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Cerebrovascular disease
Research paper
Preadmission use of ACE inhibitors or angiotensin receptor blockers and short-term mortality after stroke
  1. J Sundbøll1,2,
  2. M Schmidt1,2,
  3. E Horváth-Puhó1,
  4. CF Christiansen1,
  5. L Pedersen1,
  6. HE Bøtker2,
  7. HT Sørensen1
  1. 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark
  2. 2Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark
  1. Correspondence to Dr Jens Sundbøll, Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, Aarhus N DK-8200, Denmark; jens.sundboll{at}dce.au.dk

Abstract

Background and aim The prognostic impact of ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) on stroke mortality remains unclear. We aimed to examine whether prestroke use of ACE-Is or ARBs was associated with improved short-term mortality following ischaemic stroke, intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH).

Methods We conducted a nationwide population-based cohort study using medical registries in Denmark. We identified all first-time stroke patients during 2004–2012 and their comorbidities. We defined ACE-I/ARB use as current use (last prescription redemption <90 days before admission for stroke), former use and non-use. Current use was further classified as new or long-term use. We used Cox regression modelling to compute 30-day mortality rate ratios (MRRs) with 95% CIs, controlling for potential confounders.

Results We identified 100 043 patients with a first-time stroke. Of these, 83 736 patients had ischaemic stroke, 11 779 had ICH, and 4528 had SAH. For ischaemic stroke, the adjusted 30-day MRR was reduced in current users compared with non-users (0.85, 95% CI 0.81 to 0.89). There was no reduction in the adjusted 30-day MRR for ICH (0.95, 95% CI 0.87 to 1.03) or SAH (1.01, 95% CI 0.84 to 1.21), comparing current users with non-users. No association with mortality was found among former users compared with non-users. No notable modification of the association was observed within sex or age strata.

Conclusions Current use of ACE-Is/ARBs was associated with reduced 30-day mortality among patients with ischaemic stroke. We found no association among patients with ICH or SAH.

  • STROKE
  • CEREBROVASCULAR DISEASE
  • SUBARACHNOID HAEMORRHAGE

https://doi.org/10.1136/jnnp-2014-308948

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    Introduction

    Stroke is a major cause of disability and in coming decades is anticipated to remain a leading cause of death worldwide, exceeded only by myocardial infarction.1 ,2 First-time stroke occurs in approximately 600 000 Americans each year.3 It is associated with a 30-day mortality of approximately 11% for ischaemic stroke,4 34% for intracerebral haemorrhage (ICH)4 and 29% for subarachnoid haemorrhage (SAH).5 ACE inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are antihypertensive drugs that inhibit the renin-angiotensin-aldosterone system. The major indications for prescribing these widely used drugs are diabetes with microalbuminuria, hypertension and congestive heart failure.6

    Elevated preadmission blood pressure is associated with markedly increased mortality after stroke.7 While several large randomised controlled trials of ACE-Is8 and ARBs9 have demonstrated that these agents reduce the risk of stroke, their impact on stroke mortality remains poorly described. Prestroke inhibition of the renin-angiotensin-aldosterone system has a beneficial effect on clinical severity and degree of disability (functional outcome) after ischaemic stroke,10–12 but few and only smaller studies (<1100 patients) have examined the effect of ACE-Is/ARBs on short-term mortality following ischaemic stroke.13–16

    Considering the high prevalence of ACE-I/ARB use and high incidence and mortality from stroke, an association between ACE-I/ARB use and reduced stroke mortality would have an important public health impact and would motivate future studies on treatment strategies for patients at high risk of stroke. We therefore examined whether use of ACE-Is/ARBs at the time of stroke was associated with reduced 30-day mortality in a large, population-based setting.

    Methods

    Setting

    We conducted this nationwide population-based cohort study in Denmark. During the study period (1 July 2004–31 December 2012), the total underlying population at risk was 6 379 918 inhabitants. The study period started 6 months after the initiation of The Danish National Database of Reimbursed Prescriptions (DNDRP) on 1 January 2004, to ensure that all participants had at least 6 months of preadmission prescription history.17 The Danish National Health Service provides free universal tax-supported healthcare, guaranteeing unfettered access to general practitioners and hospitals and partial reimbursement of prescribed medications, including ACE-Is/ARBs.17 We linked medical registries using the unique central personal registry number assigned to each Danish citizen at birth and to residents on immigration.18

    Patients with stroke

    In Denmark, care for patients with stroke and other medical emergencies is provided by public hospitals.19 We used the Danish National Registry of Patients (DNRP), covering all Danish hospitals,20 to identify all persons in the total Danish population with a first-time inpatient hospitalisation for stroke in the study period. As approximately two-thirds of all unspecified strokes (International Classification of Diseases (ICD-10) code: I64) are known to be ischaemic strokes (ICD-10 code: I63), we classified unspecified strokes as ischaemic strokes.21 Follow-up was virtually complete except for one patient, who emigrated within 30 days of follow-up. The DNRP contains data on admission and discharge dates and discharge diagnoses from all Danish non-psychiatric hospitals since 1977 and on emergency room and outpatient clinic visits since 1995.20 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.20 We identified patients using primary and secondary diagnoses for ischaemic stroke, ICH and SAH.

    ACE-I/ARB use

    We used the DNDRP to identify all prescriptions redeemed for ACE-Is and ARBs by study participants.17 Pharmacies in Denmark are equipped with electronic accounting systems, primarily used to secure reimbursement from the National Health Service.17 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.17

    We defined current users as patients whose last prescription redemption for ACE-Is or ARBs was within 90 days before hospital admission for stroke. We chose an exposure window of 90 days to identify most current users, as prescriptions of ACE-Is/ARBs are seldom provided for more than 90 days at a time in Denmark. As the drugs’ effects and possible side effects may be less pronounced in long-term current users, this could lead to underestimation of the association with mortality.22 Current users were therefore further categorised into new users, who redeemed their first-ever 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.

    Mortality

    We used the Danish Civil Registration System (CRS) to obtain information on all-cause mortality.18 The CRS has recorded all changes in vital status and migration for the entire Danish population since 1968, with daily electronic updates.18

    Patient characteristics

    We used the complete inpatient and outpatient medical history available in the DNRP20 to ascertain presence of potentially confounding comorbidities. We categorised the severity of comorbidity using the Charlson Comorbidity Index (CCI), a scoring system that has been adapted for use with hospital discharge data.23 ,24 The CCI assigns between one and six points to a range of diseases, depending on the strength of their relation with mortality.23 ,24 We computed the total CCI score for each patient (excluding cerebrovascular disease and hemiplegia from the Index) and defined three categories of comorbidity based on scores of 0 (low), 1–2 (moderate) and ≥3 (high).

    We identified known prognostic factors for stroke, such as myocardial infarction, atrial fibrillation or flutter,25–27 intermittent arterial claudication,28 diabetes25 ,26 ,28 and dementia.27 We also separately identified other potential confounders with a prognostic impact on stroke or an association with ACE-I/ARB use, including congestive heart failure, angina pectoris, heart valve disease, venous thromboembolism, obesity, chronic kidney disease, hypertension, chronic obstructive pulmonary disease (COPD), alcoholism-related diseases and cancer. To increase the sensitivity of diagnoses of diabetes, COPD and alcoholism-related diseases, we searched the DNDRP for any previous prescriptions for diabetic medications, respiratory medications and alcohol deterrents. Relevant ICD and ATC codes are provided in eTable 1.

    Comedication use

    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.17 These drugs included β-blockers, calcium channel blockers, diuretics, nitrates (if two or more prescriptions were registered), statins, aspirin, clopidogrel, anticoagulant drugs, systemic glucocorticoids, non-aspirin non-steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, and bisphosphonates. Relevant ATC codes are provided in eTable 1.

    Statistical analysis

    We characterised the stroke cohorts according to sex, age group (<60, 60–69, 70–79, or ≥80 years), comorbidity level, 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 model to compute the HR 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 model 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, CCI score and presence/absence of the following conditions: myocardial infarction, congestive heart failure, atrial fibrillation or flutter, angina pectoris, hypertension, diabetes and chronic kidney disease.

    View this table:
    Table 1

    Characteristics of patients with stroke,* by preadmission use of ACE inhibitors or angiotensin receptor blockers

    Furthermore, we applied a propensity-score-matched analysis to test the robustness of our results. As previously described,29 we computed the propensity score conditional on the variables included in the Cox model for all patients with stroke and matched each ACE-I/ARB user with the non-user with the closest propensity score.30 From the propensity-score-matched mortality risk estimates we visually illustrated the cumulative mortality functions.

    We also performed several sensitivity analyses. First, to increase the positive predictive value (PPV) of the stroke diagnosis, we restricted the analyses to patients who had a CT or 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 using a 60-day instead of a 90-day exposure window. Third, we repeated the analysis separating ischaemic stroke into ‘unspecified stroke’ and ‘specified ischaemic stroke’. Fourth, we divided the combined ACE-I/ARB-exposure into separate ACI-I and ARB analyses. Fifth, to examine the sensitivity to differing time periods, we divided the study period into intervals of 2004–2008 and 2009–2012. To reduce the potential for confounding by indication for ACE-I/ARB use, we also directly compared current users with former users. Analyses were performed using SAS V.9.2 (SAS Institute Inc., Cary, North Carolina, USA).

    Results

    Patient characteristics

    Patient characteristics are shown in table 1. We identified 100 043 patients with a first-time stroke between 2004 and 2012. Of these, 83 736 (83.7%) had ischaemic stroke (median age: 74 years), 11 779 (11.8%) had ICH (median age: 72 years), and 4528 (4.5%) had SAH (median age: 58 years). One third (32.5%) of all stroke diagnoses were coded as unspecified stroke. A total of 24 882 patients (24.9%) were current users of ACE-Is/ARBs, 4570 (4.6%) were former users, and 70 591 (70.6%) were non-users. All cardiovascular diseases (other than venous thromboembolism), obesity, diabetes, chronic kidney disease, moderate and high levels of comorbidity and use of all cardiovascular drugs were more common among ACE-I/ARB users than among non-users.

    Mortality

    Mortality estimates are provided in table 2. For patients with ischaemic stroke, the adjusted 30-day MRR was 0.85 (95% CI 0.81 to 0.89) for current users and 0.99 (95% CI 0.90 to 1.09) for former users, compared with non-users. A slightly higher reduction in mortality was observed among new users (0.80, 95% CI 0.73 to 0.88) than among long-term users (0.87, 95% CI 0.82 to 0.92). There was no association between current use and haemorrhagic stroke (adjusted MRR was 0.95 (95% CI 0.87 to 1.03) for ICH and 1.01 (95% CI 0.84 to 1.21) for SAH). When current users were compared directly with former users, the adjusted MRRs for ischaemic stroke, ICH and SAH were similar to the MRRs in the primary analysis (eTable 2).

    View this table:
    Table 2

    Preadmission use of ACE inhibitors or angiotensin receptor blockers and 30-day mortality estimates following stroke

    After propensity score matching, the characteristics of ACE-I/ARB users and non-users were equally distributed (data not shown). The propensity-score-matched absolute 30-day mortality risk following ischaemic stroke was 10.7% (95% CI 10.2% to 11.1%) for current users and 13.1% (95% CI 12.7% to 13.6%) for non-users (table 2). The corresponding estimates following ICH was 38.3% (95% CI 36.2% to 40.4%) and 40.2% (95% CI 38.1% to 42.3%) and following SAH 30.0% (95% CI 26.5% to 33.9%) and 32.1% (95% CI 28.5% to 36.1%). The cumulative mortality risk for ischaemic stroke, ICH and SAH is illustrated in figure 1A–C. The propensity-score-matched analysis supported the primary analyses for all stroke subtypes with an even lower MRR following ischaemic stroke for current users (0.80, 95% CI 0.76 to 0.85).

    Figure 1
    Figure 1

    Cumulative mortality risk curves (1 minus the Kaplan-Meier curve) based on propensity-score-matched analysis for (A) ischaemic stroke, (B) ICH (intracerebral haemorrhage), and (C) SAH (subarachnoid haemorrhage). The difference in absolute mortality risk between current and non-users for ischaemic stroke is more pronounced at 30 days and starts to diverge earlier during follow-up than the ICH and SAH curves.

    There was no notable modification of the effect within strata of sex, age, congestive heart failure, hypertension, diabetes, chronic kidney disease or comorbidity level (eTable 3). However, the effect on ischaemic stroke was only present in patients without myocardial infarction, atrial fibrillation or angina pectoris (eTable 3). In search of a possible mechanism behind these findings, we stratified patients with ischaemic stroke by cardiovascular drugs commonly used among patients with myocardial infarction, atrial fibrillation or angina pectoris (eTable 4). Apart from diuretics, use of all cardiovascular drugs reduced the effect of ACE-I/ARB use on ischaemic stroke mortality (eTable 4).

    The results were robust in the analysis restricted to CT-confirmed or MRI-confirmed diagnoses (eTable 5), when using a 60-day exposure window (eTable 6), when analysing ‘unspecified stroke’ and ‘specified ischaemic stroke’ separately (eTable 7), when analysing ACE-Is and ARBs separately (eTable 8), and when dividing the study period into 2004–2008 and 2009–2012 (eTable 9).

    Discussion

    In this large nationwide population-based cohort study with complete follow-up of 100 043 patients hospitalised for a first-time stroke, we found that ACE-I/ARB use at the time of admission was associated with decreased 30-day mortality for patients with ischaemic stroke. We found no beneficial effects for patients with ICH or SAH. The results are likely generalisable to most industrial Western societies where changes in risk factor modification and treatment have followed international recommendations.

    Studies examining the association between ACE-I use and ischaemic stroke prognosis have mostly focused on functional end points such as clinical stroke severity and degree of disability.10–12 ,31 ,32 Only four studies used short-term mortality as primary outcome,13–16 and all were limited by small sample size (<1100 patients). Two of these studies, including 47513 and 71614 patients, found that preadmission use of ACE-Is was associated with reduced risk of short-term mortality in patients with ischaemic stroke (30-day OR 0.47 (95% CI 0.25 to 0.89) and 28-day OR 0.46 (95% CI 0.24 to 0.87), respectively). In our study, we observed a more modest risk reduction among patients with ischaemic stroke, which may in part be explained by statistically more imprecise results in the previous studies as indicated by wider CIs due to smaller sample sizes. The remaining two studies used in-hospital mortality as primary outcome and found that in-hospital survival was positively associated with ACE-I pretreatment (OR 3.42, 95% CI 1.9 to 8.1),16 and that no previous ACE-I use was associated with increased in-hospital mortality (OR 6.2, 95% CI 2.4 to 15.9).15 Despite differences in design, these two studies support our finding of lower mortality in patients with ischaemic stroke pretreated with ACE-Is/ARBs. Only one cohort study of 399 patients has examined ACE-I/ARB use and mortality after ICH, but the results were inconclusive due to limited sample size.33

    No previous studies have examined the effect of preadmission treatment with ACE-Is/ARBs on SAH mortality. While current ACE-I/ARB use was not associated with reduced 30-day mortality following SAH in our study, we cannot exclude a positive effect among new users. However, the statistical precision was too low to draw conclusions on the effect of new use. Among patients with ischaemic stroke, current, but not former, use of ACE-Is/ARBs was associated with a protective effect on mortality, indicating that the results reflect an actual drug effect. In the stratified analyses we found no effect among patients with myocardial infarction, atrial fibrillation or angina pectoris. To unveil a possible interaction between ACE-Is/ARBs and cardiovascular drugs common to these three conditions, we stratified patients with ischaemic stroke by common cardiovascular drugs. In these analyses, virtually every cardiovascular drug partly abolished the effect of ACE-I/ARB use on ischaemic stroke mortality. However, this presumably reflects that these drugs are markers of severe disease giving rise to higher baseline hazards among these patients, that is, the absolute risk was likely higher and use of ACE-Is/ARBs may only cause subtle changes in relative risk. Another explanation is that prescription of more than one medication may decrease adherence. Such misclassification would bias the results towards null among users of cardiovascular drugs.

    The observed reduction in mortality following ischaemic stroke could be mediated via several mechanisms but lowering of blood pressure may be the central player responsible. Thus, it has been shown that over the range of 115/75 to 185/115 mm Hg, each 20-mm Hg elevation in systolic blood pressure roughly doubles the risk of death from stroke.7 However, the effect on mortality could extend beyond blood pressure reduction. Randomised clinical trials have shown that short-term treatment with ACE-Is significantly reduces fibrinogen34 and plasminogen activator inhibitor I levels,35 thus improving fibrinolysis. This could partially explain the noticeable effect of ACE-I/ARB use on short-term mortality in patients with ischaemic stroke and the missing effect in haemorrhagic stroke (ICH and SAH). Also, animal models have demonstrated that ACE-Is increase endothelium-dependent vasodilation36 and attenuate cerebral artery remodelling.37 An alternative interpretation of the effect among patients with ischaemic stroke is that ACE-I/ARB users may be patients on appropriate medication while some non-users may have been prescribed or have indication for the use of ACE-Is/ARBs without filling a prescription.

    Several issues should be considered when interpreting our results. The main strengths of our study are its large size and population-based design within a tax-supported uniformly organised healthcare system with independently and prospectively recorded hospital and prescription history, and with complete follow-up for all patients. This setting reduces the risk of selection biases.38

    One study limitation is use of routine hospital discharge diagnoses, which may contain coding errors. The PPV of acute stroke diagnoses in the DNRP has been examined previously and found to be 97% for ischaemic stroke, 74% for ICH and 67% for SAH.21 Misclassification due to coding errors would most likely be non-differential and thus cannot explain our findings of a beneficial effect in ischaemic stroke but may explain the missing effect in ICH and patients with SAH. Because we classified unspecified strokes as ischaemic strokes, a few ICHs (approximately 6%) were inevitably misclassified as ischaemic strokes.21 However, as we found no association between ACE-I/ARB use and ICH mortality, such misclassification would bias the results for ischaemic stroke towards the null and thus cannot explain our findings.

    Data on reimbursed medications are virtually complete in the DNDRP,17 and neither ACE-Is nor ARBs are sold over-the-counter in Denmark. We therefore identified all patients with redeemed prescriptions for ACE-Is/ARBs. Although use of redeemed prescriptions as a proxy for actual drug use may not always be accurate, we based drug exposure information on actual dispensing at pharmacies rather than just on written prescriptions.17 Any misclassification of drug exposure due to non-adherence would bias the estimate of association towards the null. Mortality data, as recorded in the CRS, are complete.18

    Although we controlled for several potential confounding factors, we cannot exclude unmeasured confounding. Thus, we lacked information on smoking and blood pressure levels. However, we did adjust for hospital diagnosis of COPD and hypertension as proxy measures. Smoking and hypertension may worsen the prognosis after stroke and are likely more prevalent among ACE-I/ARB users than among non-users. However, such confounding would bias our estimates towards increased mortality among ACE-I/ARB users and thus cannot explain our findings.

    In conclusion, we found that use of ACE-Is or ARBs prior to hospital admission for ischaemic stroke was associated with improved short-term mortality, with the strongest association among new users. We found no beneficial effects of these drugs for reducing mortality among patients with ICH or SAH.

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

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    Footnotes

    • Contributors MS and HTS conceived the study idea and designed the study. HTS and LP collected the data. JS, MS and HTS reviewed the literature. MS directed the analyses, which were performed by EH-P. All authors participated in the discussion and interpretation of the results. JS organised the writing and wrote the initial draft. All authors critically revised the manuscript for intellectual content and approved the final version before submission. HTS had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    • Funding The study was supported by the Clinical Epidemiology Research Foundation and the Aarhus University Research Foundation. Neither funding source had a role in design or conduct of the study, in collection, management, analysis and interpretation of the data or in preparation, review, or approval of the manuscript.

    • Competing interests None.

    • Ethics approval The study was approved by the Danish Data Protection Agency (record number 2011-41-5755).

    • Provenance and peer review Not commissioned; externally peer reviewed.