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In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.
These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.
“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.
Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
The needle mover: LDL lowering
“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.
“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.
“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.
Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.
Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.
That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.
“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”
At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.
Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.
And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.
Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.
“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”
Other important successes and equally important failures
Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.
There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.
Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.
“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
The rise and fall of CVOTs
Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.
Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).
It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.
His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.
“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.
Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.
In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.
Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.
“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”
Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.
“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.
“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”
Clinical research for the next 20 years
Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.
Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.
RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.
“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.
RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.
Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.
“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
Time to be inclusive
Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.
“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.
“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”
In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”
The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
Stick with randomization
Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.
“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.
“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”
Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.
“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”
Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”
In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.
These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.
“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.
Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
The needle mover: LDL lowering
“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.
“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.
“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.
Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.
Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.
That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.
“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”
At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.
Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.
And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.
Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.
“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”
Other important successes and equally important failures
Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.
There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.
Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.
“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
The rise and fall of CVOTs
Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.
Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).
It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.
His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.
“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.
Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.
In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.
Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.
“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”
Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.
“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.
“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”
Clinical research for the next 20 years
Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.
Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.
RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.
“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.
RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.
Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.
“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
Time to be inclusive
Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.
“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.
“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”
In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”
The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
Stick with randomization
Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.
“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.
“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”
Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.
“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”
Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”
In February 2003, when Cardiology News published its first edition, there were a handful of articles reporting results from randomized clinical trials. These included a trial of bivalirudin for percutaneous coronary intervention (PCI) anticoagulation (REPLACE-2) and a small controlled pilot study of soy nuts for blood pressure reduction in postmenopausal women. Also included was a considered discussion of the ALLHAT findings.
These trials and the incremental gain they offered belie the enormous global impact the cardiology community has had in clinical research over the last several decades. In fact, more than any other medical specialty, cardiology has led the way in evidence-based practice.
“When you step back and take a look at the compendium of cardiology advances, it’s unbelievable how much we’ve accomplished in the last 20 years,” said Steven E. Nissen, MD.
Dr. Nissen, a prodigious researcher, is the chief academic officer at the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute, and holds the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at the Cleveland Clinic.
The needle mover: LDL lowering
“From a population health perspective, LDL cholesterol lowering is clearly the big winner,” said Christopher Cannon, MD, from Harvard Medical School and Brigham and Women’s Hospital, both in Boston, said in an interview.
“We’ve been at it with LDL cholesterol for about 50 years now, but I think things really accelerated over the last 20 years when the conversation shifted from just lowering LDL-C to recognizing that lower is better. This pushed us toward high-intensity statin treatment and add-on drugs to push LDL down further,” he said.
“Concurrent with this increase in the use of statins and other LDL-lowering drugs, cardiovascular death has fallen significantly, which in my mind is likely a result of better LDL lowering and getting people to stop smoking, which we’ve also done a better job of in the last 20 years,” said Dr. Cannon.
Indeed, until cardiovascular mortality started rising in 2020, the first year of the COVID-19 pandemic, mortality rates had been dropping steadily for several decades. The progress in the past 2 decades has been so fast, noted Dr. Cannon, that the American Heart Association’s stated goal in 1998 of reducing coronary heart disease, stroke, and risk by 25% by the year 2008 was accomplished about 4 years ahead of schedule.
Coincidentally, Dr. Cannon and Dr. Nissen were both important players in this advance. Dr. Cannon led the PROVE-IT trial, which showed in 2004 that an intensive lipid-lowering statin regimen offers greater protection against death or major cardiovascular events than does a standard regimen in patients with recent acute coronary syndrome.
That trial was published just months after REVERSAL, Dr. Nissen’s trial that showed for the first time that intensive lipid-lowering treatment reduced progression of coronary atherosclerosis, compared with a moderate lipid-lowering approach.
“Added to this, we have drugs like ezetimibe and the PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor, and now they’re even using CRISPR gene editing to permanently switch off the gene that codes for PCSK9, testing this in people with familial hypercholesterolemia,” said Dr. Cannon. “In the preclinical study, they showed that with one treatment they lowered blood PCSK9 protein levels by 83% and LDL-C by 69%..”
At the same time as we’ve seen what works, we’ve also seen what doesn’t work, added Dr. Nissen. “Shortly after we saw the power of LDL lowering, everyone wanted to target HDL and we had epidemiological evidence suggesting this was a good idea, but several landmark trials testing the HDL hypothesis were complete failures.” Debate continues as to whether HDL cholesterol is a suitable target for prevention.
Not only has the recent past in lipidology been needle-moving, but the hits keep coming. Inclisiran, a first-in-class LDL cholesterol–lowering drug that shows potent lipid-lowering efficacy and excellent safety and tolerability in phase 3 study, received Food and Drug Administration approval in December 2021. The drugs twice-a-year dosing has been called a game changer for adherence.
And at the 2023 annual scientific sessions of the American College of Cardiology in March, Dr. Nissen presented results of the CLEAR Outcomes trial on bempedoic acid (Nexletol), a 14,000-patient, placebo-controlled trial of bempedoic acid in statin intolerant patients at high cardiovascular risk. Bempedoic acid is a novel compound that inhibits ATP citrate lyase, which catalyzes a step in the biosynthesis of cholesterol upstream of HMG-CoA reductase, the target of statins.
Findings revealed a significant reduction in risk for a composite 4-point major adverse cardiovascular events endpoint of time to first cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization. The trial marks the first time an oral nonstatin drug has met the MACE-4 primary endpoint, Dr. Nissen reported.
“We also have new therapies for lowering lipoprotein(a) and outcome trials underway for antisense and short interfering RNA targeting of Lp(a), which I frankly think herald a new era in which we can have these longer-acting directly targeted drugs that work at the translation level to prevent a protein that is not desirable,” added Dr. Nissen. “These drugs will undoubtedly change the face of atherosclerotic cardiovascular disease in the next 2 decades.”
Other important successes and equally important failures
Perhaps consideration of some of the treatments we didn’t have 20 years ago is more revealing than a list of advances. Two decades ago, there were no direct direct-acting anticoagulants on the market, “so no alternative to warfarin, which is difficult to use and associated with excess bleeding,” said Dr. Cannon. These days, warfarin is little used, mostly after valve replacement, Dr. Nissen added.
There were also no percutaneous options for the treatment of valvular heart disease and no catheter ablation of atrial fibrillation, “huge developments that are now being done everywhere,” Dr. Nissen said.
Also in the catheterization laboratory, there was also a far less sophisticated understanding of the optimal role of PCI in treating coronary artery disease.
“We’ve moved from what we called the ‘oculostenotic reflex’– if you see an obstruction, you treat it – to a far more nuanced understanding of who should and shouldn’t have PCI, such that now PCI has contracted to the point where most of the time it’s being done for urgent indications like ST-segment elevation MI or an unstable non-STEMI. And this is based on a solid evidence base, which is terribly important,” said Dr. Nissen.
The rise and fall of CVOTs
Certainly, the heart failure world has seen important advances in recent years, including the first mineralocorticoid receptor antagonist, spironolactone, shown in the 1999 RALES trial to be life prolonging in patients with heart failure with reduced ejection fraction and a first in class angiotensin neprilysin inhibitor, sacubitril/valsartan. But it’s a fair guess that heart failure has never seen anything like the sodium-glucose cotransporter 2 (SGLT2) inhibitors.
Likely very few in the cardiology world had ever heard of SGLT2 inhibition 20 years ago, even though the idea of SGLT2 inhibition dates back more than 150 years, to when a French chemist isolated a substance known as phlorizin from the bark of the apple tree and subsequent investigations found that ingestion of it caused glucosuria. The SGLT2 story is one of great serendipity and one in which Dr. Nissen played a prominent role. It also hints to something that has both come and gone in the last 20 years: the FDA-mandated cardiovascular outcome trial (CVOT).
It was Dr. Nissen’s meta-analysis published in 2007 that started the ball rolling for what has been dubbed the CVOT or cardiovascular outcomes trials.
His analysis suggested increased cardiovascular risk associated with the thiazolidinedione rosiglitazone (Avandia), then a best-selling diabetes drug.
“At the time, Avandia was the top selling diabetes drug in the world, and our meta-analysis was terribly controversial,” said Dr. Nissen. In 2008, he gave a presentation to the FDA where he suggested they should require properly powered trials to rule out excess cardiovascular risk for any new diabetes drugs.
Others also recognized that the findings of his meta-analysis hinted to a failure of the approval process and the postapproval monitoring process, something which had been seen previously, with cardiac safety concerns emerging over other antihyperglycemic medications. The FDA was also responding to concerns that, given the high prevalence of cardiovascular disease in diabetes, approving a drug with cardiovascular risk could be disastrous.
In 2008 they mandated the CVOT, one of which, the EMPA-REG OUTCOME trial, showed that the SGLT2 inhibitor empagliflozin significantly reduced the risk of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 14% (P = .04), driven by a 38% relative risk reduction in cardiovascular death (P < .001).Treatment with empagliflozin was also associated with a 35% reduction in heart failure hospitalization and a 32% reduction in all-cause death in that trial.
Additional groundbreaking CVOTs of empagliflozin and other SGLT2 inhibitors went on to show significant cardiorenal benefits and risk reduction in patients across the spectrum of heart failure, including those with preserved ejection fraction and in those with kidney disease.
“I think it’s fair to say that, had the FDA not mandated CVOTs for all new diabetes drugs, then the SGLT2 inhibitors and the GLP-1 [glucagonlike peptide–1] receptor agonists would have been approved on the basis of trials involving a few thousand patients showing that they lowered blood sugar, and we might never have found out what we know now about their benefits in individuals with established cardiovascular disease, in heart failure, and their ability to help people lose weight,” said Dr. Nissen. “And, of course, Avandia is long gone, which is a good thing.”
Interestingly, the FDA no longer requires extensive cardiovascular testing for new glucose-lowering agents in the absence of specific safety signals, replacing the CVOT mandate with one requiring broader inclusion of patients with underlying CV disease, chronic kidney disease, and older patients in stage 3 clinical trials of new agents.
“The SGLT2 inhibitors are already hugely important and with the growing prevalence of diabetes, their role is just going to get bigger. And it looks like the same thing will happen with the GLP-1 receptor agonists and obesity. We don’t have the outcomes trials for semaglutide and tirzepatide yet in patients with obesity, but given every other trial of this class in patients with diabetes has shown cardiovascular benefit, assuming those trials do too, those drugs are going to be very important,” added Dr. Cannon.
“The truth is, everywhere you look in cardiology, there have been major advances,” Dr. Cannon said. “It’s a wonderful time to work in this field because we’re making important progress across the board and it doesn’t appear to be slowing down at all.”
Clinical research for the next 20 years
Twenty years ago, clinical research was relatively simple, or at least it seemed so. All that was needed was a basic understanding of the scientific method and randomized controlled trials (RCTs), a solid research question, a target sample of sufficient size to ensure statistical power, and some basic statistical analysis, et violà, evidence generation.
Turns out, that might have been in large part true because medicine was in a more simplistic age. While RCTs remain the cornerstone of determining the safety and efficacy of new therapeutic strategies, they traditionally have severely lacked in age, gender, ethnic, and racial diversity. These issues limit their clinical relevance, to the chagrin of the large proportion of the population (women, minorities, children, and anyone with comorbidities) not included in most studies.
RCTs have also grown exceedingly time consuming and expensive. “We really saw the limitations of our clinical trial system during the pandemic when so many of the randomized COVID-19 trials done in the United States had complex protocols with a focus on surrogate outcomes such that, with only the 500 patients they enrolled, they ended up showing nothing,” Dr. Cannon said in an interview.
“And then we looked at the RECOVERY trial program that Martin Landray, MBChB, PhD, and the folks at Oxford [England] University pioneered. They ran multiple trials for relatively little costs, used a pragmatic design, and asked simple straightforward questions, and included 10,000-15,000 patients in each trial and gave us answers quickly,” he said.
RECOVERY is an ongoing adaptive multicenter randomized controlled trial evaluating several potential treatments for COVID-19. The RECOVERY Collaborative are credited with running multiple streamlined and easy to administer trials that included more than 47,000 participants spread across almost 200 hospital sites in six countries. The trials resulted in finding four effective COVID-19 treatments and proving that five others clearly were not effective.
Importantly, only essential data were collected and, wherever possible, much of the follow-up information was derived from national electronic health records.
“Now the question is, Can the U.S. move to doing more of these pragmatic trials?” asked Dr. Cannon.
Time to be inclusive
Where the rules of generating evidence have changed and will continue to change over the next many years is inclusivity. Gone are the days when researchers can get away with running a randomized trial with, say, few minority patients, 20% representation of women, and no elderly patients with comorbidities.
“I’m proud of the fact that 48% of more than 14,000 participants in the CLEAR outcomes trial that I presented at the ACC meeting are women,” Dr. Nissen said in an interview.
“Should it have been like that 20 years ago? Yes, probably. But we weren’t as conscious of these things. Now we’re working very hard to enroll more women and more underrepresented groups into trials, and this is a good thing.”
In a joint statement entitled “Randomized trials fit for the 21st century,” the leadership of the European Society of Cardiology, American Heart Association, American College of Cardiology, and the World Heart Federation urge investigators and professional societies to “promote trials that are relevant to a broad and varied population; assuring diversity of participants and funded researchers (e.g., with appropriate sex, age, racial, ethnic, and socioeconomic diversity).”
The statement also recognizes that the present clinical research model is “unsustainable” and encourages wider adoption of “highly streamlined” conduct like that taken by the RECOVERY investigators during the pandemic.
Stick with randomization
Some have suggested that loosening the standards for evidence generation in medicine to include observational data, big data, artificial intelligence, and alternative trial strategies, such as Mendelian randomization and causal inference of nonrandomized data, might help drive new treatments to the clinic faster. To this, Dr. Nissen and Dr. Cannon offer an emphatic no.
“The idea that you can use big data or any kind of nonrandomized data to replace randomized control trials is a bad idea, and the reason is that nonrandomized data is often bad data,” Dr. Nissen said in an interview.
“I can’t count how many bad studies we’ve seen that were enormous in size, and where they tried to control the variables to balance it out, and they still get the wrong answer,” he added. “The bottom line is that observational data has failed us over and over again.”
Not to say that observational studies have no value, it’s just not for determining which treatments are most efficacious or safe, said Dr. Cannon. “If you want to identify markers of disease or risk factors, you can use observational data like data collected from wearables and screen for patients who, say, might be at high risk of dying of COVID-19. Or even more directly, you can use a heart rate and temperature monitor to identify people who are about to test positive for COVID-19.
“But the findings of observational analyses, no matter how much you try to control for confounding, are only ever going to be hypothesis generating. They can’t be used to say this biomarker causes death from COVID or this blood thinner is better than that blood thinner.”
Concurring with this, the ESC, AHA, ACC, and WHF statement authors acknowledged the value of nonrandomized evidence in today’s big data, electronic world, but advocated for the “appropriate use of routine EHRs (i.e. ‘real-world’ data) within randomized trials, recognizing the huge potential of centrally or regionally held electronic health data for trial recruitment and follow-up, as well as to highlight the severe limitations of using observational analyses when the purpose is to draw causal inference about the risks and benefits of an intervention.”