NPC Archive Item: Stopping clopidogrel may be associated with an increased risk of death and MI

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Ho PM, Petersen ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA 2008:299;532–9

What is the background to this? –  Based on results from the CURE study in which the average duration of treatment was 9 months following hospital discharge, current NICE guidance recommends that treatment with clopidogrel and low-dose aspirin should be continued for up to 12 months in patients with non-ST-segment-elevation acute coronary syndrome. After this time, it should be stopped and normal treatment prescribed, including low-dose aspirin.

This retrospective cohort study of 3,137 patients with acute coronary syndrome aimed to determine whether there is an increase in the number of thrombotic effects shortly after stopping clopidogrel treatment.

What does this study claim? –The study found a significantly higher risk of death or acute myocardial infarction in the 90 days after stopping treatment with clopidogrel, compared with the subsequent 90-day follow-up interval. (But see later.)

Among medically treated patients, mean (Standard Deviation) duration of clopidogrel treatment was 302 (151) days and death or AMI occurred in 17.1% (n = 268) of patients, with 60.8% (n = 163) of events occurring during 0 to 90 days, 21.3% (n = 57) during 91 to 180 days, and 9.7% (n = 26) during 181 to 270 days after stopping treatment with clopidogrel. Similarly, among PCI-treated patients with ACS, mean (SD) duration of clopidogrel treatment was 278 (169) days and death or AMI occurred in 7.9% (n = 124) of patients, with 58.9% (n = 73) of events occurring during 0 to 90 days, 23.4% (n = 29) during 91 to 180 days, and 6.5% (n = 8) during 181 to 270 days after stopping clopidogrel treatment.

This translates to an incidence rate ratio [IRR] 1.98, 95% confidence interval [CI] 1.46 to 2.69 in medically treated patients and 1.82, 95%CI 1.17 to 2.83 in patients treated with percutaneous coronary intervention.

The authors claim that the association appeared to be independent of the duration of treatment with clopidogrel.

So what?
Current NICE guidance is based on the CURE randomised controlled trial and states that the duration of clopidogrel in ACS is for a year. None of the groups in this new cohort study approached that as a mean duration of therapy and the wide standard deviations indicate most had much less time on clopidogrel than current UK policy. These data don’t really get near telling us what happens when you stop clopidogrel after 365 days.

But in at table 3 of the paper there was no difference in event rates (adjusted) for 0-90 and 91-180 days in medically treated patient who took >270day of clopidogrel. (The adjusted IRR was 1.79, 95% CI 0.96 to 3.34). In other words with longer duration of therapy it is possible there is no “excess” of events when it is stopped, but equally this could just be a statistical quirk occurring due to play of chance and / or a small number of events in that group of patients.

As the authors acknowledge, the absolute increase in rates here are VERY small and for an observational study with inherent limitations the relative differences are not at a level where we should be convinced either.  It would be a mistake to think this data proves there is a rebound problem when stopping clopidogrel under a year. Correspondence will be interesting but the bottom line has to be that, as the authors state, further randomised controlled studies are needed to confirm their findings and to validate any potential new approaches to clopidogrel treatment.

Action – Until more evidence is available it is unclear whether the risks of long-term clopidogrel treatment e.g. bleeding, outweigh the benefits. Clinicians should follow NICE guidance on clopidogrel for the treatment of non-ST-segment-elevation acute coronary syndrome. Further information on the management of acute coronary syndrome is available on the cardiovascular floor of NPC.

Study details
Design: Retrospective cohort study
Patients: 3,137 patients with acute coronary syndrome discharged from 127 Veterans Affairs hospitals between October 1st 2003 and March 31st 2005
Intervention: Clopidogrel treatment after hospital discharge
Outcomes: rate of all-cause mortality or acute myocardial infarction after stopping treatment with clopidogrel
Results: Main results outlined above.
Sponsorship: US Department of Veteran Affairs

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