Bleeding on antithrombotic treatment in secondary stroke prevention

Abstract

Stroke is a major cause of death and adult disability world wide. Approximately 20-30% of all strokes occur in patients with a previous stroke. Secondary prevention is essential to reduce risk of recurrence after a first stroke, and antithrombotic treatment is one of the key interventions in secondary prevention. However, bleeding is an important and potentially life-threatening side effect of antithrombotic drugs. The main aim of this thesis is to identify which patients are at high risk of bleeding on antithrombotic treatment and to investigate whether antithrombotic treatment can be optimised based on bleeding risk assessment. We developed the S2TOP-BLEED score to predict an individuals’ risk of major bleeding on antiplatelet treatment. The score is based on ten readily available characteristics: age, sex, Asian ethnicity, smoking, hypertension, diabetes, prior stroke, BMI, outcome on the modified Rankin scale and type of antiplatelet treatment. The score showed modest discriminatory performance in the development cohort and two subsequent external validation cohorts, but accurate calibration. In order to inform treatment decisions, the harms of antithrombotic treatment should be weighed against the benefits. We observed that those patients at highest risk of a major bleeding event were also at highest risk for recurrent ischaemic events. The risk reduction in ischaemic events was larger than the increase in major bleeds, irrespective of bleeding risk category. This was true both for patients on antiplatelet treatment and on oral anticoagulants after a TIA or stroke. We conclude that bleeding risk stratification should not guide decisions on antithrombotic treatment following a TIA or ischaemic stroke. However, bleeding risk assessment might still be useful to identify patients in whom preventive treatment should be considered. We subsequently investigated timing of bleeding on antiplatelet treatment and observed that risk of major and gastro-intestinal bleeding is highest early after start of dual antiplatelet therapy, and declines after the first 30 days. The risk of intracranial haemorrhage was stable over time. Blood pressure control is another important aspect of secondary stroke prevention, but uncertainty exists regarding the optimal target blood pressure. We studied the association between blood pressure and the risk of intracerebral haemorrhage after stroke and observed that risk of intracerebral haemorrhage increased with increasing blood pressure levels. Further studies are needed to establish whether blood pressure targets below 140 mmHg systolic confer additional benefit in terms of prevention of intracerebral haemorrhage. Last, we developed the DIAGRAM risk score to predict which patients have a high likelihood of an underlying macrovascular abnormality as cause for an intracerebral haemorrhage. This score may facilitate selection of patients for additional imaging following intracerebral haemorrhage, but requires further validation to confirm its robustness.