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Study Points to Role of ABCB1 Gene Alterations in Plavix-Treated Patients' Cardiovascular AEs


By Turna Ray

New analysis of the TRITON-TIMI 38 study presented at the American College of Cardiology's annual meeting this week adds to a growing body of pharmacogenomic knowledge on why certain patients treated with Plavix experience increased cardiovascular adverse reactions.

Primary analysis of TRITON-TIMI 38 — a head-to-head study of Eli Lilly/Daiichi’s Effient and Bristol-Myers Squibb/Sanofi-Aventis' Plavix — reported in 2007 that Effient (prasugrel) was found to be more efficacious than Plavix (clopidogrel) in preventing deaths from blood clots, non-fatal heart attacks, and non-fatal strokes in patients receiving stents. However, in the 13,000-patient study, those receiving Effient had a greater risk of life-threatening bleeding than those taking Plavix (1.4 percent versus 0.9 percent, respectively).

Other studies have looked at the lower platelet inhibition and higher cardiovascular events associated with Plavix in patients harboring certain alleles in the cytochrome P450 gene, mainly CYP2C19. The study reported at ACC's annual meeting this week, led by Jessica Mega, associate physician at Brigham and Women's Hospital and investigator at the TIMI Study Group, analyzed the impact of alterations in the ABCB1 gene on Plavix-treated patients' risk of a composite endpoint, comprising cardiovascular death, heart attack, or stroke.

Patients enrolled in the Phase III TRITON-TIMI 38 study underwent a percutaneous coronary intervention after an acute coronary syndrome and were treated with either Plavix plus aspirin or Effient plus aspirin. The retrospective substudy tested 2,943 patients enrolled in TRITON-TIMI 38 for the C3435T variant in the ABCB1 gene, which contains the genetic code for P-glycoprotein.

On Plavix, patients who were homozygous for the C3435T allele had a 72 percent increased risk of the primary efficacy endpoint of cardiovascular death, MI, or stroke. Meanwhile, researchers reported in the abstract that patients treated with Effient who were TT homozygotes showed "only a trend toward an increased risk of the primary endpoint that was not statistically significant."

With regard to the increased risk of life-threatening bleeding seen with Effient-treated patients in the primary TRITON-TIMI analysis, this subanalysis found "no association" between the C3435T genotype and bleeding with patients treated with either drug.

The researchers concluded that "ABCB1 genotyping may identify individuals less likely to be protected from recurrent ischemic events in the setting of treatment with thienopyridines." However, in a statement announcing the study results, the makers of Effient, Eli Lilly and Daiichi Sankyo, noted that the genetic subanalysis was not sufficiently powered to make efficacy comparisons between Plavix and Effient based on genetic variations.

The results of the substudy on how ABCB1 variants increased cardiovascular adverse events in Plavix-treated patients comes a few days after the US Food and Drug Administration updated the drug's label with a boxed warning on limited efficacy in patients with CYP2C19 variants [see PGx Reporter 03-12-2010].

The new pharmacogenomics warning for Plavix leaves doctors to make some difficult risk/benefit determinations about whether to genetically test their patients ahead of Plavix administration, or put them on another drug and risk different toxicities.

"Understanding the full scope of these genetic variations may help determine which drug to prescribe as part of the dual antiplatelet therapy a patient receives after an angioplasty with a stent," Mega said in a statement.

Mega previously led a study comparing Effient and Plavix, called "Cytochrome P-450 Polymorphisms and Response to Clopidogrel," that was published in the New England Journal of Medicine in 2008. That study concluded that patients with certain CYP2C19 alleles “had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers."

In the marketplace, Plavix and Effient are competing anti-platelet products. With Plavix going off patent in 2011, the makers of Effient are hoping to cut away at the competition with pharmacogenomic data that would shrink the market for generic Plavix.

In a crowded drug market, such as the anti-platelet treatment space, if doctors have the option to prescribe a drug that requires pharmacogenomic testing over one that doesn't, most might go for the latter. At least that seems to have been the experience with Pfizer's HIV drug Selzentry.

After doctors opted to prescribe other HIV drugs that didn't require pharmacogenomic testing ahead of administration, as the CCR5-antagonist Selzentry does, Pfizer enlisted the help of Medco to educate physicians about HIV treatments that are administered with the help of companion genomic tests [see PGx Reporter 03-03-2010].

Medco also has a stake in the Plavix-versus-Effient market race, since the pharmacy-benefit manager garners a significant portion of its revenues from dispensing generic drugs. As part of Medco's Genetics for Generics program — which aims to drive down healthcare costs and incur savings for its customers from greater use of generic drugs — the company is studying the cost-effectiveness and clinical utility of genetically testing patients treated with Plavix and comparing it to the outcomes in Effient-treated patients who won't be genetically tested [see PGx Reporter 10-21-2009].

Plavix, which had global sales of $9 billion in 2008, is the first blockbuster drug to have a boxed PGx warning added to its label. After being approved by the FDA in July, Effient netted $22.6 million in worldwide sales in the third quarter last year. However, Lilly reported in January that in the fourth quarter, Effient garnered $3.8 million worldwide sales.

According to reports, Eli Lilly and Daiichi Sankyo have priced Effient at an 18 percent premium to Plavix.

In a health economic substudy published in the Jan. 5 issue of Circulation, researchers compared the costs associated with treating patients on Plavix versus Effient in the TRITON-TIMI trial. In 6,705 patients, the study found that Effient treatment reduced total hospitalization costs over a period of 15 months by $221 per patient when factoring in the cost of the drugs, and by $530 per patient when the cost of the drugs was not considered.

The study also compared Effient to generic clopidogrel at a hypothetical cost of $1 per day, and found Effient to be cost-saving compared to the generic for the first 30 days of treatment. This cost-effectiveness study did not consider the impact that genetic testing could have on healthcare costs by avoiding adverse reactions.

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