Excess of MACCE in Aspirin and Dipyrone (Metamizole/Novalgin) Co-Medicated Patients: A Nationwide Study

Background: Acute and chronic pain is a major issue in aging society. Dipyrone (metamizole, novalgin) is one of the most frequently used analgesics in many countries, despite that it may cause agranulocytosis. Additionally, it has recently been shown to impair pharmacodynamic response to aspirin measured by platelet function tests. However, it is not known if this laboratory effect translates to clinical outcome. Methods: We conducted a nation-wide analysis of a health insurance database in Germany comprising 9.2 million patients. All patients with a cardiovascular event in 2014 and subsequent secondary prevention with aspirin were followed-up for 36 months. Inverse probability of treatment weighting (IPTW) analysis was conducted to investigate major adverse cardio- and cerebrovascular events (MACCE; composite of death, myocardial infarction [MI], stroke/transient ischemic attack [TIA]) between patients on aspirin-dipyrone co-medication and on aspirin-alone medication. Results: 26,200 patients received permanent aspirin-alone medication and 5,946 patients aspirin-dipyrone co-medication. In the inverse probability of treatment weighted sample MACCE was more frequent in aspirin-dipyrone co-medicated patients (24.9% vs. 33.9%; hazard ratio [HR]=1.45, 95% confidence interval [CI] 1.38-1.53; p<0.001, number needed to harm 11.11). All single components of MACCE (death, MI and stroke) were higher in the aspirin-dipyrone group as well (death: 15.6% vs. 24.4%; HR=1.66, 95% CI 1.56-1.76; p<0.001; MI: 5.2% vs. 5.9%; HR=1.18, 95% CI 1.05-1.32; p<0.01; stroke/TIA: 7.3% vs. 8.5%; HR=1.22, 95% CI 1.11-1.35; p<0.001). Conclusions: In this nationwide analysis, aspirin and dipyrone co-medication was associated with excess of MACCE. Therefore, dipyrone should be used with caution in patients on aspirin. Funding Statement: This work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University (No 46-2016 and 29-2019, to L.D., No. 16-2014 to A.P.) and by the German Research Foundation (LE 940/7-1 to B.L. and PO 2247/2-1 to A.P. and SFB1116 to A.P. and B.L.). Declaration of Interests: The authors state they have no conflicts to disclose. Ethics Approval Statement: The study conformed to the Declaration of Helsinki and was approved by the University of Dusseldorf Ethics Committee (vote n° 2018-22).