by Michael O’Riordan
September 25, 2009 (San Francisco, California) — Doubling the loading and maintenance dose of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in ST-segment-elevation-MI (STEMI) patients reduces ischemic events and stent thrombosis, without significantly increasing the risk of bleeding, a new analysis shows. The reduction in stent thrombosis occurred in patients treated with bare-metal stents and drug-eluting stents, according to investigators.
These are the results of a PCI substudy from the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT OASIS-7) study. The postrandomization analysis, dubbed CURRENT STEMI PCI, looked specifically at patients undergoing PCI for STEMI and is in line with results of all patients with acute coronary syndrome (ACS) who underwent PCI. In contrast to the ACS findings, there was no increased need for red blood cell transfusions with STEMI patients.
"The reason for this, I suppose, is that one of the biggest drivers of bleeding in an ACS cohort is age, and the STEMI patients tended to be younger," said lead investigator Dr Shamir Mehta (McMaster University, Hamilton, ON) during a morning press conference here at the TCT 2009 meeting. "The mean age of the STEMI patients was 59 years, whereas those without STEMI tended to be older, have more comorbidities, and tended to have higher rates of bleeding. This has been seen in other trials."
Commenting on the results of the study during the late-breaking clinical-trials session, moderator Dr Gregg Stone (Columbia University, New York) called the CURRENT STEMI PCI an important trial that should have an immediate impact on clinical practice. While interventionalists at Columbia were already using a 600-mg loading dose of clopidogrel, he said his group will likely begin using a 150-mg maintenance dose in the seven days following the procedure, as was the protocol in the study. Panel member Dr Cindy Grines (Beaumont Hospital, Royal Oak, MI) agreed, telling the audience that her group would follow the clopidogrel loading and maintenance protocol, while Dr Gilles Montalescot (Institut de Cardiologie, Pitié-Salpêtrière Hospital, Paris, France) said his hospital has already doubled the dose in the ACS setting.
CURRENT STEMI PCI Cohort of CURRENT OASIS-7
The overall results of the CURRENT OASIS-7 study were previously reported by heartwire , but briefly, the study is a 2x2 factorial, randomized trial studying the optimal doses of clopidogrel and aspirin in ACS patients presenting to an emergency department and scheduled to undergo an early invasive strategy with intent to perform PCI no later than 72 hours after randomization. Of the original 17 232 patients undergoing PCI, 6346 patients presented with STEMI, a significant majority of whom underwent primary PCI.
Patients assigned to high-dose clopidogrel received a 600-mg loading dose on day 1 and then 150 mg once daily for next seven days, followed by 75 mg once daily until 30 days. Patients in the standard clopidogrel arm received a 300-mg loading dose on day 1, 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.
At 30 days, there was a significant reduction in the risk of ischemic events, specifically a 37% reduction in MI, in patients who received the double dose of clopidogrel. In addition, there was a significant 46% reduction in the risk of definite stent thrombosis and a 30% reduction in risk in the combined end point of MI and all stent thrombosis. There was no increased risk of bleeding.
CURRENT STEMI PCI: Efficacy Outcomes
| Outcome | Standard clopidogrel (n=3175) | Double-dose clopidogrel (n=3171) | Hazard ratio (95% CI) |
| Definite stent thrombosis | 1.8 | 1.0 | 0.54 (0.35–0.84) |
| All stent thrombosis | 3.5 | 2.5 | 0.72 (0.54–0.96) |
| MI | 1.9 | 1.2 | 0.63 (0.41–0.94) |
| MI or stent thrombosis | 4.0 | 2.8 | 0.70 (0.54–0.92) |
| Cardiovascular death | 3.2 | 3.1 | 0.95 (0.72–1.26) |
| Stroke | 0.5 | 0.4 | 0.81 (0.39–1.69) |
CURRENT STEMI PCI: Bleeding
| Bleeding definition | Standard clopidogrel (n=3175) | Double-dose clopidogrel (n=3171) | Hazard ratio (95% CI) |
| CURRENT major | 1.2 | 1.4 | 1.16 (0.75–1.78) |
| CURRENT severe | 0.9 | 1.1 | 1.18 (0.72–1.93) |
| Fatal | 0.3 | 0.1 | 0.33 (0.09–1.23) |
| ICH | 0.03 | 0.03 | 1.00 (0.06–16.01) |
| Red blood cell transfusion >2U | 1.0 | 1.1 | 1.20 (0.74–1.95) |
| CABG-related major | 0.03 | 0.2 | 6.01 (0.72–49.88) |
ICH=intracranial hemorrhage
Discussing the results with the media and during the late-breaking clinical-trials session, Mehta said that the benefit of double-dose clopidogrel was observed early and that there was no increased risk, mainly in stent thrombosis catch-up, when clinicians switched from 150-mg to 75-mg of clopidogrel on day 7. The reduction in risk of definite stent thrombosis was significant in patients who received a bare-metal stent (37% reduction in risk) or a drug-eluting stent (50% reduction in risk).
Despite the praise of the study, some researchers were cautious in their interpretation, noting that the overall results were "flat" and that there was a significant interaction with aspirin. As reported previously by heartwire , CURRENT OASIS-7 included 7855 patients who did not undergo PCI because no significant CAD was identified on the coronary angiogram or who discontinued therapy because they were scheduled for CABG surgery, and when these were included in the overall analysis, there was no significant difference in the primary composite end point of death, MI, or stroke between the two treatment arms.
Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC) noted that this STEMI analysis was a postrandomization cohort and included all patients who underwent primary PCI, rather than those who were simply randomized to undergo the intervention. Dr Ajay Kirtane (Columbia University, New York) agreed.
"This is a postrandomization subgroup in an overall negative trial," said Kirtane. "I think we should be cautious in overinterpreting this. I think it's a very difficult question. Pathophysiologically, increased antiplatelet inhibition should theoretically lower thrombotic events, but it's a difficult conundrum we're in with this trial."
Responding to the questions, Mehta said that the intention-to-treat analysis also showed significant reductions in stent thrombosis and MI. He also said that CURRENT OASIS-7 was not "negative" because of the significant interaction with aspirin. In a 2X2 factorial designed study, if there is an interaction, researchers should look at the study arms separately, he said, and when they did this, there was a significant overall reduction in the primary end point with the double dose of clopidogrel.
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