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Early or late initiation of dabigatran versus vitamin-K-antagonists in acute ischemic stroke or TIA: The PRODAST study
Abstract
Background:
The
optimal timing of initiating or resuming anticoagulation after acute
ischemic stroke (AIS) or transient ischemic attack (TIA) in patients
with atrial fibrillation (AF) is debated. Dabigatran, a non-vitamin K
oral anticoagulant (NOAC), has shown superiority against vitamin K
antagonists (VKA) regarding hemorrhagic complications.
Aims:
In this registry study, we investigated the initiation of dabigatran in the early phase after AIS or TIA.
Methods:
PRODAST
(Prospective Record of the Use of Dabigatran in Patients with Acute
Stroke or TIA) is a prospective, multicenter, observational,
post-authorization safety study. We recruited 10,039 patients at 86
German stroke units between July 2015 and November 2020. A total of
3,312 patients were treated with dabigatran or VKA and were eligible for
the analysis that investigates risks for major hemorrhagic events
within 3 months after early (⩽ 7 days) or late (> 7 days) initiation
of dabigatran or VKA initiated at any time. Further endpoints were
recurrent stroke, ischemic stroke, TIA, systemic embolism, myocardial
infarction, death, and a composite endpoint of stroke, systemic
embolism, life-threatening bleeding and death.
Results:
Major
bleeding event rates per 10,000 treatment days ranged from 1.9 for late
administered dabigatran to 4.9 for VKA. Early or late initiation of
dabigatran was associated with a lower hazard for major hemorrhages as
compared to VKA use. The difference was pronounced for intracranial
hemorrhages with an adjusted hazard ratio (HR) of 0.47 (95% confidence
interval (CI): 0.10–2.21) for early dabigatran use versus VKA use and an
adjusted HR of 0.09 (95% CI: 0.00–13.11) for late dabigatran use versus
VKA use. No differences were found between early initiation of
dabigatran versus VKA use regarding ischemic endpoints.
Conclusions:
The
early application of dabigatran appears to be safer than VKA
administered at any time point with regards to the risk of hemorrhagic
complications and in particular for intracranial hemorrhage. This
result, however, must be interpreted with caution in view of the low
precision of the estimate.
Introduction
The
timing of initiating or resuming of anticoagulation after an acute
ischemic stroke (AIS) or transient ischemic attack (TIA) in patients
with atrial fibrillation (AF) is still a matter of debate. Early
initiation of anticoagulation may increase the risk of hemorrhagic
transformation (HT) of the infarct and thus intracranial hemorrhage
(ICH). Delaying the initiation of anticoagulation, however, may enhance
the risk of recurrent ischemic events.1 With one exception,2 results from randomized controlled trials (RCTs) on the timing of anticoagulation3–5 are not yet available and guidelines are currently based on expert opinion.6–8
Surveys among stroke practitioners on timing of anticoagulation
following AIS or TIA have shown no consensus in decision-making.9,10
Observational studies on the initiation of anticoagulation after AIS or TIA in patients with AF yielded heterogeneous findings1,11–14
and the majority of these studies were conducted in the era before
non-vitamin K dependent anticoagulants (NOAC) replaced vitamin K
antagonists (VKA). NOAC are safer compared to VKA with regard to major
hemorrhagic complications.15,16
However, the pivotal trials leading to the approval of NOAC in patients
with AF excluded patients with AIS occurring 7–14 days before
initiation of treatment.17–20
Importantly, real-world data on the application of NOAC in the first
week after AIS or TIA are scarce. We hypothesized that the hazards for
major hemorrhages, most importantly ICH, may also be substantially lower
in patients in whom NOAC are initiated early after AIS or TIA compared
to patients who receive VKA.
Aims
The
Prospective Record of the Use of Dabigatran in Patients with Acute
Stroke or TIA (PRODAST; ClinicalTrials.gov Identifier: NCT02507856)
study was initiated to provide real-world evidence on this issue. The
main objective of PRODAST was the comparison of the 3-month rates of
major hemorrhagic events between an early (⩽ 7 days) or late
(> 7 days) initiation of dabigatran in comparison to treatment with
VKA started at any time, in patients with AF and a recent AIS or TIA
(⩽ 7 days). In addition to this primary objective, we investigated
additional endpoints, such as ischemic stroke, TIA, systemic embolism,
myocardial infarction, and HT, as well as the survival status depending
on treatment. We aimed to provide real-world evidence on the early
treatment with anticoagulants in this vulnerable phase of AIS and TIA.
Methods
Study design
Methods and the study design have been published in detail.21
PRODAST is a multi-center prospective, observational,
non-interventional post-authorization safety study (PASS), which
recruited patients with AF who experienced a recent (⩽ 7 days) AIS or
TIA with AF at 86 German stroke units between July 2015 and November
2020. Inclusion criteria were age ⩾ 18 years at enrollment, written
informed consent (IC), AIS or TIA within 7 days before enrollment and a
diagnosis of non-valvular AF. Exclusion criteria included the presence
of mechanical heart valves or valve disease that was expected to require
valve replacement intervention (surgical or non-surgical) during the
next 3 months. Patients who were participating in any RCT of an
experimental drug or device, women of childbearing age without
anamnestic exclusion of pregnancy, or who were not using an effective
contraception, as well as nursing mothers, were also excluded. All
therapeutic procedures were at the discretion of the treating
physicians. Documentation of effective anticoagulation was also the
responsibility of the respective study centers. For all patients,
detailed demographic and clinical data were collected during their
hospital stay, as previously described in detail.21
All patients except those discharged with an NOAC other than dabigatran
underwent a standardized follow-up after 3 months as well as an
assessment of vital status after one year, according to the scope of the
PASS design. For the analysis of the primary study objective, all
patients who were treated with dabigatran or VKA were considered and
outcomes of patients on NOAC other than dabigatran, that is, factor Xa
inhibitors, will be reported elsewhere.
Outcomes
The
primary endpoint was defined as major bleeding event within 3 months
following the index event. Major bleeding events were defined as any of
the following: a fatal bleeding; intracranial, intraocular, intraspinal,
retroperitoneal, intraarticular or intramuscular bleeding causing a
compartment syndrome; or clinically overt bleeding associated with
either a decrease in hemoglobin concentration of > 2 g/dL, indication
for transfusion of two or more units of whole blood or packed cells, or
indication for surgical intervention. Secondary endpoints were
recurrent strokes, recurrent ischemic strokes, TIA, systemic/pulmonary
embolism, myocardial infarction, death, and the composite endpoint,
which consisted of stroke, systemic embolism, life-threatening bleeding
and death. Endpoints occurring during hospitalization were assessed by
the respective study sites. Following central and on-site data
verification, unclear outcome events were confirmed by an independent
clinical adjudication committee, taking into account all available
information. In addition, in unclear cases, medical records were
retrieved from the general practitioner.
Ethical approval
All
patients or their legal representatives provided written IC. In the
case that IC could not be obtained in a timely manner due to the
patient’s condition, the appropriate investigator was allowed to decide
on study inclusion, whereupon the IC process was rescheduled as soon as
possible. Ethical approval was provided by the institutional review
board of the University of Duisburg-Essen (No. 15-6202-BO). All
procedures were conducted in accordance with the national law, the 1964
Declaration of Helsinki and its later amendments, and the
recommendations of the guidelines on Good Clinical Practice and Good
Epidemiological Practice.
Statistical analysis
Two
types of analyses were performed: First, we analyzed the
initiation-time-specific effects of dabigatran therapy in comparison to
VKA treatment. For this, a distinction was made between dabigatran
treatment initiated early, that is, ⩽ 7 days, and late, that
is, > 7 days, and exposure was statistically considered as persistent
from the first day of dabigatran therapy until the end of the patient’s
follow-up. Prevalent use of dabigatran at the time of the index event
was considered as early dabigatran application. Second, we performed an
analysis directly comparing events under actual (current) treatment with
dabigatran with VKA independent of the initiation time. Each patient’s
observed time under the respective treatment regimen was considered
starting at the index event, from the day of treatment initiation, until
the occurrence of the endpoint event, censoring due to treatment
change, an alternative severe event (i.e. any endpoint, except TIA), or
end of follow-up. Hazard ratios (HR) were estimated using crude and
adjusted Cox-proportional hazards regression analyses. Crude models were
adjusted for age, study site (as random effect), and time-varying
antithrombotic medication in the categories NOAC, VKA, antiplatelets,
and non-oral antithrombotic medication. Adjusted models included
additional risk factors to correct for confounding or treatment by
indication bias based on directed acyclic graphs (DAGs) as described
previously21 (see online Supplemental Figure 1 and adjustment matrix Supplemental Table 1).
To account for the varying duration of the effect of antithrombotic
drugs beyond intake, the respective end of therapy was postponed by a
lag time, as previously described21 (see online Supplemental Table 2).
All analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
Results
Patients’ characteristics
We
recruited 10,039 patients in the PRODAST study. A total of 3,312
patients were treated with dabigatran or VKA and were thus eligible for
the analysis of the primary study objective. Analyses regarding
administration of other anticoagulants will be published separately.
Overall, 459 patient-years of dabigatran users and 337 patient-years of
VKA users were analyzed. Demographical and clinical characteristics of
the study population are shown in Table 1.
Patients with late initiation of dabigatran more frequently underwent
mechanical thrombectomy or thrombolysis, or had early HT shown by
initial cranial imaging. Infarct volumes and the National Institutes of
Health Stroke Scale (NIHSS) scores were higher in patients who received
dabigatran late (median NIHSS score: 5) as compared to patients who
received dabigatran early or VKA (median NIHSS score: 2 and 2,
respectively). These observations are suggestive of confounding by
indication. Supplemental Table 3 provides an overview on the actual treatment times of different anticoagulants according to the patient groups.
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