Double-Dose Clopidogrel Reduces Infarct Size in STEMI Patients

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According to the first prospective, randomized trial to compare 600-mg and 300-mg loading doses of clopidogrel in patients with ST-segment elevation myocardial infarction (STEMI) receiving percutaneous coronary intervention (PCI), the higher dose reduces infarct size and adverse events. Findings from the ARMYDA-6 MI trial appear in the October 4, 2011, issue of the Journal of the American College of Cardiology.

For ARMYDA-6 MI (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction), Germano Di Sciascio, MD, of Campus Bio-Medico University (Rome, Italy), and colleagues tested the 2 different loading doses prior to primary PCI in 201 STEMI patients treated at 5 European centers.

Procedural success was achieved in all patients, with low, equivalent rates of no-reflow and similar symptom-to-balloon times. The primary endpoint of infarct size as assessed by cardiac markers within 72 hours was reduced in the high-dose group (table 1).

Table 1. Median Cardiac Marker Levels Within 72 Hours

In addition, higher-dose clopidogrel lowered the incidence of TIMI flow grade less than 3 post intervention (5.8% vs. 16.3%; P = 0.031) and increased LVEF at discharge (52.1 ± 9.5% vs. 48.8 ± 11.3%; P = 0.026).

The composite of 30-day MACE (death, reinfarction, TVR, or stroke) was lower in the high-dose group, primarily driven by a reduction in TVR (table 2).

Table 2. Thirty-Day MACE

Other endpoints were similar between the high- and low-dose groups at 30 days, including definite or probable stent thrombosis (0.98% vs. 4.1%; P = 0.34) and major bleeding (1.9% vs. 2.0%; P = 0.65).

“ARMYDA-6 MI demonstrates that a 600-mg clopidogrel loading dose is safe and more effective than the 300-mg regimen in the context of primary PCI for STEMI,” Dr. Di Sciascio and colleagues conclude. “The results provide a randomized contribution supporting the use of 600-mg clopidogrel as the loading dose of choice in these patients.”

STEMI patients may derive the greatest benefit from more intense platelet suppression obtained by higher dose of clopidogrel, the authors add, as they are at particular risk of ischemic events in the context of high thrombotic and inflammatory activation.

In a telephone interview with TCTMD, Robert A. Harrington, MD, of the Duke Clinical Research Institute (Durham, NC), noted that, “You’ve got pharmacodynamic data, meaning platelet inhibition data, in a variety of settings that says that 600 mg reaches peak inhibitory levels of ADP faster than 300 mg. That’s essentially why you’re doing this: to [turn] platelet inhibition on faster.”

Confirming Clinical Practice

To Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), ARMYDA6-MI simply reinforces what many clinicians have been practicing. “Many people I know that are using clopidogrel for primary PCI are giving 600 mg right now,” he told TCTMD in a telephone interview. “I don’t know that [the study] would be practice changing.

“Having said that, the amount of randomized data supporting 600 before primary PCI is pretty limited,” Dr. Bhatt continued. “Even though there’s been a shift to 600 mg in this situation, I wouldn’t say it’s necessarily been evidence based, so it’s good to actually have some evidence that we can cite and justify our clinical decisions with. I do think it’s an important study for that reason.”

Dr. Harrington called the study a good example of “incrementalism,” adding that “this story has built over the years. There’s no one piece of definitive data that says 600 is better than 300, but there’s a lot of pieces that, all tied together, would suggest that 600 is a preferred choice when using clopidogrel in whatever setting your using the drug.”

Looming Issues: Generic Status, New Agents

Both Drs. Harrington and Bhatt noted that the decision to use 600-mg clopidogrel becomes complicated for 2 reasons: the drug’s shift to generic status in the United States in the near future and the emergence of new antiplatelet agents (prasugrel and ticagrelor) that rival the older drug.

“Prasugrel is superior to 300-mg clopidogrel, and ticagrelor is superior to either 600- or 300-mg clopidogrel,” Dr. Harrington said. “But given the generic clopidogrel issues that are coming, with the costs of the new drugs, the understanding of how to optimally use a drug like clopidogrel probably still has long-term value to it.”

Dr. Bhatt observed that he’s already seen a “fair amount” of prasugrel in conjunction with primary PCI. “I think primary PCI is well suited for prasugrel, because it’s fast acting and potent, and those factors are desirable in primary PCI,” he noted. “And if it turns out the patient is at high bleeding risk, one could then drop down to use clopidogrel, even though that strategy hasn’t been formally studied.”

He added that concerns over the potential for bleeding with prasugrel are less of an issue in the primary PCI population and setting, especially with an initial loading dose.

“Prasugrel is an option right now, and once ticagrelor becomes readily available, that’s an option too,” Dr. Bhatt continued. “We’ll just have to see what physicians’ comfort level is with the new drugs.”

The Cost Equation

Whatever the comfort level, cost will factor into the decision, Drs. Bhatt and Harrington agreed. “Clopidogrel will have the cost advantage over these [new drugs],” Dr. Bhatt said. “In the United States, once it’s generic, clopidogrel will be cheap compared with ticagrelor and prasugrel. That’s not a critical issue with a loading dose on the day of primary PCI. Whether it’s a few pills of clopidogrel, prasugrel, or ticagrelor, the cost is not so huge. But with a year of therapy, the incremental cost of prasugrel or ticagrelor is significant compared with clopidogrel.”

Yet another factor to consider is ticagrelor’s apparent mortality advantage. “A lot of it depends on how third party payors react to the ticagrelor data,” Dr. Bhatt said. “Will they find that mortality reduction compelling enough that it’s worth the incremental financial cost? I’m not sure. I would hope they would recognize that the mortality benefit is worth some additional health care expenditure.”

Regardless, clopidogrel will still almost certainly be an option. “I think that’s correct,” Dr. Harrington said. “Particularly with generic clopidogrel, and not just in the United States. Clopidogrel is not going to go away. It’s still going to remain a very popular agent.”

 

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Source:
Patti G, Bárczi G, Orlic D, et al. Outcome comparison of 600- and 300-mg loading doses of clopidogrel in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: Results from the ARMYDA-6 MI (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) randomized study. J Am Coll Cardiol. 2011;58:1592-1599.

 

Disclosures:

• The study was supported by an unrestricted grant from the Meijer Lavino Foundation for Cardiovascular Research.
• Dr. Di Sciascio reports no relevant conflicts of interest.
• Dr. Bhatt reports receiving research grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Medtronic, Sanofi-Aventis, and The Medicines Company.
• Dr. Harrington reports research and consulting relationships with Astra Zeneca, Eli Lilly/Daiichi Sankyo, and Sanofi-Aventis/Bristol-Myers Squibb.

 

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