Abstract

Background
Calcium channel blockers (CCBs) are used for the treatment of cardiovascular disease (CVD), including angina pectoris, and hypertension; however, the effect on survival remains uncertain. CCBs impair fibrinolysis and have been linked to elevated plasma homocysteine (Hcy), a CVD risk marker.

Objective
We explored the association between CCB use and mortality in a large prospective cohort of patients with suspected stable angina pectoris (SAP), and potential effect modifications by Hcy-lowering B-vitamin treatment (folic acid, B12, and/or B6) as 61.8% of the patients participated in a randomized placebo-controlled B-vitamin intervention trial.

Methods
Patient baseline continuous characteristics according to CCB treatment were tested by linear regression. Hazard ratios (HRs) for mortality associated with CCB treatment, also according to B-vitamin intervention, were examined using Cox regression analysis. The multivariable model included CVD risk factors, medical histories, and the use of CVD medications.

Results
A total of 3991 patients (71.5 % men) were included, of whom 907 were prescribed CCBs at discharge. During 10.3 years of median follow-up, 20.6% died and 8.9% from cardiovascular- and 11.7% from non-cardiovascular causes. Patients treated with CCBs had higher plasma Hcy, fibrinogen levels, and erythrocyte sedimentation rate (all P<0.001). Furthermore, CCB use was positively associated with mortality, also after multivariable adjustments (HRs [95% CIs]: 1.34 [1.15,1.57], 1.35 [1.08,1.70], and 1.33 [1.09,1.64] for total, CVD, and non-CVD death, respectively). Numerically stronger associations were observed among patients not treated with B-vitamins (HR [95% CI]: 1.54 [1.25, 1.88], 1.69 [1.25, 2.30], and 1.41 [1.06, 1.86] for total, CVD deaths, and non-CVD deaths, respectively), whereas no association was seen in patients treated with B-vitamins (HR [95% CI]: 1.15 [0.91, 1.46], 1.09 [0.76, 1.57], and 1.20 [0.88, 1.65]).

Conclusions
In patients with suspected SAP, CCB treatment was associated with increased mortality risk primarily among patients not treated with B-vitamins.

Introduction

Calcium channel blockers (CCBs) are widely used in patients with stable angina pectoris (SAP) for symptom relief or blood pressure control [1]. However, there is conflicting evidence that CCBs improve prognosis in the former condition or other clinical manifestations of coronary artery disease (CAD). Notably, while most studies showed no clinical benefit on survival [[2], [3], [4]], some have linked CCB treatment to higher mortality risk [[5], [6], [7]].

The B-vitamins folic acid, vitamin B12, and B6 are water-soluble nutrients essential for diverse physiological processes, including homocysteine (Hcy) metabolism [8,9]. A deficiency of these vitamins may lead to elevated circulating total Hcy (tHcy) concentrations [8], which is a risk factor for atherothrombosis [8,9]. Moreover, treatment with these vitamins is reported to have anti-inflammatory [10,11] and anti-coagulant effects [12,13], and vitamin B6 may inhibit sympathetic tone [14]. However, randomized clinical trials (RCTs) failed to reduce cardiovascular disease (CVD) risk with Hcy-lowering B-vitamins [15,16], although treatment effects may have been heterogeneous according to certain subgroup phenotypes. Notably, CCB treatment has been associated with increased systemic Hcy concentrations [[17], [18]]. Moreover, CCBs promote proinflammatory responses [19,20], decrease fibrinolytic function [21,22], and increase sympathetic activation [23], thus potentially increasing CVD risk.

Conclusions

Among patients with suspected SAP, the use of CCBs was associated with increased long-term risk of all-cause, cardiovascular, and noncardiovascular mortality. However, these associations were attenuated in patients receiving B-vitamin treatment, which may explain some of the heterogenic results in prior observational studies.