Risk of intracranial hemorrhage (RICH) in users of oral antithrombotic drugs: Nationwide pharmacoepidemiological study

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).

Patient self-management of oral anticoagulation with vitamin K antagonists in everyday practice: clinical outcomes in a single centre cohort after long-term follow-up

“…It is worthy to highlight the very low incidence of intracranial bleeding of 0.22% pt-ys in our cohort, in comparison to reported with different antithrombotic therapies. Recently, Gulati et al [17], reported the risk of intracranial hemorrhages in users of antithrombotic drugs in Norway nationwide. Users of antithrombotic drugs (as a whole) had an incidence of 0.30% pt-ys, whereas for the different oral anticoagulants, the incidences were: warfarin 0.55% pt-ys, rivaroxaban 0.51% pt-ys, dabigatran 0.25% pt-ys, and apixaban 0.45% pt-ys.…”

Surgery for herniated lumbar disc in private vs public hospitals: A pragmatic comparative effectiveness study

“…The dilemma each patient should consider is then not the effectiveness and quality of the health care, but rather their own economical capacity and possible waiting time for surgery. The role of private health insurance also comes under scrutiny in a country where the public health care system is well functioning and provides all emergency and complex in-house medical treatment [11]. Fig.…”

Previous chronic symptomatic and asymptomatic cerebral hemorrhage in patients with acute ischemic stroke

“…Patients with ischemic stroke should promptly receive antithrombotic therapy for secondary prevention if they do not have any significant contraindication, but for those with both acute ischemic stroke and PCH, symptomatic or not, long-term aggressive antithrombotic therapy should be used with caution after considering the risks and benefits to avoid re-bleeding [ 3 – 7 ]. There were no long-term randomized studies addressing this issue.…”

“…The proper management of patients with acute ischemic stroke and PCH remains controversial [ 3 – 7 , 20 , 21 ]. Our study found the PCH was not uncommon in acute ischemic stroke patients and antithrombotic medication should be used with more caution after considering risk and benefit.…”