Abstract

BackgroundThe risks of intracranial haemorrhage (ICH) associated with antithrombotic drugs outside clinical trials are gaining increased attention. The aim of this nationwide study was to investigate the risk of ICH requiring hospital admission in users of antithrombotic drugs.Methods and findingsData from the Norwegian Patient Registry and Norwegian Prescription Database were linked on an individual level. The primary outcome was incidence rates of ICH associated with use of antithrombotic drugs. Secondary endpoints were risk of ICH and fatal outcome following ICH assessed by Cox models. Among 3,131,270 individuals ≥18 years old observed from 2008 through 2014, there were 729,818 users of antithrombotic medications and 22,111 ICH hospitalizations. Annual crude ICH rates per 100 person-years were 0.076 (95% CI, 0.075–0.077) in non-users and 0.30 (95% CI, 0.30–0.31) in users of antithrombotic medication, with the highest age and sex adjusted rates observed for aspirin-dipyridamole plus clopidogrel (0.44; 95% CI, 0.19–0.69), rivaroxaban plus aspirin (0.36; 95% CI, 0.16–0.56), warfarin plus aspirin (0.34; 95% CI, 0.26–0.43), and warfarin plus aspirin and clopidogrel (0.33; 95% CI, 0.073–0.60). With no antithrombotic medication as reference, the highest adjusted hazard ratios (HR) for ICH were observed for aspirin-dypiridamole plus clopidogrel (6.29; 95% CI 3.71–10.7), warfarin plus aspirin and clopidogrel (4.38; 95% CI 2.71–7.09), rivaroxaban plus aspirin (3.82; 95% CI, 2.46–5.95), and warfarin plus aspirin (3.40; 95% CI, 2.99–3.86). All antithrombotic medication regimens were associated with an increased risk of ICH, except dabigatran monotherapy (HR 1.20; 95% CI, 0.88–1.65) and dabigatran plus aspirin (HR 1.79; 95% CI, 0.96–3.34). Fatal outcome within 90 days was more common in users (2,603 of 8,055) than non-users (3,228 of 14,056) of antithrombotic medication (32.3% vs 23.0%, p<0.001), and was associated with use of warfarin plus aspirin and clopidogrel (HR 2.89; 95% CI, 1.49–5.60), warfarin plus aspirin (HR 1.37; 95% CI, 1.11–1.68), aspirin plus clopidogrel (HR 1.30; 95% CI, 1.05–1.61), and warfarin (HR 1.19; 95% CI, 1.09–1.31). Increased one-year mortality was observed in users of antithrombotic medication following hemorrhagic stroke, subdural hemorrhage, subarachnoid hemorrhage, and traumatic ICH (all p<0.001). Limitations include those inherent to observational studies including the inability to make causal inferences, certain assumptions regarding drug exposure, and the possibility of residual confounding.ConclusionsThe real-world incidence rates and risks of ICH were generally higher than reported in randomized controlled trials. There is still major room for improvement in terms of antithrombotic medication safety (clinicaltrials.gov NCT02481011).

Highlights

  • Among hemorrhagic complications of antithrombotic medications, intracranial hemorrhage (ICH) may have devastating consequences with high morbidity and mortality rates [1, 2]

  • With no antithrombotic medication as reference, the highest adjusted hazard ratios (HR) for intracranial haemorrhage (ICH) were observed for aspirin-dypiridamole plus clopidogrel (6.29; 95% CI 3.71–10.7), warfarin plus aspirin and clopidogrel (4.38; 95% CI 2.71–7.09), rivaroxaban plus aspirin (3.82; 95% CI, 2.46–5.95), and warfarin plus aspirin

  • The registries linked were: (1) the Norwegian Patient Registry (NPR), which contains information about all admissions to Norwegian hospitals since 2008 with diagnoses coded according to the 10th revision of the International Classification of Diseases (ICD-10) and (2) The Norwegian Prescription Database (NorPD), which contains information about all prescriptions dispensed in Norway since 2004 including type of drug according to the Anatomical Therapeutic Chemical (ATC) classification system, number of Defined Daily Doses (DDD), date of dispensing, quantity dispensed, and drug strength

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Summary

Introduction

Among hemorrhagic complications of antithrombotic medications, intracranial hemorrhage (ICH) may have devastating consequences with high morbidity and mortality rates [1, 2]. Drifts in indications and treatment criteria may be seen in everyday practice and drug discontinuation due to precautionary concerns may be forgotten These factors may lead to other and potentially higher ICH rates in general clinical use than reported in RCTs. As a result, the risks of ICH associated with antithrombotic drugs outside clinical trials are gaining increased attention [2, 4,5,6,7]. The risks of intracranial haemorrhage (ICH) associated with antithrombotic drugs outside clinical trials are gaining increased attention The aim of this nationwide study was to investigate the risk of ICH requiring hospital admission in users of antithrombotic drugs

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