03:02pm Friday 28 February 2020

Cardiovascular Patients With a Certain Gene Mutation Respond Better to Higher Clopidogrel Doses

The standard clopidogrel dosage is 75 milligrams daily. But according to a new study out of Brigham and Women’s Hospital (BWH), this dose may not be effective for people who have a certain gene mutation that prevents the body from converting the medicine to a form that it can use.

Rather, a higher dose may be needed for clopidogrel to be effective in those with the gene mutation. The study will be electronically published on Nov. 16, 2011 and will be published in the Nov. 23, 2011 print issue of The Journal of the American Medical Association. It will also be presented at this year’s American Heart Association’s Scientific Sessions in Orlando, Florida on Nov. 12-16.

According to researchers of the ELEVATE-TIMI 56 study, participants with a particular mutation in a gene called CYP2C19*2  required a clopidogrel dosage of at least 225 milligrams daily to achieve similar effects seen in participants without the gene mutation who took the standard dose.

The multicenter, randomized, double-blind study included 333 participants with stable cardiovascular disease already taking the standard clopidogrel dose. Of the 333 participants, 80 had a partial gene mutation (heterozygotes), six had a full gene mutation (homozygotes), and 247 did not have any CYP2C19*2 gene mutation (non-carriers).

Participants with the mutated gene underwent four treatment periods each lasting two weeks. They were given a different dose of clopidogrel in each treatment period. The dosages were 75, 150, 225 and 300 milligrams daily given in random order. Non-carriers also underwent four treatment periods each lasting two weeks. During their treatment periods, they were given 75 and 150 milligrams daily in random order.

Researchers found that only 48 percent of the participants with the partial gene mutation responded to the standard clopidogrel dose.  But as the dose increased, so did the response to the drug, with 90 percent responding to the 225-milligram or 300-milligram dose.

The group with the full gene mutation also responded to clopidogrel at higher doses, but the response was not as significant compared to the partial gene mutation group. Twenty percent of those with the full gene mutation responded to the standard dose, and only 40 percent responded to the 300-milligram dose.

“Among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 milligrams daily in CYP2C19*2 heterozygotes was able to achieve levels of platelet reactivity similar to that seen with the standard 75 milligram dose in non-carriers,” said lead study author, Jessica L. Mega, MD, MPH, a BWH cardiologist and assistant professor at Harvard Medical School. “In contrast, for CYP2C19*2 homozygotes, doses as high as 300 milligrams did not result in comparable degrees of platelet inhibition.”

Clopidogrel works by preventing components in blood cells, called platelets, from sticking together and forming blood clots. Blood clots can lead to cardiovascular problems such as heart attack and blockage in cardiac stents. Mega notes that although the study was geared toward finding out if higher doses of clopidogrel could improve anti-platelet activity in patients with certain gene types, future studies will need to be conducted to see if actually blocking platelet activity can reduce cardiovascular problems. 

According to Marc S. Sabatine, MD, MPH, senior study author and chairman of the TIMI Study Group at BWH, the data from the study provides a framework for how to approach alternative dosing of clopidogrel in the nearly one-third of the population who harbor a genetic roadblock to metabolizing clopidogrel appropriately.

Mega also adds, “Currently most doctors provide patients with a standard dose of clopidogrel. But studies such as this one suggest that this one-size-fits-all approach may not be optimal.”

Clopidogrel is prescribed worldwide. According to Mega, the study will help define how patients with different CYP2C19 genotypes respond to the drug’s maintenance dosing strategies.

This research was supported by an investigator initiated grant from Bristol-Myers Squibb/Sanofi-aventis.

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