By Kirell Lakhman

With all the talk over the past several months supporting the link between CYP2C19 and Plavix efficacy you'd think the data behind it — not to mention FDA's recent Black Box warning — are incontrovertible.

But now comes a new, widely reported study claiming that reports of adverse events tied to CYP2C19's effect on Plavix metabolism are virtually non-existent.

The study, published a mere five months since the Black Box warning was added to the anticoagulant's label, is enough to give a clinical lab manager whiplash.

But among cardiologists and those in the clinical lab community, the study will throw into deeper disarray the debate over whether performing CYP2C19 tests on Plavix patients is even worthwhile.

Gone are the days when the toughest questions asked about the discretionary protocol were whom to test, when to test them, and who will pay for it.

According to the study, which appears in the current New England Journal of Medicine, among certain patients "the effect of [Plavix] as compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status."

The CYP2C19 results actually come from a substudy of the large, international CURE trial, which is designed to see if acute and long-term treatment with Plavix and aspirin is superior to aspirin alone in patients with acute coronary syndrome.

In the study, funded by Plavix manufacturers Sanofi-Aventis and Bristol-Myers Squibb, the drug was able to "significantly reduce" the rate of cardiovascular death, MI, and stroke in certain patients compared with a placebo "regardless of CYP2C19 genotype."

Moreover, when compared with its placebo arm, the randomized clinical trial showed that there was a 31-percent "reduction in [adverse] events" among carriers of at least one loss-of-function allele of the CYP2C19 gene, whereas non-carriers saw a 28-percent reduction.

Perhaps its time to find a shovel and a soft patch of earth and deep-six CYP2C19's Plavix indication.

But wait, there's more: Adding yet another voice to the cluttered chatter, the study found that "gain-of-function carriers derived more benefit from [Plavix] treatment as compared with placebo than did non-carriers [emphasis added]."

Perhaps you won't be needing that shovel after all?

Still, Medpage Today over the weekend found enough clues to claim that "the presence of these [CYP2C19] variants … does not influence outcomes."

Market Exploitation

As the Wall Street Journal noted yesterday, the NEJM study, which was presented at the European Society of Cardiology Congress in Stockholm last week, "underscore[s] the challenges facing doctors ... in determining how to use growing troves of genetic data to tailor treatments to individual patients."

Closer to home, the study's findings could force clinical lab managers to make tough decisions, which could include fretting over staffing or other resource-allocation decisions they've made since the spring, when the Black Box warning first made its appearance.

'Did I assign too many techs exclusively for CYP2C19 Plavix testing?' 'Should I revisit my budget estimates for the remainder of 2010 and for the next couple of years?'

These are real questions and concerns that carry big financial implications. Doctors in the US write as many as 3 million prescriptions for Plavix each month, which helped Sanofi pocket $8.6 billion in global sales of the drug last year.

These same physicians are also "debating who should get genetic testing for [it] to determine whether [it] might not work on them," according to AboutLawSuits.com, which also wrote about the NEJM study.

To be sure, many clinical labs have already begun maneuvering to fit more comfortably, more efficiently, in the 5-month-old Black Box environment. Happy to work quietly in the background (but not fond of the forced anonymity), clinical labs have used the warning to not only begin developing and offering their own CYP2C19 test for Plavix testing, but to advertise the fact. Recent examples of this otherwise atypical strategy can be found here, here, and here.

And let's not even humor the potential legal impact a Black Box warning can have on clinical labs, or how the NEJM study might influence weather patterns in the methane-rich payorsphere.

On the latter, health insurers, especially Medicare, have been nurturing a dubious relationship with genetic tests for anticoagulants for more than a year.

Whiplash

The results of the study are enough to give a cardiologist or a clinical lab manager a severe case of confusion.

Contributing most recently, and most vocally, to this emerging murkiness was a paper published last month in the Journal of the American College of Cardiology. In it, co-author Gilles Montalescot, a researcher at Hôpital Pitié-Salpêtrière in Paris, cried that a "rapid and inexpensive" test for CYP2C19 "is of the utmost importance" if physicians are to identify patients who are at "excess risk" of developing cardiovascular events and death while taking Plavix.

And (mea culpa) in March I wrote that clinical labs that perform gene-based drug-metabolism assays, and that have robust cardiovascular departments, could soon start seeing more orders for CYP2C19 testing in patients treated with Plavix. Perhaps I, too, had sipped more of the Black Box Kool-Aid than advisable.

Then there is the handful of studies, also presented at the European Society of Cardiology Congress, of drugs either approved or soon-to-be approved that are designed to compete with Plavix. As the Journal notes, these drugs appear to be better than Plavix, but "none of [them] appears to be affected by genetic variants."

But, who knows, all this may be moot even with a genetic-testing solution in hand. As Medpage Today writes, "genotype-related efficacy issues may take a back seat to [drug] adherence as the main concern for clinicians [because] many patients on long-term [Plavix] treatment stop taking the drug."

"That's probably more of a problem than the genetic variation right now," Alfred Bove, a former president of the American College of Cardiology, was quoted as saying.

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