In Sir Arthur Conan Doyle’s final Sherlock Holmes’ novel, The Valley of Fear, his beloved protagonist uttered the words that so many cardiovascular professionals have whispered regarding the FDA’s potentially premature decision to slap a black-box warning on Plavix in March. Specifically, in March, the agency added a boxed warning to the label of the widely-sold anti-clotting drug clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) for those patients who are poor metabolizers.

While a definitive verdict is still out on the prudence of the decision, the data continue to unfold this week at the European Society of Cardiology Congress (ESC) in Stockholm.

At the time of the warning, the FDA said that for Plavix to be effective, enzymes in the liver (particularly CYP2C19) must metabolize the drug to its active form, and patients who are poor metabolizers of the drug do not effectively convert Plavix to its active form. In their response, the ACC/AHA commented this warning is only relevant for “a small number of patients,” but recommended the use of genetic tests, alternate drugs or alternate dosing strategies in clinical practice. Maybe the more appropriate question is whether a black-box warning is warranted for such a small selection of patients, who could have a lack response to the drug.

Yet, several studies at ESC may continue to inform and potentially confuse this area of patient care.

An analysis of the CURE and ACTIVE A trials found that among patients with acute coronary syndromes (ACS) or atrial fibrillation, the effect of Plavix as compared with placebo is consistent, irrespective of CYP2C19 loss-of-function carrier status.

Paré et al reported that the effect of clopidogrel in reducing the rate of the primary efficacy outcome was similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not carriers of the alleles (rate among carriers, 8 percent with Plavix vs. 11.6 percent with placebo; rate among noncarriers, 9.5 vs. 13 percent). Therefore, they concluded that CYP2C19 loss-of-function variants do not modify the efficacy and safety of Plavix, and should not preclude the use of the drug at current recommended dose for ACS.

However, Mega et al suggest that prasugrel (Effient, Sanofi-Aventis/Daiichi-Sankyo) could have benefits over Plavix, especially for ACS patients who underwent PCI and carry both the ABCB1 and CYPC2C19 genotypes, and therefore, are at an increased risk for cardiovascular death, MI and stroke.  “As clinicians, professional societies and patients integrate information about genetic factors affecting the response to thienopyridines, the roles of both ABCB1 and CYP2C19 should be considered,” they wrote.

Even newer anti-platelet drugs may present the ultimate answer to this conundrum. Based on a PLATO substudy, Wallentin et al concluded that treating ACS patients with ticagrelor (Brilinta, AstraZeneca), rather than Plavix produces better results, irrespective of CYP2C19 and ABCB1 polymorphisms, while at the same time eradicates the need for genetic testing prior to dual-antiplatelet treatment.

Whether or not the FDA acted prematurely or properly, or simply reflected the new, more stringent face of the agency is not for me to say. However, as Doyle’s Sherlock Holmes speaks to the difficulty in making a decision prior to gathering all the appropriate data: "Circumstantial evidence is a very tricky thing. It may seem to point very straight to one thing, but if you shift your own point of view a little, you may find it pointing in an equally uncompromising manner to something entirely different."

On these topics, or any others, please feel free to contact me.

Justine Cadet
jcadet@cardiovascularbusiness.com