CURRENT-OASIS 7 Published: Double-Dose Clopidogrel in PCI Debated

September 03, 2010

September 3, 2010(Hamilton, Ontario) — The CURRENT-OASIS 7 trial has finally been published this week in two separate papers in the New England Journal of Medicine (NEJM) and the Lancet [1,2]. There are also editorials on the trial in both journals.

The results, showing no significant benefit of doubling the dose of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) for the first seven days in the overall population of acute coronary syndrome (ACS) patients referred for an invasive strategy but suggesting benefit in the patients who actually underwent percutaneous coronary intervention (PCI), were first presented and reported by heartwire at the European Society of Cardiology (ESC) 2009 Congress.

The trial also addressed the issue of whether aspirin was better given at high or low dose in such patients but found no major differences between the two dosing strategies, although there was a reduction in minor bleeding with the low dose.

Are the PCI Results Robust Enough?

Although conceding various limitations to the clopidogrel PCI results--mainly that they come from a postrandomization subgroup analysis and should therefore, strictly speaking, be regarded as hypothesis generating, the CURRENT-OASIS 7 authors, led by Dr Shamir Mehta (McMaster University, Hamilton, ON), say they still find the argument for use of the double-dose clopidogrel in patients undergoing PCI "compelling." The reasons they give for this include the fact that the benefit is biologically plausible and is consistent with several previous smaller studies.

Reviewing the papers for heartwire , Dr Deepak Bhatt (VA Boston Healthcare System, MA) agreed that the results probably justified doubling the dose of clopidogrel for the first week in patients who are planned to receive a stent, although identifying these patients at presentation is not always easy. He added that these results complement the trials with other more potent antiplatelet agents and that "the consistent theme among ACS patients getting stented is that more potent ADP[adenosine diphosphate]-receptor blockade does seem to matter."

The consistent theme among ACS patients getting stented is that more potent ADP-receptor blockade does seem to matter.

But Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) argues that because of several "interpretive challenges" with the PCI subgroup and the excess in bleeding, "the results of the CURRENT-OASIS 7 trial do not provide unequivocal support for 600 mg of clopidogrel as the loading dose of choice in patients with NSTE-ACS undergoing PCI."

In the NEJM editorial [3], Dr Valentin Fuster (Mount Sinai School of Medicine, New York) agrees with Kaul on the PCI data but says that he has already adopted this practice on the basis of available data and latest guidelines. He suggests that the 600-mg loading dose without the subsequent higher doses in the next six days may be the best way forward.

In the Lancet editorial [4], Dr Greg Stone (Columbia University Medical Center, New York) observes that despite impressive reductions in myocardial infarction and stent thrombosis with double-dose clopidogrel in patients who had PCI, the 30-day rates of cardiovascular death were identical in the standard-dose and double-dose clopidogrel groups. "Presumably, any benefits from reduced ischemic complications in reducing mortality were offset by increased rates of major bleeding with double-dose clopidogrel," he suggests.

In the CURRENT-OASIS 7 trial, 25 086 ACS patients referred for an invasive strategy were randomized to high-dose or standard-dose clopidogrel. The high-dose clopidogrel group received a 600-mg loading dose and then 150 mg once daily for next seven days, followed by 75 mg once daily until 30 days. Patients in the standard-dose clopidogrel arm received a 300-mg loading dose, followed by 75 mg once daily until 30 days. Patients were also assigned in an open-label manner to 300 to 325 mg of aspirin once daily or 75- to 100-mg aspirin once daily.

The main results, showing no significant difference in the primary efficacy end point but an increase in bleeding with the higher clopidogrel dose in the overall population, are the subject of the NEJM paper.

CURRENT-OASIS 7: Main Results for Clopidogrel in Overall Population

Outcome Double-dose clopidogrel (%) Standard-dose clopidogrel (%) HR (95% CI) p
CV death/MI/stroke* 4.2 4.4 0.94 (0.83–1.06) 0.30
Major bleeding 2.5 2.0 1.24 (1.05–1.46) 0.01

*Primary efficacy end point

This paper also reports the aspirin results, showing no significant difference between higher dose and lower dose with respect to the primary outcome or major bleeding.

CURRENT-OASIS 7: Main Results for Aspirin in Overall Population

Outcome High-dose aspirin (%) Low-dose aspirin (%) HR (95% CI) p
CV death/MI/stroke* 4.2 4.4 0.97 (0.86–1.09) 0.61
Major bleeding 2.3 2.3 0.99 (0.84–1.17) 0.90

*Primary efficacy end point

The prespecified analysis of the 17 263 individuals who underwent PCI is the focus of a separate paper in Lancet. This shows a "nominally significant" reduction in the primary outcome and a significant reduction in definite stent thrombosis with the higher clopidogrel dose. But this was at the cost of an increase in major bleeding, although bleeding that was intracranial, fatal, or related to CABG surgery did not increase.

CURRENT-OASIS 7: Results for Clopidogrel in PCI Subgroup

Outcome Double-dose clopidogrel (%) Standard-dose clopidogrel (%) HR (95% CI) p
CV death/MI/stroke* 3.9 4.5 0.86 (0.74–0.99) 0.039
Definite stent thrombosis 0.7 1.3 0.54 0.0001
Major bleeding 1.6 1.1 1.41(1.09–1.83) 0.009

*Primary efficacy end point

As in the overall analysis, results for high-dose and low-dose aspirin did not differ for the primary outcome or major bleeding.

How to Incorporate Into Clinical Practice

The CURRENT-OASIS 7 authors address how these results might be incorporated into clinical practice when it is not known whether a patient will ultimately receive a PCI at the time of presentation. They note that in individuals who did not receive PCI, no apparent increase was recorded in the risk of bleeding with the high-dose clopidogrel regimen, and most major bleeding events occurred after PCI rather than before PCI. Therefore, a 600-mg loading dose could be considered for all patients with ACS with planned early invasive treatment. After coronary angiography, patients receiving a PCI could continue with the double maintenance dose to complete the full-seven day regimen, whereas in those who do not have anatomy suitable for PCI, the standard dose could be used or clopidogrel could be withheld, depending on the clinical context, they suggest.

The results do not provide unequivocal support for 600 mg of clopidogrel as the loading dose of choice in patients with NSTE-ACS undergoing PCI.

They point out that guideline committees already recommend a 600-mg loading dose of clopidogrel on the basis of previous studies, and many centers are using this higher loading dose in daily practice. In individuals who have planned conservative treatment or in whom invasive assessment might be delayed beyond 72 hours, the standard dose of clopidogrel should still be used on the basis of data from previous studies, they add.

Bhatt said there were a few ways to interpret the data, "but my practical interpretation is that if you are planning to stent an ACS patient, you ought to give the double dose of clopidogrel for the first week. This should reduce stent thrombosis by almost 50%, as well as increase bleeding, though not fatal or intracranial bleeding." He added: "If you are planning to medically manage the patient initially, you should stick with standard clopidogrel dosing."

Limitations of PCI Data

Kaul noted that although the CURRENT-OASIS 7 is the largest trial to address the question of the optimal loading dose of clopidogrel, the PCI subgroup poses several interpretive challenges. These include a postrandomization analysis subgroup that is vulnerable to confounding; the failure to achieve a significant treatment effect in the overall cohort; and a nominally significant interaction unadjusted for multiple comparisons. He also believes that the modest excess in major bleeding with the double-dose clopidogrel suggests that the benefit of double-dose clopidogrel does not outweigh its risk.

Aspirin: Lower Dose Preferable?

On the aspirin data, Kaul says these are likely to be interpreted as favorable by both the low-dose and the high-dose aspirin protagonists, given no major difference in the benefit-harm tradeoff. "So, I don't expect any major change in clinical practice."

Bhatt has a similar view. "Beyond the loading dose the first day, I think either low- or higher-dose aspirin can be used for the first month after stenting. I would probably drop it down to low dose after the first month, based on some observational analyses," he commented.

Fuster says the data support the lower aspirin dose, which he points out had equivalent efficacy but lower rates of minor bleeding than the higher-dose regimen. "It is time for the proponents of higher-dose aspirin to concede defeat and modify clinical practice," he adds.

Discrepancies in Presentation and Publication

Fuster points out some pitfalls of the long delay between first presentation of the CURRENT-OASIS 7 data and its official publication. He notes that at the ESC meeting last year it was concluded that the use of double-dose clopidogrel significantly reduced major cardiovascular events in PCI patients, but that on scrutiny of the results in the publication, this is not actually strictly true. "The conclusions reported at the [ESC] meeting led many cardiologists to adopt the double-dose clopidogrel strategy, thus leading to more clopidogrel being prescribed. This outcome underscores the need for simultaneous publication of high-impact clinical trials when they are presented at international meetings," he writes.

Aspirin-Clopidogrel Interaction?

The CURRENT-OASIS 7 data also suggest a possible clopidogrel–aspirin interaction, with the lowest rate of composite ischemia after PCI seen in the group of patients who received both double-dose clopidogrel and high-dose aspirin. On this issue, Stone notes that the opposite effect was seen with aspirin and ticagrelor and no interaction has been observed with aspirin and prasugrel, so it is difficult to know whether this is a real effect or not. Kaul agrees, saying he would "caution against overinterpreting the ADP-receptor-antagonist--aspirin interaction."

CURRENT-OASIS 7 was sponsored by Sanofi-Aventis and Bristol-Myers Squibb. Mehta receives research grants from Sanofi-Aventis and Bristol-Myers Squibb and consulting fees/honoraria from AstraZeneca, Astellas, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Pfizer, and Sanofi-Aventis. Stone has served on advisory boards for Abbot Vascular and Boston Scientific and has acted as a consultant for Bristol-Myers Squibb, Sanofi-Aventis, AstraZeneca, and the Medicines Company. Bhatt reports receiving research support from AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and the Medicines Company.