A Plavix a Day Keeps MI Away?

Motivation: Last week, I was trying to coax a patient into taking aspirin every day, and he refused to give way.  He had stomach pain after every dose of aspirin.  To me, it seemed reasonable to refuse aspirin, but then again, I did not want his next stroke on my conscience either.  I wondered if there was a way out or even a better way.  How good is clopidogrel compared to aspirin for prevention of vascular events in high risk populations?

Paper: CAPRIE Steering Committee, "A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)" Lancet (1996); 348: 1329-39.

Methods: Randomised blinded trial of 19,185 adults in USA, Canada, and Europe with symptomatic atherosclerotic peripheral arterial disease, recent MI (within 5 weeks), or recent ischemic stroke (within 6 months).  Patients with bleeding disorders were excluded.  Patients were randomized to clopidogrel 75 mg daily or aspirin 325 mg daily.  Primary outcome was ischemic stroke, MI, or vascular death.  Secondary outcomes included all-cause mortality, intracranial hemorrhage, fatal bleeds, and other clusters of outcomes.  Mean duration of follow-up was 1.91 years.

Results: 
Cohort: Among 19,185 patients, 9,586 were randomized to aspirin while 9,599 were randomized to clopidogrel.  Mean age of cohort was 62.5 years, and the cohort was 72% male and 95% white.  Baseline characteristics of the patients in terms of comorbidities were evenly balanced.  Prior to end of study, 21.3% in clopidogrel group and 21.1% in aspirin group discontinued drug.  Most common cause for stopping was adverse drug effect.

Primary Outcome: For the primary outcome of ischemic stroke, MI, or vascular death, the average event rate per patient year was 5.32% in clopidogrel group and 5.83% in aspirin, yielding a relative risk reduction of 8.7% (95% CI 0.3-16.5%, p = 0.043), in favor of clopidogrel.

Secondary Outcome: For the pre-defined secondary outcome measures of vascular death, death from any cause, or cluster of ischemic/hemorrhagic stroke, MI, and death, there was no difference between aspirin and clopidogrel.

Post-Hoc Analysis: In post-hoc subgroup analysis, patients with peripheral arterial disease benefited the most from clopidogrel over aspirin.  The relative risk reduction for clopidogrel over aspirin for primary outcome was 23.8% (CI: 8.9 to 36.2), p = 0.0028.  For patients with MI or stroke, the effect of clopidogrel over aspirin was non-significant.

Adverse Effects: Frequency of rash was higher in clopidogrel over aspirin whereas GI bleed was more frequent in aspirin users.

Discussion: For secondary prevention of vascular events, clopidogrel is at least as good as aspirin.  What was surprising in the post-hoc analysis was the apparent benefit of clopidogrel over aspirin in patients with PAD but not in post-MI and post-stroke patients.  I think that this finding is a note of caution that atherosclerosis in all vascular territories is not equivalent, and benefit of a drug in a type of vascular disease does not necessarily generalize.  The trial was generally well-done, but the 21% rate of drug discontinuation in both groups remains a concern and may have masked beneficial effects in intention-to-treat analysis.  In summary, if a patient balks against aspirin for secondary prevention, daily clopidogrel is an equivalent option and may even be better if patient has PAD.

Aspirin After Stenting

Motivation: Reviewing a patient's home medication list yesterday, I found my favorite offender on the list - aspirin at 325 mg dosage.  The man had a drug eluting stent placed two years ago.  I grumbled out loud something about unnecessary risks to patients.  One of the seniors sitting within earshot struck back that in fact every patient is kept on a full dose aspirin plus clopidogrel after drug eluting stent placement.  Turns out that this fact had escaped me nine months into internship.  But, is there data to support the practice?

Paper: Mehta, S.R., Tanguay, J.-F., Eikelbloom, J.W., 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-OASIS7): a randomized factorial trial." Lancet (2010) 376: 1233-43.

Methods: Multinational randomized factorial trial.  Inclusion criteria were symptoms of acute coronary syndrome and either EKG evidence or raised biomarkers.  All patients underwent coronary angiography with intent to undergo PCI within 72 hours.  Exclusion criteria was increased risk of bleeding or active bleeding.  All patients initially got full dose aspirin.  From day two, patients were randomized to either high dose (300-325 mg) or low dose (75-100 mg) aspirin.  In the clopidogrel arm, patients either received 600 mg loading dose followed by 150 mg from days 2-7 or received 300 mg loading dosed followed by 75 mg on days 2-7.  With the factorial design, there were four groups receiving varying combinations of clopidogrel and aspirin.  Primary outcome was composite of CV death, MI, or stroke within 30 days.

Results:
When the trial was first released, the clopidogrel trial results attracted much attention and controversy.  Multiple editorials comment on the analysis of the clopidogrel piece of the trial.  I will just describe the aspirin portion of the trial.

Cohort: There were 8624 patients randomized to high dose aspirin and 8639 randomized to low dose aspirin. The two treatment arms were very similar in baseline characteristics.  Average age was about 61 years with 25% female.  About 63% of the patients had NSTEMI/UA while the remaining patients presented with STEMI.  About 37% of patients took regular aspirin, and another 20% took regular clopidogrel prior to randomization.

Angiography: After initial angiography, 8160 of the 8624 (94.6%) in the high dose ASA group received a stent (58% BMS and 42% DES).    In the low dose ASA group, 8163 of the 8639 (94.5%) received a stent (58% BMS and 42% DES).  Patient did not undergo PCI because of (1) no coronary disease - most common, (2) no suitable area for revascularization, or (3) CABG was better alternative.

Follow-up: Primary outcome of cardiovascular death, stroke, or MI did not differ between the high dose and low dose group (HR: 0.98, 95% CI 0.84-1.13, p = 0.76).  Between high and low dose aspirin, there was no difference in definite or probable stent thrombosis (0.9% vs 1.0%, CI: 0.68-1.26).  In secondary analysis, recurrent ischemia was slightly higher in low dose aspirin (0.4%) compared to high dose aspirin (0.2%) though event numbers were small to make meaningful post-hoc secondary comparisons.  In the overall trial analysis (including those who got PCI and those who did not), high dose aspirin resulted in significant increase in minor bleeding (5.0% vs 4.2%, p = 0.04).

Discussion: This trial shows that even in the acute post-PCI setting, use of a lower dose aspirin does not increase likelihood of stent thrombosis.  Some of the strengths of this trial are the randomized trial design with very large number of subjects (over 8,000 in both groups).  While this trial looks only at initial 30 day events, low dose aspirin is expected to be adequate in long-term setting as well given its equivalence to high dose aspirin in the high-risk post-procedure period.  There are no randomized trials in the long-term setting, but there have been retrospective observational studies which show that there is no increased risk of stent thrombosis with low dose aspirin.  On the other hand, there is more definite evidence showing increased risk of bleeding with high dose aspirin compared to low dose aspirin.  Current practice guidelines, however, continue to recommend prolonged administration of high dose aspirin after stenting!