Concurrent painkiller use dims outcomes in aspirin-treated patients

Comedication with the analgesic dipyrone appears to contribute to excess mortality among patients receiving aspirin for secondary cardiovascular disease (CVD) prevention, partly driven by an increase in ischaemic events, a study from Germany has found.

Compared with aspirin monotherapy, aspirin–dipyrone comedication was associated with a 66-percent higher risk of death (hazard ratio [HR], 1.66, 95 percent confidence interval [CI], 1.56–1.76; p<0.0001), as well as an increase in the risks of myocardial infarction (MI; HR, 1.18, 95 percent CI, 1.05–1.32; p=0.0066; relative risk [RR] 1.14, number needed to harm 140) and stroke/transient ischaemic attack (HR, 1.22, 95 percent CI, 1.11–1.35; p<0.0001; RR 1.17, number needed to harm 82) in an inverse probability of treatment weighted sample. [J Am Heart Assoc 2021;doi:10.1161/JAHA.121.022299]

“Rate of neoplasia was very low in this study (<4 percent). Hence, it seems reasonable that mortality was driven by cardiovascular events, because this is the most common cause of death in Western countries,” according to the investigators. [Lancet 2015;385:117-171]

Interaction at COX-1

Aspirin has been shown to exert its antiplatelet effects by irreversible acetylation of serine 530 near the active site of cyclooxygenase (COX)-1, facilitating platelet inhibition during the life span of the platelet. Dipyrone, on the other hand, conducts its analgesic effects by reversible hydrogen bonds with serine 530 and tyrosin 385 in the COX. [J Thromb Thrombolysis 2007;23:213-222; World J Cardiol 2015;7:383-391; J Am Coll Cardiol 2013;62:1725-1726]

“Aspirin plasma half‐life is ≈20 minutes, [while] dipyrone plasma half‐life is substantially longer (>2 hours). Hence, dipyrone may hinder aspirin access to COX when (short‐lived) aspirin is administered during the (longer) time interval where dipyrone is present at pharmacologically active concentrations in plasma,” the investigators explained. [Eur J Pharmacol 2013;721:215-224]

“This direct drug–drug interaction at the level of COX‐1 frequently causes impaired aspirin antiplatelet effects. In a previous study, we showed that the order of medication intake is crucial: ingestion of aspirin 30 minutes before metamizole prevents high on‐treatment platelet reactivity to aspirin. Additionally, oral intake and lowest possible doses are favourable, because they reduce the occurrence of high on‐treatment platelet reactivity,” they added. [J Am Coll Cardiol 2013;62:1725-1726; Eur J Clin Pharmacol 2019;75:13-20]

Exploring alternatives

In the current analysis, the investigators drew data from a nationwide registry in Germany that comprised 9.2 million patients. All patients with a cardiovascular event in 2014 and subsequent secondary prevention with aspirin were followed up for 36 months. The inverse probability of treatment weighting sample included 26,200 patients who received aspirin monotherapy and 5,946 patients who received aspirin–dipyrone comedication. Mean dipyrone dose was 2.06 g per day.

Mean age was 70 years in the aspirin‐alone group vs 74 years in the aspirin–dipyrone group (p<0.001), with a greater proportion of men in the former (58.5 percent vs 47.0 percent). Patients in the aspirin–dipyrone group more often had chronic kidney disease, heart failure, type 2 diabetes, atrial fibrillation, prior MI, and malignant neoplasia.

The excess mortality risk associated with aspirin–dipyrone comedication is not only a laboratory phenomenon but has clinical implications, according to the investigators, who also acknowledged the dearth of potential alternatives to pain management and antithrombotic strategies.

“Many physicians consider dipyrone as indispensable because of the lack of alternatives. It works very effectively with tumour, chronic, or colicky pain and has a spasmolytic component, where other nonsteroidal anti‐inflammatory drugs are less potent,” they said.

Meanwhile, opioids are only recommended as second‐line analgesics, considering the current “opioid crisis” and the side effects of such drugs. [World Health Organ Tech Rep Ser 1990;804:1-75]

In terms of alternative antithrombotic therapies, factor Xa inhibition has been shown to have direct antiplatelet effects. However, a large trial showed that while factor Xa inhibition alone reduced cardiovascular events, it was not superior to aspirin. This may be the reason why aspirin remains an important mainstay in antiplatelet therapy, although its role in primary prevention of high‐risk patients is still the subject of much debate. [Circ Res 2020;126:486-500; N Engl J Med 2017;377:1319-1330]

In closing, the investigators underscored an urgent need for optimal pain management or alternative antithrombotic strategies in the population of patients receiving aspirin–dipyrone comedication.