Association of antithrombotic drug use with the risk of intracerebral haemorrhage

Intracerebral haemorrhage (ICH) accounts for 10-15% of all strokes, each year affecting >3 million people worldwide. ICH is the deadliest type of stroke with a 30-day mortality of ~40%. Survivors of ICH are often severely disabled.

ICH is a feared complication of antithrombotic drug use. Over the past decades, the use of antithrombotic drugs has undergone major changes; direct oral anticoagulants (DOACs) have entered the market and more aggressive drug regimens with dual and triple antithrombotic drugs are increasingly common. concurrently, demographics are changing in the Western countries with an increasing number of older people who may require antithrombotic therapy.

The Danish constellation of universal health care, well-organised stroke services and numerous health registries with population coverage provides a unique setting for epidemiological ICH
research. However, knowledge about data quality is essential for optimal use of register data and only few previous studies have reported on the validity of ICH diagnoses in Danish registries.
Information on ICH location (i.e., lobar or non-lobar) is important in the assessment of an underlying aetiology. However, this information is not collected in Danish registries.

The aims of this thesis was to establish the validity of ICH diagnoses in the Danish Stroke Registry (DNR) and the Danish National Patient Registry (DNPR) in an unselected inception cohort of persons with first-ever ICH (study 1). Further, we aimed to estimate the strength of association between antithrombotic drug use and risk of ICH, and to investigate the effect of changes in
antithrombotic drug use on the incidence of ICH (study 2)

In study 1, we estimated the positive predictive value (PPV) and sensitivity with 95% confidence intervals (CIs) of first-ever ICH diagnosis codes according to DSR or DNPR for persons residing in
the Region of Southern Denmark (population 1.2 million) during 2009-2017 (n=3,956). In DSR, PPV was 86.5% (95% CI, 85.1– 87.8) for a-ICH (any non-traumatic ICH) and 81.8% (95% CI, 80.2–83.3) for s-ICH (spontaneous ICH; no underlying structural cause). Corresponding numbers were 76.2% (95% CI, 74.7–77.6) for a-ICH and 70.2% (95% CI, 68.6–71.8) for s-ICH in DNPR (inpatient, primary diagnosis). The sensitivity in DSR was 76.4% (95% CI, 74.8– 78.0) for a-ICH and 78.7% (95% CI, 77.1–80.2) for s-ICH. In DNPR, sensitivity for a-ICH and s-ICH was 87.3% (95% CI, 86.0–88.5) and 87.7% (95% CI, 86.3–88.9), respectively. Location of verified s-ICH was classified as lobar (39%), deep (33.6%), infratentorial (13.2%), large unclassifiable (11%), isolated
intraventricular (1.9%), or unclassifiable due to insufficient information (1.3%).

In study 2, a nation-wide case-control study (population 5.8 million), cases of first-ever ICH during 2005-2018 were identified in DSR (n=16,765) and matched on age, sex and calendar year to general population controls (n=660,477). Using conditional logistic regression, we calculated adjusted odds ratios (aORs) for the association of antithrombotic drug use and risk of ICH. Risk of ICH was associated with current use of low-dose aspirin (ASA; aOR, 1.51; 95% CI, 1.44-1.59), clopidogrel (aOR, 1.65; 95% CI, 1.47-1.84), DOACs (aOR, 1.83; 95% CI, 1.61-2.07), and vitamin K antagonist (VKA; aOR, 2.76; 95% CI, 2.58-2.96). In analyses for concurrent use of antithrombotic drugs, the lowest risk of ICH was found with ASA and dipyridamole (aOR, 1.49; 95% CI, 1.31-1.69), and the highest risk of ICH was found with triple therapy comprising VKA, ASA, and clopidogrel (aOR, 5.84; 95% CI, 3.34-10.22). When comparing individual DOACs with warfarin, current use of dabigatran was associated with the lowest risk of ICH (aOR, 0.34; 95% CI, 0.25-0.44), and rivaroxaban was associated with the highest risk of ICH (aOR, 1.20; 95% CI, 1.03-1.41).

We calculated prevalence ratios (PRs) of current antithrombotic drug use among general population controls comparing the prevalence in the second half of the study period with that of the first half (2012-2018 vs 2005-2011). Use of oral anticoagulants (OACs) increased (PR, 1.78; 95% CI, 1.74- 1.81), mainly due to an increased use of DOAC (PR, 196; 95% CI, 152-251), whereas use of antiplatelets decreased slightly (PR, 0.90; 95% CI, 0.89-0.90). The annual standardised incidence rate (sIR) for ICH overall decreased from 29.9 (95% CI, 29.3-30.5) per 100,000 person-years in the first half on the study period (2005-2011) to 26.2 (95% CI, 25.6-26.7) per 100,000 person-years in the second half (2012-2018), corresponding to an incidence rate ratio of 0.87 (95% CI, 0.85-0.90).

In conclusion, data quality in both DSR and DNPR was sufficiently high to support their use in epidemiological studies on ICH. Use of antithrombotic drugs was associated with an increased risk
of ICH. However, the substantial increase in use of antithrombotic drugs during the study period – especially an increased use of DOACs – was not mirrored in an increased incidence of ICH.
Nonetheless, subanalyses indicated that incidence rates of ICH levelled in recent years and may even increased slightly in the oldest age group (85+ years).