Nissen and Topol Clash Over Genetics and Personalized Medicine Reply

Steve Nissen and Eric Topol, former colleagues and collaborators, have staked out opposite positions on the future of medicine. Topol has been a leading advocate for genomics and personalized medicine, while Nissen has now publicly questioned whether the enthusiasm for these technologies has outpaced their value in medicine today. In an editorial in JAMANissen writes that “in the popular press, the concept of personalized medicine has taken on a nearly cult like following with public pronouncements describing how future physicians will use therapies that reflect the specific genetic makeupof individual patients.”

For many years Nissen and Topol were colleagues at the Cleveland Clinic, where Topol was the chair of the department of cardiovascular medicine and Nissen served as his deputy. The two collaborated on numerous papers, most famously the JAMA paper that initiated the Vioxx controversy. Topol was replaced by Nissen when Topol lost his bid to become the Clinic’s CEO. The two have not collaborated since.

From his current perch as the chief academic officer at Scripps Health and the director of the Scripps Translational Science Institute Topol has been a staunch and highly vocal advocate for genomics and personalized medicine. His forthcoming book, The Creative Destruction of Medicine, rejects the worth of “one size fits all” medicine based on evidence derived from large clinical trials in favor of highly individualized medicine based on the individual genome, wireless monitors, and other digital technologies.

Scripps was the first major institution to offer routine genetic testing of clopidogrel responsiveness.  Topol explained the decision to heartwire:

The increased risk of patients with this gene variant is incontrovertible. We can’t just do nothing and leave them like sitting ducks. The biology is clear. The only thing that isn’t clear is what you do for that individual patient. But it is too difficult to study that in a randomized trial, as there are too many factors that have to be taken into account, such as bleeding risk on prasugrel, risk status of coronary anatomy, cardiac function, etc. This is individualized medicine on two levels—ascertaining the genotype of each patient, and using this to guide therapy choices based on each individual patient’s characteristics.

But in the new editorial (click here for our story about the JAMA meta-analysis that found no benefit for clopidogrel genotyping) Nissen takes a much more skeptical view of the same topic:

…the success of pharmacogenomics in some fields of medicine has led to unrealistic expectations for many other specialties, including cardiovascular medicine. In oncology, pharmacogenomic approaches have revolutionized treatment…. Unfortunately, in the popular press, the concept of personalized medicine has taken on a nearly cult like following with public pronouncements describing how future physicians will use therapies that reflect the specific genetic makeup of individual patients. No matter how promising, parmacogenetic approaches to treatment must withstand the same scrutiny required of all therapeutic advances—careful evaluation through well-designed randomized clinical trials.

In the case of clopidogrel pharmacogenomics, what went wrong? First, most initial studies that supported genetic testing were primarily based on analysis of surrogate markers, typically examining the association between CYP2C19 loss-of- function alleles and clopidogrel metabolites, platelet reactivity, or both. Over the last several decades, clinicians and researchers have learned painful lessons about the substitution of surrogate end points, such as relying on cholesterol or glucose levels as alternatives for clinically important cardiovascular events such as death, myocardial infarction, or stroke. Repeatedly, drugs that improve biochemical or physiological measures of disease have failed to favorably affect clinical outcomes. Examples include estrogen, rosiglitazone, torcetrapib, and nesiritide. Accordingly, when examining the pharmacogenetic factors influencing the efficacy of a drug such as clopidogrel, the effects of CYP2C19 loss-of-function alleles on antiplatelet efficacy cannot be equated to increases in cardiovascular morbidity and mortality.

Click here to see a response to the JAMA meta-analysis from Topol and Matthew Price.

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