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. 2016 Aug 2;2016(8):CD011205.
doi: 10.1002/14651858.CD011205.pub2.

Guanylate cyclase stimulators for pulmonary hypertension

Andrew J Wardle  1 , Matthew J Seager, Richard Wardle, Robert M R Tulloh, J Simon R Gibbs
Affiliations

Guanylate cyclase stimulators for pulmonary hypertension

Andrew J Wardle et al. Cochrane Database Syst Rev. .

Abstract

Background: Pulmonary hypertension is a condition of complex aetiology that culminates in right heart failure and early death. Soluble guanylate cyclase (sGC) stimulators are a promising class of agents that have recently gained approval for use.

Objectives: To evaluate the efficacy of sGC stimulators in pulmonary hypertension.

Search methods: We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE and the reference lists of articles. Searches are current as of 12 February 2016.

Selection criteria: We selected randomised controlled trials (RCTs) involving participants with pulmonary hypertension of all ages, severities and durations of treatment.

Data collection and analysis: AW, MS and RW independently selected studies, assessed evidence quality and extracted data. This process was overseen by RT and SG. All included studies were sponsored by the drug manufacturer.

Main results: Five trials involving 962 participants are included in this review. All trials were of relatively short duration (< 16 weeks). Due to the heterogenous aetiology of pulmonary hypertension in participants, results are best considered according to each pulmonary hypertension subtype.Pooled analysis shows a mean difference (MD) increase in six-minute walking distance (6MWD) of 30.13 metres (95% CI 5.29 to 54.96; participants = 659; studies = 3). On subgroup analysis, for pulmonary arterial hypertension (PAH) there was no effect noted (6MWD; MD 11.91 metres, 95% CI -44.92 to 68.75; participants = 398; studies = 2), and in chronic thromboembolic pulmonary hypertension (CTEPH) sGC stimulators improved 6MWD by an MD of 45 metres (95% CI 23.87 to 66.13; participants = 261; studies = 1). Data for left heart disease-associated PH was not available for pooling. Importantly, when participants receiving phosphodiesterase inhibitors were excluded, sGC stimulators increased 6MWD by a MD of 36 metres in PAH. The second primary outcome, mortality, showed no change on pooled analysis against placebo (Peto odds ratio (OR) 0.57, 95% CI 0.18 to 1.80).Pooled secondary outcomes include an increase in World Health Organization (WHO) functional class (OR 1.53, 95% CI 0.87 to 2.72; participants = 858; studies = 4), no effect on clinical worsening (OR 0.45, 95% CI 0.17 to 1.14; participants = 842; studies = 3), and a reduction in mean pulmonary artery pressure (MD -2.77 mmHg, 95% CI -4.96 to -0.58; participants = 744; studies = 5). There was no significant difference in serious adverse events on pooled analysis (OR 1.12, 95% CI 0.66 to 1.90; participants = 818; studies = 5) or when analysed at PAH (MD -3.50, 95% CI -5.54 to -1.46; participants = 344; studies = 1), left heart disease associated subgroups (OR 1.56, 95% CI 0.78 to 3.13; participants = 159; studies = 2) or CTEPH subgroups (OR 1.29, 95% CI 0.65 to 2.56; participants = 261; studies = 1).It is important to consider the results for PAH in the context of a person who is not also receiving a phosphodiesterase-V inhibitor, a contra-indication to sGC stimulator use. It should also be noted that CTEPH results are applicable to inoperable or recurrent CTEPH only.Evidence was rated according to the GRADE scoring system. One outcome was considered high quality, two were moderate, and eight were of low or very low quality, meaning that for many of the outcomes the true effect could differ substantially from our estimate. There were only minor concerns regarding the risk of bias in these trials, all being RCTs largely following the original protocol. Most trials employed an intention-to-treat analysis.

Authors' conclusions: sGC stimulators improve pulmonary artery pressures in people with PAH (who are treatment naive or receiving a prostanoid or endothelin antagonist) or those with recurrent or inoperable CTEPH. In these settings this can be achieved without notable complication. However, sGC stimulators should not be taken by people also receiving phosphodiestase-V inhibitors or nitrates due to the risks of hypotension, and there is currently no evidence supporting their use in pulmonary hypertension associated with left heart disease. There is no evidence supporting their use in children. These conclusions are based on data with limitations, including unavailable data from two of the trials.

PubMed Disclaimer

Conflict of interest statement

AW, MS, RW: none known. SG: has received payments for consultancy and lecture fees from Actelion, Bayer, Gilead, GSK, Novartis, Pfizer and United Therapeutics and is a Trustee/Company Director of Breathing PLC and the Preventive Cardiology Trust. Professor Tulloh has received lecture fees / honoraria from companies that supply other pharmaceutical agents in pulmonary hypertension, including Pfizer, GSK and Actelion.

Figures

1
1
Study Selection Flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 Ricociguat versus placebo, Outcome 1 Change in Exercise Capacity (6MWD).
1.2
1.2. Analysis
Comparison 1 Ricociguat versus placebo, Outcome 2 Mortality.
1.3
1.3. Analysis
Comparison 1 Ricociguat versus placebo, Outcome 3 Improvement in WHO Functional Class.
1.4
1.4. Analysis
Comparison 1 Ricociguat versus placebo, Outcome 4 Clinical worsening.
1.5
1.5. Analysis
Comparison 1 Ricociguat versus placebo, Outcome 5 Serious Adverse Events (Participants with one or more events).
1.6
1.6. Analysis
Comparison 1 Ricociguat versus placebo, Outcome 6 Change in Mean Pulmonary Artery Pressure.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD011205

References

References to studies included in this review

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