Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis

Abstract

Importance: Sleep apnea (obstructive and central) is associated with adverse cardiovascular risk factors and increased risks of cardiovascular disease. Positive airway pressure (PAP) provides symptomatic relief, whether delivered continuously (CPAP) or as adaptive servo-ventilation (ASV), but the associations with cardiovascular outcomes and death are unclear.

Objective: To assess the association of PAP vs control with cardiovascular events and death in patients with sleep apnea.

Data sources and study selection: MEDLINE, EMBASE, and the Cochrane Library were systematically searched from inception date to March 2017 for randomized clinical trials that included reporting of major adverse cardiovascular events or deaths.

Data extraction and synthesis: Two authors independently extracted data using standardized forms. Summary relative risks (RRs), risk differences (RDs) and 95% CIs were obtained using random-effects meta-analysis.

Main outcomes and measures: The main outcomes were a composite of acute coronary syndrome (ACS) events, stroke, or vascular death (major adverse cardiovascular events); cause-specific vascular events; and death.

Results: The analyses included data from 10 trials (9 CPAP; 1 ASV) of patients with sleep apnea (N = 7266; mean age, 60.9 [range, 51.5 to 71.1] years; 5847 [80.5%] men; mean [SD] body mass index, 30.0 [5.2]. Among 356 major adverse cardiovascular events and 613 deaths recorded, there was no significant association of PAP with major adverse cardiovascular events (RR, 0.77 [95% CI, 0.53 to 1.13]; P = .19 and RD, -0.01 [95% CI, -0.03 to 0.01]; P = .23), cardiovascular death (RR, 1.15 [95% CI, 0.88 to 1.50]; P = .30 and RD -0.00 [95% CI, -0.02 to 0.02]; P = .87), or all-cause death (RR, 1.13 [95% CI, 0.99 to 1.29]; P = .08 and RD, 0.00 [95% CI, -0.01 to 0.01]; P = .51). The same was true for ACS, stroke, and heart failure. There was no evidence of different associations for CPAP vs ASV (all P value homogeneity >.24), and meta-regressions identified no associations of PAP with outcomes for different levels of apnea severity, follow-up duration, or adherence to PAP (all P values > .13).

Conclusions and relevance: The use of PAP, compared with no treatment or sham, was not associated with reduced risks of cardiovascular outcomes or death for patients with sleep apnea. Although there are other benefits of treatment with PAP for sleep apnea, these findings do not support treatment with PAP with a goal of prevention of these outcomes.

Figure 1.. Flow Diagram of Literature Search

Figure 2.. Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Events and Death

Box sizes are proportional to study weight (box center positioned at point estimate of effect). Horizontal lines indicate 95% CIs. The I² value indicates the percentage of variability across the pooled estimates attributable to heterogeneity beyond chance (0%-25%, low likelihood; 26%-75%. moderate likelihood; 76%-100%, high likelihood), and the P value is for a test of heterogeneity across all studies (P value <.05 indicates likely variation across pooled estimates beyond chance). If 0 events were reported for 1 cell in a comparison, a value of 0.5 was added to both cells automatically before calculating the risk ratio (95% CI). Risk ratio data are rounded to 2 decimal places but plotted to exact values. ^aMajor adverse cardiovascular events consist of cardiovascular death, nonfatal acute coronary syndrome, and nonfatal stroke. ^bPlus indicates major adverse cardiovascular events in addition to hospitalization for unstable angina.

Figure 3.. Meta-analysis of the Association of Positive Airway Pressure With Cardiovascular Outcomes

Box sizes are proportional to study weight (box center positioned at point estimate of effect). Horizontal lines indicate 95% CIs. The I² value indicates the percentage of variability across the pooled estimates attributable to heterogeneity beyond chance (0%-25%, low likelihood; 26%-75%. moderate likelihood; 76%-100%, high likelihood), and the P value is for a test of heterogeneity across all studies (P value <.05 indicates likely variation across pooled estimates beyond chance). If 0 events were reported for 1 cell in a comparison, a value of 0.5 was added to both cells automatically before calculating the risk ratio (95% CI). Risk ratio data are rounded to 2 decimal places but plotted to exact values.

Figure 4.. Meta-Regressions of Selected Trial Characteristics and Individual Trial Risk Ratios for Major Adverse Cardiovascular Events

A, Meta-regression of risk ratio (RR) for major adverse cardiovascular events according to length of follow-up with regression coefficient of −0.01 [95% CI, −0.04 to 0.02]; P = .52. B, Meta-regression on RR of major adverse cardiovascular events according to adherence to intervention or control with regression coefficient of −0.11 [−0.41 to 0.19]; P =.40. C, Meta-regression on RR of major adverse cardiovascular events according to apnea-hypopnea index at baseline with regression coefficient of −0.08 [−0.19 to 0.04]; P =.13. Major adverse cardiovascular events comprise cardiovascular death, nonfatal acute coronary syndrome, and nonfatal stroke. Circle sizes indicate the weight given to each study (centered on the intersection of the RR for major adverse cardiovascular events on the y-axis and the mean trial value of the metric of interest on the x-axis).

Figure 5.. Association of Positive Airway Pressure With Vascular Outcomes and Deaths in Trial Subgroups

Box sizes are proportional to study weight (box center positioned at point estimate of effect). The I² value indicates the percentage of variability across the pooled estimates attributable to heterogeneity beyond chance (0%-25%, low likelihood; 26%-75%, moderate likelihood; 76%-100%, high likelihood), and the P value is for a test of heterogeneity across all studies. Abbreviations: ASV, adaptive servo-ventilation; CPAP, continuous positive airway pressure; CSA, central sleep apnea; OSA: obstructive sleep apnea; PAP, positive airway pressure. ^aMajor adverse cardiovascular events comprise cardiovascular death, nonfatal acute coronary syndrome, and nonfatal stroke. ^bPlus indicates major adverse cardiovascular events in addition to hospitalization for unstable angina.