Daiichi Sankyo, Eli Lilly respond to ACCF/AHA clinical alert on FDA's clopidogrel boxed warning

Jun 29 2010

Daiichi Sankyo, Inc. and Eli Lilly and Company appreciate the availability of a "Clinical Alert" from the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) in response to the FDA's Boxed Warning about Plavix® (clopidogrel), and commend the leading cardiovascular medical societies for providing perspective on the importance of genetic make-up and the variability in response of certain oral anti-platelet (OAP) therapy for patients with acute coronary syndrome (ACS) who are managed with angioplasty and stenting (known as PCI). This statement is being issued in light of references in the Clinical Alert to the companies' co-developed product, Effient® (prasugrel).

"We believe the medical community will find the clinical alert from the leading cardiovascular medical societies on this important issue both timely and welcome," said LeRoy LeNarz, MD, senior medical director, Cardiovascular, Lilly USA, LLC. "It is important for physicians – and patients – to recognize the potential impact of a variety of factors, including genetics, on clopidogrel response, as well as the prevalence of these genetic variations in the general population, and we look forward to working with physicians as they identify ways to help manage these issues while the science continues to evolve."

Common Genetic Variations:  No Impact on Effient  

Unlike clopidogrel, there is no relevant effect of genetic variation in CYP2C19 on the pharmacokinetics of the active metabolite of Effient or its inhibition of platelet aggregation.  Genetic variation in CYP2B6, CYP2C9 or CYP3A5 also has no impact on its active metabolite or inhibition of platelet aggregation.

The clopidogrel boxed warning states that patients considered "poor metabolizers" (those with two copies of the CYP2C19 variant) may have an increased risk of thrombotic cardiovascular (CV) events.  In addition, the label also notes that some patients with at least one reduced-function allele (copy) of CYP2C19 (also known as intermediate metabolizers) may also have a reduced response to clopidogrel.  The prevalence of poor metabolizers is estimated at 2 percent for Caucasians, 4 percent for Blacks, and 14 percent for Chinese. The prevalence of intermediate metabolizers is 28 percent for Caucasians, 33 percent for Blacks and 64 percent for Chinese.

In addition, the ACCF/AHA Clinical Alert suggests genetic variations in other genes, such as ABCB1, may also contribute to variability in response to clopidogrel.  A retrospective analysis of the TRITON-TIMI 38 trial suggested that patients treated with Effient with two variants in ABCB1 did not have an increased risk of thrombotic CV events when compared to patients treated with Effient without these variants.  

"The ability to convert Effient to its active metabolite is not known to be impacted by the key genetic variations discussed in the Clinical Alert," said Rogelio Braceras, MD, senior medical director, thrombosis at Daiichi Sankyo, Inc.  "In addition, other high-risk patient types mentioned in the Clinical Alert, such as those with diabetes or those who are more susceptible to recurrent events, such as STEMI patients, achieved reductions in the primary composite endpoint of CV death, nonfatal heart attack or nonfatal stroke in TRITON-TIMI 38 that were consistent with those observed in the UA/NSTEMI cohort and the overall all ACS population.  This benefit, however, should be weighed against the potential risk of clinically significant bleeding, which in TRITON-TIMI 38 was significantly higher with Effient when compared with clopidogrel."

As pointed out in the Clinical Alert, research has shown other factors beyond genetics can negatively impact response to clopidogrel in some ACS-PCI patients. These factors include diabetes status, heart attack severity, stent type and concomitant medications.

In TRITON-TIMI 38, Effient produced reductions in the primary composite endpoint of CV death, nonfatal heart attack or nonfatal stroke that were consistent with that observed in the overall UA/NSTEMI and STEMI populations.  In the UA/NSTEMI population, the rate of the primary composite endpoint was 10 percent in patients with diabetes treated with Effient versus 15 percent in patients with diabetes treated with clopidogrel.  In the STEMI population, the rate of the primary composite endpoint was 9 percent in patients with diabetes treated with Effient versus 13.6 percent in patients with diabetes treated with clopidogrel.  In TRITON-TIMI 38 patients with diabetes, the risk of non-CABG TIMI major or minor bleeding was 4.9 percent for Effient versus 4.5 percent for clopidogrel.  In STEMI patients, the risk of non-CABG TIMI major or minor bleeding was 4.8 percent for Effient versus 4.5 percent for clopidogrel.  In the overall population TRITON-TIMI 38, the rates of non-CABG TIMI major or minor bleeding were 4.9 percent for prasugrel and 3.4 percent for clopidogrel.

In TRITON-TIMI 38, there were 50 percent fewer stent thromboses (p<0.001) reported among patients randomized to Effient (0.9 percent) than among patients randomized to clopidogrel (1.8 percent).  The differences manifested early and were maintained though one year of follow-up, and findings were similar with bare metal and drug-eluting stents.

Finally, Effient can be administered with drugs that are inducers or inhibitors of cytochrome P450 enzymes.

Effient is indicated to reduce the risk of future heart-related events, such as heart attack or blood clot in a stent, in patients with acute coronary syndrome (ACS) managed with a procedure called angioplasty.