Letters to Lancet Take on PCI Substudy of CURRENT-OASIS 7

The somewhat conflicting results of CURRENT-OASIS 7 have inspired new correspondence in the January 22, 2011, issue of the Lancet that question how best to implement the study’s findings regarding antiplatelet dosing for patients with acute coronary syndromes (ACS) slated to undergo early invasive treatment.

Although the overall trial found no benefit from 7 days of double-dose clopidogrel in 25,086 ACS patients intended for early PCI, a separate analysis that focused just on those patients who eventually did undergo PCI showed clinical benefit from the increased clopidogrel dose: a 14% reduction in the primary endpoint (CV death, MI, or stroke) at 30-day follow-up. Increasing the dose of aspirin had no significant effect.

The main CURRENT-OASIS 7 results were published in September 2010 in the New England Journal of Medicine, and the PCI subanalysis appeared 1 month later in the Lancet.

In telephone interviews with TCTMD, Paul A. Gurbel, MD, of the Sinai Hospital of Baltimore (Baltimore, MD), and Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), said the letters make valid points in trying to clarify the study’s take-home message for clinicians. In the letters, the authors criticize the PCI subanalysis’ seemingly contradictory results compared with the overall trial, as well as the lack of potentially confounding PPI data.

Dr. Gurbel urged a strict interpretation of the trial results. “If you want to be a purist, the CURRENT-OASIS 7 trial was negative,” he said, “so how kosher is it to do a subanalysis in the PCI population and use that as a basis for changing therapy?”

Does One Size Fit All?

An unresolved issue is whether to err on the side of caution by giving double-dose clopidogrel to all ACS patients before their treatment is fully decided, notes François Schiele, MD, PhD, of the University Hospital Jean Minjoz (Besançon, France), in his letter to the Lancet.

The CURRENT-OASIS 7 investigators admit in the Lancet subanalysis that “in practical terms, identification of patients who will eventually undergo PCI is difficult,” but they see no harm in using double-dose clopidogrel across the board because no excess bleeding was seen in patients who did not undergo PCI, Dr. Schiele writes. “This proposal is at odds with the approach advocated by the same authors” in the overall population, he says.

CURRENT-OASIS 7 investigators Shamir R. Mehta, MD, John W. Ekelboom, MD, and Salim Yusuf, MBBS, all of McMaster University (Hamilton, Canada), stand by their conclusions, however. They reply that findings from the PCI cohort illustrate the “clear benefit of the double-dose clopidogrel regimen” but characterize the overall results of the trial as “neutral.”

This is not unexpected, they explain, since patients who did not undergo PCI either had no clinically significant CAD or received only the 600-mg loading dose prior to CABG. Given the lack of bleeding in these non-PCI subjects, “all patients presenting with [ACS] who are planned for early invasive management should be considered for a 600-mg loading dose at first medical contact,” they advise. “Double-dose clopidogrel can be discontinued after coronary angiography in patients who do not proceed to PCI. This approach will maximize the benefit and minimize the harm associated with the higher dosing regimen.”

Dr. Kirtane told TCTMD that, despite the inherent limitations of a subanalysis of a negative trial, “it’s not unreasonable to think that the patients who actually underwent PCI might get a benefit from more potent platelet inhibition,” not only based on CURRENT-OASIS 7 but also on studies that looked at other agents. TRITON and PLATO both showed reductions in stent thrombosis with more potent platelet inhibition, he said, “but I don’t think we can say definitively one way or the other” whether a one-size-fits-all strategy is best.

“The [potential] downsides would be bleeding and cost. Overall, it doesn’t appear to be that different in terms of these data,” Dr. Kirtane noted, proposing that the main challenge comes in implementation. “From a practical standpoint, adherence to clopidogrel is something that’s really important. And when you start saying, ‘You do [150 mg] for a week, then switch the dose,’” it can confuse patients, who may not remember how many pills to take and sometimes expect to receive a new prescription, he said.

A Role for Aspirin

Another issue raised by Dr. Schiele is the interaction between aspirin and clopidogrel dosing (P = 0.026), which he says makes it impossible to tease out the effects of each medication. “Although not clearly stated, the reduction in the events composing the primary endpoint only seems to be seen when the double dose of clopidogrel is associated with the double dose of aspirin,” he concludes.

Dr. Mehta and colleagues counter that an “interaction between 2 treatments in a 2x2 factorial design trial is not the same as an additive effect of the 2 treatments.

“We believe that a conservative interpretation of this interaction is warranted since it lacks a known biological mechanism and was only nominally significant,” they comment, acknowledging that there appears to be no downside to combining higher-dose aspirin with double-dose clopidogrel.

But there is evidence of a biological mechanism, Dr. Gurbel argued. “Higher-dose aspirin is associated with greater platelet inhibition, dependent on the ex vivo tests you choose to study the platelet function,” he said. Based on his own research, Dr. Gurbel noted, “it makes sense to me that the high-dose aspirin could confer better antithrombotic effect [in patients] than low-dose aspirin.”

In fact, the lowest event rate for the primary endpoint was seen in patients who received both double-dose clopidogrel and high-dose aspirin, Dr. Gurbel said. Therefore, the message from CURRENT-OASIS 7 is “that high-dose clopidogrel works when you use high-dose aspirin,” he advised, not simply that either aspirin regimen is acceptable with increased clopidogrel.

That being said, “[w]e still don’t know how to optimally dose aspirin, even in this day and age in 2011. The way aspirin inhibits platelet physiology is still unclear,” Dr. Gurbel observed, as is the exact nature of aspirin’s interaction with P2Y12 inhibitors, including not only clopidogrel but also ticagrelor. “So we need to do more work in this area.”

Dr. Kirtane agreed that the aspirin-clopidogrel interaction is “problematic” but not entirely unexpected. The difficulty lies in designing a trial that is properly powered to test 2 agents. “It would’ve been a clearer study if they had not tried to answer the aspirin question in the same trial. But that having been said, this is still a very large trial and we have to deal with the data as they are. It just makes it a little confusing,” he commented.

Does PPI Use Confound Results?

Another letter, by Vassilis S. Vassiliou, MBBS, of the University of Cambridge (Cambridge, United Kingdom), points out that details about proton-pump inhibitor (PPI) use are unavailable for 23.2% of the PCI cohort. Of the data that do exist, no specifics are given on individual PPI types. “We know that omeprazole and esomeprazole can interfere with clopidogrel’s metabolism and efficacy and are less safe than pantoprazole and lansoprazole,” he comments, noting that results could be skewed if PPIs are imbalanced among the treatment arms.

Moreover, after the time of randomization, PPI use more than doubled from 16.4% to 42.0% in the PCI cohort, he adds. “After concern about clopidogrel-PPI interactions, practice has changed and PPIs are now very rarely used for prophylaxis,” Dr. Vassiliou writes. “Consequently, interpretation of the results is difficult because they do not represent current practice with much less PPI use.”

The reason for the lack of specifics on PPI use in CURRENT-OASIS 7 is simple, the investigators reply: The question of an interaction between PPIs and clopidogrel was not apparent until after the trial had started. Despite this omission, they claim that the study findings are “consistent with the results of other large-scale observational analyses as well as those of the COGENT randomized trial and support the conclusions of a 2010 expert consensus document that the pharmacodynamic drug interaction between clopidogrel and PPIs is not clinically relevant.”

Dr. Gurbel criticized the response by Dr. Mehta and colleagues, characterizing it as dismissive.

“You have this overwhelming body of data saying that PPIs interact in a negative way with the pharmacodynamic effect of clopidogrel,” as well as nonrandomized studies that see no clinical effect, he said. “So we’re at an impasse.” The COGENT trial, though randomized, was stopped early due to lack of funding and also looked at a novel combination form of clopidogrel and omeprazole in a single pill, added Dr. Gurbel, who concluded that its reassuring results are therefore “not definitive.”

Moreover, he took issue with the CURRENT-OASIS 7 investigators’ interpretation of the consensus document, which does not, in fact, characterize the interaction as “not clinically relevant.” Instead, he explained, the document “basically said that we don’t have the data to support a clinical interaction.”

Dr. Kirtane, on the other hand, disagreed with Dr. Vassiliou’s contention that clinicians are now less likely to combine PPIs with clopidogrel. “I think that the more recent data from COGENT and other studies show that there probably isn’t a clinically significant interaction, so many people are just doing it anyway,” he said.

Study Details

CURRENT-OASIS 7 tested combinations of 2 antiplatelet regimens:

• Clopidogrel: double dose (600-mg loading dose, then 150 mg/day for 1 week followed by 75 mg/day for 1 month) or standard dose (300-mg loading dose, then 75 mg/day)
• Aspirin: high dose (300-325 mg/day) or low dose (75-100 mg/day)

 

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Sources:
1. CURRENT-OASIS 7 investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010;363:930-942.

2. Mehta SR, Tanguay J-F, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): A randomized factorial trial. Lancet. 2010;376:1233-1243.

3. Schiele F. Double-dose clopidogrel in patients undergoing PCI for ACS [letter to the editor]. Lancet. 2011;377:297.

4. Vassiliou V. Double-dose clopidogrel in patients undergoing PCI for ACS [letter to the editor]. Lancet. 2011;377:297.

5. Mehta SR, Eikelboom JW, Yusuf S. Double-dose clopidogrel in patients undergoing PCI for ACS [author reply]. Lancet. 2011;377:298.

 

 

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