12:58pm Saturday 22 February 2020

Triple-dose clopidogrel can work in people with genetic resistance to it

ORLANDO, FLA. — Higher doses of clopidogrel were more effective than standard dosing in patients with a gene variant that blocks some of the drug’s anti-clotting effect, according to late-breaking research presented at the American Heart Association’s Scientific Sessions 2011.
The study is simultaneously published in the Journal of the American Medical Association.
One of the most frequently prescribed drugs, clopidogrel, also called Plavix, helps prevent heart attacks in patients with a prior heart attack or stents in their heart vessels. It reduces the chances of blood clots by blocking blood components called platelets from binding to each other.
However, nearly one-third of patients don’t respond optimally to the currently recommended dose of clopidogrel and remain at increased risk for these clots that can cause heart attacks. Previous research has linked this unresponsiveness partially to a variation in the CYP2C19 gene, which prevents the drug from being converted into the effective form.
“We know that someone’s genetic predisposition can affect their response to clopidogrel,” said Jessica L. Mega, M.D., M.P.H., the study lead author and associate physician at Brigham & Women’s Hospital at Harvard Medical School in Boston, Mass. “Because of this, giving this drug in the same dose to all people may not be the right approach.”
ELEVATE-TIMI 56 is the first study to systematically examine high maintenance doses of clopidogrel up to 300 mg per day (four times the usual dose) in patients with particular CYP2C19 gene variations. The researchers found that boosting drug levels improved the anti-platelet effect in patients with one copy of the CYP2C19 gene variation. When doses were tripled and quadrupled, only 10 percent of patients didn’t have the optimal response when platelet function was assessed. In contrast, the usual dose failed to achieve the desired anti-platelet effect in about half of patients who had a mutation in the CYP2C19 gene.
“These data provide a rational framework for how to start to approach alternative dosing of clopidogrel in the nearly one-third of the population who harbor a genetic roadblock to metabolizing clopidogrel appropriately,” said Marc S. Sabatine, M.D., M.P.H., study senior author and chairman of the TIMI Study Group, Brigham & Women’s Hospital.
Researchers found on average:
  • Fifty-two percent of patients with one copy of the CYP2C19 gene variation didn’t respond optimally at the standard 75 milligrams (mg).
  • Twenty-six percent didn’t respond at 150 mg.
  • Ten percent didn’t respond at 225 and 300 mg.
“These data suggest that people with particular genetic modifications, especially those who have the CYP2C19 variation, may need a higher clopidogrel dose than the standard 75 milligrams daily,” Mega said.
Patients without the gene mutation received either 75 or 150 milligrams. After an initial blood test to measure platelet function, patients underwent testing every two weeks for eight weeks. Researchers found no significant increase in side effects as dosage increased during the duration of the study.
The study, conducted October 2010 to September 2011, included 335 patients from 32 U.S. sites who suffered a heart attack or underwent procedures to open blocked heart vessels. Their average age was 60 years, 88 percent were Caucasian, and 75 percent were men.
Similar to the general population, 24 percent of study participants carried one copy and 2 percent had two copies of the CYP2C19 genetic variation. Among the small number of patients with two gene copies, even the higher drug doses were ineffective.
While the results do suggest that most patients with one copy of the relevant gene could achieve platelet inhibition with these higher doses of clopidogrel, this study was not designed to assess the clinical outcomes produced by the higher doses. 
Co-authors are Willibald Hochholzer, M.D.; Andrew L. Frelinger III, Ph.D.; Michael J. Kluk, M.D., Ph.D.; Steven Isserman, M.D.; William J. Rogers, M.D.; Dominick J. Angiolillo, M.D.; Dean J. Kereiakes, M.D.; Christian T. Ruff, M.D., M.P.H.; David D. Berg, M.D.; John Cyr, P.A.; Benjamin M. Scirica, M.D., M.P.H.; Laura Grip, B.A.; Robert A. Mesa, B.S.; John F. Mattimore, B.A.; Janina A. Longtine, M.D., Ph.D.; Alan D. Michelson, M.D.; and Marc S. Sabatine, M.D., M.P.H.
The study was funded by an investigator-initiated grant from Bristol-Myers Squibb and Sanofi-Aventis.
Statements and conclusions of study authors that are presented at American Heart Association scientific meetings are solely those of the study authors and do not necessarily reflect association policy or position. The association makes no representation or warranty as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events.  The association has strict policies to prevent these relationships from influencing the science content. Revenues from pharmaceutical and device corporations are available at www.heart.org/corporatefunding. External link
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