Cardiovascular protection with antihypertensive drugs in dialysis patients: systematic review and meta-analysis

Abstract

Epidemiological studies demonstrate that a lower blood pressure and decline in blood pressure over months or years are associated with higher mortality in dialysis patients. In contrast, randomized, controlled trials lack power to establish benefits of antihypertensive therapy. Patients on long-term dialysis participating in randomized, controlled trials and receiving antihypertensive drug therapy were the subject of this meta-analysis. Outcomes assessed were the hazard ratio of cardiovascular events and all-cause mortality in treated group compared with controls. Among 1202 patients who we identified in 5 studies, the overall benefit of antihypertensive therapy compared with the control or placebo group had a combined hazard ratio for cardiovascular events of 0.69 (95% CI: 0.56 to 0.84) using a fixed-effects model and 0.62 (95% CI: 0.45 to 0.86) using a random-effects model. In a sensitivity analysis, we found that the hypertensive group had a pooled hazard ratio of 0.49 (95% CI: 0.35 to 0.67), but when normotensives were included in the trial, lesser cardiovascular protection was seen (pooled hazard ratio of 0.86 [95% CI: 0.67 to 1.12]). Test for heterogeneity between hypertensive and "normotensive-included" groups was significant (P<0.006). Similar results were seen for risk ratio for death and cardiovascular events. There was evidence of publication bias based on Egger's test and funnel plot. Randomized trials suggested a benefit of antihypertensive therapy among hemodialysis patients. Adequately powered randomized trials are required to confirm these observations, especially among those with hypertension.

Figures

Figure 1

Inclusion and exclusion diagram for articles finally selected for meta-analysis

Figure 2

Forest plot shows the hazard ratios of antihypertensive therapy on cardiovascular events. When studies were divided based on inclusion of normotensive subjects, it was found that those studies that included normotensive subjects did not consistently demonstrate cardiovascular protection, whereas those which included only hypertensive subjects provided significant protection. The test for interaction based on the grouping variable of presence or absence of normotension was significant (p=0.004). There was still significant heterogeneity between studies in hypertensive hemodialysis patients only. This may be due to study design. For example Takahashi et al studied primary prevention, whereas Suzuki and Tepel did not exclude patients with prior cardiovascular events.

Figure 3

Forest plot shows the risk ratios of antihypertensive therapy on cardiovascular events. When studies were divided based on inclusion of normotensive subjects, it was found that those studies that included normotensive subjects did not consistently demonstrate cardiovascular protection, whereas those which included only hypertensive subjects provided significant protection. The test for interaction based on the grouping variable of presence or absence of normotension was significant (p=0.037). The heterogeneity between studies that included normotensive subjects may be due to study designs: Cice et al study was conducted in hemodialysis patients with dilated cardiomyopathy whereas Zannad et al study was conducted in hemodialysis patients with left ventricular hypertrophy and excluded patients with symptomatic heart failure.

Figure 4

Forest plot shows the risk ratios of antihypertensive therapy on all-cause mortality. The test for interaction based on the grouping variable of presence or absence of normotension was not significant (p>0.2). Risk ratio for all-cause mortality was moderately heterogeneous but showed protection with antihypertensive therapy with the fixed effects model only.

Figure 5

Funnel plot with pseudo 95% confidence intervals. Studies with low precision and high hazard ratios may have not have been published. The Egger's test showed evidence of publication bias.