Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study

We thank Jankowski and colleagues for their response to our paper:
Proton pump inhibitor use and risk of adverse cardiovascular events in
aspirin treated patients with first time myocardial infarction: nationwide
propensity score matched study (1)

We share their thoughts regarding the importance of residual
confounding and unmeasured confounders and we have thoroughly discussed
this in our paper. We conducted careful calculations to estimate the size
of a potential confounder or combination of confounders and found that it
would have to elevate the risk by a factor 4 to explain the observed risk
associated with concomitant treatment with aspirin and PPIs. The existence
of a confounder or combination of confounders with an effect of this size
is unlikely, although not impossible. Consequently, as discussed in our
paper, we cannot rule out that the increased risk is caused by differences
in unmeasured confounders or residual confounding.

Jankowski and colleagues argue that the fact that we did not find an
increased risk associated with the use of H2 receptor blockers may be
related to lack of power. In our study there are relatively few patients
treated with H2 receptor blockers (n=661) compared to patients treated
with PPI (n=4306), but we do not believe that more power would change the
estimate, which showed a HR of 1.04 with confidence limits 0.79 to 1.38
and a p-value of 0.78. We cannot exclude a Type I error in this analysis,
but we consider it to be unlikely.

Ex vivo studies on healthy volunteers and patients with coronary
artery disease show conflicting results on whether PPI treatment
significantly influences aspirin-induced inhibition of platelet
aggregation (2-4). Importantly, the largest of these studies was performed
on patients with coronary artery disease and support the hypothesis of a
pharmacodynamical interaction between aspirin and PPIs (4). Jankowski and
colleagues also point out that the COGENT trial (5) did not find an
increased risk related to PPI treatment in patients treated with
clopidogrel and aspirin. This trial was unfortunately underpowered and as
the authors conclude, the results do not rule out a clinically meaningful
difference in cardiovascular events due to use of a PPI (5).

Jankowski and colleagues point out in their conflict of interest that
their biggest COI is that they are gastroenterologists and they do not
want to be woken at 2am with a serious aspirin-related bleed that could
have been avoided by the use of PPIs. As cardiologists, we have similar
concerns. If the same patient had been treated with PPIs, he could end up
waking us up at 3am with a myocardial infarction needing acute
intervention.

Nevertheless, our study is only a small piece in the puzzle of
possible drug interactions with antiplatelet treatment and, for now, we
definitely agree that patients with a clear indication for PPI treatment
should indeed be treated with PPIs to reduce their risk of
gastrointestinal bleeding, especially as we know that bleeding in patients
with prior MI is associated with worse outcome. (6)

1. Charlot M, Grove EL, Hansen PR, Olesen JB, Ahlehoff O, Selmer C,
et al. Proton pump inhibitor use and risk of adverse cardiovascular events
in aspirin treated patients with first time myocardial infarction:
nationwide propensity score matched study. BMJ. 2011;342:d2690.

2. Nefesoglu FZ, Ayanoglu-Dulger G, Ulusoy NB, Imeryuz N. Interaction
of omeprazole with enteric-coated salicylate tablets. Int J Clin Pharmacol
Ther. 1998 Oct;36(10):549-53.

3. Niazi M, Andersson T, Naucler E, Sundin M, Naesdal J. Evaluation
of the pharmacokinetic interaction between esomeprazole (40 mg) and
acetylsalicylic acid (325 mg) in healthy volunteers. Int J Clin Pharmacol
Ther. 2009 Sep;47(9):564-9.

4. Wurtz M, Grove EL, Kristensen SD, Hvas AM. The antiplatelet effect
of aspirin is reduced by proton pump inhibitors in patients with coronary
artery disease. Heart. Mar;96(5):368-71.

5. Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, et
al. Clopidogrel with or without Omeprazole in Coronary Artery Disease. New
England Journal of Medicine. 2010;363(20):1909-17.

6. Sorensen R, Abildstrom SZ, Hansen PR, Hvelplund A, Andersson C,
Charlot M, et al. Efficacy of post-operative clopidogrel treatment in
patients revascularized with coronary artery bypass grafting after
myocardial infarction. J Am Coll Cardiol. 2011 Mar 8;57(10):1202-9.