In low-weight patients with stable coronary artery disease (CAD), cutting the standard 10-mg dose of prasugrel in half provides platelet inhibition similar to that achieved with the normal dose in heavier individuals, according to pharmacodynamic data published online October 17, 2012, ahead of print in the Journal of the American College of Cardiology. Moreover, the findings suggest that the lower dose yields bleeding rates similar to maintenance clopidogrel without compromising prasugrel’s efficacy advantage over the older thienopyridine.

Results of the randomized FEATHER trial were originally presented at the American College of Cardiology/i2 Annual Scientific Session in March 2012.

Investigators led by David Erlinge, MD, PhD, of Lund University (Lund, Sweden), divided 72 patients with stable CAD into 2 groups by body weight: low (< 60 kg; n = 34) and higher (≥ 60 kg; n = 38) weight. After a run-in period (5-21 days) in which all patients received aspirin alone, the low-weight group added prasugrel 5 mg daily, and the higher-weight group added prasugrel 10 mg daily, both for 12 ± 2 days. Then the low-weight group was randomized to prasugrel 10 mg or clopidogrel 75 mg, while the high-weight group was randomized to prasugrel 5 mg or clopidogrel 75 mg, again for 12 ± 2 days. Finally, each group crossed over to the opposite regimen for a similar period.

Relative to baseline, each treatment regimen substantially reduced platelet aggregation in both cohorts, with no difference in maximal platelet aggregation in response to 20 µM ADP (76.3% ± 9.5% for low weight and 77.9% ± 12.3% for higher weight; P = 0.53).

Low Dose Noninferior to Standard Dose

In the primary endpoint analysis, median maximal platelet aggregation in low-weight patients receiving prasugrel 5 mg was noninferior to the 75th percentile of such aggregation in higher-weight patients receiving prasugrel 10 mg (-10.1% difference; 95% CI -23.4% to 0.2%).

In addition, both prasugrel 5 mg in the low-weight arm and prasugrel 10 mg in the higher-weight group were associated with lower maximal platelet aggregation (to 20 µM ADP) compared with clopidogrel (difference -3.7% and -16.9%, respectively), although the reduction was more substantial with the higher prasugrel dose.

Platelet aggregation in response to prasugrel 5 mg in low-weight patients and prasugrel 10 mg in higher-weight patients was similar regardless of whether it was measured by various light transmission aggregometry standards, VerifyNow P2Y12 reaction units, or vasodilator-associated phosphoprotein platelet reactivity index (VASP-PRI).

In low-weight patients, prasugrel 5 mg was associated with a greater antiplatelet effect than clopidogrel, the difference reaching statistical significance by 2 measures (maximal platelet aggregation in response to 5 mg and 20 mM ADP) and showing a trend toward significance in several others.

Moreover, the proportion of patients exhibiting high on-treatment platelet reactivity was no different between the low-weight group receiving 5 mg and the higher-weight group receiving 10 mg of prasugrel.

Importantly, in the low-weight cohort, a smaller percentage of patients receiving the 5-mg dose had high on-treatment platelet reactivity compared with those on clopidogrel by all definitions, although the difference achieved statistical significance only for the VASP PRI (table 1).

Table 1. High On-Treatment Platelet Reactivity in Low-Weight Patients

Abbreviations: MPA, maximal platelet aggregation; VASP-PRI, vasodilator-associated stimulated phosphoprotein-platelet reactivity index.

For any given treatment, low-weight patients had higher rates of treatment-related bleeding than higher-weight patients, although most events were not clinically significant. However, in the low-weight group, bleeding-related adverse event rates were similar after treatment with prasugrel 5 mg and clopidogrel 75 mg (29.4% and 25.0%, respectively; P = 0.62). No drug-related bleeding events were considered severe or resulted in drug discontinuation.

The authors caution that because the findings derive from a pharmacodynamic/pharmacokinetic study performed in a small number of stable patients over a relatively short period of time, additional randomized trials are needed before firm clinical conclusions can be drawn. Nonetheless, they say, the results suggest that low-dose prasugrel “could provide better risk-benefit balance for [low-body-weight] patients.”

Data Shore Up Label Recommendation

In a telephone interview with TCTMD, study coauthor Dominick J. Angiolillo, MD, PhD, of the University of Florida College of Medicine (Jacksonville, FL), said that the trial was “specifically designed to address questions raised by drug-regulating agencies with regard to the pharmacokinetics and pharmacodynamics of a modified dose of prasugrel for low-weight patients.”

Prasugrel 5 mg is the current label recommendation for low-weight patients, he noted, even though until now no randomized study had compared the effects of the different doses and clopidogrel in various populations by body weight.

According to Dr. Angiolillo, preliminary data from a parallel randomized trial looking at the effect of prasugrel 5 mg in patients age 75 and older, presented at the European Society of Cardiology Congress 2012, also proved the noninferiority of the lower dose compared with the standard dose.

Looking forward, he said the outcomes specifically for low-weight and older subgroups who received prasugrel 5 mg in the TRILOGY ACS trial, expected soon, should help clarify the issue. The original study found no difference in MACE rates between prasugrel and clopidogrel in medically managed ACS patients at a median 17 months (Roe MT, et al. N Engl J Med. 2012;367:1297-1309).

“I think our data will complement data from TRILOGY ACS very nicely, but the main driver for use of a specific drug at a specific dose will be clinical outcomes,” Dr. Angiolillo said. For now, “if there is a clinical indication to use prasugrel, as in ACS patients undergoing PCI, a 5-mg dose appears to lead to sustainable levels of platelet inhibition—greater than that achieved with clopidogrel—with lower rates of resistance.”

Dr. Angiolillo said he doubts that most clinicians currently follow this practice for low-weight patients but that “these data will provide some more guidance.”

Study Details 

Most participants had a history of MI (58.3%), hypertension (63.9%), and/or hyperlipidemia (79.2%). Overall, the 2 cohorts were well matched. However, compared with higher-weight patients, those with low weight were more likely to be women, smokers, and have a history of CABG.

 

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Source:
Erlinge D, Ten Berg J, Foley D, et al. Reduction in platelet reactivity with prasugrel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients: Results from the FEATHER trial. J Am Coll Cardiol. 2012;Epub ahead of print.

 

 

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