The death rate from cardiovascular disease has been falling steadily for years. Yet breakthrough discoveries that apply to general patient populations are becoming fewer and farther between. “We’ve made enormous progress in the management of patients with cardiovascular disease in the last decade,” said Paulus Kirchhof, MD, chair in cardiovascular medicine at University of Birmingham, U.K. “It’s a remarkable success and I think we can be proud of it.”
Despite these advances, a new approach is needed to push medicine forward, according to experts. “The path of progress that we have followed so far has probably reached the end or is nearing its end,” Kirchhof said.
Jean-Claude Tardif, MD, director of the research center at the Montreal Heart Institute and professor of medicine at the University of Montreal, agreed. “Despite massive investments of pharma in drug development … the number of drugs that reach stage three and reach approval by [the Food and Drug Administration] FDA has actually gone down tremendously,” he said. “That may very well be because our view of the science and the world was probably too simplistic.”
Cardiology is increasingly turning toward a new approach: personalized medicine, the use of genetics and biomarkers to understand and treat disease. Kirchhof was lead author of a position paper from the European Society of Cardiology exploring the promise and challenges of personalized medicine (Eur Heart J 2014; doi:10.093/eurheart/ehu312).
“The need is large,” said J. Wouter Jukema, MD, PhD, professor of cardiology at Leiden University Medical Center in the Netherlands, who was not involved in the study. “A lot of medication prescriptions, operations, and device implantations are done on the basis of the average patient. This is clearly suboptimal from many points of view.”
Improving Existing Therapies
So far, much of the research in personalized cardiovascular medicine has explored biomarkers or pharmacogenomics to personalize the dosing of existing drugs. For example, several studies have looked at B-type natriuretic peptide (BNP) and NT-proBNP as markers to guide heart failure therapy in terms of choice and dosing of beta blockers and angiotensin-converting-enzyme (ACE) inhibitors (J Am Coll Cardiol 2009;55:61–4).
“These have had varying degrees of success,” said Alan H.B. Wu, PhD, professor of laboratory medicine at the University of California, San Francisco and section chief of clinical chemistry at San Francisco General Hospital. “Some studies have shown good success and others have shown success in only certain populations.”
Trials have also explored genotype-guided dosing of the anticoagulant warfarin. Polymorphisms in two genes, CYP2C9 and VKORC1, appeared to be associated with variations in dosage requirement. Despite high hopes, two large clinical trials found that genotyping at the beginning of warfarin treatment did not help patients avoid bleeding and strokes (N Engl J Med 2013;369:2283–93 and N Engl J Med 2013;369:2294–303).
“This has led to a lot of questions about the value of pharmacogenomics, at least in regard to therapeutic dosing,” Wu said.
Likewise, researchers identified a liver enzyme abnormality encoded in the CYP2C19 gene that appeared to make some patients unable to activate the antiplatelet drug clopidogrel (Plavix), which is administered after coronary stent placement. Yet a study exploring genotype-based dosing of clopidogrel showed no effect.
Perhaps genetic tests will prove more useful in drug selection rather than dosing, Wu said. He is awaiting the results of the TAILOR-PCI trial, which asks if a different antiplatelet drug, ticagrelor (Brilinta), works better than clopidogrel in patients who have the liver enzyme abnormality, known as the *2 or *3 alleles.
New Drugs for Small Populations
Beyond improving the use of existing drugs, personalized cardiovascular medicine offers the promise of developing new drugs specifically for certain subgroups of patients. Tardif and his colleagues have just published a study of the drug dalcetrapib, developed by F. Hoffman-La Roche to raise high-density lipoprotein cholesterol (HDL-C) (Circ Cardiovasc Genet 2015; doi:10.1161/CIRCGENETICS.114.000663).
The drug failed a phase III clinical trial involving 15,871 patients who had been hospitalized for acute coronary syndrome. Dalcetrapib raised HDL-C levels but did not prevent future illness or death (N Engl J Med 2012;367:2089–9).
This sent Tardif and his co-authors back to conduct a genome-wide association study on more than 5,000 blood samples collected during that trial. They identified single nucleotide polymorphisms on one particular gene, ADCY9, that were associated with the effect of the drug. When patients were stratified by genotype, the drug appeared to protect some and harm others.
“This is really the first time that the effect of a cardiovascular drug on heart events—meaning cardiovascular death, heart attack, stroke, and so forth—is determined by the genetic profile,” Tardif said. “It could be the opening of a new way of looking at drug development and treating patients with cardiovascular disease, where it’s going to be much more personalized.”
His team is now meeting with regulators to plan a prospective study to find out if dalcetrapib benefits patients screened for the appropriate genotype. If it does, the drug could be available in as little as 3–4 years, Tardif said.
“It begs the question, how many other drugs that have not been tested with pharmacogenomics and precision diagnostics … are sitting on shelves in a drug company because in studies they appeared to have no effect?” Tardif said. “There might be other drugs that actually can be resurrected by that kind of approach.”
Back to Basics?
Aside from the immediate implications, the dalcetrapib study also raises questions about the ADCY9 gene and how it might be connected to cardiovascular disease mechanisms. It is just one example of how genomic testing and other personalized medicine techniques are bringing new insight into fundamental cardiovascular disease processes.
That return to basic science, with a new understanding of the genetic contributors or modifiers of cardiovascular disease, will hopefully lead to new drugs and therapies, Kirchhof said. “This is a vision, so it’s not something that will be implemented next year,” he cautioned. “But this is already happening.”
For example, researchers now know that heart failure and atrial fibrillation are caused by such a variety of mechanisms that eventually they will require a new taxonomy, and new tests to better classify and treat patients, Kirchhof noted.
A New Role for
the Clinical Laboratory
As personalized medicine advances, the clinical laboratory will become even more indispensable in treating cardiovascular patients. “We’re going to see more specialty type laboratory tests that are linked to a particular disease,” Wu emphasized. “And more importantly—linked to a particular therapeutic or management position.” There may even be a role for the laboratory to work directly with patients on cardiovascular disease prevention, he said.
Biomarkers such as troponin could help a patient monitor whether exercise is decreasing their disease risk. Genetic tests could perhaps distinguish which smokers are at risk for disease or which sleep apnea sufferers have cardiac involvement. “So it becomes almost our job as laboratory professionals to educate the public as to the dangers of these behaviors,” Wu said.
We are just beginning to see the effects of advances in genome sequencing, bioinformatics, data processing, and statistics that enable personalized medicine, noted Tardif. “The possibilities are almost infinite right now,” he said. “I really think there will be a revolution in the personalization of therapies.”
Julie Kirkwood is a freelance writer who lives in Rochester, New York.