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Patients on prasugrel therapy have greater platelet inhibition than those taking maintenance doses of clopidogrel and thus require a longer time to return to baseline reactivity after stopping the drug. The pharmacodynamic findings, published in the June 19, 2012, issue of the Journal of the American College of Cardiology, support current guidelines recommending waiting periods of 5 and 7 days before surgery after cessation of maintenance clopidogrel and prasugrel, respectively.

For the 4-site Recovery trial, investigators led by Matthew J. Price, MD, of the Scripps Clinic (La Jolla, CA), randomized 56 stable CAD patients on aspirin to maintenance clopidogrel (75 mg; n = 27) or prasugrel (10 mg; n = 29) for 7 days, after which all discontinued therapy. The researchers then analyzed the timing of platelet function recovery. Platelet activity was assessed with the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) at baseline, 24 hours after drug cessation, and at multiple time points over a 12-day washout period.

Platelet recovery was defined as values within 60 P2Y12 reaction units (PRU) of baseline, or the end of the washout period if platelet function did not return to baseline.

Return to Baseline Delayed with Prasugrel

Pretreatment platelet reactivity levels were similar between the prasugrel and clopidogrel groups (285 ± 46 PRU and 298 ± 47 PRU, respectively). However, among the 54 patients eligible for analysis, residual platelet reactivity was markedly lower at 24 hours after the last drug dose in the prasugrel arm compared with the clopidogrel arm (78 ± 36 PRU vs. 196 ± 81 PRU). Eleven patients (42%) assigned to clopidogrel showed high residual platelet reactivity, defined as > 230 PRU.

Overall, patients discontinuing prasugrel took longer to return to baseline platelet reactivity than those discontinuing clopidogrel. At 5 days, more than 75% of clopidogrel patients had returned to baseline, while a comparable percentage of prasugrel patients did not fully recover until 7 days (table 1).

Table 1. Proportion of Patients Returning to Baseline Platelet Reactivity^a

^a ≤ 60 PRU of value before drug exposure.

In multivariate analysis, the level of platelet reactivity before study drug exposure and the inhibition of platelet aggregation at 24 hours after study drug discontinuation were independently associated with the number of days to return to baseline platelet function (P < 0.0001). On the other hand, treatment assignment was not associated with recovery time.

In terms of safety, treatment-emergent adverse events were experienced by 10 patients in the prasugrel group (4 study drug related) and 5 patients in the clopidogrel group (2 study drug related). None of the 15 events involved bleeding or were considered serious.

“Our findings are consistent with, and provide pharmacodynamic support for, current guidelines regarding the recommended waiting time for surgery after prasugrel discontinuation,” the authors write.

One important lesson, Dr. Price told TCTMD in a telephone interview, is that “everybody responds to clopidogrel differently. Half the patients fully recover function by 3 days. On the other hand, for some 7 days [off drug] may be better because they are strong responders. Giving a prescription for x number of days [to delay surgery] doesn’t really make sense.”

An Opportunity for Platelet Testing

The variability in clopidogrel response supports the concept of individualizing the delay to surgery based on platelet function testing, Dr. Price asserted, suggesting, “Why not take advantage of the variability wherever possible.”

For example, if testing shows that a patient is a poor responder, there would be no reason to delay surgery beyond a few days since whatever small inhibition was present will have been lost and reactivity will not recover further. The shorter delay minimizes ischemic risk without increasing the risk of surgical bleeding. And by abbreviating hospital waiting time, it lowers costs, Dr. Price added.

In a telephone interview with TCTMD, Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), agreed that platelet testing may have a role in this setting. “For example, if [testing shows that] a patient is a nonresponder, he can go to surgery right away,” he noted.

But according to Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), the “missing piece” of this story is the connection to clinical outcomes. “People might be tempted to assume that pharmacodynamics equals events, but that’s not been proven,” he told TCTMD in a telephone interview. In fact, arguing against an easy assumption of increased risk with low platelet reactivity, he noted, is the fact that patients with platelet dysfunction undergo surgery all the time without experiencing significant bleeding problems.

Dr. Bates made the same point. “We have to remember that platelet function analyzer results are just surrogate endpoints, and these don’t always predict clinical endpoints,” he said.

Dr. Price readily agreed that the strategy of platelet function testing is hampered by a paucity of data linking bleeding risk to specific PRU cutpoints.

Another complicating factor is patient risk. For practical reasons, the current pharmacodynamic study was performed in stable patients, Dr. Price said, but clearly ACS would change the equation. “The next step is to study [platelet recovery] in ACS patients and evaluate clinical outcomes,” he said, although that will be a tall order. Dr. Brener agreed that such a study would be highly desirable but doubted its feasibility.

Source:

Price MJ, Walder JS, Baker BA, et al. Recovery of platelet function after discontinuation of prasugrel or clopidogrel maintenance dosing in aspirin-treated patients with stable coronary disease: The Recovery trial. J Am Coll Cardiol. 2012;59:2338-2343.

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• TRITON-TIMI 38 Analysis: In CABG Patients, Mortality Benefit with Prasugrel Despite Higher Bleeding Risk
• Ticagrelor Shows More Rapid, Powerful Platelet Inhibition Than Clopidogrel

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