Response to Letter Regarding Article, “Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome”
To the Editor:
Drs Potter and Le Lorier note that a large number of patients in our study had no recorded clopidogrel use within 7 days of hospital discharge.1 We believe the primary cause of the low use of clopidogrel is the fact that the study covered the period between 2001 and 2005. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO) trials were published in 2001 and 2002, respectively, and other relevant trials (Clopidogrel as Adjunctive Reperfusion Therapy [CLARITY], Clopidogrel and Metoprolol in Myocardial Infarction Trial [COMMIT], PCI-CLARITY) were not published until 2005. As a result, the guidelines in place during most of our study period did not recommend the routine use of clopidogrel for all patients with acute coronary syndrome. Further, a substantial lag often exists between the publication of important trial data and meaningful changes in community-based practice.
We also considered less likely explanations for this observation, including the possibility that clopidogrel prescriptions were filled but not recorded in the databases we studied. This is unlikely because the prescription benefit programs have near-complete recording of all drugs that the programs pay for; for an expensive covered medication such as clopidogrel, insurance-eligible patients would generally not choose to pay out of pocket. A second possibility is that the 7-day time frame was too short to identify clopidogrel initiation. As Drs Potter and Le Lorier noted, at 7 days after hospital discharge, 31% of patients had recorded use of clopidogrel; that figure increased to 35% at 14 days, 40% at 90 days, and 45% at 180 days, suggesting that the 7-day window was not an important cause of underascertainment of clopidogrel use. Given the study period and the clinical context noted above, we believe that 45% of patients with percutaneous coronary intervention or acute coronary syndrome in routine care with a filled prescription within 180 days of discharge were compatible with practice at the time. Although defining exposure using a greater number of days after discharge would have yielded a larger study cohort, it also would have eliminated many early outcome events. A 7-day period provided a good balance of cohort size and study power.
Drs Potter and Le Lorier also note that, in the British Columbia population, there was 1 estimated relative risk (RR) for 1 outcome (revascularization) whose confidence interval did not contain the null value, whereas a second estimate of the RR of that outcome showed a null result. They attribute the difference in RR to the use of standard propensity scores versus high-dimensional propensity scores (hd-PS). In fact, both analyses used hd-PS. One adjusted for decile of hd-PS (RR=1.64, 95% confidence interval, 1.15 to 2.35), whereas the other matched on hd-PS (RR=1.30, 95% confidence interval, 0.81 to 2.08). Consequently, these figures are not fully comparable. The matched analysis examined a subgroup (n=2514) of the 10 391 patients in the British Columbia population. These were the patients for whom the hd-PS indicated that there was clinical equipoise between treatment with clopidogrel plus a proton pump inhibitor versus clopidogrel alone. Because the overall British Columbia population and the smaller matched subgroup may have differed in the severity of illness, we believe that the 2 results are not inconsistent, particularly for an end point such as revascularization, which involves some clinical discretion. Indeed, for the “harder” end points of myocardial infarction hospitalization and death, the results of the decile-adjusted and matched analyses were quite similar and showed no meaningful increase in risk.
Dr Schneeweiss had previously received an unrelated investigator-initiated research grant from Pfizer to study the safety of COX-2 inhibitors after the withdrawal of rofecoxib from the market and is a paid scientific advisory board member for HealthCore and ii4sm. The other authors report no conflicts.