Increased risk of intracranial hemorrhage with aspirine use in those without symptomatic CVD

Frequency of Intracranial Hemorrhage With Low-Dose Aspirin in Individuals Without Symptomatic Cardiovascular Disease - A Systematic Review and Meta-analysis

Literature - Huang W-Y, Saver JL, Wu Y-L, et al. - JAMA Neurol 2019; doi:10.1001/jamaneurol.2019.1120

Introduction and methods

Benefits of low-dose aspirin in prevention of myocardial infarction and ischemic stroke outweigh the harm of increased bleeding risk in a population with CVD. However, this benefit-risk balance is less clear for primary prevention of CVD, because in individuals without previous CVD the risk of CV events is lower and increased risk of bleeding may offset the benefit of aspirin [1-3].

A systematic review and meta-analysis were conducted to examine the association between aspirin use and risk of bleeding in those without symptomatic CVD for the following reasons. Intracranial hemorrhage is strongly associated with high mortality risk and poor outcomes [4,5]. Meta-analyses have shown conflicting results for risk of intracranial hemorrhage with use of aspirin for primary prevention of CVD [2,3,6-9]. In addition, specific subtypes of intracranial hemorrhage have not been investigated in previously published meta-analyses. And finally, there are new data from 3 recently published large trials showing controversial results [10-12].

PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from January 1966 to October 30, 2018. Inclusion criteria were: randomized clinical trial, comparison of aspirin with placebo or no aspirin, report of all intracranial hemorrhages, all hemorrhagic strokes, intracerebral hemorrhages, subdural or extradural hemorrhages, or subarachnoid hemorrhages, total participants and those with an endpoint were reported separately, aspirin dose ≤100 mg once daily, and treatment duration >6 months.

Main results

  • 13 trials were identified, with 134,446 patients and follow-up duration was 2.3-8.2 years.
  • Aspirin use was associated with increased risk of all intracranial hemorrhage compared to control (8 trials; 0.63% vs. 0.46%; RR: 1.37; 95%CI: 1.13-1.66; I² = 0%). Use of aspirin would be associated with 2 additional intracranial hemorrhages in 1000 people.
  • There was no association of aspirin use with higher risk of intracerebral hemorrhage (10 trials; 0.30% vs. 0.24%; RR: 1.23; 95%CI:0.98-1.54, I² = 0%).
  • Compared to control, aspirin use was associated with an increased risk of subdural or extradural hemorrhage (4 trials; 0.31% vs. 0.20%,RR: 1.53; 95%CI:1.08-2.18, I² = 0%). Use of aspirin would be associated with an additional 1 subdural or extradural hemorrhage in 1000 people.
  • There was no association of aspirin use with higher risk of subarachnoid hemorrhage (5 trials; 0.14% vs. 0.12%; RR: 1.13; 95%CI:0.70-1.83, I² = 0%).
  • In subgroup analyses, aspirin use was associated with increased risk of intracerebral hemorrhage compared to control in trials enrolling Asian populations vs. trials with non-Asian populations (I² = 56%, Asian-population trials: 2 trials; RR: 1.84; 95%CI:1.04-3.27; and non-Asian population trials: 8 trials; RR: 1.14, 95%CI:0.89-1.46).
  • In subgroup analyses, aspirin use, compared to control, was also associated with increased risk of intracerebral hemorrhage in populations with a mean BMI<25 vs. populations with mean BMI ≥25 (I² = 62%, trials with mean population BMI <25: 2 trials, RR: 1.84; 95%CI:1.04-3.27 and trials with mean population BMI ≥25: 5 trials, RR:1.08, 95%CI:0.79-1.46).

Conclusion

Results of a meta-analysis of 13 trials comprising 134,446 individuals showed that in people without symptomatic CVD, use of low-dose aspirin was associated with increased risk for any intracranial hemorrhage compared to control. More specific, risk of subdural or extradural hemorrhage was increased in those who took aspirin compared to control. Subgroup analyses showed that those of Asian race or BMI <25 had a higher risk of intracerebral hemorrhage when taking aspirin compared to control. The authors of this study suggest to be cautious when considering use of low-dose aspirin for primary prevention of CVD.

References

1.Capodanno D, Angiolillo DJ. Aspirin for primary cardiovascular risk prevention and beyond in diabetes mellitus. Circulation. 2016;134:1579-1594.

2. Guirguis-Blake JM, Evans CV, Senger CA, et al. Aspirin for the Primary Prevention of Cardiovascular Events: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2015.

3. Lei H, Gao Q, Liu SR, et al. The benefit and safety of aspirin for primary prevention of ischemic stroke: a meta-analysis of randomized trials. Front Pharmacol. 2016;7:440.

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6. Connolly BJ, Pearce LA, Kurth T, et al. Aspirin therapy and risk of subdural hematoma: meta-analysis of randomized clinical trials. J Stroke Cerebrovasc Dis. 2013;22:444-448.

7. Hart RG, Halperin JL, McBride R, et al. Aspirin for the primary prevention of stroke and other major vascular events: meta-analysis and hypotheses. Arch Neurol. 2000;57:326-332.

8. Raju N, Sobieraj-Teague M, Hirsh J, et al. Effect of aspirin on mortality in the primary prevention of cardiovascular disease. Am J Med. 2011;124:621-629.

9. Zheng SL, Roddick AJ. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis. JAMA. 2019;321:277-287.

10.Gaziano JM, Brotons C, Coppolecchia R, et al; ARRIVE Executive Committee. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet. 2018;392:1036-1046.

11. Bowman L, Mafham M,Wallendszus K, et al;nASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018;379(16):1529-1539.

12. McNeil JJ,Wolfe R,Woods RL, et al; ASPREE Investigator Group. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379:1509-1518.

Find this article online at JAMA Neurol

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