Impact of preadmission treatment with calcium channel blockers or beta blockers on short-term mortality after stroke: a nationwide cohort study

We conducted this nationwide population-based cohort study in Denmark. During the study period (1 July 2004 to 31 December 2012), the total underlying population at risk was 6,379,918 inhabitants. The study period commenced 6 months after establishment of the Danish National Database of Reimbursed Prescriptions (DNDRP) on 1 January 2004, to ensure availability of at least 6 months of preadmission prescription history for all participants [13]. The Danish National Health Service provides universal tax-supported health care, guaranteeing unfettered access to general practitioners and hospitals and partial reimbursement for prescribed medications, including CCBs and BBs [13]. We linked medical registries using the unique central personal registry number assigned to every Danish citizen at birth and to residents upon immigration [14].

In Denmark, care for patients with stroke and other medical emergencies is provided by public hospitals [15]. We used the Danish National Registry of Patients (DNRP), covering all Danish hospitals [16], to identify all patients with a first-time inpatient hospitalization for stroke during the study period. Because more than two-thirds of all unspecified strokes (International Classification of Diseases (ICD-10) code: I64) are known to be ischemic strokes (ICD-10 code: I63) [17], we classified unspecified strokes (32% of all stroke diagnoses [12]) as ischemic strokes. The DNRP contains data on admission and discharge dates and discharge diagnoses from all non-psychiatric hospitals since 1977 and on emergency room and outpatient clinic visits since 1995 [16]. Each hospital discharge is assigned one primary diagnosis and up to 19 secondary diagnoses classified according to the International Classification of Diseases, 8th revision (ICD-8) until the end of 1993 and 10th revision (ICD-10) thereafter [16]. We identified patients using both primary and secondary diagnoses for ischemic stroke, ICH, and SAH.

We used the DNDRP to identify all prescriptions redeemed for CCBs and BBs by study participants [13]. Pharmacies in Denmark are equipped with electronic accounting systems, primarily used to secure reimbursement from the National Health Service. For each redeemed prescription, the patient’s central personal registry number, the amount and type of drug prescribed according to the Anatomical Therapeutic Chemical (ATC) classification system, and the date the drug was dispensed are transferred electronically from the pharmacies to the DNDRP [13].

We defined current users as patients whose last prescription redemption for CCBs or BBs was <90 days before hospital admission for stroke. We chose an exposure window of 90 days to identify most current users, as prescriptions of CCBs/BBs are seldom provided for more than 90 days at a time in Denmark. As the drugs’ effects and potential side effects may be less pronounced in long-term users [18], this could lead to underestimation of the association with mortality [18]. Consequently, current users were further categorized into new users, who redeemed their first-ever CCB or BB prescription within 90 days before their admission date, and long-term users, who redeemed their first-ever prescription more than 90 days before their admission date. We defined former users as patients whose last prescription redemption was between 90 and 180 days before admission, and non-users as patients with no prescription redemption within 180 days before admission.

We used the Danish Civil Registration System (CRS) to obtain information on all-cause mortality [14]. The CRS has recorded all changes in vital status and migration for the entire Danish population since 1968, with daily electronic updates [14].

The complete inpatient and outpatient medical history available in the DNRP [16] provided information on known prognostic factors (myocardial infarction, atrial fibrillation or flutter, intermittent arterial claudication, diabetes, and dementia) [19] and other potential confounders (Table 1).

To increase the sensitivity of diagnoses of diabetes, COPD, and alcoholism-related diseases, we searched the DNDRP for any previous prescriptions for anti-diabetic medications, respiratory medications, and alcohol deterrents. Relevant ICD and ATC codes are provided in Additional file 1: Table S1.

We obtained information from the DNDRP on concurrent use (last prescription redemption within 90 days before admission) of other drugs that may potentially affect stroke prognosis [13]. Relevant ATC codes are provided in Additional file 1: Table S1.

We characterized the stroke cohort according to sex, age group (<60, 60–69, 70–79, ≥80 years), individual comorbidities, and comedication use. We followed all patients from hospital admission date until death, emigration, or 30 days of follow up, whichever came first.

We used a Cox proportional-hazards regression analysis to compute the hazard ratio as a measure of the mortality rate ratio (MRR) within 30 days of hospital admission for current, new, long-term, and former use compared with non-use. The analysis was adjusted for sex, age groups, and the individual comorbidities and comedications listed in Table 1. The proportional hazard assumption was assessed using log–log plots and found valid. We repeated the analysis stratifying by sex, age group, and presence/absence of myocardial infarction, congestive heart failure, atrial fibrillation or flutter, angina pectoris, hypertension, diabetes, and chronic kidney disease.

We performed four sensitivity analyses. First, to increase the positive predictive value (PPV) of the stroke diagnosis, we restricted the analyses to patients who had a computed tomography (CT) or magnetic resonance imaging (MRI) scan registered in the DNRP during the stroke admission. Second, to examine the sensitivity of the estimates to differences in exposure definitions, we repeated the analysis substituting 60-day and 30-day exposure windows for the 90-day exposure window. Third, to reduce the potential for confounding by indication for CCB and BB use, we directly compared current users with former users. Fourth, we repeated the analysis separating ischemic stroke into “unspecified stroke” and “specified ischemic stroke”. Analyses were performed using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). The study was approved by the Danish Data Protection Agency (record number 2011-41-5755). As this study did not involve contact with patients or any intervention, it was not required to obtain permission from the Danish Scientific Ethical Committee or to obtain patient consents.