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Compared with the standard maintenance dose of clopidogrel, doubling the daily dosage following percutaneous coronary intervention (PCI) not only reduces platelet reactivity but improves endothelial function and lowers the level of high-sensitivity C-reactive protein (hsCRP), all of which are associated with risk for future ischemic events, according to findings published in the February 15, 2011, issue of the Journal of the American College of Cardiology. The study, though, was not powered to determine any differences in clinical outcomes.

For the ARMYDA-150 mg (Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty) study, investigators led by Giuseppe Patti, MD, of Campus Bio-Medico University of Rome (Rome, Italy), evaluated the functional response to high- vs. standard-dose maintenance clopidogrel in 50 consecutive patients undergoing PCI for stable angina or non-STEMI ACS. All patients received a 600-mg loading dose of clopidogrel before PCI and a 75-mg maintenance dose for 30 days. They then were randomized to continue on the standard dose or receive a double maintenance dose for another 30 days. At that time, the 2 groups switched doses (cross-over) and continued for another 30 days.

Three functional parameters were assessed at randomization, cross-over, and 30 days after cross-over:

• Platelet reactivity, measured by VerifyNow (Accumetrics, San Diego, CA) and expressed as P2Y12 reaction units (PRU) and percent inhibition
• Endothelial function, determined by flow-mediated and nitroglycerin-mediated brachial artery dilation
• hsCRP

During the study period, no patient in either group experienced adverse cardiovascular events (death, MI, stent thrombosis, or repeat revascularization) or bleeding complications.

Positive Effect on All 3 Parameters

At the end of the study period (90 days post PCI), PRU values and the percentage of patients with a PRU above or equal to 240—a cut-point suggested by studies to predict 30-day post-PCI outcomes—were lower among patients receiving the high clopidogrel dose (table 1). Similarly, flow-mediated dilation of the brachial artery was improved and the incidence of impaired brachial artery reactivity was reduced in the double-dose group (table 1). Finally, hsCRP levels and the percentage of patients with hsCRP levels greater than 3 mg/L (indicating inflammatory status) were lower in high-dose patients.

Table 1. Functional Outcomes at 90 Days

Abbreviations: PRU, P2Y12 reaction units; FMD, flow-mediated dilation; hsCRP, high-sensitivity C-reactive protein.

Endpoint values for the 2 dose groups varied over the stages of the cross-over study. In the 30 days after initial randomization, platelet reactivity, hsCRP, and nitroglycerin-mediated dilation values remained largely unchanged in the 75-mg arm, and flow-mediated dilation values decreased slightly (P = 0.08), while in the 150-mg arm, platelet reactivity and hsCRP declined (P = 0.0001 and P = 0.028, respectively) and overall endothelial function improved (P = 0.05).

The dose-dependent effect of clopidogrel was clear when the 2 cohorts crossed over. Switching from 75-mg to 150-mg clopidogrel was associated with a reduction in both platelet reactivity (P = 0.0001) and hsCRP (P = 0.004), an increase in flow-mediated dilation (P = 0.048) and a trend toward improved nitroglycerin-mediated dilation (P = 0.10). Conversely, switching from the high dose to the standard regimen resulted in a rise in PRU (P = 0.002) and worsening of flow-mediated dilation (P = 0.001) while hsCRP tended to increase (P = 0.12) and nitroglycerin-mediated dilation to decrease (P = 0.09).   

Flow-mediated dilation and hsCRP values were weakly correlated with residual platelet reactivity (P = 0.06 and P = 0.043, respectively).

Implications for Practice?

According to the investigators, the 42% reduction seen in impaired brachial artery reactivity “might have an impact on practice patterns in light of recent data showing that endothelial dysfunction after PCI is associated with a higher risk of in-stent restenosis in patients undergoing bare-metal stent implantation, and may theoretically predispose to stent thrombosis after drug-eluting stent implantation.”

They also note that the reduction in hsCRP achieved by high-dose clopidogrel should be viewed in the context of data indicating that elevated levels may increase the risk of cardiac events after PCI.

The authors point out that at the end of the study, after both groups had undergone a 30-day stint on high-dose clopidogrel, there were no differences in platelet reactivity, endothelial impairment, or inflammatory status. “[T]hus, it is possible that the beneficial effects of the 150-mg dose do not wane completely after 1 month; in particular, [flow-mediated dilation] and hsCRP levels did not come back to baseline values after 1 month on 75-mg clopidogrel,” they observe.

The authors acknowledge that the study was not powered to evaluate clinical events. Nonetheless, they say, “ARMYDA-150 indicates that a high clopidogrel maintenance dose, in addition to a stronger antiplatelet effect, is associated with significant ‘pleiotropic’ effects, which may potentially translate into a significant clinical benefit for patients undergoing PCI.”

Been There, Seen That

“It’s not surprising that a regimen that is associated with attenuation of platelet reactivity attenuated inflammation,” said Paul A. Gurbel, MD, of the Sinai Center for Thrombosis Research (Baltimore, MD), noting that platelet reactivity has been linked to increases in a host of inflammatory markers by his own group (eg, Antonino AJ, Am J Cardiol. 2009;103;1546-1550 and Tantry US. Platelets. 2010;Epub ahead of print). “In fact, one of the weaknesses of this paper is that they only looked at hsCRP,” he added in a telephone interview with TCTMD.   

An effect of platelet reactivity on endothelial function also has been previously reported, Dr. Gurbel said, although the monitoring of brachial artery reactivity over time in ARMYDA-150 is novel.

In addition to the small number of patients, another important limitation of this study is the “void of information” on the study parameters during the first 30 days after PCI, he commented.

With regard to the observation that the effect of higher-dose clopidogrel appears to persist for a time, Dr. Gurbel commented, “That may have nothing to do with the residual impact of 150 mg of clopidogrel.” He suggested that it may instead be attributable to the natural decline in platelet reactivity and inflammation with increasing time from PCI. Another potential influence, he added, is the anti-inflammatory effect of statins and other concomitant medications.

Dr. Gurbel acknowledged that these functional findings have little clinical relevance in the wake of the negative results of the large, randomized GRAVITAS trial, which found no benefit of double-dose clopidogrel in elective patients with high on-treatment platelet reactivity. (GRAVITAS findings had not been reported at the time this paper was accepted for publication.) However, he added, the biologic mechanisms behind clopidogrel’s pleiotropic effects are still worth exploring.

Study Details

All patients received daily aspirin (100 mg). To avoid potential interference with clopidogrel, use of lipophilic statins and PPIs and cigarette smoking were forbidden during the study period. 

Source:

Patti G, Grieco D, Dicuonzo G, et al. High versus standard clopidogrel maintenance dose after percutaneous coronary intervention and effects on platelet inhibition, endothelial function, and inflammation: Results of the ARMYDA-150 mg (Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty) randomized study. J Am Coll Cardiol. 2011;57:771-778.

Disclosures:

• Dr. Patti reports no relevant conflicts of interest.
• Dr. Gurbel reports receiving research grants, honoraria, and consulting fees from AstraZeneca, Bayer Healthcare, Boston Scientific, Eli Lilly/Daiichi Sankyo, Haemoscope, Medtronic, Portola Pharmaceuticals, Pozen, Sanofi-Aventis, and Schering Plough.

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