Plavix Blood Thinner Effectiveness Influenced By Gene Variants

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Main Category: Cardiovascular / Cardiology
Also Included In: Genetics;  Blood / Hematology;  Stroke
Article Date: 24 Dec 2008 - 3:00 PDT

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Two studies of heart patients showed that the blood thinner clopidogrel (brand name Plavix) was less effective in carriers of certain variants of a gene known to affect how the drug prevents blood clots than non-carriers.

Both studies appear in the 22 December online issue of the New England Journal of Medicine, NEJM.

In both studies, the researchers examined a gene that controls blood enzymes that metabolize Plavix to an active form that in turn breaks down blood platelets to stop them clumping into dangerous arterial clots. Several of the many versions (alleles) of the gene are thought to reduce its effect on Plavix metabolism, but detailed research on links with particular adverse outcomes is missing.

In the first study, Dr Jessica L Mega from Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues from other research centres in the US, found that the antiplatelet effect of Plavix was reduced, resulting in less clinical benefit in patients with acute coronary syndrome, if patients had a reduced function variant of the CYP2C19 gene.

For the study, Mega and colleagues gave 162 healthy patients Plavix and then tested them for variants of CYP genes, blood levels of the active drug metabolite, and platelet inhibition, and looked for links among these variables.

They then looked at the link between these genetic variants and cardiovascular outcomes in a separate group of 1,477 patients with acute coronary syndrome who were taking Plavix as participants in the TRITON-TIMI 38 trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38).

The results showed that:

• Among the healthy patients who took Plavix, compared to non-carriers, those who carried at least one copy (allele) of the less active variant of CYP2C19 (about 30 per cent of patients), had a significant relative reduction of 32.4 per cent in plasma exposure to the active drug metabolite.


• Carriers also had a 9 per cent absolute reduction in maximal platelet aggregation compared to non-carriers.


• Among the trial patients treated with Plavix, carriers had a 53 per cent higher relative risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with non-carriers (12.1 vs. 8.0 per cent hazard ratio for carriers).


• Among the trial patients treated with Plavix, carriers also had a 3 times higher risk of stent thrombosis.

The authors concluded that:

"Among persons treated with clopidogrel [Plavix], carriers of a reduced-function CYP2C19 allele 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 second study, Dr Tabassome Simon at the Université Pierre et Marie Curie (UPMC) in Paris and colleagues from other research centres in France, found that patients treated with Plavix after a heart attack had a higher rate of cardiovascular events during the following 12 months if they had a particular variant of CYP2C19.

For the study, Simon and colleagues enrolled 2,208 acute myocardial infarction (heart attack) patients across France who were being treated with Plavix. They then assessed the relations among variants of several genes that affect Plavix metabolism and biological activity, and various outcomes, such as death from any cause, non-fatal stroke, or another heart attack during 12 months of follow up.

The results showed that:

• 225 patients died.


• 94 patients had a heart attack or stroke.


• None of the gene variants of CYP3A5, P2RY12, or ITGB3 was linked to a risk of an adverse outcome.


• Patients with two copies of a variant of ABCB1 (where the code shows TT at nucleotide 3435) had a higher rate of cardiovascular events at 12 months than patients with the ABCB1 wild-type variant (where the code is CC at nucleotide 3435).


• Patients who had two copies of any of the variants of CYP2C19 that reduces Plavix effectiveness (loss of function alleles *2, *3, *4, or *5), had a higher risk of adverse events than patients who had none (21.5 vs 13.3 per cent adjusted hazard ratio).


• Among the 1,535 patients who had heart procedures while in hospital, the rate of cardiovascular events among those who had two copies of the reduced function version of CYP2C19 was nearly 4 times the rate of those who had none.

The authors concluded that:

"Among patients with an acute myocardial infarction who were receiving clopidogrel [Plavix], those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention [heart procedures]."

Another new study in the Lancet has also found that among young heart attack survivors treated with Plavix, those who had the reduced function version of the CYP2C19 gene had a higher risk of death or further cardiovascular event compared with non-carriers.

"Cytochrome P-450 Polymorphisms and Response to Clopidogrel
Mega, Jessica L., Close, Sandra L., Wiviott, Stephen D., Shen, Lei, Hockett, Richard D., Brandt, John T., Walker, Joseph R., Antman, Elliott M., Macias, William, Braunwald, Eugene, Sabatine, Marc S.
N Engl J Med Published online December 22, 2008.
DOI: 10.1056/NEJMoa0809171

Click here for Article.

"Genetic Determinants of Response to Clopidogrel and Cardiovascular Events."
Simon, Tabassome, Verstuyft, Celine, Mary-Krause, Murielle, Quteineh, Lina, Drouet, Elodie, Meneveau, Nicolas, Steg, P. Gabriel, Ferrieres, Jean, Danchin, Nicolas, Becquemont, Laurent, the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators.
N Engl J Med Published online December 22, 2008.
DOI: 10.1056/NEJMoa0808227

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Sources: NEJM, Lancet.

Written by: Catharine Paddock, PhD


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