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Antithrombotic drugs and interactions in ischemic heart disease a pharmaco-epidemiological study

Mette Gitz Charlot


The widespread use of antithrombotic treatment makes it a cornerstone in modern cardiology and in depth knowledge about the precise effects and side effects of the antithrombotic drugs is essential. 

This thesis was conceived to examine specific effects and side effects of antithrombotic treatment, through three observational pharmaco-epidemiological studies using data from Danish nationwide registries containing information on hospitalizations, prescription claims, causes of death, and socioeconomic data. Information was linked through Statistics Denmark and differences in cardiovascular risk were analyzed for patients treated with different combinations of drugs as well as for patients that discontinued treatment. 

1: There has been and still is an intense debate internationally about whether there is an increased cardiovascular risk associated with concomitant treatment with clopidogrel and proton pump inhibitors (PPIs). Analyzing data on 56406 patients with first-time myocardial infarction 2000-2006, demonstrated that PPI use appeared associated with increased cardiovascular risk regardless of clopidogrel use. Treatment with concomitant PPI and clopidogrel was not associated with any additional increase in cardiovascular risk, adjusted hazard ratio 1.29 (1.21- 1.37) than the risk observed for patients prescribed PPI alone, adjusted hazard ratio 1.29 (1.17- 1.42). There was no interaction between the two drugs (p=0.72). The increased cardiovascular risk associated with PPI use may be caused by differences in unmeasured confounders. The results appear to refute the concern about increased cardiovascular risk during concomitant treatment with PPIs and clopidogrel. 

2: The main focus has been on the possible interaction between clopidogrel and PPIs, but an interaction between aspirin and PPIs has also been proposed. Several ex vivo studies have demonstrated that concomitant treatment with aspirin and PPIs is associated with significantly reduced antiplatelet effect of aspirin and thus a potential increase in risk of adverse cardiovascular effects. Investigating the clinical significance of the proposed interaction in a cohort of 19925 patients with first-time myocardial infarction between 1997 and 2006 showed an increased cardiovascular risk associated with combination therapy with aspirin and PPIs, 39 adjusted hazard ratio 1.46 (1.33 to 1.61; p<.001). It is possible, but unlikely that the observed cardiovascular risk is caused by differences in unmeasured confounders. 

3: There is internationally disagreement about the optimal duration of clopidogrel therapy following myocardial infarction as well as whether there is an increased cardiovascular risk after discontinuation of clopidogrel, even after the guideline recommended 12 months of treatment. Our results, based on a cohort of 29268 clopidogrel treated patients from 2004-2009, demonstrate an increased cardiovascular risk in the first 90 day period of clopidogrel discontinuation 12 month after myocardial infarction for patients who had undergone percutaneous coronary intervention (PCI), adjusted incidence rate ratio 1.59 (1.11-2.30; p=0.013) compared to the next 90 day period of discontinuation. There was no risk associated with discontinuation for patients that had not undergone PCI, adjusted incidence rate ratio 1.07 (0.65-1.76; p=0.79). This adds to the evidence of a benefit beyond 12 months of clopidogrel treatment for patients who have undergone PCI.