MADONNA: Repeat Antiplatelet Doses in Poor Responders Improves Outcomes After PCI

MUNICH, Germany—In patients who show poor clopidogrel response after PCI, an individually tailored regimen involving repeat loading doses of clopidogrel and/or prasugrel can improve outcomes at 1 month compared with standard treatment. The findings, presented August 26 at the European Society of Cardiology Congress 2012, lend support to the idea of personalized antiplatelet therapy. 

For the MADONNA trial, Jolanta Siller-Matula, MD, PhD, of Kaiser Franz Josef Hospital (Vienna, Austria), measured responsiveness to clopidogrel in 798 CAD patients undergoing PCI. Nonresponse was defined as greater than 50 ADP-induced aggregation units on multiple electrode aggregometry at 24 hours after loading. Subjects—both responders and nonresponders—were assigned to 1 of 2 strategies:

• Guided (n = 403): responders given standard treatment while nonresponders received prasugrel 60 mg or up to 4 loading doses of clopidogrel 600 mg as necessary
• Non-Guided (n = 395): patients given standard treatment regardless of initial responsiveness 

Within the guided group, 106 patients (26%) were classified as nonresponders after the initial loading dose of clopidogrel and therefore received a second loading dose, either prasugrel (n = 56) or clopidogrel (n = 50). All prasugrel-loaded patients achieved sufficient platelet inhibition, whereas 7 of the clopidogrel reloaded patients remained unresponsive. These 7 received a third loading dose of clopidogrel and 5 still did not respond. After a fourth loading dose, 3 remained nonresponders; one was given a clopidogrel maintenance dose of 150 in lieu of further attempts and 2 were given a prasugrel loading dose, 1 of whom still failed to respond. 

In the end, 2 patients out of 403 (0.5%) failed to respond to the guided strategy of clopidogrel and/or prasugrel reloading.

Definite/probable stent thrombosis occurred less frequently in the guided group than in the non-guided group, amounting to a nearly 8-fold increase in risk on multivariate analysis for conventionally treated patients (OR 7.9, 95% CI 1.08-69.2; P = 0.048). Likewise, the rate of ACS was lower for patients in the guided group, though cardiac death and TIMI major bleeding were statistically similar between the 2 strategies (table 1).

Table 1. One-Month Outcomes By Antiplatelet Strategy

Moreover, results of platelet testing provided the ability to “distinguish between patients who will and will not develop stent thrombosis with an area under the curve of 0.85,” Dr. Siller-Matula said, reporting that the test’s sensitivity to detect definite/probable stent thrombosis was 65% and the specificity 85%.

She concluded that “personalized antiplatelet treatment according to functional testing improved efficacy [while] having no impact on safety.”

Ten Years of Research on Clopidogrel Response

Poor response to clopidogrel was first described a decade ago, Dr. Siller-Matula said. “In this time frame, a huge amount of data has been generated. More than 60 studies show a clear association between nonresponsiveness to clopidogrel and adverse ischemic events, with the strongest association with short-term events like stent thrombosis.” 

Genetic and clinical factors, drug-drug interactions, aspects of clopidogrel’s hepatic metabolism all are at the root of nonresponsiveness. Prasugrel metabolism is more efficient, “which means there’s no metabolic waste,” she explained. “This improvement in metabolism mirrors the [newer drug’s] clinical efficacy . . . but the reduction in ischemic events [accompanies] a rise in major bleeding.” 

The target, Dr. Siller-Matula observed, is a therapeutic window for platelet inhibition that achieves net clinical benefit. 

Prasugrel the Preferred Choice 

It would be more feasible to favor prasugrel when using the reloading strategy, because additional clopidogrel loading can only overcome nonresponsiveness in patients who are heterozygous for the CYP2C19 allele, she explained. “If you have [a homozygote], you can’t overcome this nonresponsiveness.” 

Though crediting the study for its “very beautiful design,” an attendee pointed out that prasugrel muddies the picture. “Did you categorize the data according to those who received prasugrel and those who received clopidogrel? Because in line with the GRAVITAS trial, it seems that increasing clopidogrel dose doesn’t do anything.” 

The main issue with GRAVITAS, Dr. Siller-Matula countered, is that 40% of patients were nonresponders even after clopidogrel reloading. “This is an inadequate individualization of the therapy,” she said. “In our study, all prasugrel responders have a higher level of platelet inhibition than those who are reloaded with clopidogrel. That’s why now we’re just using the novel platelet inhibitors.” 

The MADONNA sample size is too small to analyze results of the 2 drugs separately, she added. 

Source:
Siller-Matula J. Personalized antiplatelet treatment after percutaneous coronary intervention: The MADONNA study. Presented at: European Society of Cardiology Congress; August 26, 2012; Munich, Germany. 

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• GRAVITAS: ‘Personalized’ Clopidogrel Dosing Yields No Benefits in PCI Patients
• Some Clopidogrel Poor Responders Helped by Higher Dosing
• Double-Dose Clopidogrel Lowers CV Events in ACS Patients Undergoing PCI