August 28, 2012

August 28, 2012 (Munich, Germany) — The debate as to whether platelet function should be routinely measured in patients undergoing PCI has been raised again with two new studies presented at the European Society of Cardiology 2012 Congress suggesting benefits of such an approach.

In the Multiple Electrode Aggregometry in Patients Receiving Dual Antiplatelet Therapy to Guide Treatment with Novel Platelet Antagonists (MADONNA) trial, patients who received personalized antiplatelet therapy after platelet-function testing had a much lower rate of stent thrombosis than a comparator group of patients treated with standard doses of clopidogrel.

A second trial used data from the Responsiveness to Clopidogrel and Stent Thrombosis 2--Acute Coronary Syndromes (RECLOSE 2 ACS) study to show that measuring platelet responsiveness to both clopidogrel and aspirin is better than measuring response to clopidogrel alone in identifying patients at higher risk of clinical events. The authors concluded: "Responsiveness to both aspirin and clopidogrel should be assessed in all patients with ACS in order to identify and reduce their risk of ischemic events."

Disagreement

But the chair of a press conference at which the two studies were discussed, Dr Kurt Huber (Wilhelminen Hospital, Vienna, Austria), told heartwire that he does not think routine platelet-function testing is needed at present. "I use prasugrel [Effient, Lilly/Daiichi-Sanyo] or ticagrelor [Brilinta, AstraZeneca] in all my ACS patients, and only use clopidogrel in stable patients undergoing PCI in whom the risk of stent thrombosis is much lower, so hyporesponsiveness is less of an issue. I would say platelet function should still be regarded as a scientific tool at present," he commented.

However, MADONNA investigator Dr Jolanta Siller-Matula (Medical University of Vienna, Austria), argued that a strategy of testing everyone and only using prasugrel/ticagrelor in the clopidogrel hyporesponders was preferable in two ways: "It is more economical and it would also pick up hyperresponders, who number about 20% to 30% of patients. These patients have a higher bleeding risk and so really should not be given a more potent agent," she told heartwire . Huber countered that whether hyperresponders are at higher bleeding risk has not yet been proven, but it is of scientific interest.

MADONNA

In the MADONNA study, 798 patients underwent platelet testing and were classified as clopidogrel responders or nonresponders. They were then allocated to the guided or nonguided group. In the guided group (n=403), clopidogrel nonresponders (26%) received up to four loading doses of clopidogrel or prasugrel, when it became available. In the nonguided group (n=395), clopidogrel nonresponders (25%) were treated with the standard dose of clopidogrel.

Results showed that patients in the nonguided group had an eightfold higher risk of stent thrombosis and were also at higher risk of an ACS event compared with the patients in the guided group.

MADONNA: Personalized vs Nonpersonalized Antiplatelet Treatment

Event Personalized (%) Nonpersonalized (%) p
Stent thrombosis 0.2 1.9 0.027
ACS events 0 2.5 0.001

There were no between-group differences in rates of cardiac death or major bleeding.

Siller-Matula said that the test takes just 10 minutes to do and would save about €410 per patient each year compared with the routine use of the more potent antiplatelet drugs prasugrel or ticagrelor.

"Physicians would never adjust doses of antihypertensive drugs without knowing blood pressure; statins, without knowing cholesterol levels; or antidiabetic drugs without knowing HbA1c," she added. "So why are we still treating our patients with platelet inhibitors without being aware of levels of platelet inhibition?"

RECLOSE 2 ACS: Measure Both Aspirin and Clopidogrel Response

In the RECLOSE 2 ACS analysis, Dr Rossella Marcucci (University of Florence, Italy) reported that approximately 20% of the 1789 patients in the study had a high platelet reactivity to aspirin and were classified as aspirin nonresponders. These patients had a significantly higher prevalence of an ischemic event or cardiac death at the two-year follow-up.

Risk of Major Adverse Cardiac Events or Cardiac Death in Aspirin Nonresponders

Event Aspirin nonresponders, HR (95% CI) p
Major adverse cardiac events 1.4 (1.0–1.8) 0.04
Cardiac death 1.7 (1.2–2.6) 0.004

A previous analysis of the data showed that 14% of patients had high residual platelet reactivity to clopidogrel, and these patients had a doubling in event risk.

Marcucci reported that 9% of patients were nonresponders to both clopidogrel and aspirin and were classified as having "global high-platelet reactivity." These patients had a significantly increased risk of cardiovascular ischemic events and cardiac death in a Cox-regression analysis.

Risk of Major Adverse Cardiac Events or Cardiac Death if Nonresponders to Both Aspirin and Clopidogrel

Event Aspirin and clopidogrel nonresponders, HR (95% CI) p
Major adverse cardiac events 1.5 (1.0–2.2) 0.02
Cardiac death 1.9 (1.2–3.2) 0.008

The net reclassification index was said to be "highly significant" (0.098, p=0.001), showing that adding aspirin responsiveness increases the predictive value.

Marcucci said she now routinely performs both tests and that nonresponders to clopidogrel are given either prasugrel or ticagrelor, while nonresponders to aspirin would be given higher aspirin doses.

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