ACS Patients Benefit After Switching from Prasugrel to Clopidogrel but at a Cost

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In patients with acute coronary syndromes (ACS) who experience low platelet reactivity while on prasugrel, switching to clopidogrel comes with mixed results. The strategy reduces the overly high level of platelet inhibition and decreases bleeding but also reveals certain patients who are clopidogrel nonresponders, according to a registry study published in the February 2013 issue of JACC: Cardiovascular Interventions.

Gilles Montalescot, MD, PhD, and colleagues prospectively evaluated 300 ACS patients who underwent PCI at Pitié-Salpêtrière University Hospital (Paris, France) and were taking prasugrel 10 mg per day. At physician discretion, some patients at high risk of bleeding and/or displaying low on-treatment platelet reactivity, defined as less than 30 P2Y₁₂ reaction units (PRU) on the VerifyNow assay (Accumetrics, San Diego, CA), at 15 days were switched to clopidogrel 75 mg daily. Platelet function testing was then performed again 15 days later to evaluate the new regimen’s effects.

Marked Changes in Reactivity Seen

Nearly half of patients (45.6%) displayed low reactivity on the 10-mg prasugrel dose, while 4.3% had high reactivity (PRU < 208). In all, 31 patients (10.3%) changed to the 75-mg clopidogrel dose, of whom 29 (93.5%) had shown poor platelet response on prasugrel.

Patients on the clopidogrel regimen, as a whole, experienced a tenfold increase in PRU level after switching drugs (14.23 ± 21.98 PRU vs. 155.0 ± 87.24 PRU; P < 0.0001). The prevalence of low platelet reactivity dropped to less than 10%; however, while none had displayed high platelet reactivity with prasugrel, the proportion of poor responders grew to 29% with clopidogrel therapy. Factors associated with poor clopidogrel response were age (P = 0.056) and creatinine clearance (P = 0.01).

At 1 month, patients taking prasugrel experienced no TIMI major bleeding. BARC 1 and 2 bleeding events were experienced by 17.1% and 3.2% of patients, respectively. No ischemic events occurred. Patients who switched to clopidogrel had a numerically higher rate of bleeding events while on the initial prasugrel regimen than those who did not change drugs (32.3% vs. 18.1%; P = 0.078). Among the switched patients, bleeding events were more prevalent during prasugrel therapy than during clopidogrel therapy (32.2% vs. 9.7%; P = 0.03).

A Window into Decision Making

“Switching from a potent platelet inhibitor with a higher bleeding hazard to a weaker agent of the same class of thienopyridines might be justified, especially in patients at higher risk of bleeding,” the investigators note, citing cost and likelihood of compliance as possible factors that might affect decision making. “In the present study,” they add, “patients were all fully supported by our universal health care system, and drug cost was not considered in the decision to switch treatment.”

Dr. Montalescot told TCTMD in an e-mail communication that switching from a more to less potent antiplatelet drug “is quite common” in today’s practice. As to why a segment of patients were not switched—despite having low on-prasugrel platelet reactivity—he explained that the “physicians felt they were at high ischemic risk without excess bleeding risk. [A] young patient with large anterior STEMI and no prior history of bleeding would certainly stay on prasugrel for a year when the drug is well tolerated (even with [low platelet reactivity]).”

Switching, Platelet Testing Still ‘Unknown Waters’

In an accompanying editorial, Dominick J. Angiolillo, MD, PhD, and Fabiana Rollini, MD, both of the University of Florida (Jacksonville, FL), note that “Defining how and when to optimally switch antiplatelet therapy remained an unmet clinical need.”

But they emphasize the pharmacodynamic endpoints of the current study, which “was not designed to assess the clinical impact of this switching approach.” Moreover, they add, its observational nature may bias the results and does not provide insight into what clinical or genetic characteristics might have led to patients having low on-prasugrel platelet reactivity in the first place.

Drs. Angiolillo and Rollini advise that further study is needed in patients with more wide-ranging levels of platelet reactivity. “Most importantly, an improved understanding of how switching from newer-generation P2Y₁₂ receptor inhibitors, which provide more effective anti-ischemic protection but increased bleeding potential compared with clopidogrel, impacts patient outcomes,” they conclude. “Only larger-scale registry and randomized clinical trial data will better delineate the safety and efficacy of such switching antiplatelet strategy and thus guide clinicians navigating in these unknown waters.”

Agreeing that larger registries “would be helpful on this issue,” Dr. Montalescot pointed out that, on the other hand, “What we see on bleeding events [in the current study] at least makes sense with what was measured on platelet function.”

He also concurred with the editorial that routine testing is not ready for ‘prime time.’ Platelet function testing, Dr. Montalescot said, “is a good evaluation of the global patient risk and of the drug effect but is not useful to adjust therapy in patients with low to intermediate risk undergoing coronary stenting.”

Both GRAVITAS and ARCTIC provided negative results regarding treatment adjustment based on platelet function testing, Dr. Montalescot pointed out. He noted that the ongoing ANTARTIC trial, which is comparing normal vs. tailored prasugrel dosing in ACS patients, “is testing the concept now in a very high-risk population.”

Study Details

Compared with those who remained on prasugrel, the patients who switched to clopidogrel were older (65.25 ± 11.99 years vs. 60.28 ± 12.64 years; P = 0.04), had lower body weight (72.81 ± 12.69 kg vs. 78.47 ± 13.74 kg; P = 0.03), and were more likely to be taking ACE inhibitors (96.77 ± 17.96% vs. 82.16 ± 38.36%; P = 0.04).

Sources:

1. Kerneis M, Silvain J, Abtan J, et al. Switching acute coronary syndrome patients from prasugrel to clopidogrel. J Am Coll Cardiol Intv. 2013;6:158-165.
2. Angiolillo DJ, Rollini F. Switching from prasugrel to clopidogrel: Navigating in unknown waters. J Am Coll Cardiol Intv. 2013;6:166-168.

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• Prasugrel Reloading Feasible After Clopidogrel Pretreatment in ACS Patients
• Prasugrel Effective in Stable Patients With Poor Response to Clopidogrel
• Tailored Clopidogrel Therapy Bests Prasugrel at Control of Platelet Reactivity in ACS