Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves

Abstract

Aims: Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH.

Methods and results: We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03).

Conclusion: Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.

Figure 1

Study profile and numbers of participants. Individual level data of 2504 patients with anticoagulation-associated intracerebral haemorrhage were pooled and screened for the study. We identified 166 patients with mechanical heart valves in situ. For analysis of anticoagulation reversal, we excluded 18 patients because of early treatment restriction without follow-up imaging. For analysis of anticoagulation resumption, because of the predefined quarantine period of 72 h, we excluded additional 11 patients with early (<72 h) in-hospital death. For outcome analyses, 137 mechanical heart valve patients were eligible and were dichotomized into patients restarted on therapeutic anticoagulation vs. those without therapeutic anticoagulation. Therapeutic anticoagulation consisted either of restarting vitamin-K antagonists (n = 13) or systemic heparinization (n = 53). We defined major haemorrhagic complications as primary safety outcome measure consisting of (i) any intracranial haemorrhage, i.e. new intracerebral haemorrhage distant from the initial haematoma, any delayed haematoma enlargement >33% occurring beyond the 72 h quarantine period, and new subarachnoid or sub-/epidural haemorrhage, as well as (ii) any major extracranial hemorrhage [i.e. acute decrease (<24 h) in haemoglobin ≥3 g/dL, transfusion ≥2 units packed red blood cells, bleeding in critical site: intraspinal, intraocular, pericardial, articular, retroperitoneal, or fatal bleeding). We defined thromboembolic complications as intracranial, i.e. ischaemic stroke (unrelated to intracranial interventions scored upon serial follow-up imaging), or extracranial thromboembolic complications, i.e. systemic embolism, myocardial infarction (ST-elevated myocardial infarction and non-ST-elevated myocardial infarction with troponin elevation >99th percentile upper reference limit), valve thrombosis (evaluated through routine echocardiography or computed tomography), or symptomatic pulmonary embolism. Coincidence of intra- and extracranial thromboembolic complications were scored as intracranial, e.g. valve thrombosis with ischemic stroke. ICH, intracerebral haemorrhage; OAC, oral anticoagulation; VTE, venous thromboembolism.

Figure 2

Details on haemorrhagic and thromboembolic complications during hospital stay. Haemorrhagic or thromboembolic complications occurred in 29 patients with mechanical heart valves, dichotomized according to treatment exposure (therapeutic anticoagulation shown dark grey bars, no therapeutic anticoagulation shown as light grey bars). Complications were adjudicated according to anticoagulation treatment present immediately prior to clinical occurrence or diagnosis of haemorrhagic and thromboembolic complications. The mechanical valve position is indicated by ‘A’, ‘M’, ‘B’, either ‘aortic’, ‘mitral’, or ‘both’. The time-point of occurrence and the type of complication is depicted by coloured arrows (haemorrhagic shown as red, thromboembolic as blue). The classification of complications as intra- or extracranial is shown at the right hand side, ‘I’, intracranial and ‘E’, extracranial. The cross indicates the time-point of in-hospital mortality. The length of hospital stay after the censoring complication is depicted as light grey bars with white horizontal stripes. For definitions of haemorrhagic and thromboembolic complications please see methods. ICH, intracerebral haemorrhage.

Figure 3

Timing of therapeutic anticoagulation and clinical outcome. Adjusted cox proportional hazard models were used to visualize the association between the day of restarting therapeutic anticoagulation after intracerebral haemorrhage and (A) haemorrhagic complications and (B) the composite of haemorrhagic and thromboembolic complications during hospital stay. Patients were dichotomized according to treatment exposure (therapeutic anticoagulation vs. no therapeutic anticoagulation) and sequentially included into analyses at the day therapeutic anticoagulation was restarted. Specifically, we calculated hazard ratio estimates (y-axis) for both outcomes at each day after intracerebral haemorrhage using time-patient-clusters (3 day intervals) of patients that restarted therapeutic anticoagulation at a median of the presented day on the x-axis, and compared these with patients without therapeutic anticoagulation with available datapoints within these time-patient-clusters. Hazard ratio estimates were weighted and smoothed by the method of moving averages to correct for overestimation. ’Patients at risk‘ represents the number of individuals with attributed treatment exposure (either therapeutic anticoagulation or no therapeutic anticoagulation) at that specific day post-intracerebral haemorrhage. Stepwise-forward Cox proportional hazard modelling was adjusted for haemorrhagic and thromboembolic risk (CHADS₂ and HAS-BLED scores) as well as for statistical imbalances among baseline characteristics (Glasgow Coma Scale, intracerebral haemorrhage volume). The thick lines (red for haemorrhagic complications, blue for the composite of haemorrhagic and thromboembolic complications) represent the hazard ratio estimates generated for every single day after intracerebral haemorrhage; the thin lines with shaded area indicate the 95% confidence intervals. The distribution of mortality and functional outcome (C and D) at discharge is displayed using the modified Rankin Scale. Analyses of in-hospital mortality and functional outcome at discharge in patients who received therapeutic anticoagulation (including three patients who died before 72 h but were restarted on therapeutic anticoagulation before) is displayed as dichotomized comparison at the identified time-threshold for (D) haemorrhagic complications and for the (C) composite of haemorrhagic and thromboembolic complications. Each score on the modified Rankin Scale is separated by dashed lines. Thick lines separate the proportion of patients with favourable (modified Rankin Scale 0–3) and unfavourable (modified Rankin Scale 4–6) outcome as well as patients with and without in-hospital mortality. HR, hazard ratio; ICH, intracerebral haemorrhage.

Take home figure

In-hospital management of therapeutic anticoagulation in patients with ICH and MHV – from reversal until restarting therapy.