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.

Keppra for Subdurals

Motivation: As a medicine intern last year, I often scoffed at the algorithmic recommendation by neurosurgery of Keppra for seven days after every small subdural hemorrhage.  Two nights ago, I self-consciously found myself writing the same recommendation while consulting as neurology for a patient after a fall.  What is the data?

Turns out that there is no high quality randomized trial testing anti-epileptics in acute sub-dural hematomas.  The practice is drawn from literature in traumatic brain injury.

Paper: Chang, B.S. and Lowenstein, D.H.  "Practice Parameter: Antiepileptic drug prophylaxis in severe traumatic brain injury." Neurology (2003); 60: 10-16.

Method: A meta-analysis of prospective placebo controlled trials testing anti-epileptic drugs in traumatic brain injury.  Literature search revealed that data existed only for severe TBI - typically with loss of consciousness or amnesia for 12 to 24 hours, depressed skull fracture, or brain contusion on CT scan.  No constraint was placed on the choice of AED.  Authors separated analysis by prevention of early or late seizures.

Results:
Prevention of Early Seizures: Four randomized trials examined early (less than 7 days) prevention of seizure from TBI.  Three studies used phenytoin and one used carbamazepine.   The pooled RR for seizure on AED compared to placebo was 0.37 (CI: 0.18-0.74).  Of the four studies, one did not find any benefit with AED though that study was hindered by low event rate.  There was no significant increase in frequency of adverse effects in group taking AED.

Prevention of Late Seizures: Five high quality trials tested long-term AED for prevention of seizures.  The treatment duration was 6 months to 2 years (most trials were 1-2 years) with median follow-up of 2 years (five trials) with range of 18 months to 2 years.  Trials used phenytoin, carbamazepine, or valproic acid.  The pooled RR for seizure on AED compared to placebo was 1.05 (CI: 0.82-1.35) demonstrating no benefit - none of the individual studies showed benefit.  Some unblinded studies (not included in pooled analysis) showed benefit.  Adverse effects (particularly rash) was significantly higher in the intervention group than placebo group.

Discussion: In severe TBI, anti-epileptic drugs appear beneficial in preventing seizures in the short term (7 days) but ineffective in the long-term.  This landmark meta-analysis, though, has been commonly extended to justify prescribing anti-epileptics for many minor to mild TBI without changes in consciousness or brain contusions.  Although probably beneficial, the practice is still more opinion based rather than evidence based.    Also, the trials used mostly phenytoin as the anti-epileptic of choice while current practice is more heavily biased towards levetiracetam (Keppra).  While I do not plan to rebel against the seven day course of Keppra for subdurals, there is need for data in this common clinical situation.