Most Secondary Prevention Patients Are Eligible for Multiple Drugs
Many fit multiple RCT criteria, and it can be vexing for doctors deciding which drug to prescribe on top of statins and aspirin.
For most patients with ischemic heart disease or myocardial infarction, there is randomized controlled trial evidence supporting the use of adding another medication to reduce the risk of atherosclerotic cardiovascular disease or death, according to a new analysis.
Among participants in the Copenhagen General Population Study (CGPS), 80% of those with ischemic heart disease and 99% of those with a prior MI would meet the enrollment criteria for at least one randomized trial testing a novel preventive therapy. In fact, there was a fair amount of overlap in trial eligibility, with more than one-third of the 6,292 patients with ischemic heart disease eligible for at least four medications based on the trial enrollment criteria and 80% of the 2,277 patients with prior MI eligible for four or more new drugs simultaneously.
“There are so many new evidence-based options in secondary prevention,” study co-author Michael Blaha, MD (Johns Hopkins Hospital, Baltimore, MD), told TCTMD. “In secondary prevention, of course we’re going to put a patient on a statin and aspirin, but what do you add next? We like to debate that amongst ourselves and at meetings, so this study is a description of the problem. If you sit down and think about the patient in front of you who might meet certain clinical trial criteria, we [will] usually say this is a COMPASS patient or this is a FOURIER patient, for example. If you start saying that, many of these patients fit the criteria for multiple trials.”
The new study, published online January 2, 2020, in JAMA Cardiology, highlights the challenges of practicing cardiology in an era when several new drug classes have succeeded in clinical trials and are commercially available. It also raises potential societal implications given the price tag of the new medications. “Cost makes this relevant,” said Blaha. “If these drugs were all generic and cheap, it wouldn’t be as interesting.”
The 12 Big Cardiology Trials
In the analysis, Blaha, along with lead author Martin Bødtker Mortensen, MD, PhD (Aarhus University Hospital, Denmark), and Børge Grønne Nordestgaard, MD (Copenhagen University Hospital, Denmark), determined CGPS patient eligibility for 12 cardiovascular trials testing various drugs shown to reduce major cardiovascular events. The studies, which included IMPROVE-IT, PEGASUS-TIMI 54, EMPA-REG OUTCOME, LEADER, SUSTAIN-6, FOURIER, CANVAS, REVEAL, CANTOS, COMPASS, ODYSSEY OUTCOMES, and REDUCE-IT, tested a range of drug classes such as PCSK9 inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) analogues, as well as a prescription-strength omega-3 fatty acid and an anti-inflammatory agent targeting interleukin-1β, among others.
“I have been in the field for many years and we’ve seen so many things given on top of statins and nothing worked,” Nordestgaard told TCTMD. “Suddenly we have all these different drugs and of course it comes back then to the question of which ones do we give to patients.”
Overall, patient eligibility was highest for the COMPASS trial, a study testing rivaroxaban (Xarelto; Bayer/Janssen) in addition to aspirin in patients with stable ischemic heart disease. Roughly 70% of the CGPS patients with a prior MI were eligible for rivaroxaban based on the COMPASS criteria, as were more than 60% of those with ischemic heart disease. Trial eligibility was lowest for the studies testing the antidiabetic agents, with less than 20% of the population eligible for one of the SGLT2 inhibitors or GLP-1 receptor agonists.
Suddenly we have all these different drugs and of course it comes back then to the question of which ones do we give to patients. Børge Grønne Nordestgaard
Assessing trial eligibility based on the four drug classes—lipid-modifying, antithrombotic, anti-inflammatory, or antidiabetic—41% of ischemic heart disease patients in the CGPS and 81% of those with a prior MI would be eligible to receive treatment from two or more drug classes simultaneously.
The researchers also estimated the percentage of major cardiovascular events or death that could be prevented with adding each new therapy, noting that it ranged from 1% to 20%. The maximum potential reduction of major cardiovascular events observed was 20% based on adding rivaroxaban to patients with a previous MI, as shown in COMPASS. “We’re not saying that one drug is better than another, but the easiest-to-use drug might be one that’s most beneficial and most widely applicable,” said Blaha. “That would be ideal.”
Most physicians, said Blaha, aren’t adding two or three expensive agents at once, but rather a single agent to the patient’s current treatment.
Nordestgaard said that when encountering patients with stable ischemic heart disease it can be confusing about which drugs to prescribe patients, but added that “it’s a privilege” to have so many options. “We got stuck there for a little while after statins came in,” he said. “Nothing moved much. Even when they tried to do things with lowering glucose, nothing much happened, but this is a new opportunity.”
The study also highlights the challenges facing clinical guideline writers who must recommend treatments for patients, given the plethora of evidence supporting different agents. “It’s very easy to write a guideline for a ‘very narrow’ drug,” said Blaha. “I’m not sure of any other field of medicine right now where we have as much overlapping innovation and multiple different pathways targeting disease. I think it’s a very good problem to have, but it’s also unprecedented in terms of the solution.”
Mortensen MB, Blaha MJ, Nordestgaard BG. Eligibility and preventive potential for new evidence-based cardiovascular drugs in secondary prevention. JAMA Cardiol. 2020;Epub ahead of print.
- Blaha reports receiving grants from the National Institutes of Health, US Food and Drug Administration, American Heart Association, and Aetna Foundation, as well as grants and personal fees from Amgen, Sanofi, Regeneron, Novartis, Bayer, and Novo Nordisk outside the submitted work.
- Nordestgaard reports receiving personal fees from AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Amarin, Novo Nordisk, and Silence Therapeutics during the conduct of the study.