giacoppo agreed that the French registry are generally supportive of DOACs over VKA in TAVR patients with an indication for oral anticoagulation, but he cautioned that blanket statements are difficult. He anticipates better information from a randomized trial called ENVISAGE-TAVI AF, which is comparing edoxaban with VKA following TAVR in atrial fibrillation patients who have an indication for oral anticoagulation, but he indicated that some individualization of choice will be needed among those high or low relative risks of thrombotic events or bleeding.

“The concerns related to DOACs after TAVR are most confined to patients without an indication for oral anticoagulation,” Dr. Giacoppo said in an interview. In patients with an indication, “oral anticoagulation alone without antithrombotic therapy significantly reduced the risk of bleeding” in several studies, he added, citing in particular the POPular TAVI trial.

Issues about when to employ – or not employ – both oral anticoagulation and antithrombotic therapy based on such factors as bleeding risk remain unresolved, but “in aggregate, waiting for additional high-quality data, the use of a DOAC in patients with an indication for oral anticoagulation who underwent TAVR seems to be safe,” Dr. Giacoppo said. He thinks that the “higher predictability of DOACS compared to vitamin K antagonists might translate into lower bleeding rates over time in a real-world, unselected population.”
 

Benefit-to-risk ratio requires attention

A similar concern about balancing risks and benefits of oral anticoagulation in TAVR patients with an indication for oral anticoagulation was emphasized by Ron Waksman, MD, associate director, division of cardiology, MedStar Washington (D.C.) Hospital Center.

“The TAVR population is elderly in general and so are at high risk for bleeding with any additional anticoagulation,” Dr. Waksman said. He cited data that bring into question the utility of using a DOAC in TAVR patients without an additional indication for anticoagulation, but he believes DOACs do make sense in those who were on and had an indication for a DOAC even before TAVR.

Patients who had atrial fibrillation or another indication “should continue to take the DOAC after TAVR. This population can be assumed to have less bleeding risk as they are vetted as safe for DOACs before their TAVR procedure,” he said.

Although mortality was the primary endpoint of the French registry evaluation, it is the bleeding risk that is a dominant concern, according to Romain Didier, MD, PhD, the first author of this study who performed this work in collaboration with Dr. Gilard.

“We really believe that VKA use in real life after TAVR, even with INR monitoring, is associated with a higher risk of bleeding as compared to DOACs,” he said. It is for this reason that “we currently use DOACs as a first choice in patients who require anticoagulant after TAVR.”

Dr. Gilard, Dr. Didier, and Dr. Giacoppo reported no potential conflicts of interest. Dr. Waksman reported financial relationships with Amgen, AstraZeneca, Boston Scientific, Cardioset, Cardiovascular Systems, Chiesi, MedAlliance, Medtronic, and Pi-Cardia.

Following a transcatheter aortic valve replacement (TAVR), direct oral anticoagulants (DOACs) are preferable to vitamin K antagonists (VKAs) in patients who are candidates for oral anticoagulants, according to data drawn from a large multicenter French TAVR registry.

When oral anticoagulation is appropriate following TAVR, such as in patients with atrial fibrillation, “DOACs are associated with improved survival and lower incidence of bleeding, compared to VKA,” reported a team of investigators led by Martine Gilard, MD, PhD, director of interventional cardiology, Brest (France) University Hospital Center.

The comparison, using propensity score matching, is not definitive, but it might be the best data currently available to support DOACs over VKA until a randomized trial is completed, according to Dr. Gilard, senior author of the newly published study.

Asked in an interview if DOACs should now be used preferentially after TAVR when patients are indicated for oral anticoagulation, Dr. Gilard replied, “My answer is yes.”

Of more than 24,000 TAVR patients in the French TAVI and FRANCE2 multicenter registries, which are linked to the French single-payer claims database (SNDS), 8,962 (36.4%) received an oral anticoagulant following their procedure. Of these, 2,180 (24.3%) received a DOAC and the remaining received VKA.

By linking data from the registries to the SNDS, outcomes were tracked. Propensity matching was employed to control for differences in baseline characteristics, including age, body mass index, functional class, diabetes, comorbidities, and past medical history.

On the primary endpoint of mortality at the end of 3 years, the rates were 35.6% and 31.2% for VKA and DOACs, respectively. This translated in a 37% greater hazard ratio for death among those treated with VKA (P < .005).

The rate of major bleeding, a secondary endpoint, was also higher (12.3% vs. 8.4%) and significantly different (HR, 1.65; P < .005) for VKA versus DOACs. The rates of ischemic stroke, acute coronary syndrome, and hemorrhagic stroke were all numerically higher in patients treated with VKA than DOACs, although none of these differences reached statistical significance.
 

Residual confounding cannot be discounted

“The large number of events allowed for taking into account a higher number of potential confounders with appropriate statistical power,” according to the authors. However, they acknowledged that residual confounding cannot be eliminated by propensity matching and conceded that prospective data are needed for a definitive comparison.

In an accompanying editorial, Daniele Giacoppo, MD, a cardiologist at Alto Vicentino Hospital, Santorso, Italy, enlarged on this point . In addition to the inherent limitations of retrospective data, he also noted that data from other studies addressing the same question have been inconsistent.

Of these studies, he pointed to the ATLANTIS trial, presented 2 months ago at the annual meeting of the American College of Cardiology. This study failed to show an advantage for the DOAC apixaban over VKA in TAVR patients for the primary composite outcome of time to death, myocardial infarction, systemic emboli, valve thrombosis, or major bleeding. Although this study was not limited to patients with an indication for oral anticoagulants, Dr. Giacoppo pointed out that there was no advantage, even among the subgroup of patients who did have an indication.
 

Data are supportive in absence of trial results

In general, Dr. Giacoppo agreed that the French registry are generally supportive of DOACs over VKA in TAVR patients with an indication for oral anticoagulation, but he cautioned that blanket statements are difficult. He anticipates better information from a randomized trial called ENVISAGE-TAVI AF, which is comparing edoxaban with VKA following TAVR in atrial fibrillation patients who have an indication for oral anticoagulation, but he indicated that some individualization of choice will be needed among those high or low relative risks of thrombotic events or bleeding.

“The concerns related to DOACs after TAVR are most confined to patients without an indication for oral anticoagulation,” Dr. Giacoppo said in an interview. In patients with an indication, “oral anticoagulation alone without antithrombotic therapy significantly reduced the risk of bleeding” in several studies, he added, citing in particular the POPular TAVI trial.

Issues about when to employ – or not employ – both oral anticoagulation and antithrombotic therapy based on such factors as bleeding risk remain unresolved, but “in aggregate, waiting for additional high-quality data, the use of a DOAC in patients with an indication for oral anticoagulation who underwent TAVR seems to be safe,” Dr. Giacoppo said. He thinks that the “higher predictability of DOACS compared to vitamin K antagonists might translate into lower bleeding rates over time in a real-world, unselected population.”
 

Benefit-to-risk ratio requires attention

A similar concern about balancing risks and benefits of oral anticoagulation in TAVR patients with an indication for oral anticoagulation was emphasized by Ron Waksman, MD, associate director, division of cardiology, MedStar Washington (D.C.) Hospital Center.

“The TAVR population is elderly in general and so are at high risk for bleeding with any additional anticoagulation,” Dr. Waksman said. He cited data that bring into question the utility of using a DOAC in TAVR patients without an additional indication for anticoagulation, but he believes DOACs do make sense in those who were on and had an indication for a DOAC even before TAVR.

Patients who had atrial fibrillation or another indication “should continue to take the DOAC after TAVR. This population can be assumed to have less bleeding risk as they are vetted as safe for DOACs before their TAVR procedure,” he said.

Although mortality was the primary endpoint of the French registry evaluation, it is the bleeding risk that is a dominant concern, according to Romain Didier, MD, PhD, the first author of this study who performed this work in collaboration with Dr. Gilard.

“We really believe that VKA use in real life after TAVR, even with INR monitoring, is associated with a higher risk of bleeding as compared to DOACs,” he said. It is for this reason that “we currently use DOACs as a first choice in patients who require anticoagulant after TAVR.”

Dr. Gilard, Dr. Didier, and Dr. Giacoppo reported no potential conflicts of interest. Dr. Waksman reported financial relationships with Amgen, AstraZeneca, Boston Scientific, Cardioset, Cardiovascular Systems, Chiesi, MedAlliance, Medtronic, and Pi-Cardia.

Following a transcatheter aortic valve replacement (TAVR), direct oral anticoagulants (DOACs) are preferable to vitamin K antagonists (VKAs) in patients who are candidates for oral anticoagulants, according to data drawn from a large multicenter French TAVR registry.

When oral anticoagulation is appropriate following TAVR, such as in patients with atrial fibrillation, “DOACs are associated with improved survival and lower incidence of bleeding, compared to VKA,” reported a team of investigators led by Martine Gilard, MD, PhD, director of interventional cardiology, Brest (France) University Hospital Center.

The comparison, using propensity score matching, is not definitive, but it might be the best data currently available to support DOACs over VKA until a randomized trial is completed, according to Dr. Gilard, senior author of the newly published study.

Asked in an interview if DOACs should now be used preferentially after TAVR when patients are indicated for oral anticoagulation, Dr. Gilard replied, “My answer is yes.”

Of more than 24,000 TAVR patients in the French TAVI and FRANCE2 multicenter registries, which are linked to the French single-payer claims database (SNDS), 8,962 (36.4%) received an oral anticoagulant following their procedure. Of these, 2,180 (24.3%) received a DOAC and the remaining received VKA.

By linking data from the registries to the SNDS, outcomes were tracked. Propensity matching was employed to control for differences in baseline characteristics, including age, body mass index, functional class, diabetes, comorbidities, and past medical history.

On the primary endpoint of mortality at the end of 3 years, the rates were 35.6% and 31.2% for VKA and DOACs, respectively. This translated in a 37% greater hazard ratio for death among those treated with VKA (P < .005).

The rate of major bleeding, a secondary endpoint, was also higher (12.3% vs. 8.4%) and significantly different (HR, 1.65; P < .005) for VKA versus DOACs. The rates of ischemic stroke, acute coronary syndrome, and hemorrhagic stroke were all numerically higher in patients treated with VKA than DOACs, although none of these differences reached statistical significance.
 

Residual confounding cannot be discounted

“The large number of events allowed for taking into account a higher number of potential confounders with appropriate statistical power,” according to the authors. However, they acknowledged that residual confounding cannot be eliminated by propensity matching and conceded that prospective data are needed for a definitive comparison.

In an accompanying editorial, Daniele Giacoppo, MD, a cardiologist at Alto Vicentino Hospital, Santorso, Italy, enlarged on this point . In addition to the inherent limitations of retrospective data, he also noted that data from other studies addressing the same question have been inconsistent.

Of these studies, he pointed to the ATLANTIS trial, presented 2 months ago at the annual meeting of the American College of Cardiology. This study failed to show an advantage for the DOAC apixaban over VKA in TAVR patients for the primary composite outcome of time to death, myocardial infarction, systemic emboli, valve thrombosis, or major bleeding. Although this study was not limited to patients with an indication for oral anticoagulants, Dr. Giacoppo pointed out that there was no advantage, even among the subgroup of patients who did have an indication.
 

Data are supportive in absence of trial results

In general, Dr. Giacoppo agreed that the French registry are generally supportive of DOACs over VKA in TAVR patients with an indication for oral anticoagulation, but he cautioned that blanket statements are difficult. He anticipates better information from a randomized trial called ENVISAGE-TAVI AF, which is comparing edoxaban with VKA following TAVR in atrial fibrillation patients who have an indication for oral anticoagulation, but he indicated that some individualization of choice will be needed among those high or low relative risks of thrombotic events or bleeding.

“The concerns related to DOACs after TAVR are most confined to patients without an indication for oral anticoagulation,” Dr. Giacoppo said in an interview. In patients with an indication, “oral anticoagulation alone without antithrombotic therapy significantly reduced the risk of bleeding” in several studies, he added, citing in particular the POPular TAVI trial.

Issues about when to employ – or not employ – both oral anticoagulation and antithrombotic therapy based on such factors as bleeding risk remain unresolved, but “in aggregate, waiting for additional high-quality data, the use of a DOAC in patients with an indication for oral anticoagulation who underwent TAVR seems to be safe,” Dr. Giacoppo said. He thinks that the “higher predictability of DOACS compared to vitamin K antagonists might translate into lower bleeding rates over time in a real-world, unselected population.”
 

Benefit-to-risk ratio requires attention

A similar concern about balancing risks and benefits of oral anticoagulation in TAVR patients with an indication for oral anticoagulation was emphasized by Ron Waksman, MD, associate director, division of cardiology, MedStar Washington (D.C.) Hospital Center.

“The TAVR population is elderly in general and so are at high risk for bleeding with any additional anticoagulation,” Dr. Waksman said. He cited data that bring into question the utility of using a DOAC in TAVR patients without an additional indication for anticoagulation, but he believes DOACs do make sense in those who were on and had an indication for a DOAC even before TAVR.

Patients who had atrial fibrillation or another indication “should continue to take the DOAC after TAVR. This population can be assumed to have less bleeding risk as they are vetted as safe for DOACs before their TAVR procedure,” he said.

Although mortality was the primary endpoint of the French registry evaluation, it is the bleeding risk that is a dominant concern, according to Romain Didier, MD, PhD, the first author of this study who performed this work in collaboration with Dr. Gilard.

“We really believe that VKA use in real life after TAVR, even with INR monitoring, is associated with a higher risk of bleeding as compared to DOACs,” he said. It is for this reason that “we currently use DOACs as a first choice in patients who require anticoagulant after TAVR.”

Dr. Gilard, Dr. Didier, and Dr. Giacoppo reported no potential conflicts of interest. Dr. Waksman reported financial relationships with Amgen, AstraZeneca, Boston Scientific, Cardioset, Cardiovascular Systems, Chiesi, MedAlliance, Medtronic, and Pi-Cardia.

Data from a long-term study suggest that testosterone replacement therapy (TRT) for men with hypogonadism may reduce the risk for major adverse cardiovascular events. Previous studies have yielded conflicting results on whether there is a benefit.

The latest results come from a study of 805 men with hypogonadism from Germany and Qatar who were followed for nearly a decade. For those who received parenteral testosterone 1,000 mg every 12 weeks, there were improvements in classical cardiovascular risk factors, such as obesity, lipid level, and inflammatory markers, whereas among those who chose not to take testosterone (control patients), all of these factors worsened.

In addition, there were only 16 deaths among patients in the TRT group, and none of the deaths were from myocardial infarction or stroke. In contrast, there were 74 deaths among the control patients, as well as 70 cases of MI and 59 strokes.

The men in the study were all at relatively high risk for cardiovascular adverse events. In the TRT group, the mean Framingham Risk score was 15.5; in the control group, it was 15.8. This translates into mean 10-year risks of 22.7% and 23.5%, respectively.

“Given that all these men would normally have been expected to suffer a heart attack or stroke in the next 5-10 years with no other intervention, it was a real surprise to see no cardiovascular events at all in the group on testosterone therapy. It’s clear that this treatment can significantly reduce the risks in this particular group,” commented lead investigator Omar Aboumarzouk, MD, from Hamad Medical in Doha, Qatar.

He presented the new data at the 2021 annual congress of the European Association of Urology.

Dr. Aboumarzouk emphasized, however, that, “while men need testosterone for certain psychological and biological functions, only those with low levels who display other symptoms are likely to benefit from testosterone therapy.”

Maarten Albersen, MD, a urologist at the University of Leuven (Belgium), who was not involved in the study, noted that, although the study showed a reduction in major adverse cardiovascular events and mortality among the men who received TRT, the risk scores were in the intermediate range, and the men in the TRT group were slightly younger and were at slightly lower risk at baseline.

“The study was long enough to see differences in the rate of cardiovascular events. However, the numbers involved and the fact that the trial was not randomized mean it’s still difficult to draw any hard conclusions,” he said.
 

Registry study

The data came from a cumulative registry study begun in 2004 to assess the long-term efficacy and safety of TRT every 3 months in men with hypogonadism. The study, conducted in Bremen, Dresden, and Muenster in Germany, as well as in Doha, Qatar, is ongoing.

At total of 805 men were enrolled; 412 received TRT, and 393 declined testosterone replacement and served as control patients.

The investigators reported 10-year data. Statistical models controlled for age, body mass index, smoking, alcohol, total and HDL cholesterol level, systolic blood pressure, and type 2 diabetes.

The median age at baseline was lower among those in the TRT arm, at 57.7 years versus 63.7 years for control patients (P < .001).

All classical cardiovascular risk factors, including obesity, glycemic control, lipid pattern, and C-reactive protein, improved in the TRT group and worsened in the control group.

Dr. Albersen noted that “a new trial is now underway, aiming to recruit 6,000 participants, and this should provide definitive answers on the cardiovascular risks or even benefits of hormone therapy in men with low testosterone.”

No funding source for the study was reported. Dr. Aboumarzouk and Dr. Albersen have disclosed no relevant financial relationships.

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

Data from a long-term study suggest that testosterone replacement therapy (TRT) for men with hypogonadism may reduce the risk for major adverse cardiovascular events. Previous studies have yielded conflicting results on whether there is a benefit.

The latest results come from a study of 805 men with hypogonadism from Germany and Qatar who were followed for nearly a decade. For those who received parenteral testosterone 1,000 mg every 12 weeks, there were improvements in classical cardiovascular risk factors, such as obesity, lipid level, and inflammatory markers, whereas among those who chose not to take testosterone (control patients), all of these factors worsened.

In addition, there were only 16 deaths among patients in the TRT group, and none of the deaths were from myocardial infarction or stroke. In contrast, there were 74 deaths among the control patients, as well as 70 cases of MI and 59 strokes.

The men in the study were all at relatively high risk for cardiovascular adverse events. In the TRT group, the mean Framingham Risk score was 15.5; in the control group, it was 15.8. This translates into mean 10-year risks of 22.7% and 23.5%, respectively.

“Given that all these men would normally have been expected to suffer a heart attack or stroke in the next 5-10 years with no other intervention, it was a real surprise to see no cardiovascular events at all in the group on testosterone therapy. It’s clear that this treatment can significantly reduce the risks in this particular group,” commented lead investigator Omar Aboumarzouk, MD, from Hamad Medical in Doha, Qatar.

He presented the new data at the 2021 annual congress of the European Association of Urology.

Dr. Aboumarzouk emphasized, however, that, “while men need testosterone for certain psychological and biological functions, only those with low levels who display other symptoms are likely to benefit from testosterone therapy.”

Maarten Albersen, MD, a urologist at the University of Leuven (Belgium), who was not involved in the study, noted that, although the study showed a reduction in major adverse cardiovascular events and mortality among the men who received TRT, the risk scores were in the intermediate range, and the men in the TRT group were slightly younger and were at slightly lower risk at baseline.

“The study was long enough to see differences in the rate of cardiovascular events. However, the numbers involved and the fact that the trial was not randomized mean it’s still difficult to draw any hard conclusions,” he said.
 

Registry study

The data came from a cumulative registry study begun in 2004 to assess the long-term efficacy and safety of TRT every 3 months in men with hypogonadism. The study, conducted in Bremen, Dresden, and Muenster in Germany, as well as in Doha, Qatar, is ongoing.

At total of 805 men were enrolled; 412 received TRT, and 393 declined testosterone replacement and served as control patients.

The investigators reported 10-year data. Statistical models controlled for age, body mass index, smoking, alcohol, total and HDL cholesterol level, systolic blood pressure, and type 2 diabetes.

The median age at baseline was lower among those in the TRT arm, at 57.7 years versus 63.7 years for control patients (P < .001).

All classical cardiovascular risk factors, including obesity, glycemic control, lipid pattern, and C-reactive protein, improved in the TRT group and worsened in the control group.

Dr. Albersen noted that “a new trial is now underway, aiming to recruit 6,000 participants, and this should provide definitive answers on the cardiovascular risks or even benefits of hormone therapy in men with low testosterone.”

No funding source for the study was reported. Dr. Aboumarzouk and Dr. Albersen have disclosed no relevant financial relationships.

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

Data from a long-term study suggest that testosterone replacement therapy (TRT) for men with hypogonadism may reduce the risk for major adverse cardiovascular events. Previous studies have yielded conflicting results on whether there is a benefit.

The latest results come from a study of 805 men with hypogonadism from Germany and Qatar who were followed for nearly a decade. For those who received parenteral testosterone 1,000 mg every 12 weeks, there were improvements in classical cardiovascular risk factors, such as obesity, lipid level, and inflammatory markers, whereas among those who chose not to take testosterone (control patients), all of these factors worsened.

In addition, there were only 16 deaths among patients in the TRT group, and none of the deaths were from myocardial infarction or stroke. In contrast, there were 74 deaths among the control patients, as well as 70 cases of MI and 59 strokes.

The men in the study were all at relatively high risk for cardiovascular adverse events. In the TRT group, the mean Framingham Risk score was 15.5; in the control group, it was 15.8. This translates into mean 10-year risks of 22.7% and 23.5%, respectively.

“Given that all these men would normally have been expected to suffer a heart attack or stroke in the next 5-10 years with no other intervention, it was a real surprise to see no cardiovascular events at all in the group on testosterone therapy. It’s clear that this treatment can significantly reduce the risks in this particular group,” commented lead investigator Omar Aboumarzouk, MD, from Hamad Medical in Doha, Qatar.

He presented the new data at the 2021 annual congress of the European Association of Urology.

Dr. Aboumarzouk emphasized, however, that, “while men need testosterone for certain psychological and biological functions, only those with low levels who display other symptoms are likely to benefit from testosterone therapy.”

Maarten Albersen, MD, a urologist at the University of Leuven (Belgium), who was not involved in the study, noted that, although the study showed a reduction in major adverse cardiovascular events and mortality among the men who received TRT, the risk scores were in the intermediate range, and the men in the TRT group were slightly younger and were at slightly lower risk at baseline.

“The study was long enough to see differences in the rate of cardiovascular events. However, the numbers involved and the fact that the trial was not randomized mean it’s still difficult to draw any hard conclusions,” he said.
 

Registry study

The data came from a cumulative registry study begun in 2004 to assess the long-term efficacy and safety of TRT every 3 months in men with hypogonadism. The study, conducted in Bremen, Dresden, and Muenster in Germany, as well as in Doha, Qatar, is ongoing.

At total of 805 men were enrolled; 412 received TRT, and 393 declined testosterone replacement and served as control patients.

The investigators reported 10-year data. Statistical models controlled for age, body mass index, smoking, alcohol, total and HDL cholesterol level, systolic blood pressure, and type 2 diabetes.

The median age at baseline was lower among those in the TRT arm, at 57.7 years versus 63.7 years for control patients (P < .001).

All classical cardiovascular risk factors, including obesity, glycemic control, lipid pattern, and C-reactive protein, improved in the TRT group and worsened in the control group.

Dr. Albersen noted that “a new trial is now underway, aiming to recruit 6,000 participants, and this should provide definitive answers on the cardiovascular risks or even benefits of hormone therapy in men with low testosterone.”

No funding source for the study was reported. Dr. Aboumarzouk and Dr. Albersen have disclosed no relevant financial relationships.

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

Support for a cardiovascular benefit of omega-3 fatty acids, particularly eicosapentaenoic acid (EPA), has come from a new systematic review and meta-analysis of randomized trials.

The meta-analysis of 38 randomized controlled trials found that omega-3 fatty acids improved cardiovascular outcomes, with a greater reduction in cardiovascular risk in studies of EPA alone rather than of combined eicosapentaenoic plus docosahexaenoic acid (DHA) supplements.

The paper was published online in EClinicalMedicine.

Senior author Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, was also lead investigator of the REDUCE-IT trial, which is included in the analysis and showed a 25% relative risk reduction in major cardiovascular events with a high-dose EPA product.

But the REDUCE-IT trial has been mired in controversy, with suggestions that the benefit seen might have been exaggerated because of the use of a harmful placebo. In addition, a second large trial of high-dose omega-3 fatty acids, STRENGTH (which tested a combination EPA/DHA product) showed no benefit on cardiovascular outcomes.

Dr. Bhatt said the new meta-analysis provides “a totality of evidence” that “supports a robust and consistent benefit of EPA.”

In the review, the authors concluded: “In this systematic review and meta-analysis, we noted moderate certainty of evidence favoring omega-3 fatty acids for reducing cardiovascular mortality and outcomes. ... The magnitude of relative reductions was robust in EPA trials versus those of EPA+DHA, suggesting differential effects of EPA and DHA in cardiovascular risk reduction.”
 

Controversy continues

But commenting on the publication for an interview, Steven Nissen, MD, Cleveland Clinic, who led the STRENGTH trial, pointed out that 85% of the EPA data in the new meta-analysis came from REDUCE-IT, so the results were a “foregone conclusion.”

“The purpose of a meta-analysis is to answer scientific questions when existing studies are too small to yield statistically robust results. That is not the case here,” Dr. Nissen stated.

He added: “There are only two major trials of EPA and both have important flaws. REDUCE-IT used a questionable placebo (mineral oil) and JELIS was an open-label trial that studied patients with baseline LDL [cholesterol] of 180 mg/dL that was not appropriately treated. A meta-analysis is only as good as the studies that it includes. The other EPA plus DHA studies were essentially neutral.”

Dr. Bhatt responded that, “to date, every randomized trial of EPA only has been positive. Some have been placebo controlled, some have been open label. This meta-analysis corroborates the results of each of those trials in a statistically robust way.”

He added: “Of course, REDUCE-IT is the most rigorous, contemporary trial of EPA. However, in our meta-analysis, even when excluding REDUCE-IT (or for that matter, JELIS), the EPA trials still significantly reduced cardiovascular events.”

Dr. Bhatt also pointed out that two randomized imaging studies, CHERRY and EVAPORATE, have shown benefits of EPA.

“Beyond the clinical trial data, there is a growing amount of evidence supporting the unique biological actions of different omega-3 fatty acids. EPA, in particular, appears to have the strongest basic science evidence supporting cardiovascular benefits. Overall, it is a remarkably consistent scientific story in support of EPA’s beneficial effects on cardiovascular health,” he stated.
 

38 trials included

For the current paper, Dr. Bhatt and coauthors performed a comprehensive literature search for randomized trials comparing omega-3 fatty acids with control (placebo, no supplementation, or lower dose of omega-3 fatty acids) in adults, with a follow-up of at least 12 months, and mortality and cardiovascular outcomes as endpoints.

Ultimately, 38 trials encompassing 149,051 patients were included. Of these, four trials compared EPA with control, 34 trials compared EPA+DHA with control, and 22 trials were in primary prevention. The dose of omega-3 fatty acids ranged from 0.4 g/day to 5.5 g/day.

A total of 25 trials with 143,514 individuals reported 5,550 events of cardiovascular mortality, and 24 trials with 140,983 individuals reported 10,795 events of all-cause mortality.

Omega-3 fatty acids were associated with reduced cardiovascular mortality (rate ratio, 0.93; P = .01), but not all-cause mortality (RR, 0.97; P = .27). The meta-analysis showed reduction in cardiovascular mortality with EPA monotherapy (RR, 0.82; P = .04) and EPA+DHA combination (RR, 0.94; P = .02).

A total of 20 trials with 125,611 individuals reported 2,989 nonfatal myocardial infarction events, and 29 trials with 144,384 individuals reported 9,153 coronary heart disease (CHD) events.

Omega-3 fatty acids were associated with reducing nonfatal MI (RR, 0.87; P = .0001) and CHD (RR, 0.91; P = .0002). The meta-analysis showed higher risk reductions in nonfatal MI with EPA monotherapy (RR, 0.72; P = .00002) than with EPA+DHA combination (RR, 0.92; P = .05), and also for CHD events with EPA monotherapy (RR, 0.73; P = .00004) than with EPA+DHA combination (RR, 0.94; P = .01).

A total of 17 trials (n = 135,019) reported 13,234 events of MACE, and 13 trials (n = 117,890) reported 7,416 events of revascularization.

Omega-3 fatty acids were associated with reducing MACE (RR, 0.95; P = .002) and revascularization (RR, 0.91; P = .0001). The meta-analysis showed higher risk reductions in MACE with EPA monotherapy (RR, 0.78; P = .00000001), whereas EPA+DHA combination did not reduce MACE (RR, 0.99; P = .48). This effect was consistent for revascularization.

A total of eight trials with 65,404 individuals reported 935 nonfatal strokes, and eight trials with 51,336 individuals reported 1,572 events of atrial fibrillation (AFib).

Omega-3 fatty acids did not significantly reduce nonfatal stroke (RR, 1.04; P = .55), but EPA monotherapy was associated with a reduction of nonfatal stroke, compared with control (RR: 0.71; P = .01).

Conversely, omega-3 fatty acids were associated with increased risk for AFib (RR, 1.26; P = .004), with a higher risk with EPA monotherapy than with control (RR, 1.35; P = .004).

Overall, omega-3 fatty acids did not prevent sudden cardiac death or increase gastrointestinal-related adverse events, total bleeding, or major or minor bleeding; however, the meta-analysis showed a higher risk of total bleeding with EPA monotherapy than with control (RR, 1.49; P = .006).

An influence analysis with stepwise exclusion of one trial at a time, including REDUCE-IT, did not alter the overall summary estimates. “Despite the exclusion of REDUCE-IT, EPA monotherapy reduced MACE by 23%, compared with the control,” the authors reported.

They said these new findings also have important implications for clinical practice and treatment guidelines.

“After REDUCE-IT, several national and international guidelines endorsed EPA in their therapeutic recommendations. However, the publication of two recent negative trials of EPA + DHA has created some confusion in the scientific community about the value of omega-3 FAs in preventing atherosclerotic cardiovascular disease [ASCVD],” they stated.

“This meta-analysis provides reassurance about the role of omega-3 fatty acids, specifically EPA, in the current treatment framework of ASCVD residual cardiovascular risk reduction and encourages investigators to explore further the cardiovascular effects of EPA across different clinical settings,” they added.

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for the work Dr. Bhatt did as the trial chair and as the international principal investigator. The present analysis was unfunded.

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

Support for a cardiovascular benefit of omega-3 fatty acids, particularly eicosapentaenoic acid (EPA), has come from a new systematic review and meta-analysis of randomized trials.

The meta-analysis of 38 randomized controlled trials found that omega-3 fatty acids improved cardiovascular outcomes, with a greater reduction in cardiovascular risk in studies of EPA alone rather than of combined eicosapentaenoic plus docosahexaenoic acid (DHA) supplements.

The paper was published online in EClinicalMedicine.

Senior author Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, was also lead investigator of the REDUCE-IT trial, which is included in the analysis and showed a 25% relative risk reduction in major cardiovascular events with a high-dose EPA product.

But the REDUCE-IT trial has been mired in controversy, with suggestions that the benefit seen might have been exaggerated because of the use of a harmful placebo. In addition, a second large trial of high-dose omega-3 fatty acids, STRENGTH (which tested a combination EPA/DHA product) showed no benefit on cardiovascular outcomes.

Dr. Bhatt said the new meta-analysis provides “a totality of evidence” that “supports a robust and consistent benefit of EPA.”

In the review, the authors concluded: “In this systematic review and meta-analysis, we noted moderate certainty of evidence favoring omega-3 fatty acids for reducing cardiovascular mortality and outcomes. ... The magnitude of relative reductions was robust in EPA trials versus those of EPA+DHA, suggesting differential effects of EPA and DHA in cardiovascular risk reduction.”
 

Controversy continues

But commenting on the publication for an interview, Steven Nissen, MD, Cleveland Clinic, who led the STRENGTH trial, pointed out that 85% of the EPA data in the new meta-analysis came from REDUCE-IT, so the results were a “foregone conclusion.”

“The purpose of a meta-analysis is to answer scientific questions when existing studies are too small to yield statistically robust results. That is not the case here,” Dr. Nissen stated.

He added: “There are only two major trials of EPA and both have important flaws. REDUCE-IT used a questionable placebo (mineral oil) and JELIS was an open-label trial that studied patients with baseline LDL [cholesterol] of 180 mg/dL that was not appropriately treated. A meta-analysis is only as good as the studies that it includes. The other EPA plus DHA studies were essentially neutral.”

Dr. Bhatt responded that, “to date, every randomized trial of EPA only has been positive. Some have been placebo controlled, some have been open label. This meta-analysis corroborates the results of each of those trials in a statistically robust way.”

He added: “Of course, REDUCE-IT is the most rigorous, contemporary trial of EPA. However, in our meta-analysis, even when excluding REDUCE-IT (or for that matter, JELIS), the EPA trials still significantly reduced cardiovascular events.”

Dr. Bhatt also pointed out that two randomized imaging studies, CHERRY and EVAPORATE, have shown benefits of EPA.

“Beyond the clinical trial data, there is a growing amount of evidence supporting the unique biological actions of different omega-3 fatty acids. EPA, in particular, appears to have the strongest basic science evidence supporting cardiovascular benefits. Overall, it is a remarkably consistent scientific story in support of EPA’s beneficial effects on cardiovascular health,” he stated.
 

38 trials included

For the current paper, Dr. Bhatt and coauthors performed a comprehensive literature search for randomized trials comparing omega-3 fatty acids with control (placebo, no supplementation, or lower dose of omega-3 fatty acids) in adults, with a follow-up of at least 12 months, and mortality and cardiovascular outcomes as endpoints.

Ultimately, 38 trials encompassing 149,051 patients were included. Of these, four trials compared EPA with control, 34 trials compared EPA+DHA with control, and 22 trials were in primary prevention. The dose of omega-3 fatty acids ranged from 0.4 g/day to 5.5 g/day.

A total of 25 trials with 143,514 individuals reported 5,550 events of cardiovascular mortality, and 24 trials with 140,983 individuals reported 10,795 events of all-cause mortality.

Omega-3 fatty acids were associated with reduced cardiovascular mortality (rate ratio, 0.93; P = .01), but not all-cause mortality (RR, 0.97; P = .27). The meta-analysis showed reduction in cardiovascular mortality with EPA monotherapy (RR, 0.82; P = .04) and EPA+DHA combination (RR, 0.94; P = .02).

A total of 20 trials with 125,611 individuals reported 2,989 nonfatal myocardial infarction events, and 29 trials with 144,384 individuals reported 9,153 coronary heart disease (CHD) events.

Omega-3 fatty acids were associated with reducing nonfatal MI (RR, 0.87; P = .0001) and CHD (RR, 0.91; P = .0002). The meta-analysis showed higher risk reductions in nonfatal MI with EPA monotherapy (RR, 0.72; P = .00002) than with EPA+DHA combination (RR, 0.92; P = .05), and also for CHD events with EPA monotherapy (RR, 0.73; P = .00004) than with EPA+DHA combination (RR, 0.94; P = .01).

A total of 17 trials (n = 135,019) reported 13,234 events of MACE, and 13 trials (n = 117,890) reported 7,416 events of revascularization.

Omega-3 fatty acids were associated with reducing MACE (RR, 0.95; P = .002) and revascularization (RR, 0.91; P = .0001). The meta-analysis showed higher risk reductions in MACE with EPA monotherapy (RR, 0.78; P = .00000001), whereas EPA+DHA combination did not reduce MACE (RR, 0.99; P = .48). This effect was consistent for revascularization.

A total of eight trials with 65,404 individuals reported 935 nonfatal strokes, and eight trials with 51,336 individuals reported 1,572 events of atrial fibrillation (AFib).

Omega-3 fatty acids did not significantly reduce nonfatal stroke (RR, 1.04; P = .55), but EPA monotherapy was associated with a reduction of nonfatal stroke, compared with control (RR: 0.71; P = .01).

Conversely, omega-3 fatty acids were associated with increased risk for AFib (RR, 1.26; P = .004), with a higher risk with EPA monotherapy than with control (RR, 1.35; P = .004).

Overall, omega-3 fatty acids did not prevent sudden cardiac death or increase gastrointestinal-related adverse events, total bleeding, or major or minor bleeding; however, the meta-analysis showed a higher risk of total bleeding with EPA monotherapy than with control (RR, 1.49; P = .006).

An influence analysis with stepwise exclusion of one trial at a time, including REDUCE-IT, did not alter the overall summary estimates. “Despite the exclusion of REDUCE-IT, EPA monotherapy reduced MACE by 23%, compared with the control,” the authors reported.

They said these new findings also have important implications for clinical practice and treatment guidelines.

“After REDUCE-IT, several national and international guidelines endorsed EPA in their therapeutic recommendations. However, the publication of two recent negative trials of EPA + DHA has created some confusion in the scientific community about the value of omega-3 FAs in preventing atherosclerotic cardiovascular disease [ASCVD],” they stated.

“This meta-analysis provides reassurance about the role of omega-3 fatty acids, specifically EPA, in the current treatment framework of ASCVD residual cardiovascular risk reduction and encourages investigators to explore further the cardiovascular effects of EPA across different clinical settings,” they added.

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for the work Dr. Bhatt did as the trial chair and as the international principal investigator. The present analysis was unfunded.

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

Support for a cardiovascular benefit of omega-3 fatty acids, particularly eicosapentaenoic acid (EPA), has come from a new systematic review and meta-analysis of randomized trials.

The meta-analysis of 38 randomized controlled trials found that omega-3 fatty acids improved cardiovascular outcomes, with a greater reduction in cardiovascular risk in studies of EPA alone rather than of combined eicosapentaenoic plus docosahexaenoic acid (DHA) supplements.

The paper was published online in EClinicalMedicine.

Senior author Deepak Bhatt, MD, Brigham and Women’s Hospital, Boston, was also lead investigator of the REDUCE-IT trial, which is included in the analysis and showed a 25% relative risk reduction in major cardiovascular events with a high-dose EPA product.

But the REDUCE-IT trial has been mired in controversy, with suggestions that the benefit seen might have been exaggerated because of the use of a harmful placebo. In addition, a second large trial of high-dose omega-3 fatty acids, STRENGTH (which tested a combination EPA/DHA product) showed no benefit on cardiovascular outcomes.

Dr. Bhatt said the new meta-analysis provides “a totality of evidence” that “supports a robust and consistent benefit of EPA.”

In the review, the authors concluded: “In this systematic review and meta-analysis, we noted moderate certainty of evidence favoring omega-3 fatty acids for reducing cardiovascular mortality and outcomes. ... The magnitude of relative reductions was robust in EPA trials versus those of EPA+DHA, suggesting differential effects of EPA and DHA in cardiovascular risk reduction.”
 

Controversy continues

But commenting on the publication for an interview, Steven Nissen, MD, Cleveland Clinic, who led the STRENGTH trial, pointed out that 85% of the EPA data in the new meta-analysis came from REDUCE-IT, so the results were a “foregone conclusion.”

“The purpose of a meta-analysis is to answer scientific questions when existing studies are too small to yield statistically robust results. That is not the case here,” Dr. Nissen stated.

He added: “There are only two major trials of EPA and both have important flaws. REDUCE-IT used a questionable placebo (mineral oil) and JELIS was an open-label trial that studied patients with baseline LDL [cholesterol] of 180 mg/dL that was not appropriately treated. A meta-analysis is only as good as the studies that it includes. The other EPA plus DHA studies were essentially neutral.”

Dr. Bhatt responded that, “to date, every randomized trial of EPA only has been positive. Some have been placebo controlled, some have been open label. This meta-analysis corroborates the results of each of those trials in a statistically robust way.”

He added: “Of course, REDUCE-IT is the most rigorous, contemporary trial of EPA. However, in our meta-analysis, even when excluding REDUCE-IT (or for that matter, JELIS), the EPA trials still significantly reduced cardiovascular events.”

Dr. Bhatt also pointed out that two randomized imaging studies, CHERRY and EVAPORATE, have shown benefits of EPA.

“Beyond the clinical trial data, there is a growing amount of evidence supporting the unique biological actions of different omega-3 fatty acids. EPA, in particular, appears to have the strongest basic science evidence supporting cardiovascular benefits. Overall, it is a remarkably consistent scientific story in support of EPA’s beneficial effects on cardiovascular health,” he stated.
 

38 trials included

For the current paper, Dr. Bhatt and coauthors performed a comprehensive literature search for randomized trials comparing omega-3 fatty acids with control (placebo, no supplementation, or lower dose of omega-3 fatty acids) in adults, with a follow-up of at least 12 months, and mortality and cardiovascular outcomes as endpoints.

Ultimately, 38 trials encompassing 149,051 patients were included. Of these, four trials compared EPA with control, 34 trials compared EPA+DHA with control, and 22 trials were in primary prevention. The dose of omega-3 fatty acids ranged from 0.4 g/day to 5.5 g/day.

A total of 25 trials with 143,514 individuals reported 5,550 events of cardiovascular mortality, and 24 trials with 140,983 individuals reported 10,795 events of all-cause mortality.

Omega-3 fatty acids were associated with reduced cardiovascular mortality (rate ratio, 0.93; P = .01), but not all-cause mortality (RR, 0.97; P = .27). The meta-analysis showed reduction in cardiovascular mortality with EPA monotherapy (RR, 0.82; P = .04) and EPA+DHA combination (RR, 0.94; P = .02).

A total of 20 trials with 125,611 individuals reported 2,989 nonfatal myocardial infarction events, and 29 trials with 144,384 individuals reported 9,153 coronary heart disease (CHD) events.

Omega-3 fatty acids were associated with reducing nonfatal MI (RR, 0.87; P = .0001) and CHD (RR, 0.91; P = .0002). The meta-analysis showed higher risk reductions in nonfatal MI with EPA monotherapy (RR, 0.72; P = .00002) than with EPA+DHA combination (RR, 0.92; P = .05), and also for CHD events with EPA monotherapy (RR, 0.73; P = .00004) than with EPA+DHA combination (RR, 0.94; P = .01).

A total of 17 trials (n = 135,019) reported 13,234 events of MACE, and 13 trials (n = 117,890) reported 7,416 events of revascularization.

Omega-3 fatty acids were associated with reducing MACE (RR, 0.95; P = .002) and revascularization (RR, 0.91; P = .0001). The meta-analysis showed higher risk reductions in MACE with EPA monotherapy (RR, 0.78; P = .00000001), whereas EPA+DHA combination did not reduce MACE (RR, 0.99; P = .48). This effect was consistent for revascularization.

A total of eight trials with 65,404 individuals reported 935 nonfatal strokes, and eight trials with 51,336 individuals reported 1,572 events of atrial fibrillation (AFib).

Omega-3 fatty acids did not significantly reduce nonfatal stroke (RR, 1.04; P = .55), but EPA monotherapy was associated with a reduction of nonfatal stroke, compared with control (RR: 0.71; P = .01).

Conversely, omega-3 fatty acids were associated with increased risk for AFib (RR, 1.26; P = .004), with a higher risk with EPA monotherapy than with control (RR, 1.35; P = .004).

Overall, omega-3 fatty acids did not prevent sudden cardiac death or increase gastrointestinal-related adverse events, total bleeding, or major or minor bleeding; however, the meta-analysis showed a higher risk of total bleeding with EPA monotherapy than with control (RR, 1.49; P = .006).

An influence analysis with stepwise exclusion of one trial at a time, including REDUCE-IT, did not alter the overall summary estimates. “Despite the exclusion of REDUCE-IT, EPA monotherapy reduced MACE by 23%, compared with the control,” the authors reported.

They said these new findings also have important implications for clinical practice and treatment guidelines.

“After REDUCE-IT, several national and international guidelines endorsed EPA in their therapeutic recommendations. However, the publication of two recent negative trials of EPA + DHA has created some confusion in the scientific community about the value of omega-3 FAs in preventing atherosclerotic cardiovascular disease [ASCVD],” they stated.

“This meta-analysis provides reassurance about the role of omega-3 fatty acids, specifically EPA, in the current treatment framework of ASCVD residual cardiovascular risk reduction and encourages investigators to explore further the cardiovascular effects of EPA across different clinical settings,” they added.

REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for the work Dr. Bhatt did as the trial chair and as the international principal investigator. The present analysis was unfunded.

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.

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.

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.

Courtesy Cardiovascular Research Foundation

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.

Courtesy Cardiovascular Research Foundation

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.

Courtesy Cardiovascular Research Foundation

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.

Deprescribing may help in reducing inappropriate medication use and adverse events, but for cardiovascular care in the elderly, eliminating statins among patients taking other medications may have negative effects that far outweigh the benefits, a new study suggests.

In a large cohort study, researchers found that the withdrawal of statins from an elderly population receiving polypharmacy was associated with an increase in the risk for hospital admission for heart failure and any cardiovascular outcome, as well as death from any cause.

Statins are “lifesaving” drugs, and “according to the findings of our study, the discontinuation of this therapy has significant effects,” lead study author Federico Rea, PhD, research fellow, Laboratory of Healthcare Research and Pharmacoepidemiology, the department of statistics and quantitative methods, the University of Milano-Bicocca, said in an interview.

The article was published online June 14, 2021, in JAMA Network Open.

Negative clinical consequences, including adverse drug reactions leading to hospitalizations, are causing more physicians to consider deprescribing as a way to reduce problems associated with polypharmacy, the researchers noted.

Statins are “the most widely prescribed medication in the Western world, being a pivotal component in the primary and secondary prevention of cardiovascular (CV) diseases,” they wrote, but because randomized trials usually exclude patients with serious clinical conditions, the precise role statins play for frail patients, such as those with polypharmacy, “is still unclear.”

The population-based cohort study examined 29,047 Italian residents aged 65 years and older who were receiving uninterrupted treatment with statins as well as blood pressure–lowering, antidiabetic, and antiplatelet agents over 16 months. The follow-up period was more than 3 years.

The cohort members were followed to identify those for whom statins were discontinued. Those who continued taking other therapies during the first 6 months after stopping statins were propensity score matched in a 1:1 ratio with patients who did not discontinue taking statins or other drugs. The patient pairs were then followed for fatal and nonfatal outcomes to estimate the risk associated with statin discontinuation.

Of the overall cohort exposed to polypharmacy, 5819 (20.0%) discontinued statins while continuing to take their other medications. Of those, 4,010 were matched with a comparator.

Compared with the maintaining group, those who discontinued statins had the following outcomes: an increased risk for hospital admissions for heart failure (hazard ratio, 1.24; 95% confidence interval, 1.07-1.43), any cardiovascular outcomes (HR, 1.14; 95% CI, 1.03-1.26), death from any cause (HR, 1.15; 95% CI, 1.02-1.30), and emergency admissions for any cause (HR, 1.12; 95% CI, 1.01-1.19)

The increased risk occurred in patients with mild or severe profiles, regardless of gender and whether statins were prescribed as primary or secondary CV prevention.

“We expected that the discontinuation of statins could reduce the risk of access to the emergency department for neurological causes, considered a proxy for the onset of episodes of delirium, [but] this was not observed, suggesting that statin therapy has essential benefits on the reduction of fatal/nonfatal cardiovascular events with no harm effect,” said Dr. Rea, “at least considering major adverse events like hospital and emergency department admissions.”
 

Findings no surprise

Neil Stone, MD, Bonow Professor of Medicine (Cardiology) and Preventive Medicine at Northwestern University, Chicago, said the study results aren’t surprising.

“Older patients have a higher absolute risk of dying, and withdrawing proven therapy shown to reduce risk of coronary/stroke events in randomized, controlled trials would be expected to result in more cardiovascular events,” Dr. Stone said.

Although polypharmacy is a concern for the elderly and is a factor in decreased adherence, he said better solutions are needed than withdrawing proven, effective therapy. “In that sense, this study indirectly supports more research in the use of polypills to address cardiovascular risk factors,” he said. Giving a single pill that combines medications of proven value in reducing blood pressure and cholesterol might be preferable to reducing the total number of medications.

Given the complexity of polypharmacy, the study investigators say more attention is needed from all health care professionals who care for elderly patients.

“We hope that future studies can shed light on the best way to balance the undeniable benefit of [statins] and the harms, especially among the elderly exposed to polypharmacy,” said Rea.

Further research is also needed into why statins are discontinued in the first place, added Dr. Stone. “We know that statins often are stopped due to symptoms that on further scrutiny may not be related to statin use.”

The study was funded by grants from Fondo d’Ateneo per la Ricerca and Modelling Effectiveness, Cost-effectiveness, and Promoting Health Care Value in the Real World: the Motive Project from the Italian Ministry of the Education, University, and Research. One coauthor served on the advisory board of Roche and has received grants from Bristol Myers Squibb, GlaxoSmithKline, and Novartis outside the submitted work. The other authors disclosed no relevant financial relationships.

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

Deprescribing may help in reducing inappropriate medication use and adverse events, but for cardiovascular care in the elderly, eliminating statins among patients taking other medications may have negative effects that far outweigh the benefits, a new study suggests.

In a large cohort study, researchers found that the withdrawal of statins from an elderly population receiving polypharmacy was associated with an increase in the risk for hospital admission for heart failure and any cardiovascular outcome, as well as death from any cause.

Statins are “lifesaving” drugs, and “according to the findings of our study, the discontinuation of this therapy has significant effects,” lead study author Federico Rea, PhD, research fellow, Laboratory of Healthcare Research and Pharmacoepidemiology, the department of statistics and quantitative methods, the University of Milano-Bicocca, said in an interview.

The article was published online June 14, 2021, in JAMA Network Open.

Negative clinical consequences, including adverse drug reactions leading to hospitalizations, are causing more physicians to consider deprescribing as a way to reduce problems associated with polypharmacy, the researchers noted.

Statins are “the most widely prescribed medication in the Western world, being a pivotal component in the primary and secondary prevention of cardiovascular (CV) diseases,” they wrote, but because randomized trials usually exclude patients with serious clinical conditions, the precise role statins play for frail patients, such as those with polypharmacy, “is still unclear.”

The population-based cohort study examined 29,047 Italian residents aged 65 years and older who were receiving uninterrupted treatment with statins as well as blood pressure–lowering, antidiabetic, and antiplatelet agents over 16 months. The follow-up period was more than 3 years.

The cohort members were followed to identify those for whom statins were discontinued. Those who continued taking other therapies during the first 6 months after stopping statins were propensity score matched in a 1:1 ratio with patients who did not discontinue taking statins or other drugs. The patient pairs were then followed for fatal and nonfatal outcomes to estimate the risk associated with statin discontinuation.

Of the overall cohort exposed to polypharmacy, 5819 (20.0%) discontinued statins while continuing to take their other medications. Of those, 4,010 were matched with a comparator.

Compared with the maintaining group, those who discontinued statins had the following outcomes: an increased risk for hospital admissions for heart failure (hazard ratio, 1.24; 95% confidence interval, 1.07-1.43), any cardiovascular outcomes (HR, 1.14; 95% CI, 1.03-1.26), death from any cause (HR, 1.15; 95% CI, 1.02-1.30), and emergency admissions for any cause (HR, 1.12; 95% CI, 1.01-1.19)

The increased risk occurred in patients with mild or severe profiles, regardless of gender and whether statins were prescribed as primary or secondary CV prevention.

“We expected that the discontinuation of statins could reduce the risk of access to the emergency department for neurological causes, considered a proxy for the onset of episodes of delirium, [but] this was not observed, suggesting that statin therapy has essential benefits on the reduction of fatal/nonfatal cardiovascular events with no harm effect,” said Dr. Rea, “at least considering major adverse events like hospital and emergency department admissions.”
 

Findings no surprise

Neil Stone, MD, Bonow Professor of Medicine (Cardiology) and Preventive Medicine at Northwestern University, Chicago, said the study results aren’t surprising.

“Older patients have a higher absolute risk of dying, and withdrawing proven therapy shown to reduce risk of coronary/stroke events in randomized, controlled trials would be expected to result in more cardiovascular events,” Dr. Stone said.

Although polypharmacy is a concern for the elderly and is a factor in decreased adherence, he said better solutions are needed than withdrawing proven, effective therapy. “In that sense, this study indirectly supports more research in the use of polypills to address cardiovascular risk factors,” he said. Giving a single pill that combines medications of proven value in reducing blood pressure and cholesterol might be preferable to reducing the total number of medications.

Given the complexity of polypharmacy, the study investigators say more attention is needed from all health care professionals who care for elderly patients.

“We hope that future studies can shed light on the best way to balance the undeniable benefit of [statins] and the harms, especially among the elderly exposed to polypharmacy,” said Rea.

Further research is also needed into why statins are discontinued in the first place, added Dr. Stone. “We know that statins often are stopped due to symptoms that on further scrutiny may not be related to statin use.”

The study was funded by grants from Fondo d’Ateneo per la Ricerca and Modelling Effectiveness, Cost-effectiveness, and Promoting Health Care Value in the Real World: the Motive Project from the Italian Ministry of the Education, University, and Research. One coauthor served on the advisory board of Roche and has received grants from Bristol Myers Squibb, GlaxoSmithKline, and Novartis outside the submitted work. The other authors disclosed no relevant financial relationships.

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

Deprescribing may help in reducing inappropriate medication use and adverse events, but for cardiovascular care in the elderly, eliminating statins among patients taking other medications may have negative effects that far outweigh the benefits, a new study suggests.

In a large cohort study, researchers found that the withdrawal of statins from an elderly population receiving polypharmacy was associated with an increase in the risk for hospital admission for heart failure and any cardiovascular outcome, as well as death from any cause.

Statins are “lifesaving” drugs, and “according to the findings of our study, the discontinuation of this therapy has significant effects,” lead study author Federico Rea, PhD, research fellow, Laboratory of Healthcare Research and Pharmacoepidemiology, the department of statistics and quantitative methods, the University of Milano-Bicocca, said in an interview.

The article was published online June 14, 2021, in JAMA Network Open.

Negative clinical consequences, including adverse drug reactions leading to hospitalizations, are causing more physicians to consider deprescribing as a way to reduce problems associated with polypharmacy, the researchers noted.

Statins are “the most widely prescribed medication in the Western world, being a pivotal component in the primary and secondary prevention of cardiovascular (CV) diseases,” they wrote, but because randomized trials usually exclude patients with serious clinical conditions, the precise role statins play for frail patients, such as those with polypharmacy, “is still unclear.”

The population-based cohort study examined 29,047 Italian residents aged 65 years and older who were receiving uninterrupted treatment with statins as well as blood pressure–lowering, antidiabetic, and antiplatelet agents over 16 months. The follow-up period was more than 3 years.

The cohort members were followed to identify those for whom statins were discontinued. Those who continued taking other therapies during the first 6 months after stopping statins were propensity score matched in a 1:1 ratio with patients who did not discontinue taking statins or other drugs. The patient pairs were then followed for fatal and nonfatal outcomes to estimate the risk associated with statin discontinuation.

Of the overall cohort exposed to polypharmacy, 5819 (20.0%) discontinued statins while continuing to take their other medications. Of those, 4,010 were matched with a comparator.

Compared with the maintaining group, those who discontinued statins had the following outcomes: an increased risk for hospital admissions for heart failure (hazard ratio, 1.24; 95% confidence interval, 1.07-1.43), any cardiovascular outcomes (HR, 1.14; 95% CI, 1.03-1.26), death from any cause (HR, 1.15; 95% CI, 1.02-1.30), and emergency admissions for any cause (HR, 1.12; 95% CI, 1.01-1.19)

The increased risk occurred in patients with mild or severe profiles, regardless of gender and whether statins were prescribed as primary or secondary CV prevention.

“We expected that the discontinuation of statins could reduce the risk of access to the emergency department for neurological causes, considered a proxy for the onset of episodes of delirium, [but] this was not observed, suggesting that statin therapy has essential benefits on the reduction of fatal/nonfatal cardiovascular events with no harm effect,” said Dr. Rea, “at least considering major adverse events like hospital and emergency department admissions.”
 

Findings no surprise

Neil Stone, MD, Bonow Professor of Medicine (Cardiology) and Preventive Medicine at Northwestern University, Chicago, said the study results aren’t surprising.

“Older patients have a higher absolute risk of dying, and withdrawing proven therapy shown to reduce risk of coronary/stroke events in randomized, controlled trials would be expected to result in more cardiovascular events,” Dr. Stone said.

Although polypharmacy is a concern for the elderly and is a factor in decreased adherence, he said better solutions are needed than withdrawing proven, effective therapy. “In that sense, this study indirectly supports more research in the use of polypills to address cardiovascular risk factors,” he said. Giving a single pill that combines medications of proven value in reducing blood pressure and cholesterol might be preferable to reducing the total number of medications.

Given the complexity of polypharmacy, the study investigators say more attention is needed from all health care professionals who care for elderly patients.

“We hope that future studies can shed light on the best way to balance the undeniable benefit of [statins] and the harms, especially among the elderly exposed to polypharmacy,” said Rea.

Further research is also needed into why statins are discontinued in the first place, added Dr. Stone. “We know that statins often are stopped due to symptoms that on further scrutiny may not be related to statin use.”

The study was funded by grants from Fondo d’Ateneo per la Ricerca and Modelling Effectiveness, Cost-effectiveness, and Promoting Health Care Value in the Real World: the Motive Project from the Italian Ministry of the Education, University, and Research. One coauthor served on the advisory board of Roche and has received grants from Bristol Myers Squibb, GlaxoSmithKline, and Novartis outside the submitted work. The other authors disclosed no relevant financial relationships.

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

Among patients with atherosclerotic cardiovascular disease (ASCVD), 2 years after release of treat-to-target guidelines from the American Heart Association and the European Society of Cardiology and European Atherosclerosis Society, most patients with LDL cholesterol higher than 70 mg/dL did not receive intensification of therapy, and two-thirds continued to have LDL levels above that level, according to a prospective registry study.

Both guidelines recommend driving LDL-C levels to 50% or below of baseline levels; results from the Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry suggest this is rarely achieved. “Unfortunately it’s not a total surprise, but it’s disappointing,” said Christopher Cannon, MD, the study’s lead author.

“Therapeutic inertia seems to be the rule in clinical practice,” said Jennifer G. Robinson, MD, MPH, who was asked to comment on the study. Dr. Robinson is professor epidemiology and cardiology at the University of Iowa, Iowa City.

Patients hesitant

Changes in practice following guidelines can often be slow, but in this case may have been complicated by the fact that statins have a reputation for causing side effects, so some patients may be refusing treatment based on what they’ve seen on the Internet. Even though the study looked at all lipid-lowering agents, the misinformation around statins may be spilling over, according to Dr. Cannon. “There’s in general so much misinformation around COVID and every other topic in the world. That makes people question what is real [about] anything,” said Dr. Cannon, a cardiologist at Brigham and Women’s hospital and professor of medicine at Harvard Medical School, both in Boston.

Patient characteristics may partly explain slow uptake. “Clinicians may not think further LDL-C lowering is a high enough priority in terms of potential benefit for a given patient in light of the effort being expended to take care of all their other issues and chronic health problems. If the clinician does bring it up to the patient, there may be barriers in terms of additional medication burden, cost, or acquisition issues,” said Dr. Robinson.

The answer may be better evidence and a more personalized approach. Clinical trials that explore defined patient populations could convince patients of a benefit, and payers to reimburse, according to Dr. Robinson.
 

Changing guidance

Another complication is that both the guidelines and the field are rapidly changing. The 2013 AHA guidelines did not include a treatment to goal and focused instead on use of high-dose statins. But the 2018 update reversed course after randomized studies demonstrated a benefit to treating to target. The researchers found no increase in the frequency of treating to target after the release of the 2018 guidelines. “Publication and announcement of guidelines doesn’t mean that people are getting treated better. We really have to implement them,” said Dr. Cannon.

On a positive note, the GOULD researchers found high acceptance of the new proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors, with over 90% of patients continuing those medications after 2 years. “That’s nice and high. If people do get onto the very intensive lipid-lowing therapies, they tend to stay on them,” said Dr. Cannon.
 

What’s next

Still, the lack of intensification is concerning, and the findings led to some consternation in Twitter exchanges, said Dr. Cannon. “People posted ‘Well, what do we do now?’ ” Dr. Cannon’s team is addressing the issue with an algorithm-based risk management program with prospective enrollment. They have conducted educational webinars and provided site-specific reports on LDL status among patients at each center compared to others, and hope that information will improve compliance. In 2020, the group published an interim analysis of the first 5,000 enrollees, and Dr. Cannon expects to finish that study by the end of the year.

Dr. Navar agreed that physicians need to do a better job of testing LDL-C levels after treatment to identify patients who require more aggressive therapy. That can be deferred in some primary prevention patients with high LDL-C but normal particle numbers as measured with ApoB. “But in those at high risk for disease and those with established CVD who are not at goal, as long as they don’t have a life-limiting condition, we should always up-titrate therapy. It’s one of the safest, most effective ways to lower cardiovascular risk,” said Dr. Navar.

Key study results

The prospective study included 5,006 patients at 119 centers with a mean age of 68 years. About 40% were women, and 86.1% were White. All had ASCVD and LDL levels of at least 70 mg/dL. After 2 years, 17% had undergone intensification of lipid-lowering therapy (LLT). Among patients with LDL-C levels ≥ 100 mg/dL, 22% underwent LLT intensification, compared with 14% of patients with LDL-C levels of 70-99 mg/dL.

The vast majority, 92%, of patients who underwent LLT via addition of PCSK9 inhibitors were still taking the drug after 2 years.

Three-quarters (3,768) had lipid level measurements at least once during follow-up, and median LDL-C levels dropped from 120 to 95 mg/dL in the ≥100-mg/dL cohort (P < .001), and from 82 to 77 mg/dL in the 70- to 99-mg/dL cohort (P <. 001). There was no significant difference in the median values in the patients on PCSK9 inhibitors.

In all, 21% of the ≥100-mg/dL cohort achieved LDL-C levels <70 mg/dL at 2 years, versus 34% in the 77- to 99-mg/dL cohort and 52% of patients taking PCSK9 inhibitors.

Patients seen at teaching hospitals were more likely to undergo LLT intensification compared to nonteaching hospitals (25% versus 17%; P < .001), as were those where lipid protocols were in place (22% versus 15%; P < .001), and those treated in cardiology (22%) compared to treatment in internal or family medicine (12%; P <.001). The study was published online June 16 in JAMA Cardiology.

Dr. Cannon, Dr. Navar, and Dr. Robinson disclosed ties with Amgen, which funded the study, and other companies.

Among patients with atherosclerotic cardiovascular disease (ASCVD), 2 years after release of treat-to-target guidelines from the American Heart Association and the European Society of Cardiology and European Atherosclerosis Society, most patients with LDL cholesterol higher than 70 mg/dL did not receive intensification of therapy, and two-thirds continued to have LDL levels above that level, according to a prospective registry study.

Both guidelines recommend driving LDL-C levels to 50% or below of baseline levels; results from the Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry suggest this is rarely achieved. “Unfortunately it’s not a total surprise, but it’s disappointing,” said Christopher Cannon, MD, the study’s lead author.

“Therapeutic inertia seems to be the rule in clinical practice,” said Jennifer G. Robinson, MD, MPH, who was asked to comment on the study. Dr. Robinson is professor epidemiology and cardiology at the University of Iowa, Iowa City.

Patients hesitant

Changes in practice following guidelines can often be slow, but in this case may have been complicated by the fact that statins have a reputation for causing side effects, so some patients may be refusing treatment based on what they’ve seen on the Internet. Even though the study looked at all lipid-lowering agents, the misinformation around statins may be spilling over, according to Dr. Cannon. “There’s in general so much misinformation around COVID and every other topic in the world. That makes people question what is real [about] anything,” said Dr. Cannon, a cardiologist at Brigham and Women’s hospital and professor of medicine at Harvard Medical School, both in Boston.

Patient characteristics may partly explain slow uptake. “Clinicians may not think further LDL-C lowering is a high enough priority in terms of potential benefit for a given patient in light of the effort being expended to take care of all their other issues and chronic health problems. If the clinician does bring it up to the patient, there may be barriers in terms of additional medication burden, cost, or acquisition issues,” said Dr. Robinson.

The answer may be better evidence and a more personalized approach. Clinical trials that explore defined patient populations could convince patients of a benefit, and payers to reimburse, according to Dr. Robinson.
 

Changing guidance

Another complication is that both the guidelines and the field are rapidly changing. The 2013 AHA guidelines did not include a treatment to goal and focused instead on use of high-dose statins. But the 2018 update reversed course after randomized studies demonstrated a benefit to treating to target. The researchers found no increase in the frequency of treating to target after the release of the 2018 guidelines. “Publication and announcement of guidelines doesn’t mean that people are getting treated better. We really have to implement them,” said Dr. Cannon.

On a positive note, the GOULD researchers found high acceptance of the new proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors, with over 90% of patients continuing those medications after 2 years. “That’s nice and high. If people do get onto the very intensive lipid-lowing therapies, they tend to stay on them,” said Dr. Cannon.
 

What’s next

Still, the lack of intensification is concerning, and the findings led to some consternation in Twitter exchanges, said Dr. Cannon. “People posted ‘Well, what do we do now?’ ” Dr. Cannon’s team is addressing the issue with an algorithm-based risk management program with prospective enrollment. They have conducted educational webinars and provided site-specific reports on LDL status among patients at each center compared to others, and hope that information will improve compliance. In 2020, the group published an interim analysis of the first 5,000 enrollees, and Dr. Cannon expects to finish that study by the end of the year.

Dr. Navar agreed that physicians need to do a better job of testing LDL-C levels after treatment to identify patients who require more aggressive therapy. That can be deferred in some primary prevention patients with high LDL-C but normal particle numbers as measured with ApoB. “But in those at high risk for disease and those with established CVD who are not at goal, as long as they don’t have a life-limiting condition, we should always up-titrate therapy. It’s one of the safest, most effective ways to lower cardiovascular risk,” said Dr. Navar.

Key study results

The prospective study included 5,006 patients at 119 centers with a mean age of 68 years. About 40% were women, and 86.1% were White. All had ASCVD and LDL levels of at least 70 mg/dL. After 2 years, 17% had undergone intensification of lipid-lowering therapy (LLT). Among patients with LDL-C levels ≥ 100 mg/dL, 22% underwent LLT intensification, compared with 14% of patients with LDL-C levels of 70-99 mg/dL.

The vast majority, 92%, of patients who underwent LLT via addition of PCSK9 inhibitors were still taking the drug after 2 years.

Three-quarters (3,768) had lipid level measurements at least once during follow-up, and median LDL-C levels dropped from 120 to 95 mg/dL in the ≥100-mg/dL cohort (P < .001), and from 82 to 77 mg/dL in the 70- to 99-mg/dL cohort (P <. 001). There was no significant difference in the median values in the patients on PCSK9 inhibitors.

In all, 21% of the ≥100-mg/dL cohort achieved LDL-C levels <70 mg/dL at 2 years, versus 34% in the 77- to 99-mg/dL cohort and 52% of patients taking PCSK9 inhibitors.

Patients seen at teaching hospitals were more likely to undergo LLT intensification compared to nonteaching hospitals (25% versus 17%; P < .001), as were those where lipid protocols were in place (22% versus 15%; P < .001), and those treated in cardiology (22%) compared to treatment in internal or family medicine (12%; P <.001). The study was published online June 16 in JAMA Cardiology.

Dr. Cannon, Dr. Navar, and Dr. Robinson disclosed ties with Amgen, which funded the study, and other companies.

Among patients with atherosclerotic cardiovascular disease (ASCVD), 2 years after release of treat-to-target guidelines from the American Heart Association and the European Society of Cardiology and European Atherosclerosis Society, most patients with LDL cholesterol higher than 70 mg/dL did not receive intensification of therapy, and two-thirds continued to have LDL levels above that level, according to a prospective registry study.

Both guidelines recommend driving LDL-C levels to 50% or below of baseline levels; results from the Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry suggest this is rarely achieved. “Unfortunately it’s not a total surprise, but it’s disappointing,” said Christopher Cannon, MD, the study’s lead author.

“Therapeutic inertia seems to be the rule in clinical practice,” said Jennifer G. Robinson, MD, MPH, who was asked to comment on the study. Dr. Robinson is professor epidemiology and cardiology at the University of Iowa, Iowa City.

Patients hesitant

Changes in practice following guidelines can often be slow, but in this case may have been complicated by the fact that statins have a reputation for causing side effects, so some patients may be refusing treatment based on what they’ve seen on the Internet. Even though the study looked at all lipid-lowering agents, the misinformation around statins may be spilling over, according to Dr. Cannon. “There’s in general so much misinformation around COVID and every other topic in the world. That makes people question what is real [about] anything,” said Dr. Cannon, a cardiologist at Brigham and Women’s hospital and professor of medicine at Harvard Medical School, both in Boston.

Patient characteristics may partly explain slow uptake. “Clinicians may not think further LDL-C lowering is a high enough priority in terms of potential benefit for a given patient in light of the effort being expended to take care of all their other issues and chronic health problems. If the clinician does bring it up to the patient, there may be barriers in terms of additional medication burden, cost, or acquisition issues,” said Dr. Robinson.

The answer may be better evidence and a more personalized approach. Clinical trials that explore defined patient populations could convince patients of a benefit, and payers to reimburse, according to Dr. Robinson.
 

Changing guidance

Another complication is that both the guidelines and the field are rapidly changing. The 2013 AHA guidelines did not include a treatment to goal and focused instead on use of high-dose statins. But the 2018 update reversed course after randomized studies demonstrated a benefit to treating to target. The researchers found no increase in the frequency of treating to target after the release of the 2018 guidelines. “Publication and announcement of guidelines doesn’t mean that people are getting treated better. We really have to implement them,” said Dr. Cannon.

On a positive note, the GOULD researchers found high acceptance of the new proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) inhibitors, with over 90% of patients continuing those medications after 2 years. “That’s nice and high. If people do get onto the very intensive lipid-lowing therapies, they tend to stay on them,” said Dr. Cannon.
 

What’s next

Still, the lack of intensification is concerning, and the findings led to some consternation in Twitter exchanges, said Dr. Cannon. “People posted ‘Well, what do we do now?’ ” Dr. Cannon’s team is addressing the issue with an algorithm-based risk management program with prospective enrollment. They have conducted educational webinars and provided site-specific reports on LDL status among patients at each center compared to others, and hope that information will improve compliance. In 2020, the group published an interim analysis of the first 5,000 enrollees, and Dr. Cannon expects to finish that study by the end of the year.

Dr. Navar agreed that physicians need to do a better job of testing LDL-C levels after treatment to identify patients who require more aggressive therapy. That can be deferred in some primary prevention patients with high LDL-C but normal particle numbers as measured with ApoB. “But in those at high risk for disease and those with established CVD who are not at goal, as long as they don’t have a life-limiting condition, we should always up-titrate therapy. It’s one of the safest, most effective ways to lower cardiovascular risk,” said Dr. Navar.

Key study results

The prospective study included 5,006 patients at 119 centers with a mean age of 68 years. About 40% were women, and 86.1% were White. All had ASCVD and LDL levels of at least 70 mg/dL. After 2 years, 17% had undergone intensification of lipid-lowering therapy (LLT). Among patients with LDL-C levels ≥ 100 mg/dL, 22% underwent LLT intensification, compared with 14% of patients with LDL-C levels of 70-99 mg/dL.

The vast majority, 92%, of patients who underwent LLT via addition of PCSK9 inhibitors were still taking the drug after 2 years.

Three-quarters (3,768) had lipid level measurements at least once during follow-up, and median LDL-C levels dropped from 120 to 95 mg/dL in the ≥100-mg/dL cohort (P < .001), and from 82 to 77 mg/dL in the 70- to 99-mg/dL cohort (P <. 001). There was no significant difference in the median values in the patients on PCSK9 inhibitors.

In all, 21% of the ≥100-mg/dL cohort achieved LDL-C levels <70 mg/dL at 2 years, versus 34% in the 77- to 99-mg/dL cohort and 52% of patients taking PCSK9 inhibitors.

Patients seen at teaching hospitals were more likely to undergo LLT intensification compared to nonteaching hospitals (25% versus 17%; P < .001), as were those where lipid protocols were in place (22% versus 15%; P < .001), and those treated in cardiology (22%) compared to treatment in internal or family medicine (12%; P <.001). The study was published online June 16 in JAMA Cardiology.

Dr. Cannon, Dr. Navar, and Dr. Robinson disclosed ties with Amgen, which funded the study, and other companies.

Statin therapy likely didn’t lead to dementia or even mild cognitive impairment (MCI) in older patients taking the drugs for cardiovascular (CV) primary prevention in a post hoc analysis of a trial that required normal cognitive ability for entry.

Nor did statins, whether lipophilic or hydrophilic, appear to influence changes in cognition or affect separate domains of mental performance, such as memory, language ability, or executive function, over the trial’s follow-up, which averaged almost 5 years.

Although such findings aren’t novel – they are consistent with observations from a number of earlier studies – the new analysis included a possible signal for a statin association with new-onset dementia in a subgroup of more than 18,000 patients. Researchers attribute the retrospective finding, from a trial not designed to explore the issue, to confounding or chance.

Still, the adjusted risk for dementia seemed to go up by a third among statin users who at baseline placed in the lowest quartile for cognitive function, based on a composite test score, in the ASPREE trial, a test of primary-prevention low-dose aspirin in patients 65 or older. The better the baseline cognitive score by quartile, the lower the risk for dementia ( interaction P < .001).

The bottom-quartile association of statins with dementia was driven by new diagnoses of Alzheimer’s disease, as opposed to the study’s other “mixed presentation” dementia subtype, wrote the authors of analysis, published June 21, 2021, in the Journal of the American College of Cardiology), led by Zhen Zhou, PhD, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.

“I wouldn’t overinterpret that,” said senior author Mark R. Nelson, MBBS, PhD, of the same institution. Indeed, it should be “reassuring” for physicians prescribing statins to older patients that there was no overall statin effect on cognition or new-onset dementia, he said in an interview.

“This is a post hoc analysis within a dataset, although a very-high-quality dataset, it must be said.” The patients were prospectively followed for a range of cognition domains, and the results were adjudicated, Dr. Nelson observed. Although the question of statins and dementia risk is thought to be largely settled, the analysis “was just too tempting not to do.”

On the basis of the current analysis and the bulk of preceding evidence, “lipid lowering in the short term does not appear to result in improvement or deterioration of cognition irrespective of baseline LDL cholesterol levels and medication used,” Christie M. Ballantyne, MD, and Vijay Nambi, MD, PhD, both from Baylor College of Medicine, Houston, wrote in an accompanying editorial.

The current study “provides additional information that the lipo- or hydrophilicity of the statin does not affect changes in cognition. However, the potential increased risk for Alzheimer’s disease, especially among patients with baseline cognitive impairment, requires further investigation.”

The current analysis is reassuring that the likelihood of such statin effects on cognition “is vanishingly small,” Neil J. Stone MD, Northwestern University, Chicago, said in an interview. In fact, its primary finding of no such association “best summarizes what we know in 2021 about statin therapy” after exploration of the issue in a number of prospective trials and systematic reviews, said Dr. Stone, who was not a coauthor on the report.

The observed interaction between statin use and baseline neurocognitive ability “is hypothesis raising at best. It should be explored in randomized, controlled trials that can look at this question in an unbiased manner,” he agreed.

If patients believe or suspect that a statin is causing symptoms that suggest cognitive dysfunction, “what they really need to do is to stop it for 3 weeks and check out other causes. And in rechallenging, the guidelines say, if they think that it’s causing a memory problem that occurs anecdotally, then they can be given another statin, usually, which doesn’t cause it.”

ASPREE compared daily low-dose aspirin with placebo in a community-based older population numbering about 19,000 in Australia and the United States. Patients were initially without known CV disease, dementia, or physical disabilities. It did not randomize patients by statin therapy.

Of note, entry to the trial required a score of at least 78 on the Modified Mini-Mental State Examination (3MS), corresponding to normal cognition.

Aspirin showed no significant benefit for disability-free survival, an endpoint that included death and dementia, or CV events over a median of 4.7 years. It was associated with slightly more cases of major hemorrhage, as previously reported.

A subsequent ASPREE analysis suggested that the aspirin had no effect on risks of mild cognitive impairment, cognitive decline, or dementia.

Of the 18,846 patients in the current post hoc analysis, the average age of the patients was 74 years, and 56.4% were women; 31.3% were taking statins at baseline. The incidence of dementia per 1,000 person-years for those taking statins in comparison with those not taking statins was 6.91 and 6.48, respectively. Any cognitive changes were tracked by the 3MS and three other validated tests in different domains of cognition, with results contributing to the composite score.

The corresponding incidence of dementia considered probable Alzheimer’s disease was 2.97 and 2.65 for those receiving versus not receiving statins, respectively. The incidence of dementia with mixed presentation was 3.94 and 3.84, respectively.

There were no significant differences in risk for dementia overall or for either dementia subtype in multivariate analyses. Adjustments included demographics, CV lifestyle risk factors, family medical history, including dementia, ASPREE randomization group, and individual scores on the four tests of cognition.

Results for development of MCI mirrored those for dementia, as did results stratified for baseline lipids and for use of lipophilic statins, such as atorvastatin or simvastatin versus hydrophilic statins, including pravastatin and rosuvastatin.

Significant interactions were observed between composite cognitive scores and statin therapy at baseline; as scores increased, indicating better cognitive performance, the risks for dementia and its subtypes went down. Statins were associated with incident dementia at the lowest cognitive performance quartile.

That association is probably a function of the cohort’s advanced age, Dr. Nelson said. “If you get into old age, and you’ve got high cognitive scores, you’ve probably got protective factors. That’s how I would interpret that.”

Dr. Ballantyne and Dr. Nambi also emphasized the difficulties of controlling for potential biases even with extensive covariate adjustments. The statin dosages at which patients were treated were not part of the analysis, “and achieved LDL [cholesterol levels over the study period were not known,” they wrote.

“Furthermore, patients who were treated with statins were more likely to have diabetes, hypertension, chronic kidney disease, and obesity, all of which are known to increase risk for cognitive decline, and, as might have been predicted, statin users therefore had significantly lower scores for global cognition and episodic memory.”

Dr. Nelson pointed to an ongoing prospective atorvastatin trial that includes dementia in its primary endpoint and should be “the definitive study.” STAREE (Statin Therapy for Reducing Events in the Elderly) is running throughout Australia with a projected enrollment of 18,000 and primary completion by the end of 2022. “We’ve already enrolled 8,000 patients.”

Less far along is the PREVENTABLE (Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults) trial, based in the United States and also randomizing to atorvastatin or placebo, that will have an estimated 20,000 older patients and completion in 5 years. The primary endpoint is new dementia or persistent disability.

Both trials “are powered to enable firm conclusions concerning any statin effects,” said Dr. Ballantyne and Dr. Nambi. “In the meantime, practicing clinicians can have confidence and share with their patients that short-term lipid-lowering therapy in older patients, including with statins, is unlikely to have a major impact on cognition.”

ASPREE was supported by grants from the U.S. National Institute on Aging and the National Cancer Institute and the National Health and Medical Research Council of Australia, by Monash University, and by the Victorian Cancer Agency. Dr. Nelson reported receiving honoraria from Sanofi and Amgen; support from Bayer for ASPREE; and grant support for STAREE. Disclosures for the other authors are in the report. Dr. Ballantyne disclosed grant and research support from Abbott Diagnostic, Akcea, Amgen, Esperion, Ionis, Novartis, Regeneron, and Roche Diagnostics; and consulting for Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Corvidia, Denka Seiken, Esperion, Genentech, Gilead, Matinas BioPharma, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostics, and Sanofi-Synthelabo. Dr. Nambi is a coinvestigator on a provisional patent along with Baylor College of Medicine and Roche on the use of biomarkers to predict heart failure, and a site principal investigator for studies sponsored by Amgen and Merck. Dr. Stone had no disclosures.

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

Statin therapy likely didn’t lead to dementia or even mild cognitive impairment (MCI) in older patients taking the drugs for cardiovascular (CV) primary prevention in a post hoc analysis of a trial that required normal cognitive ability for entry.

Nor did statins, whether lipophilic or hydrophilic, appear to influence changes in cognition or affect separate domains of mental performance, such as memory, language ability, or executive function, over the trial’s follow-up, which averaged almost 5 years.

Although such findings aren’t novel – they are consistent with observations from a number of earlier studies – the new analysis included a possible signal for a statin association with new-onset dementia in a subgroup of more than 18,000 patients. Researchers attribute the retrospective finding, from a trial not designed to explore the issue, to confounding or chance.

Still, the adjusted risk for dementia seemed to go up by a third among statin users who at baseline placed in the lowest quartile for cognitive function, based on a composite test score, in the ASPREE trial, a test of primary-prevention low-dose aspirin in patients 65 or older. The better the baseline cognitive score by quartile, the lower the risk for dementia ( interaction P < .001).

The bottom-quartile association of statins with dementia was driven by new diagnoses of Alzheimer’s disease, as opposed to the study’s other “mixed presentation” dementia subtype, wrote the authors of analysis, published June 21, 2021, in the Journal of the American College of Cardiology), led by Zhen Zhou, PhD, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.

“I wouldn’t overinterpret that,” said senior author Mark R. Nelson, MBBS, PhD, of the same institution. Indeed, it should be “reassuring” for physicians prescribing statins to older patients that there was no overall statin effect on cognition or new-onset dementia, he said in an interview.

“This is a post hoc analysis within a dataset, although a very-high-quality dataset, it must be said.” The patients were prospectively followed for a range of cognition domains, and the results were adjudicated, Dr. Nelson observed. Although the question of statins and dementia risk is thought to be largely settled, the analysis “was just too tempting not to do.”

On the basis of the current analysis and the bulk of preceding evidence, “lipid lowering in the short term does not appear to result in improvement or deterioration of cognition irrespective of baseline LDL cholesterol levels and medication used,” Christie M. Ballantyne, MD, and Vijay Nambi, MD, PhD, both from Baylor College of Medicine, Houston, wrote in an accompanying editorial.

The current study “provides additional information that the lipo- or hydrophilicity of the statin does not affect changes in cognition. However, the potential increased risk for Alzheimer’s disease, especially among patients with baseline cognitive impairment, requires further investigation.”

The current analysis is reassuring that the likelihood of such statin effects on cognition “is vanishingly small,” Neil J. Stone MD, Northwestern University, Chicago, said in an interview. In fact, its primary finding of no such association “best summarizes what we know in 2021 about statin therapy” after exploration of the issue in a number of prospective trials and systematic reviews, said Dr. Stone, who was not a coauthor on the report.

The observed interaction between statin use and baseline neurocognitive ability “is hypothesis raising at best. It should be explored in randomized, controlled trials that can look at this question in an unbiased manner,” he agreed.

If patients believe or suspect that a statin is causing symptoms that suggest cognitive dysfunction, “what they really need to do is to stop it for 3 weeks and check out other causes. And in rechallenging, the guidelines say, if they think that it’s causing a memory problem that occurs anecdotally, then they can be given another statin, usually, which doesn’t cause it.”

ASPREE compared daily low-dose aspirin with placebo in a community-based older population numbering about 19,000 in Australia and the United States. Patients were initially without known CV disease, dementia, or physical disabilities. It did not randomize patients by statin therapy.

Of note, entry to the trial required a score of at least 78 on the Modified Mini-Mental State Examination (3MS), corresponding to normal cognition.

Aspirin showed no significant benefit for disability-free survival, an endpoint that included death and dementia, or CV events over a median of 4.7 years. It was associated with slightly more cases of major hemorrhage, as previously reported.

A subsequent ASPREE analysis suggested that the aspirin had no effect on risks of mild cognitive impairment, cognitive decline, or dementia.

Of the 18,846 patients in the current post hoc analysis, the average age of the patients was 74 years, and 56.4% were women; 31.3% were taking statins at baseline. The incidence of dementia per 1,000 person-years for those taking statins in comparison with those not taking statins was 6.91 and 6.48, respectively. Any cognitive changes were tracked by the 3MS and three other validated tests in different domains of cognition, with results contributing to the composite score.

The corresponding incidence of dementia considered probable Alzheimer’s disease was 2.97 and 2.65 for those receiving versus not receiving statins, respectively. The incidence of dementia with mixed presentation was 3.94 and 3.84, respectively.

There were no significant differences in risk for dementia overall or for either dementia subtype in multivariate analyses. Adjustments included demographics, CV lifestyle risk factors, family medical history, including dementia, ASPREE randomization group, and individual scores on the four tests of cognition.

Results for development of MCI mirrored those for dementia, as did results stratified for baseline lipids and for use of lipophilic statins, such as atorvastatin or simvastatin versus hydrophilic statins, including pravastatin and rosuvastatin.

Significant interactions were observed between composite cognitive scores and statin therapy at baseline; as scores increased, indicating better cognitive performance, the risks for dementia and its subtypes went down. Statins were associated with incident dementia at the lowest cognitive performance quartile.

That association is probably a function of the cohort’s advanced age, Dr. Nelson said. “If you get into old age, and you’ve got high cognitive scores, you’ve probably got protective factors. That’s how I would interpret that.”

Dr. Ballantyne and Dr. Nambi also emphasized the difficulties of controlling for potential biases even with extensive covariate adjustments. The statin dosages at which patients were treated were not part of the analysis, “and achieved LDL [cholesterol levels over the study period were not known,” they wrote.

“Furthermore, patients who were treated with statins were more likely to have diabetes, hypertension, chronic kidney disease, and obesity, all of which are known to increase risk for cognitive decline, and, as might have been predicted, statin users therefore had significantly lower scores for global cognition and episodic memory.”

Dr. Nelson pointed to an ongoing prospective atorvastatin trial that includes dementia in its primary endpoint and should be “the definitive study.” STAREE (Statin Therapy for Reducing Events in the Elderly) is running throughout Australia with a projected enrollment of 18,000 and primary completion by the end of 2022. “We’ve already enrolled 8,000 patients.”

Less far along is the PREVENTABLE (Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults) trial, based in the United States and also randomizing to atorvastatin or placebo, that will have an estimated 20,000 older patients and completion in 5 years. The primary endpoint is new dementia or persistent disability.

Both trials “are powered to enable firm conclusions concerning any statin effects,” said Dr. Ballantyne and Dr. Nambi. “In the meantime, practicing clinicians can have confidence and share with their patients that short-term lipid-lowering therapy in older patients, including with statins, is unlikely to have a major impact on cognition.”

ASPREE was supported by grants from the U.S. National Institute on Aging and the National Cancer Institute and the National Health and Medical Research Council of Australia, by Monash University, and by the Victorian Cancer Agency. Dr. Nelson reported receiving honoraria from Sanofi and Amgen; support from Bayer for ASPREE; and grant support for STAREE. Disclosures for the other authors are in the report. Dr. Ballantyne disclosed grant and research support from Abbott Diagnostic, Akcea, Amgen, Esperion, Ionis, Novartis, Regeneron, and Roche Diagnostics; and consulting for Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Corvidia, Denka Seiken, Esperion, Genentech, Gilead, Matinas BioPharma, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostics, and Sanofi-Synthelabo. Dr. Nambi is a coinvestigator on a provisional patent along with Baylor College of Medicine and Roche on the use of biomarkers to predict heart failure, and a site principal investigator for studies sponsored by Amgen and Merck. Dr. Stone had no disclosures.

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

Statin therapy likely didn’t lead to dementia or even mild cognitive impairment (MCI) in older patients taking the drugs for cardiovascular (CV) primary prevention in a post hoc analysis of a trial that required normal cognitive ability for entry.

Nor did statins, whether lipophilic or hydrophilic, appear to influence changes in cognition or affect separate domains of mental performance, such as memory, language ability, or executive function, over the trial’s follow-up, which averaged almost 5 years.

Although such findings aren’t novel – they are consistent with observations from a number of earlier studies – the new analysis included a possible signal for a statin association with new-onset dementia in a subgroup of more than 18,000 patients. Researchers attribute the retrospective finding, from a trial not designed to explore the issue, to confounding or chance.

Still, the adjusted risk for dementia seemed to go up by a third among statin users who at baseline placed in the lowest quartile for cognitive function, based on a composite test score, in the ASPREE trial, a test of primary-prevention low-dose aspirin in patients 65 or older. The better the baseline cognitive score by quartile, the lower the risk for dementia ( interaction P < .001).

The bottom-quartile association of statins with dementia was driven by new diagnoses of Alzheimer’s disease, as opposed to the study’s other “mixed presentation” dementia subtype, wrote the authors of analysis, published June 21, 2021, in the Journal of the American College of Cardiology), led by Zhen Zhou, PhD, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.

“I wouldn’t overinterpret that,” said senior author Mark R. Nelson, MBBS, PhD, of the same institution. Indeed, it should be “reassuring” for physicians prescribing statins to older patients that there was no overall statin effect on cognition or new-onset dementia, he said in an interview.

“This is a post hoc analysis within a dataset, although a very-high-quality dataset, it must be said.” The patients were prospectively followed for a range of cognition domains, and the results were adjudicated, Dr. Nelson observed. Although the question of statins and dementia risk is thought to be largely settled, the analysis “was just too tempting not to do.”

On the basis of the current analysis and the bulk of preceding evidence, “lipid lowering in the short term does not appear to result in improvement or deterioration of cognition irrespective of baseline LDL cholesterol levels and medication used,” Christie M. Ballantyne, MD, and Vijay Nambi, MD, PhD, both from Baylor College of Medicine, Houston, wrote in an accompanying editorial.

The current study “provides additional information that the lipo- or hydrophilicity of the statin does not affect changes in cognition. However, the potential increased risk for Alzheimer’s disease, especially among patients with baseline cognitive impairment, requires further investigation.”

The current analysis is reassuring that the likelihood of such statin effects on cognition “is vanishingly small,” Neil J. Stone MD, Northwestern University, Chicago, said in an interview. In fact, its primary finding of no such association “best summarizes what we know in 2021 about statin therapy” after exploration of the issue in a number of prospective trials and systematic reviews, said Dr. Stone, who was not a coauthor on the report.

The observed interaction between statin use and baseline neurocognitive ability “is hypothesis raising at best. It should be explored in randomized, controlled trials that can look at this question in an unbiased manner,” he agreed.

If patients believe or suspect that a statin is causing symptoms that suggest cognitive dysfunction, “what they really need to do is to stop it for 3 weeks and check out other causes. And in rechallenging, the guidelines say, if they think that it’s causing a memory problem that occurs anecdotally, then they can be given another statin, usually, which doesn’t cause it.”

ASPREE compared daily low-dose aspirin with placebo in a community-based older population numbering about 19,000 in Australia and the United States. Patients were initially without known CV disease, dementia, or physical disabilities. It did not randomize patients by statin therapy.

Of note, entry to the trial required a score of at least 78 on the Modified Mini-Mental State Examination (3MS), corresponding to normal cognition.

Aspirin showed no significant benefit for disability-free survival, an endpoint that included death and dementia, or CV events over a median of 4.7 years. It was associated with slightly more cases of major hemorrhage, as previously reported.

A subsequent ASPREE analysis suggested that the aspirin had no effect on risks of mild cognitive impairment, cognitive decline, or dementia.

Of the 18,846 patients in the current post hoc analysis, the average age of the patients was 74 years, and 56.4% were women; 31.3% were taking statins at baseline. The incidence of dementia per 1,000 person-years for those taking statins in comparison with those not taking statins was 6.91 and 6.48, respectively. Any cognitive changes were tracked by the 3MS and three other validated tests in different domains of cognition, with results contributing to the composite score.

The corresponding incidence of dementia considered probable Alzheimer’s disease was 2.97 and 2.65 for those receiving versus not receiving statins, respectively. The incidence of dementia with mixed presentation was 3.94 and 3.84, respectively.

There were no significant differences in risk for dementia overall or for either dementia subtype in multivariate analyses. Adjustments included demographics, CV lifestyle risk factors, family medical history, including dementia, ASPREE randomization group, and individual scores on the four tests of cognition.

Results for development of MCI mirrored those for dementia, as did results stratified for baseline lipids and for use of lipophilic statins, such as atorvastatin or simvastatin versus hydrophilic statins, including pravastatin and rosuvastatin.

Significant interactions were observed between composite cognitive scores and statin therapy at baseline; as scores increased, indicating better cognitive performance, the risks for dementia and its subtypes went down. Statins were associated with incident dementia at the lowest cognitive performance quartile.

That association is probably a function of the cohort’s advanced age, Dr. Nelson said. “If you get into old age, and you’ve got high cognitive scores, you’ve probably got protective factors. That’s how I would interpret that.”

Dr. Ballantyne and Dr. Nambi also emphasized the difficulties of controlling for potential biases even with extensive covariate adjustments. The statin dosages at which patients were treated were not part of the analysis, “and achieved LDL [cholesterol levels over the study period were not known,” they wrote.

“Furthermore, patients who were treated with statins were more likely to have diabetes, hypertension, chronic kidney disease, and obesity, all of which are known to increase risk for cognitive decline, and, as might have been predicted, statin users therefore had significantly lower scores for global cognition and episodic memory.”

Dr. Nelson pointed to an ongoing prospective atorvastatin trial that includes dementia in its primary endpoint and should be “the definitive study.” STAREE (Statin Therapy for Reducing Events in the Elderly) is running throughout Australia with a projected enrollment of 18,000 and primary completion by the end of 2022. “We’ve already enrolled 8,000 patients.”

Less far along is the PREVENTABLE (Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults) trial, based in the United States and also randomizing to atorvastatin or placebo, that will have an estimated 20,000 older patients and completion in 5 years. The primary endpoint is new dementia or persistent disability.

Both trials “are powered to enable firm conclusions concerning any statin effects,” said Dr. Ballantyne and Dr. Nambi. “In the meantime, practicing clinicians can have confidence and share with their patients that short-term lipid-lowering therapy in older patients, including with statins, is unlikely to have a major impact on cognition.”

ASPREE was supported by grants from the U.S. National Institute on Aging and the National Cancer Institute and the National Health and Medical Research Council of Australia, by Monash University, and by the Victorian Cancer Agency. Dr. Nelson reported receiving honoraria from Sanofi and Amgen; support from Bayer for ASPREE; and grant support for STAREE. Disclosures for the other authors are in the report. Dr. Ballantyne disclosed grant and research support from Abbott Diagnostic, Akcea, Amgen, Esperion, Ionis, Novartis, Regeneron, and Roche Diagnostics; and consulting for Abbott Diagnostics, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Corvidia, Denka Seiken, Esperion, Genentech, Gilead, Matinas BioPharma, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostics, and Sanofi-Synthelabo. Dr. Nambi is a coinvestigator on a provisional patent along with Baylor College of Medicine and Roche on the use of biomarkers to predict heart failure, and a site principal investigator for studies sponsored by Amgen and Merck. Dr. Stone had no disclosures.

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