eCardioVascular Beat

Exploring a personalized approach to medication dosing

Ty Gluckman, M.D., F.A.C.C.

Cardiologist, Providence St. Vincent Medical Center
Providence St. Vincent Heart Clinic-Cardiology

What do aspirin, atenolol, lisinopril and simvastatin have in common? All are frequently prescribed cardiovascular medications and none require dose adjustment based on height or weight.

But should the same dose be prescribed for a 6-foot-6-inch man weighing 275 pounds as it would be for a 5-foot, 112-pound woman? Given the many steps that medications go through to be activated or metabolized, does this make sense? How do genetic differences affect patients’ responses to medication?

Unfortunately, this topic received little attention – until now.

Clopidogrel, also marketed as Plavix, is the second-most-prescribed drug in the world after atorvastatin. Beginning in 2003, reports surfaced that there was wide variability among individuals in how effectively clopidogrel inhibited platelets. These initial reports were based on ex vivo studies of platelet function.

They have been followed by 28 different observational and randomized studies linking decreased on-treatment platelet inhibition (high platelet reactivity) to a significantly higher rate of adverse cardiovascular events.

In other words, there appears to be increased risk for those who do not achieve adequate platelet inhibition with standard-dose clopidogrel.

Such findings have now prompted an extremely important question: Should we tailor an individual’s antiplatelet treatment regimen based on ex vivo assessment of platelet function? If we could identify patients who are more or less likely to achieve the desired antiplatelet effect, should the dose of the drug – or the drug itself – be adjusted accordingly?

Five randomized clinical trials using a personalized approach to guide dosing of antiplatelet therapy have been completed or are under way: GRAVITAS, DANTE, ARCTIC-PCI, TOPAS-1 and TRIGGER-PCI.

The GRAVITAS trial, the only one that has been completed, was presented in November 2010 at the American Heart Association Scientific Sessions. This study screened 5,429 patients with stable or unstable coronary artery disease who were undergoing placement of a drug-eluting stent.

All of these patients underwent point-of-care testing with the Accumetrics VerifyNow assay to assess their response to standard-dose clopidogrel 12 to 24 hours after percutaneous coronary intervention. A total of 2,214 (41 percent) patients were identified as having high on-treatment platelet reactivity (i.e., less platelet inhibition) and were randomized to six months of standard-dose clopidogrel (75 mg daily) versus high-dose clopidogrel (150 mg daily).

At six months, the primary end point of cardiovascular death, nonfatal MI or stent thrombosis was no different between the two arms, suggesting the lack of benefit from high-dose clopidogrel among those with high on-treatment platelet reactivity.

Currently enrolling for prasugrel trial

Given the absence of benefit with higher-dose clopidogrel, would a more potent platelet inhibitor such as prasugrel work better in patients with high on-treatment platelet reactivity? We are fortunate at Providence St. Vincent Medical Center to be one of only 11 sites in the United States participating in the TRIGGER-PCI trial, which we hope will answer this question.

This trial anticipates enrolling 2,150 patients undergoing drug-eluting stent placement for stable coronary artery disease. Following the administration of standard-dose clopidogrel (600 mg loading dose and 75 mg maintenance dose), patients will undergo point-of-care platelet testing with the Accumetrics VerifyNow assay.

Only those patients demonstrating high on-treatment platelet reactivity will be randomized in a double-blind, double-dummy fashion to continue standard therapy with clopidogrel (75 mg daily) versus treatment with the more potent platelet inhibitor, prasugrel (60 mg loading dose and 10 mg maintenance dose), for six months. The primary end point is a composite of cardiovascular death or nonfatal myocardial infarction.

Will prasugrel be a better treatment for patients experiencing less platelet inhibition with clopidogrel? Is there a role for phenotyping all patients to assess their platelet function? TRIGGER-PCI serves an important role in potentially answering both of these questions.

If you have patients you believe are eligible for this study, contact Heather Aiona, C.C.R.C., clinical research coordinator, at heather.aiona@providence.org or 503-216-2099.