Calcium channel blockers, survival and ischaemic stroke in patients with dementia: a Swedish registry study

Abstract

Background: The effect of calcium channel blockers (CCB) on mortality and ischaemic stroke risk in dementia patients is understudied.

Objectives: To calculate the risk of death and ischaemic stroke in dementia patients treated with CCBs, considering individual agents and dose response.

Methods: Longitudinal cohort study with 18 906 hypertensive dementia patients from the Swedish Dementia Registry (SveDem), 2008-2014. Other Swedish national registries contributed information on comorbidities, dispensed medication and outcomes. Individual CCB agents and cumulative defined daily doses (cDDD) were considered.

Results: In patients with hypertension and dementia, nifedipine was associated with increased mortality risk (aHR 1.32; CI 1.01-1.73; P < 0.05) compared to non-CCB users. Patients diagnosed with Alzheimer's dementia (AD) or dementia with Lewy bodies/Parkinson's disease dementia (DLB-PDD) taking amlodipine had lower mortality risk (aHR, 0.89; CI, 0.80-0.98; P < 0.05 and aHR 0.58; CI, 0.38-0.86; P < 0.01, respectively), than those taking other CCBs. Amlodipine was associated with lower stroke risk in patients with Alzheimer's dementia compared to other CCBs (aHR 0.63; CI, 0.44-0.89; P < 0.05). Sensitivity analyses with propensity score-matched cohorts repeated the results for nifedipine (aHR 1.35; 95% CI, 1.02-1.78; P < 0.05) and amlodipine in AD (aHR, 0.87; CI, 0.78-0.97; P < 0.05) and DLB-PDD (aHR, 0.56, 95%CI, 0.37-0.85; P < 0.05).

Conclusion: Amlodipine was associated with reduced mortality risk in dementia patients diagnosed with AD and DLB-PDD. AD patients using amlodipine had a lower risk of ischaemic stroke compared to other CCB users.

Keywords: alzheimer’s disease; antihypertensive drugs; calcium; dementia; mortality; stroke.

Fig. 1

Patient selection. SveDem, Swedish Dementia Registry; n, number of patients; MMSE, Mini‐Mental State Examination; baseline, date at the time of dementia diagnosis; CCBs, Calcium Channel Blockers; AD, Alzheimer’s disease; VaD, Vascular dementia; DLB‐PDD, Dementia with Lewy Bodies‐Parkinson’s disease dementia; FTD, Frontotemporal dementia.

Fig. 2

Association between CCB use and (a) all‐cause mortality and (b) ischaemic stroke risk in dementia patients, adjusted for propensity score of CCB treatment. CCBs, Calcium Channel Blockers; DHPs, dihydropyridines; baseline, date at the time of dementia diagnosis. Propensity score (PS) included age, sex, dementia type, Mini‐mental state examination score (MMSE) at baseline, comorbidities (hypertension with organ damage, diabetes, arrhythmia, atrial fibrillation, heart failure [congestive heart failure, left ventricular heart failure and heart failure unspecified], renal disease, alcohol‐related diseases, angina pectoris, previous myocardial infarction (MI), previous cerebral stroke – only used in survival analysis), medication (β‐blockers, angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor (ARB) blockers, other antihypertensives), statins, diuretics, antithrombotics, acetylsalicylic acid, nonsteroidal anti‐inflammatory drugs (NSAIDs)). Multiple different interactions between the above factors were also included. For the analysis of ischaemic stroke, we performed Fine–Gray models taking death due to stroke causes as a competing event.¹ Reference: 1. Austin PC, Fine JP, Practical recommendations for reporting Fine–Gray model analyses for competing risk data. Stat Med. 2017 Nov 30;36(27):4391‐4400.

Fig. 3

Amlodipine dose‐dependent hazard for death and ischaemic stroke calculated using Cox hazard regression models in AD patients for (a) mortality, (b) ischaemic stroke, and (c) histogram representing proportion of patients prescribed each cumulative defined daily dose. Hazard ratios (HR) and 95% confidence intervals (CI) for death and ischaemic stroke associated with cumulative defined daily dose (cDDD) of amlodipine. The defined daily dose (DDD) of a medication is defined by the World Health Organization and is the assumed average maintenance dose per day for a drug used for its main indication in adults. In the case of amlodipine, 1 DDD corresponds to 5mg per day. A patient taking 5mg per day of amlodipine during 1 year would have a cDDD of 365, and 1095 cDDD if this same dose was continued for 3 years. Vertical dotted lines mark the equivalent DDD resulting from 5mg of amlodipine during 3 years and from 10mg amlodipine during 3 years. Model adjusted for propensity score. The risk associated to amlodipine was modelled using linear splines with knots at fixed values of cDDD distribution (550, 1095, 1645, 2190). Estimates were adjusted for propensity score and Mini‐Mental State Examination measurements at baseline. cDDD = 0 was used as reference. (a) All‐cause mortality, (b) ischaemic stroke, (c) distribution of patients taking each cDDD during 3 years. A dose effect is evident at increasing cDDD of amlodipine up to the equivalent of 1DDD per day during 3 years. At higher doses, the effect is lost, possibly due to reduced sample size as is evident in the histogram (c).