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A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers.

ABSTRACT: AIM: Recently, a polymorphism in the NOS1AP gene (rs10494366), a regulator of neuronal nitric oxide synthase (nNOS), was associated with QTc prolongation. Both nNOS and calcium channel blockers (CCBs) regulate intracellular calcium levels and have an important role in cardiovascular homeostasis. The aim was to investigate whether this polymorphism is associated with cardiovascular mortality in users of CCBs. METHODS: The data from the Rotterdam study, a population-based closed cohort study of Caucasian individuals of > or =55 years of age, were used. We identified 1113 participants in the Rotterdam Study who were prescribed CCBs for the first time between 1991 and 2005. All-cause and cardiovascular mortality was assessed in participants who were prescribed CCBs with different NOS1AP rs10494366 genotypes using Cox proportional hazard models. RESULTS: In participants starting on dihydropyridine CCBs (amlodipine, nifedipine and others) all-cause mortality (n = 79) risks were higher in participants with the TG [hazard ratio (HR) 2.57, 95% confidence interval (CI) 1.24, 5.34] or the GG genotype (HR 3.18, 95% CI 1.18, 8.58) than in participants with the referent TT genotype. Cardiovascular mortality (n = 54) risks were 3.51 (95% CI 1.41, 8.78) for the TG genotype and 6.00 (95% CI 1.80, 20.0) for the GG genotype. No differences in all-cause mortality or cardiovascular mortality were seen in participants starting with the nondihydropyridine CCBs verapamil or diltiazem. CONCLUSION: The minor G allele of rs10494366 in the NOS1AP gene is associated with increased all-cause and cardiovascular mortality in Caucasian users of dihydropyridine CCBs. The mechanism underlying the observed association is unknown.

SUBMITTER: Becker ML

PROVIDER: S-EPMC2668085 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers.

Becker Matthijs L ML Visser Loes E LE Newton-Cheh Christopher C Hofman Albert A Uitterlinden André G AG Witteman Jacqueline C M JC Stricker Bruno H Ch BH

British journal of clinical pharmacology 20081117 1

<h4>Aim</h4>Recently, a polymorphism in the NOS1AP gene (rs10494366), a regulator of neuronal nitric oxide synthase (nNOS), was associated with QTc prolongation. Both nNOS and calcium channel blockers (CCBs) regulate intracellular calcium levels and have an important role in cardiovascular homeostasis. The aim was to investigate whether this polymorphism is associated with cardiovascular mortality in users of CCBs.<h4>Methods</h4>The data from the Rotterdam study, a population-based closed cohor ...[more]

PMID: 19076153

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Project description:ImportanceCalcium channel blockers (CCBs) are commonly prescribed agents for hypertension that can cause peripheral edema. A prescribing cascade occurs when the edema is misinterpreted as a new medical condition and a diuretic is subsequently prescribed to treat the edema. The extent to which this prescribing cascade occurs at a population level is not well understood.ObjectiveTo measure the association between being newly dispensed a CCB and subsequent dispensing of a loop diuretic in older adults with hypertension.Design, setting, and participantsA population-based cohort study was performed using linked health administrative databases of community-dwelling adults 66 years or older with hypertension and new prescription drug claims from September 30, 2011, to September 30, 2016, in Ontario, Canada. The dates of analysis were September 1, 2018, to May 30, 2019.ExposuresIndividuals who were newly dispensed a CCB were compared with the following 2 groups: (1) individuals who were newly dispensed an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and (2) individuals who were newly dispensed an unrelated medication.Main outcomes and measuresHazard ratios (HRs) with 95% CIs were estimated for individuals who were dispensed a loop diuretic within 90 days of follow-up using Cox proportional hazards regression models.ResultsThe cohort included 41 086 older adults (≥66 years) with hypertension who were newly dispensed a CCB, 66 494 individuals who were newly dispensed another antihypertensive medication, and 231 439 individuals who were newly dispensed an unrelated medication. At index (ie, the dispensing date), the mean (SD) age was 74.5 (6.9) years, and 191 685 (56.5%) were women. Individuals who were newly dispensed a CCB had a higher cumulative incidence at 90 days of being dispensed a loop diuretic than individuals in both control groups (1.4% vs 0.7% and 0.5%, P < .001). After adjustment, individuals who were newly dispensed a CCB had increased relative rates of being dispensed a loop diuretic compared with individuals who were newly dispensed an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (HR, 1.68; 95% CI, 1.38-2.05 in the first 30 days after index [days 1-30]; 2.26; 95% CI, 1.76-2.92 in the subsequent 30 days [days 31-60]; and 2.40; 95% CI, 1.84-3.13 in the third month of follow-up [days 61-90]) and individuals who were newly dispensed unrelated medications (HR, 2.51; 95% CI, 2.13-2.96 for 1-30 days after index; 2.99; 95% CI, 2.43-3.69 for 31-60 days after index; and 3.89; 95% CI, 3.11-4.87 for 61-90 days after index). This association persisted, although slightly attenuated, from 90 days to up to 1 year of follow-up and when restricted to a subgroup of individuals who were newly dispensed amlodipine.Conclusions and relevanceMany older adults with hypertension who are newly dispensed a CCB subsequently receive a loop diuretic. Given how widely CCBs are prescribed, interventions are needed to raise clinicians' awareness of this common prescribing cascade to reduce the prescribing of potentially unnecessary medications that may cause harm.

Project description:Although both angiotensin receptor blockers (ARBs) and dihydropyridine calcium channel blockers (CCBs) are all suitable for the initiation of antihypertensive treatment, studies investigating efficacy and safety between ARBs and CCBs are limited, and there is no previous study comparing their clinical outcomes during long-term follow-up periods in real world setting. We compared cardiovascular (CV) events between ARBs and CCBs in 464,948 hypertensive adults using the Korean National Health Insurance Service database during a 3-year follow-up. The patients with hypertension without heart failure, ischemic heart disease, cerebrovascular disease, or peripheral artery disease were enrolled. The CV events between only single prescription of CCBs and ARBs were finally compared. The primary endpoint for this study was the first occurrence of a major adverse CV events, defined as the composite of all-cause death, cardiac death, nonfatal myocardial infarction, or nonfatal stroke. ARB was significantly more administered in male and patients with higher income, diabetes mellitus, chronic kidney diseases, and higher Charlson comorbidity index. The primary endpoints occurred in 10,526 patients (5.2%) in the ARB group and in 19,363 patients (7.3%) in the CCB group (p < 0.001) during a 3-year follow-up (HR 0.96, 95% CI 0.93-0.98). All the components of CV events including all-cause death, cardiac death, nonfatal myocardial infarction, and nonfatal stroke occurred more frequently in the CCB group. With multivariable models adjusting age, sex, income, diabetes, chronic kidney disease, and Charlson comorbidity index, the primary endpoints less frequently developed in the ARB group than in the CCB group (HR 0.957, 95% CI 0.933-0.983, p < 0.001). After the propensity-score matching, baseline characteristics were similar and still showed significantly better primary endpoints in ARB group than CCB group (5.3% vs. 5.8%, p < 0.001). In this nationwide population-based simple hypertension study, administration of ARBs showed superior protection against CV events than CCBs during a 3-year follow-up. Our results suggest that ARBs could be preferred over CCBs as the initial choice of antihypertensive treatment regardless of age in real-world practice.

Dataset Information

A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers.

Publications

A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers.

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