ACC 2016

Twelve weeks of treatment with the anti-inflammatory drug losmapimod did not prevent cardiovascular death, myocardial infarction, or severe recurrent ischemia in patients hospitalized with acute MI, based on the results of LATITUDE-TIMI 60, a multicenter placebo-controlled phase 3 trial.

Losmapimod also did not significantly affect secondary outcomes such as all-cause mortality, said Dr. Michelle O’Donoghue at Brigham and Women’s Hospital in Boston and her associates.

“The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population,” they concluded at the annual meeting of the American College of Cardiology and in a report published online April 4 in JAMA.

Losmapimod selectively inhibits pro-inflammatory p38 mitogen-activated protein kinase, which contributes to atherosclerosis and plaque destabilization and is activated by stressors such as oxidized low-density lipoprotein cholesterol, hypertension, ischemia, and volume overload. In a prior 12-week phase 2 study, losmapimod failed to reduce inflammatory biomarker levels or myonecrosis, but showed a trend toward lower rates of mortality, MI, recurrent ischemia, stroke, and heart failure, as well as improved left ventricular function.

Based on those observations, Dr. O’Donoghue and her associates randomly assigned 3,503 hospitalized patients with acute MI and at least one other cardiovascular risk factor to receive either losmapimod (7.5 mg twice daily) or placebo, along with guideline-recommended therapy for 12 weeks. Patients averaged 66 years old, about 90% were white, and about 30% were women. The primary endpoint was a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization (JAMA 2016 April 4 doi: 10.1001/jama.2016.3609).

The endpoint was met for 139 (8.1%) losmapimod patients and 123 (7%) placebo patients, for a non-significant hazard ratio of 1.16, said the researchers. Losmapimod was, however, associated with significant decreases in levels of high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide as compared with placebo, with durable effects at 12 weeks. Serious adverse events affected 16% of losmapimod patients and 14% of placebo patients, and rates of premature treatment discontinuation were 15.5% with losmapimod and nearly 14% with placebo. Losmapimod did not appear to increase the risk of infections compared with placebo at week 12, but did show a non-significant trend toward mildly increased hepatic transaminases.

“Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events,” the researchers noted. “However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing. Ongoing clinical trials are currently evaluating additional anti-inflammatory therapeutics in patients with atherosclerosis, and will provide further insight into pathways that contribute to vascular disease.”

Pharmacodynamic data on losmapimod do not suggest that its anti-inflammatory effects increase at higher doses, the researchers also noted.

GlaxoSmithKline developed losmapimod and funded the study. Dr. O’Donoghue reported grant funding from Eisai, Merck, and AstraZeneca. The senior author and several coinvestigators disclosed relationships with numerous pharmaceutical companies.

Twelve weeks of treatment with the anti-inflammatory drug losmapimod did not prevent cardiovascular death, myocardial infarction, or severe recurrent ischemia in patients hospitalized with acute MI, based on the results of LATITUDE-TIMI 60, a multicenter placebo-controlled phase 3 trial.

Losmapimod also did not significantly affect secondary outcomes such as all-cause mortality, said Dr. Michelle O’Donoghue at Brigham and Women’s Hospital in Boston and her associates.

“The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population,” they concluded at the annual meeting of the American College of Cardiology and in a report published online April 4 in JAMA.

Losmapimod selectively inhibits pro-inflammatory p38 mitogen-activated protein kinase, which contributes to atherosclerosis and plaque destabilization and is activated by stressors such as oxidized low-density lipoprotein cholesterol, hypertension, ischemia, and volume overload. In a prior 12-week phase 2 study, losmapimod failed to reduce inflammatory biomarker levels or myonecrosis, but showed a trend toward lower rates of mortality, MI, recurrent ischemia, stroke, and heart failure, as well as improved left ventricular function.

Based on those observations, Dr. O’Donoghue and her associates randomly assigned 3,503 hospitalized patients with acute MI and at least one other cardiovascular risk factor to receive either losmapimod (7.5 mg twice daily) or placebo, along with guideline-recommended therapy for 12 weeks. Patients averaged 66 years old, about 90% were white, and about 30% were women. The primary endpoint was a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization (JAMA 2016 April 4 doi: 10.1001/jama.2016.3609).

The endpoint was met for 139 (8.1%) losmapimod patients and 123 (7%) placebo patients, for a non-significant hazard ratio of 1.16, said the researchers. Losmapimod was, however, associated with significant decreases in levels of high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide as compared with placebo, with durable effects at 12 weeks. Serious adverse events affected 16% of losmapimod patients and 14% of placebo patients, and rates of premature treatment discontinuation were 15.5% with losmapimod and nearly 14% with placebo. Losmapimod did not appear to increase the risk of infections compared with placebo at week 12, but did show a non-significant trend toward mildly increased hepatic transaminases.

“Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events,” the researchers noted. “However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing. Ongoing clinical trials are currently evaluating additional anti-inflammatory therapeutics in patients with atherosclerosis, and will provide further insight into pathways that contribute to vascular disease.”

Pharmacodynamic data on losmapimod do not suggest that its anti-inflammatory effects increase at higher doses, the researchers also noted.

GlaxoSmithKline developed losmapimod and funded the study. Dr. O’Donoghue reported grant funding from Eisai, Merck, and AstraZeneca. The senior author and several coinvestigators disclosed relationships with numerous pharmaceutical companies.

Twelve weeks of treatment with the anti-inflammatory drug losmapimod did not prevent cardiovascular death, myocardial infarction, or severe recurrent ischemia in patients hospitalized with acute MI, based on the results of LATITUDE-TIMI 60, a multicenter placebo-controlled phase 3 trial.

Losmapimod also did not significantly affect secondary outcomes such as all-cause mortality, said Dr. Michelle O’Donoghue at Brigham and Women’s Hospital in Boston and her associates.

“The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population,” they concluded at the annual meeting of the American College of Cardiology and in a report published online April 4 in JAMA.

Losmapimod selectively inhibits pro-inflammatory p38 mitogen-activated protein kinase, which contributes to atherosclerosis and plaque destabilization and is activated by stressors such as oxidized low-density lipoprotein cholesterol, hypertension, ischemia, and volume overload. In a prior 12-week phase 2 study, losmapimod failed to reduce inflammatory biomarker levels or myonecrosis, but showed a trend toward lower rates of mortality, MI, recurrent ischemia, stroke, and heart failure, as well as improved left ventricular function.

Based on those observations, Dr. O’Donoghue and her associates randomly assigned 3,503 hospitalized patients with acute MI and at least one other cardiovascular risk factor to receive either losmapimod (7.5 mg twice daily) or placebo, along with guideline-recommended therapy for 12 weeks. Patients averaged 66 years old, about 90% were white, and about 30% were women. The primary endpoint was a composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization (JAMA 2016 April 4 doi: 10.1001/jama.2016.3609).

The endpoint was met for 139 (8.1%) losmapimod patients and 123 (7%) placebo patients, for a non-significant hazard ratio of 1.16, said the researchers. Losmapimod was, however, associated with significant decreases in levels of high-sensitivity C-reactive protein and N-terminal pro-brain natriuretic peptide as compared with placebo, with durable effects at 12 weeks. Serious adverse events affected 16% of losmapimod patients and 14% of placebo patients, and rates of premature treatment discontinuation were 15.5% with losmapimod and nearly 14% with placebo. Losmapimod did not appear to increase the risk of infections compared with placebo at week 12, but did show a non-significant trend toward mildly increased hepatic transaminases.

“Because inflammation is believed to play a key role in atherogenesis, there remains intense interest to identify an anti-inflammatory therapeutic that will reduce the risk of cardiovascular events,” the researchers noted. “However, because inflammation acts along multiple redundant and interconnected pathways, the identification of an appropriate target may be difficult, and it is challenging to predict clinical efficacy prior to phase 3 testing. Ongoing clinical trials are currently evaluating additional anti-inflammatory therapeutics in patients with atherosclerosis, and will provide further insight into pathways that contribute to vascular disease.”

Pharmacodynamic data on losmapimod do not suggest that its anti-inflammatory effects increase at higher doses, the researchers also noted.

GlaxoSmithKline developed losmapimod and funded the study. Dr. O’Donoghue reported grant funding from Eisai, Merck, and AstraZeneca. The senior author and several coinvestigators disclosed relationships with numerous pharmaceutical companies.

CHICAGO – The results of the Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) presented at the annual meeting of the American College of Cardiology ought to change the clinical management of patients with coronary artery disease and heart failure with severe left ventricular dysfunction, according to Dr. Robert O. Bonow.

STICHES is the 10-year follow-up of 1,212 such patients who were randomized to coronary artery bypass graft surgery plus optimal guideline-directed medical therapy or to the medical therapy alone. At 10 years, the CABG group showed a significant survival advantage: an all-cause mortality rate of 58.9%, a significant 16% relative risk reduction compared with the 66.1% rate in the medically managed group. Secondary endpoints were also strongly in favor of the CABG group.

These findings indicate CABG is beneficial in patients with ischemic cardiomyopathy, and patients deserve to be so informed, according to Dr. Bonow, a member of the STICHES publication committee and professor of cardiology and director of the Center for Cardiovascular Innovation at Northwestern University in Chicago, who discussed the findings in this video interview.

He reported having no financial conflicts regarding this National Institutes of Health–funded study.

[email protected]

CHICAGO – The results of the Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) presented at the annual meeting of the American College of Cardiology ought to change the clinical management of patients with coronary artery disease and heart failure with severe left ventricular dysfunction, according to Dr. Robert O. Bonow.

STICHES is the 10-year follow-up of 1,212 such patients who were randomized to coronary artery bypass graft surgery plus optimal guideline-directed medical therapy or to the medical therapy alone. At 10 years, the CABG group showed a significant survival advantage: an all-cause mortality rate of 58.9%, a significant 16% relative risk reduction compared with the 66.1% rate in the medically managed group. Secondary endpoints were also strongly in favor of the CABG group.

These findings indicate CABG is beneficial in patients with ischemic cardiomyopathy, and patients deserve to be so informed, according to Dr. Bonow, a member of the STICHES publication committee and professor of cardiology and director of the Center for Cardiovascular Innovation at Northwestern University in Chicago, who discussed the findings in this video interview.

He reported having no financial conflicts regarding this National Institutes of Health–funded study.

[email protected]

CHICAGO – The results of the Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) presented at the annual meeting of the American College of Cardiology ought to change the clinical management of patients with coronary artery disease and heart failure with severe left ventricular dysfunction, according to Dr. Robert O. Bonow.

STICHES is the 10-year follow-up of 1,212 such patients who were randomized to coronary artery bypass graft surgery plus optimal guideline-directed medical therapy or to the medical therapy alone. At 10 years, the CABG group showed a significant survival advantage: an all-cause mortality rate of 58.9%, a significant 16% relative risk reduction compared with the 66.1% rate in the medically managed group. Secondary endpoints were also strongly in favor of the CABG group.

These findings indicate CABG is beneficial in patients with ischemic cardiomyopathy, and patients deserve to be so informed, according to Dr. Bonow, a member of the STICHES publication committee and professor of cardiology and director of the Center for Cardiovascular Innovation at Northwestern University in Chicago, who discussed the findings in this video interview.

He reported having no financial conflicts regarding this National Institutes of Health–funded study.

[email protected]

CHICAGO – The results of the Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) presented at the annual meeting of the American College of Cardiology ought to change the clinical management of patients with coronary artery disease and heart failure with severe left ventricular dysfunction, according to Dr. Robert O. Bonow.

STICHES is the 10-year follow-up of 1,212 such patients who were randomized to coronary artery bypass graft surgery plus optimal guideline-directed medical therapy or to the medical therapy alone. At 10 years, the CABG group showed a significant survival advantage: an all-cause mortality rate of 58.9%, a significant 16% relative risk reduction compared with the 66.1% rate in the medically managed group. Secondary endpoints were also strongly in favor of the CABG group.

These findings indicate CABG is beneficial in patients with ischemic cardiomyopathy, and patients deserve to be so informed, according to Dr. Bonow, a member of the STICHES publication committee and professor of cardiology and director of the Center for Cardiovascular Innovation at Northwestern University in Chicago, who discussed the findings in this video interview.

He reported having no financial conflicts regarding this National Institutes of Health–funded study.

[email protected]

CHICAGO – The results of the Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) presented at the annual meeting of the American College of Cardiology ought to change the clinical management of patients with coronary artery disease and heart failure with severe left ventricular dysfunction, according to Dr. Robert O. Bonow.

STICHES is the 10-year follow-up of 1,212 such patients who were randomized to coronary artery bypass graft surgery plus optimal guideline-directed medical therapy or to the medical therapy alone. At 10 years, the CABG group showed a significant survival advantage: an all-cause mortality rate of 58.9%, a significant 16% relative risk reduction compared with the 66.1% rate in the medically managed group. Secondary endpoints were also strongly in favor of the CABG group.

These findings indicate CABG is beneficial in patients with ischemic cardiomyopathy, and patients deserve to be so informed, according to Dr. Bonow, a member of the STICHES publication committee and professor of cardiology and director of the Center for Cardiovascular Innovation at Northwestern University in Chicago, who discussed the findings in this video interview.

He reported having no financial conflicts regarding this National Institutes of Health–funded study.

[email protected]

CHICAGO – The results of the Surgical Treatment for Ischemic Heart Failure Extension Study (STICHES) presented at the annual meeting of the American College of Cardiology ought to change the clinical management of patients with coronary artery disease and heart failure with severe left ventricular dysfunction, according to Dr. Robert O. Bonow.

STICHES is the 10-year follow-up of 1,212 such patients who were randomized to coronary artery bypass graft surgery plus optimal guideline-directed medical therapy or to the medical therapy alone. At 10 years, the CABG group showed a significant survival advantage: an all-cause mortality rate of 58.9%, a significant 16% relative risk reduction compared with the 66.1% rate in the medically managed group. Secondary endpoints were also strongly in favor of the CABG group.

These findings indicate CABG is beneficial in patients with ischemic cardiomyopathy, and patients deserve to be so informed, according to Dr. Bonow, a member of the STICHES publication committee and professor of cardiology and director of the Center for Cardiovascular Innovation at Northwestern University in Chicago, who discussed the findings in this video interview.

He reported having no financial conflicts regarding this National Institutes of Health–funded study.

[email protected]

CHICAGO – A new American College of Cardiology expert consensus decision pathway for the use of nonstatin therapies to lower cholesterol in high-risk patients addresses situations not covered by an evidence-based 2013 guideline on managing atherosclerotic cardiovascular disease risk.

Like the 2013 guideline (the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults), the new guidance emphasizes the importance of a healthy lifestyle, but also addresses the use of two monoclonal antibodies–proprotein convertase subtilisin/kexon 9 (PCSK9) inhibitors–approved for certain patient groups since the 2013 guideline was released, as well as other nonstatin therapies, including ezetimibe and bile acid sequestrants.

“At the time [the 2013 guideline was published] the only really good outcomes data ... were for statin medication and there were no data from clinical trials that showed additional benefit of medications over and above being on the maximally tolerated dose of a statin,” according to Dr. Donald M. Lloyd-Jones, a professor at Northwestern University, Chicago and chair of the writing committee for the new guidance. “However, since 2013, a number of trials have been published that actually move the field forward in our understanding of which patients might benefit from adding non statin therapy on top of effective statin therapy.”

The guidance was developed to address gaps in care until the guidelines can be updated, which will likely take a few years.

Based on findings from recent studies, including the IMPROVE IT trial, which examined ezetimibe as statin add-on therapy after acute coronary syndromes, the HPS2-THRIVE study, which examined use of niacin in high-risk patients, and short-term outcomes studies of PCSK9 inhibitors, which have been shown to dramatically reduce low-density lipoprotein cholesterol levels beyond the lowering provided by statin therapy, the committee developed algorithms for the four main high-risk statin benefit patient groups:

•Adults aged 21 years and older with clinical atherosclerotic cardiovascular disease (ASCVD), on statin for secondary prevention.

•Adults aged 21 years and older with LDL-C greater than or equal to 190 mg/dL not due to secondary modifiable causes, on statin for primary prevention.

•Adults aged 40-75 years without ASCVD but with diabetes and LDL-C of 70-189 mg/dL, on statin for primary prevention.

•Adults aged 40-75 years without clinical ASCVD or diabetes, with LDL-C of 70-189 mg/dL and an estimated 10-year risk for ASCVD of at least 7.5%, on statin for primary prevention.

The guidance suggests a number of steps to take with patients who fail to achieve treatment goals (such as addressing treatment adherence, intensifying lifestyle modifications, using a high-intensity stain, and evaluating for statin intolerance), and lists “clinician-patient discussion factors” to consider for each of a number of patient scenarios (including the potential benefits and risks associated with nonstatin therapies, as well as patient preferences).

Included for each of the patient scenarios is an algorithm for which nonstatin therapies to use in which order, building on the “rock-solid confidence” that for the four statin benefit groups, statins remain the starting point, Dr. Lloyd-Jones said. He discussed the guidance in a video interview.

In general, ezetimibe for those patients who are not achieving the types of reduction in LDL or the amount of risk reduction desired, “should probably be the first choice,” he said.

Bile acid sequestrants can be considered in those who are ezetimibe intolerant and who have triglycerides less than 300 mg/dL.

PCSK9 inhibitors are suggested for consideration only in very high-risk patients with ASCVD or with the familial hypercholesterolemia phenotype who are still not achieving the goal (ideally, a 50% reduction in LDL cholesterol), he said.

The committee did not recommend use of niacin, stating that there is no clear indication for the routine use of niacin preparations as additional nonstatin therapies due to an unfavorable risk-benefit profile.

Additionally, PCSK9 inhibitors are not recommended in any primary prevention scenarios, he noted.

Dr. Neil J. Stone, chair of the 2013 guideline writing committee, said the new guidance provides a useful tool for clinicians, extending, in a practical way, the current guideline as the field awaits the long-term outcomes data for PCSK9 inhibitors.

Despite some backlash in the wake of the 2013 guideline, which marked a move away from specific cholesterol treatment targets to a cardiovascular disease risk-based approach, the cardiovascular risk calculation formula introduced in that guideline has been shown to be useful and accurate, said Dr. Stone, also of Northwestern University.

“[The new guidance] is simply an amplification and extension of the guideline,” he said, adding that “it’s about a risk discussion, not automatic treatment.”

Dr. Lloyd-Jones and Dr. Stone each reported having no disclosures.

[email protected]

CHICAGO – A new American College of Cardiology expert consensus decision pathway for the use of nonstatin therapies to lower cholesterol in high-risk patients addresses situations not covered by an evidence-based 2013 guideline on managing atherosclerotic cardiovascular disease risk.

Like the 2013 guideline (the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults), the new guidance emphasizes the importance of a healthy lifestyle, but also addresses the use of two monoclonal antibodies–proprotein convertase subtilisin/kexon 9 (PCSK9) inhibitors–approved for certain patient groups since the 2013 guideline was released, as well as other nonstatin therapies, including ezetimibe and bile acid sequestrants.

“At the time [the 2013 guideline was published] the only really good outcomes data ... were for statin medication and there were no data from clinical trials that showed additional benefit of medications over and above being on the maximally tolerated dose of a statin,” according to Dr. Donald M. Lloyd-Jones, a professor at Northwestern University, Chicago and chair of the writing committee for the new guidance. “However, since 2013, a number of trials have been published that actually move the field forward in our understanding of which patients might benefit from adding non statin therapy on top of effective statin therapy.”

The guidance was developed to address gaps in care until the guidelines can be updated, which will likely take a few years.

Based on findings from recent studies, including the IMPROVE IT trial, which examined ezetimibe as statin add-on therapy after acute coronary syndromes, the HPS2-THRIVE study, which examined use of niacin in high-risk patients, and short-term outcomes studies of PCSK9 inhibitors, which have been shown to dramatically reduce low-density lipoprotein cholesterol levels beyond the lowering provided by statin therapy, the committee developed algorithms for the four main high-risk statin benefit patient groups:

•Adults aged 21 years and older with clinical atherosclerotic cardiovascular disease (ASCVD), on statin for secondary prevention.

•Adults aged 21 years and older with LDL-C greater than or equal to 190 mg/dL not due to secondary modifiable causes, on statin for primary prevention.

•Adults aged 40-75 years without ASCVD but with diabetes and LDL-C of 70-189 mg/dL, on statin for primary prevention.

•Adults aged 40-75 years without clinical ASCVD or diabetes, with LDL-C of 70-189 mg/dL and an estimated 10-year risk for ASCVD of at least 7.5%, on statin for primary prevention.

The guidance suggests a number of steps to take with patients who fail to achieve treatment goals (such as addressing treatment adherence, intensifying lifestyle modifications, using a high-intensity stain, and evaluating for statin intolerance), and lists “clinician-patient discussion factors” to consider for each of a number of patient scenarios (including the potential benefits and risks associated with nonstatin therapies, as well as patient preferences).

Included for each of the patient scenarios is an algorithm for which nonstatin therapies to use in which order, building on the “rock-solid confidence” that for the four statin benefit groups, statins remain the starting point, Dr. Lloyd-Jones said. He discussed the guidance in a video interview.

In general, ezetimibe for those patients who are not achieving the types of reduction in LDL or the amount of risk reduction desired, “should probably be the first choice,” he said.

Bile acid sequestrants can be considered in those who are ezetimibe intolerant and who have triglycerides less than 300 mg/dL.

PCSK9 inhibitors are suggested for consideration only in very high-risk patients with ASCVD or with the familial hypercholesterolemia phenotype who are still not achieving the goal (ideally, a 50% reduction in LDL cholesterol), he said.

The committee did not recommend use of niacin, stating that there is no clear indication for the routine use of niacin preparations as additional nonstatin therapies due to an unfavorable risk-benefit profile.

Additionally, PCSK9 inhibitors are not recommended in any primary prevention scenarios, he noted.

Dr. Neil J. Stone, chair of the 2013 guideline writing committee, said the new guidance provides a useful tool for clinicians, extending, in a practical way, the current guideline as the field awaits the long-term outcomes data for PCSK9 inhibitors.

Despite some backlash in the wake of the 2013 guideline, which marked a move away from specific cholesterol treatment targets to a cardiovascular disease risk-based approach, the cardiovascular risk calculation formula introduced in that guideline has been shown to be useful and accurate, said Dr. Stone, also of Northwestern University.

“[The new guidance] is simply an amplification and extension of the guideline,” he said, adding that “it’s about a risk discussion, not automatic treatment.”

Dr. Lloyd-Jones and Dr. Stone each reported having no disclosures.

[email protected]

CHICAGO – A new American College of Cardiology expert consensus decision pathway for the use of nonstatin therapies to lower cholesterol in high-risk patients addresses situations not covered by an evidence-based 2013 guideline on managing atherosclerotic cardiovascular disease risk.

Like the 2013 guideline (the 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease Risk in Adults), the new guidance emphasizes the importance of a healthy lifestyle, but also addresses the use of two monoclonal antibodies–proprotein convertase subtilisin/kexon 9 (PCSK9) inhibitors–approved for certain patient groups since the 2013 guideline was released, as well as other nonstatin therapies, including ezetimibe and bile acid sequestrants.

“At the time [the 2013 guideline was published] the only really good outcomes data ... were for statin medication and there were no data from clinical trials that showed additional benefit of medications over and above being on the maximally tolerated dose of a statin,” according to Dr. Donald M. Lloyd-Jones, a professor at Northwestern University, Chicago and chair of the writing committee for the new guidance. “However, since 2013, a number of trials have been published that actually move the field forward in our understanding of which patients might benefit from adding non statin therapy on top of effective statin therapy.”

The guidance was developed to address gaps in care until the guidelines can be updated, which will likely take a few years.

Based on findings from recent studies, including the IMPROVE IT trial, which examined ezetimibe as statin add-on therapy after acute coronary syndromes, the HPS2-THRIVE study, which examined use of niacin in high-risk patients, and short-term outcomes studies of PCSK9 inhibitors, which have been shown to dramatically reduce low-density lipoprotein cholesterol levels beyond the lowering provided by statin therapy, the committee developed algorithms for the four main high-risk statin benefit patient groups:

•Adults aged 21 years and older with clinical atherosclerotic cardiovascular disease (ASCVD), on statin for secondary prevention.

•Adults aged 21 years and older with LDL-C greater than or equal to 190 mg/dL not due to secondary modifiable causes, on statin for primary prevention.

•Adults aged 40-75 years without ASCVD but with diabetes and LDL-C of 70-189 mg/dL, on statin for primary prevention.

•Adults aged 40-75 years without clinical ASCVD or diabetes, with LDL-C of 70-189 mg/dL and an estimated 10-year risk for ASCVD of at least 7.5%, on statin for primary prevention.

The guidance suggests a number of steps to take with patients who fail to achieve treatment goals (such as addressing treatment adherence, intensifying lifestyle modifications, using a high-intensity stain, and evaluating for statin intolerance), and lists “clinician-patient discussion factors” to consider for each of a number of patient scenarios (including the potential benefits and risks associated with nonstatin therapies, as well as patient preferences).

Included for each of the patient scenarios is an algorithm for which nonstatin therapies to use in which order, building on the “rock-solid confidence” that for the four statin benefit groups, statins remain the starting point, Dr. Lloyd-Jones said. He discussed the guidance in a video interview.

In general, ezetimibe for those patients who are not achieving the types of reduction in LDL or the amount of risk reduction desired, “should probably be the first choice,” he said.

Bile acid sequestrants can be considered in those who are ezetimibe intolerant and who have triglycerides less than 300 mg/dL.

PCSK9 inhibitors are suggested for consideration only in very high-risk patients with ASCVD or with the familial hypercholesterolemia phenotype who are still not achieving the goal (ideally, a 50% reduction in LDL cholesterol), he said.

The committee did not recommend use of niacin, stating that there is no clear indication for the routine use of niacin preparations as additional nonstatin therapies due to an unfavorable risk-benefit profile.

Additionally, PCSK9 inhibitors are not recommended in any primary prevention scenarios, he noted.

Dr. Neil J. Stone, chair of the 2013 guideline writing committee, said the new guidance provides a useful tool for clinicians, extending, in a practical way, the current guideline as the field awaits the long-term outcomes data for PCSK9 inhibitors.

Despite some backlash in the wake of the 2013 guideline, which marked a move away from specific cholesterol treatment targets to a cardiovascular disease risk-based approach, the cardiovascular risk calculation formula introduced in that guideline has been shown to be useful and accurate, said Dr. Stone, also of Northwestern University.

“[The new guidance] is simply an amplification and extension of the guideline,” he said, adding that “it’s about a risk discussion, not automatic treatment.”

Dr. Lloyd-Jones and Dr. Stone each reported having no disclosures.

[email protected]

CHICAGO – The success in the HOPE-3 trial of a two-pronged strategy of a statin plus moderate-dose antihypertensive therapy has expanded the boundaries of primary preventive pharmacotherapy to incorporate many intermediate-cardiovascular-risk patients without cardiovascular disease.

In the Heart Outcomes Evaluation (HOPE)-3 trial, the combination of rosuvastatin (Crestor) at 10 mg/day plus antihypertensive therapy with 16 mg/day of candesartan and 12.5 mg/day of hydrochlorothiazide reduced cardiovascular events in intermediate-risk patients with hypertension, regardless of their baseline LDL-cholesterol and inflammatory biomarker levels. In nonhypertensive study participants, however, blood pressure-lowering therapy provided no added benefit beyond that achieved with the statin alone, which yielded a 25% relative risk reduction in cardiovascular events compared with placebo, Dr. Salim Yusuf reported at the annual meeting of the American College of Cardiology.

The HOPE-3 trial was the first formal study of the polypill concept of fixed-dose, low-dose combination therapy as a public health tool for primary prevention in an intermediate-risk population without cardiovascular disease. It’s a simple, low-cost, safe, pragmatic preventive strategy that doesn’t require baseline laboratory measurements, dose titration visits, or frequent safety monitoring, he noted.

“The original concept of the polypill was to give it to everyone over age 55. We found in HOPE-3 that the polypill concept is not valid for everybody. It demonstrated benefit in hypertensives but not in nonhypertensives, where a statin alone was beneficial,” said Dr. Yusuf, professor of medicine and executive director of the Population Health Research Institute at McMaster University in Hamilton, Ont.

“The clinical implication is that statins should be used much more widely than they currently are. Most guidelines for hypertension don’t say to give a statin. But HOPE-3 is saying hypertensives will benefit. About half of the 40% reduction in the risk of cardiovascular events we saw with combination therapy in patients in the highest third for baseline systolic blood pressure – that is, above 143.5 mm Hg, with a mean of 154 mm Hg – was due to the rosuvastatin and half to the antihypertensive therapy. Our study suggests you can essentially double the benefit of lowering blood pressure in hypertensives if you also lower cholesterol simultaneously,” he noted. Dr. Yusuf discussed the findings in a video interview.

The double-blind trial included a diverse population of 12,705 men age 55 or older and women age 65 or older in 21 countries. All were at intermediate cardiovascular risk by conventional stratification methods; none had a history of cardiovascular disease. They were randomized to rosuvastatin or placebo, dual antihypertensive therapy or placebo, or to all three medications or double placebo. The combined-therapy group experienced a 33.7 mg/dL greater drop in LDL-cholesterol and a 6.2 mm Hg bigger reduction in systolic blood pressure than in patients on dual placebo.

During a median followup of 5.6 years, the composite rate of cardiovascular death, nonfatal MI, or nonfatal stroke was 3.6% in the combined-therapy group and 5.0% with dual placebo, for a relative risk reduction of 29%. The number needed to treat for 5.6 years in order to prevent one event of the composite outcome was 72. However, the separation in the event rate curves for the two groups grew larger over time. With an additional planned followup of 3-5 years in HOPE-3, it’s likely the benefits will become even greater, according to Dr. Yusuf.

Combination therapy proved safe. Muscle aches and weakness as well as lightheadedness were more common in the combined treatment group than with dual placebo. However, permanent discontinuation rates were similar in the two groups.

HOPE-3 coinvestigator Dr. Eva Lonn presented the comparison between patients randomized to antihypertensive therapy without rosuvastatin or to placebo. In a prespecified subgroup analysis, active treatment resulted in a significant 27% reduction in the risk of the composite outcome compared with placebo in patients in the top one-third of baseline systolic blood pressure, no benefit in those with a systolic blood pressure of 131.6-143.5 mm Hg, and a suggestion of possible harm in patients whose systolic pressure at enrollment was 131.5 mm Hg or less.

Thus, the study helps define the minimum blood pressure at which antihypertensive therapy becomes beneficial, noted Dr. Lonn, professor of cardiology at McMaster University.

Dr. Yusuf said enthusiasm for the polypill concept as a means of reducing the growing global burden of cardiovascular disease remains strong among many experts. There is broad interest in a polypill for secondary prevention that will include aspirin, a beta blocker, and an ACE inhibitor of angiotensin receptor blocker as a low-cost means of improving medication adherence. And several large clinical trials of the polypill concept for primary prevention are underway, including a randomized trial conducted by Dr. Yusuf and coworkers in which several thousand high-risk subjects without baseline cardiovascular disease will receive a combination of a statin plus not two but three antihypertensive drugs.

Discussant Dr. Donald M. Lloyd-Jones commented, “What strikes me about HOPE-3 is that this is a population at risk, but not at particularly high risk.” And yet these patients benefited from statin therapy regardless of their baseline LDL, noted Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University, Chicago, and an architect of the risk-based approach to statin use that’s a centerpiece of the current ACC/AHA guidelines on atherosclerotic cardiovascular risk reduction.

In an interview, Dr. Sidney C. Smith, Jr., said the HOPE-3 data are “worthy of consideration” as experts meet at ACC 16 to begin updating guidelines for the treatment of hypertension. In particular, the key findings that moderate-risk hypertensive patients benefited from a statin regardless of their baseline LDL and initiation of blood pressure-lowering therapy was beneficial for patients with a systolic blood pressure in the 140s but not in those with a systolic pressure in the 120s and 130s could be practice changing, according to Dr. Smith, professor of medicine at the University of North Carolina, Chapel Hill.

Drs. Yusuf and Lonn reported receiving institutional research grants from the Canadian Institutes of Health Research and AstraZeneca, which funded the trial.

Simultaneous with the presentation of the HOPE-3 results at ACC 16 in Chicago, the study on cholesterol lowering and the study on blood pressure and cholesterol lowering led by Dr. Yusef as well as the study on blood pressure lowering led by Dr. Lonn were published online at NEJM.org.

[email protected]

CHICAGO – The success in the HOPE-3 trial of a two-pronged strategy of a statin plus moderate-dose antihypertensive therapy has expanded the boundaries of primary preventive pharmacotherapy to incorporate many intermediate-cardiovascular-risk patients without cardiovascular disease.

In the Heart Outcomes Evaluation (HOPE)-3 trial, the combination of rosuvastatin (Crestor) at 10 mg/day plus antihypertensive therapy with 16 mg/day of candesartan and 12.5 mg/day of hydrochlorothiazide reduced cardiovascular events in intermediate-risk patients with hypertension, regardless of their baseline LDL-cholesterol and inflammatory biomarker levels. In nonhypertensive study participants, however, blood pressure-lowering therapy provided no added benefit beyond that achieved with the statin alone, which yielded a 25% relative risk reduction in cardiovascular events compared with placebo, Dr. Salim Yusuf reported at the annual meeting of the American College of Cardiology.

The HOPE-3 trial was the first formal study of the polypill concept of fixed-dose, low-dose combination therapy as a public health tool for primary prevention in an intermediate-risk population without cardiovascular disease. It’s a simple, low-cost, safe, pragmatic preventive strategy that doesn’t require baseline laboratory measurements, dose titration visits, or frequent safety monitoring, he noted.

“The original concept of the polypill was to give it to everyone over age 55. We found in HOPE-3 that the polypill concept is not valid for everybody. It demonstrated benefit in hypertensives but not in nonhypertensives, where a statin alone was beneficial,” said Dr. Yusuf, professor of medicine and executive director of the Population Health Research Institute at McMaster University in Hamilton, Ont.

“The clinical implication is that statins should be used much more widely than they currently are. Most guidelines for hypertension don’t say to give a statin. But HOPE-3 is saying hypertensives will benefit. About half of the 40% reduction in the risk of cardiovascular events we saw with combination therapy in patients in the highest third for baseline systolic blood pressure – that is, above 143.5 mm Hg, with a mean of 154 mm Hg – was due to the rosuvastatin and half to the antihypertensive therapy. Our study suggests you can essentially double the benefit of lowering blood pressure in hypertensives if you also lower cholesterol simultaneously,” he noted. Dr. Yusuf discussed the findings in a video interview.

The double-blind trial included a diverse population of 12,705 men age 55 or older and women age 65 or older in 21 countries. All were at intermediate cardiovascular risk by conventional stratification methods; none had a history of cardiovascular disease. They were randomized to rosuvastatin or placebo, dual antihypertensive therapy or placebo, or to all three medications or double placebo. The combined-therapy group experienced a 33.7 mg/dL greater drop in LDL-cholesterol and a 6.2 mm Hg bigger reduction in systolic blood pressure than in patients on dual placebo.

During a median followup of 5.6 years, the composite rate of cardiovascular death, nonfatal MI, or nonfatal stroke was 3.6% in the combined-therapy group and 5.0% with dual placebo, for a relative risk reduction of 29%. The number needed to treat for 5.6 years in order to prevent one event of the composite outcome was 72. However, the separation in the event rate curves for the two groups grew larger over time. With an additional planned followup of 3-5 years in HOPE-3, it’s likely the benefits will become even greater, according to Dr. Yusuf.

Combination therapy proved safe. Muscle aches and weakness as well as lightheadedness were more common in the combined treatment group than with dual placebo. However, permanent discontinuation rates were similar in the two groups.

HOPE-3 coinvestigator Dr. Eva Lonn presented the comparison between patients randomized to antihypertensive therapy without rosuvastatin or to placebo. In a prespecified subgroup analysis, active treatment resulted in a significant 27% reduction in the risk of the composite outcome compared with placebo in patients in the top one-third of baseline systolic blood pressure, no benefit in those with a systolic blood pressure of 131.6-143.5 mm Hg, and a suggestion of possible harm in patients whose systolic pressure at enrollment was 131.5 mm Hg or less.

Thus, the study helps define the minimum blood pressure at which antihypertensive therapy becomes beneficial, noted Dr. Lonn, professor of cardiology at McMaster University.

Dr. Yusuf said enthusiasm for the polypill concept as a means of reducing the growing global burden of cardiovascular disease remains strong among many experts. There is broad interest in a polypill for secondary prevention that will include aspirin, a beta blocker, and an ACE inhibitor of angiotensin receptor blocker as a low-cost means of improving medication adherence. And several large clinical trials of the polypill concept for primary prevention are underway, including a randomized trial conducted by Dr. Yusuf and coworkers in which several thousand high-risk subjects without baseline cardiovascular disease will receive a combination of a statin plus not two but three antihypertensive drugs.

Discussant Dr. Donald M. Lloyd-Jones commented, “What strikes me about HOPE-3 is that this is a population at risk, but not at particularly high risk.” And yet these patients benefited from statin therapy regardless of their baseline LDL, noted Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University, Chicago, and an architect of the risk-based approach to statin use that’s a centerpiece of the current ACC/AHA guidelines on atherosclerotic cardiovascular risk reduction.

In an interview, Dr. Sidney C. Smith, Jr., said the HOPE-3 data are “worthy of consideration” as experts meet at ACC 16 to begin updating guidelines for the treatment of hypertension. In particular, the key findings that moderate-risk hypertensive patients benefited from a statin regardless of their baseline LDL and initiation of blood pressure-lowering therapy was beneficial for patients with a systolic blood pressure in the 140s but not in those with a systolic pressure in the 120s and 130s could be practice changing, according to Dr. Smith, professor of medicine at the University of North Carolina, Chapel Hill.

Drs. Yusuf and Lonn reported receiving institutional research grants from the Canadian Institutes of Health Research and AstraZeneca, which funded the trial.

Simultaneous with the presentation of the HOPE-3 results at ACC 16 in Chicago, the study on cholesterol lowering and the study on blood pressure and cholesterol lowering led by Dr. Yusef as well as the study on blood pressure lowering led by Dr. Lonn were published online at NEJM.org.

[email protected]

CHICAGO – The success in the HOPE-3 trial of a two-pronged strategy of a statin plus moderate-dose antihypertensive therapy has expanded the boundaries of primary preventive pharmacotherapy to incorporate many intermediate-cardiovascular-risk patients without cardiovascular disease.

In the Heart Outcomes Evaluation (HOPE)-3 trial, the combination of rosuvastatin (Crestor) at 10 mg/day plus antihypertensive therapy with 16 mg/day of candesartan and 12.5 mg/day of hydrochlorothiazide reduced cardiovascular events in intermediate-risk patients with hypertension, regardless of their baseline LDL-cholesterol and inflammatory biomarker levels. In nonhypertensive study participants, however, blood pressure-lowering therapy provided no added benefit beyond that achieved with the statin alone, which yielded a 25% relative risk reduction in cardiovascular events compared with placebo, Dr. Salim Yusuf reported at the annual meeting of the American College of Cardiology.

The HOPE-3 trial was the first formal study of the polypill concept of fixed-dose, low-dose combination therapy as a public health tool for primary prevention in an intermediate-risk population without cardiovascular disease. It’s a simple, low-cost, safe, pragmatic preventive strategy that doesn’t require baseline laboratory measurements, dose titration visits, or frequent safety monitoring, he noted.

“The original concept of the polypill was to give it to everyone over age 55. We found in HOPE-3 that the polypill concept is not valid for everybody. It demonstrated benefit in hypertensives but not in nonhypertensives, where a statin alone was beneficial,” said Dr. Yusuf, professor of medicine and executive director of the Population Health Research Institute at McMaster University in Hamilton, Ont.

“The clinical implication is that statins should be used much more widely than they currently are. Most guidelines for hypertension don’t say to give a statin. But HOPE-3 is saying hypertensives will benefit. About half of the 40% reduction in the risk of cardiovascular events we saw with combination therapy in patients in the highest third for baseline systolic blood pressure – that is, above 143.5 mm Hg, with a mean of 154 mm Hg – was due to the rosuvastatin and half to the antihypertensive therapy. Our study suggests you can essentially double the benefit of lowering blood pressure in hypertensives if you also lower cholesterol simultaneously,” he noted. Dr. Yusuf discussed the findings in a video interview.

The double-blind trial included a diverse population of 12,705 men age 55 or older and women age 65 or older in 21 countries. All were at intermediate cardiovascular risk by conventional stratification methods; none had a history of cardiovascular disease. They were randomized to rosuvastatin or placebo, dual antihypertensive therapy or placebo, or to all three medications or double placebo. The combined-therapy group experienced a 33.7 mg/dL greater drop in LDL-cholesterol and a 6.2 mm Hg bigger reduction in systolic blood pressure than in patients on dual placebo.

During a median followup of 5.6 years, the composite rate of cardiovascular death, nonfatal MI, or nonfatal stroke was 3.6% in the combined-therapy group and 5.0% with dual placebo, for a relative risk reduction of 29%. The number needed to treat for 5.6 years in order to prevent one event of the composite outcome was 72. However, the separation in the event rate curves for the two groups grew larger over time. With an additional planned followup of 3-5 years in HOPE-3, it’s likely the benefits will become even greater, according to Dr. Yusuf.

Combination therapy proved safe. Muscle aches and weakness as well as lightheadedness were more common in the combined treatment group than with dual placebo. However, permanent discontinuation rates were similar in the two groups.

HOPE-3 coinvestigator Dr. Eva Lonn presented the comparison between patients randomized to antihypertensive therapy without rosuvastatin or to placebo. In a prespecified subgroup analysis, active treatment resulted in a significant 27% reduction in the risk of the composite outcome compared with placebo in patients in the top one-third of baseline systolic blood pressure, no benefit in those with a systolic blood pressure of 131.6-143.5 mm Hg, and a suggestion of possible harm in patients whose systolic pressure at enrollment was 131.5 mm Hg or less.

Thus, the study helps define the minimum blood pressure at which antihypertensive therapy becomes beneficial, noted Dr. Lonn, professor of cardiology at McMaster University.

Dr. Yusuf said enthusiasm for the polypill concept as a means of reducing the growing global burden of cardiovascular disease remains strong among many experts. There is broad interest in a polypill for secondary prevention that will include aspirin, a beta blocker, and an ACE inhibitor of angiotensin receptor blocker as a low-cost means of improving medication adherence. And several large clinical trials of the polypill concept for primary prevention are underway, including a randomized trial conducted by Dr. Yusuf and coworkers in which several thousand high-risk subjects without baseline cardiovascular disease will receive a combination of a statin plus not two but three antihypertensive drugs.

Discussant Dr. Donald M. Lloyd-Jones commented, “What strikes me about HOPE-3 is that this is a population at risk, but not at particularly high risk.” And yet these patients benefited from statin therapy regardless of their baseline LDL, noted Dr. Lloyd-Jones, chair of the department of preventive medicine at Northwestern University, Chicago, and an architect of the risk-based approach to statin use that’s a centerpiece of the current ACC/AHA guidelines on atherosclerotic cardiovascular risk reduction.

In an interview, Dr. Sidney C. Smith, Jr., said the HOPE-3 data are “worthy of consideration” as experts meet at ACC 16 to begin updating guidelines for the treatment of hypertension. In particular, the key findings that moderate-risk hypertensive patients benefited from a statin regardless of their baseline LDL and initiation of blood pressure-lowering therapy was beneficial for patients with a systolic blood pressure in the 140s but not in those with a systolic pressure in the 120s and 130s could be practice changing, according to Dr. Smith, professor of medicine at the University of North Carolina, Chapel Hill.

Drs. Yusuf and Lonn reported receiving institutional research grants from the Canadian Institutes of Health Research and AstraZeneca, which funded the trial.

Simultaneous with the presentation of the HOPE-3 results at ACC 16 in Chicago, the study on cholesterol lowering and the study on blood pressure and cholesterol lowering led by Dr. Yusef as well as the study on blood pressure lowering led by Dr. Lonn were published online at NEJM.org.

[email protected]

CHICAGO – The HOPE-3 trial has brought the primary prevention of cardiovascular disease front-and-center as a hot topic of discussion at the annual meeting of the American College of Cardiology.

The large, randomized trial provides new evidence of a significant reduction in cardiovascular events in an intermediate-risk population that hasn’t previously been the focus of risk reduction via pharmacotherapy.

The double-blind study randomized nearly 13,000 intermediate-risk men and women with no baseline cardiovascular disease to lipid-lowering with rosuvastatin (Crestor) at 10 mg/day or placebo, dual-antihypertensive therapy with candesartan plus chlorothiazide or placebo regardless of baseline blood pressure, or all three drugs or placebo. After a median of 5.6 years, the combined-therapy group had a 29% reduction in the composite of cardiovascular death or nonfatal MI or stroke compared with placebo-treated controls. Impressively, the benefit was similar regardless of baseline LDL-cholesterol level; however, only subjects with hypertension benefited from the dual-antihypertensive therapy.

In this interview, Dr. B. Hadley Wilson of the Sanger Clinic in Charlotte, N.C., explains why he considers HOPE-3 to be a giant step forward in preventive cardiolo

[email protected]

CHICAGO – The HOPE-3 trial has brought the primary prevention of cardiovascular disease front-and-center as a hot topic of discussion at the annual meeting of the American College of Cardiology.

The large, randomized trial provides new evidence of a significant reduction in cardiovascular events in an intermediate-risk population that hasn’t previously been the focus of risk reduction via pharmacotherapy.

The double-blind study randomized nearly 13,000 intermediate-risk men and women with no baseline cardiovascular disease to lipid-lowering with rosuvastatin (Crestor) at 10 mg/day or placebo, dual-antihypertensive therapy with candesartan plus chlorothiazide or placebo regardless of baseline blood pressure, or all three drugs or placebo. After a median of 5.6 years, the combined-therapy group had a 29% reduction in the composite of cardiovascular death or nonfatal MI or stroke compared with placebo-treated controls. Impressively, the benefit was similar regardless of baseline LDL-cholesterol level; however, only subjects with hypertension benefited from the dual-antihypertensive therapy.

In this interview, Dr. B. Hadley Wilson of the Sanger Clinic in Charlotte, N.C., explains why he considers HOPE-3 to be a giant step forward in preventive cardiolo

[email protected]

CHICAGO – The HOPE-3 trial has brought the primary prevention of cardiovascular disease front-and-center as a hot topic of discussion at the annual meeting of the American College of Cardiology.

The large, randomized trial provides new evidence of a significant reduction in cardiovascular events in an intermediate-risk population that hasn’t previously been the focus of risk reduction via pharmacotherapy.

The double-blind study randomized nearly 13,000 intermediate-risk men and women with no baseline cardiovascular disease to lipid-lowering with rosuvastatin (Crestor) at 10 mg/day or placebo, dual-antihypertensive therapy with candesartan plus chlorothiazide or placebo regardless of baseline blood pressure, or all three drugs or placebo. After a median of 5.6 years, the combined-therapy group had a 29% reduction in the composite of cardiovascular death or nonfatal MI or stroke compared with placebo-treated controls. Impressively, the benefit was similar regardless of baseline LDL-cholesterol level; however, only subjects with hypertension benefited from the dual-antihypertensive therapy.

In this interview, Dr. B. Hadley Wilson of the Sanger Clinic in Charlotte, N.C., explains why he considers HOPE-3 to be a giant step forward in preventive cardiolo

[email protected]