Date Published: October 11, 2018
Publisher: Public Library of Science
Author(s): Charles-Antoine Guay, Louis-Vincent Morin-Thibault, Sebastien Bonnet, Yves Lacasse, Caroline Lambert, Jean-Christophe Lega, Steeve Provencher, Guy A. MacGowan.
Pulmonary hypertension (PH) due to left heart failure (HF) is the most common form of PH. However, treatment is unclear because there are conflicting results about safety and efficacy of PH-targeted therapies.
To assess the effects of PH-targeted therapy on exercise capacity in HF patients.
MEDLINE, EMBASE and the Cochrane Library were searched from January 1990 to July 2017 for randomized controlled trials comparing PH-targeted therapies to conventional therapy in HF. The primary outcome was to assess the effects on exercise capacity. Secondary outcomes included mortality, hospitalisation, NT-proBNP levels, echocardiographic and hemodynamics parameters and discontinuation rate.
22 studies were included (n = 5448), including 3, 8 and 11 studies with low, high and unknown risk of bias, respectively. PH-targeted therapies were associated with an improvement of exercise capacity (standardized mean difference 0.29;95%CI:0.08–0.50, p = 0.006). Pre-specified subgroup analyses found that this improvement was predominantly observed in studies evaluating phosphodiesterase-5 inhibitors and prostanoids and in patients with reduced ejection fraction. Moreover, systolic pulmonary artery pressure measured by echocardiography was improved (mean difference: -7.5mmHg; [95%CI]: -14.9,-0.1, p = 0.05), which was also entirely driven by studies evaluating phosphodiesterase-5 inhibitors. However, PH-targeted therapies were associated with an increased treatment discontinuation rates and a potential increase in mortality compared to standard treatment.
In conclusion, PH-targeted therapies and especially phosphodiesterase-5 inhibitors may improve exercise capacity in patients with HF. However, an increase in adverse outcomes was likely. Moreover, most studies were at high or unknown risk of bias, precluding confident conclusions about the effects of PH-targeted therapies.
Pulmonary hypertension due to left heart disease (PH-LHD) appears to be the most common form of PH. Epidemiological studies suggest that PH develops in up to 80% of patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction . When present, PH-LHD is associated with more severe symptoms and worse exercise tolerance, and exerts a negative impact on outcomes, doubling the risk of mortality as compared to patients with HFpEF/HFrEF without PH.
The methods for this systematic review are in accordance with the methodological guidelines for systematic reviews of randomized control trials from «Cochrane Handbook for Systematic Reviews of Interventions». The complete study protocol is available on PROSPERO (CRD42017083114).
The present systematic review with meta-analysis documented that PH-targeted therapies may modestly improve exercise capacity in patients with HFpEF/HFrEF. These findings were similar when only studies with a low or an unknown risk of bias were taken into consideration and when the fixed-effects model was used, substantiating the robustness of these results. However, significant heterogeneity was noted and predefined subgroup analyses suggested that this observation was driven by studies 1) of longer duration; 2) evaluating the effects of PDE5-inhibitors or prostanoids; 3) using VO2 peak as the evaluative modality and; 4) recruiting patients with HFrEF. Intriguingly, the presence of PH did not influence the primary outcome. PDE5-inhibitors were also associated with a significant decrease in sPAP and exploratory analyses suggested they might be associated with decreased cardiac-specific hospitalizations in heart failure patient but not in patients with corrected valvulopathy and persistent PH. Importantly, however, these results should be cautiously tempered by the fact that PH-targeted therapies were associated with an increase in treatment discontinuation, that most studies had high or unknown risk of bias and that sensitivity analyses suggested that an increased mortality with PH-targeted therapies cannot be ruled out.