Background

Pulmonary hypertension is defined as a mean artery pressure of 25 mmHg or greater at rest as determined by right-heart catheterization. If left untreated this increase in pulmonary artery pressure results in increased right ventricular afterload and can lead to right-heart failure and death.1

Pulmonary hypertension is classified into five groups by the WHO based on clinical presentations and pathophysiological and haemodynamic characteristics, and this classification is used to guide treatment regimes. These groups include the following:

1. Group 1: Pulmonary arterial hypertension (PAH).

2. Group 2: Pulmonary hypertension due to left heart disease.

3. Group 3: Pulmonary hypertension due to lung disease.

4. Group 4: Pulmonary hypertension due to blood clots in the lungs.

5. Group 5: Blood and other rare disorders that lead to pulmonary hypertension.

It is important to note that the presence of pulmonary hypertension, irrespective of WHO classification, generally indicates the presence of a progressive and often fatal condition. Predictors of poor prognosis include WHO functional class and poor performance in 6-min walk test.2

The goals of treatment in pulmonary hypertension are to maintain right ventricular function, reduce the risk of mortality, while also improving quality of life and exercise tolerance. The underlying pathophysiology of PAH facilitates the use of targeted treatments including phosphodiesterase type 5 (PDE5) inhibitors.1 This class of drug is thought to induce the same levels of oxidation as inhaled nitric oxide.3 Research of this drug has largely focused on patients in this group.

Objective/s

The primary objective of this review was to determine the efficacy of PDE5 inhibitors for the treatment of pulmonary hypertension in adults and children.

Intervention/Methods

The review included single-blinded or double-blinded randomized controlled trials where PDE5 inhibitors are compared with a placebo or to any other treatment. Participants included those with a diagnosis of pulmonary hypertension from any cause who required medical treatment for their condition.

The primary outcomes measures considered were

1. change in WHO functional class,

2. 6-min walk distance (6MWD) and

3. mortality.

The secondary outcome measures included haemodynamic parameters, exercise capacity (other than 6MWD), dyspnoea score, hospitalization/intervention and adverse events.

Results

There were 36 studies included in this review that reported on the results for 2999 participants.4

There were 19 trials that focused on patients with Group 1 PAH. There was high-certainty evidence to suggest that patients treated with PDE5 inhibitors were more likely to have an improvement in their WHO functional class, to walk 48 m further in 6MWD and were less likely to die (mean duration of 14 weeks) compared with those treated with a placebo. There was an increased noted in adverse events including headaches, gastrointestinal upset and muscle aches and joint pains for those treated with PDE5 inhibitors compared with placebo.

A small number of trials compared PDE5 with placebo while the patient was on another PAH-specific therapy. Participants on PDE5 inhibitors and combination therapy walked further (19.66 m) in the 6 min compared with placebo, based on moderate-certainty evidence.

There were five trials that compared PDE5 inhibitors with placebo in pulmonary hypertension secondary to left-heart disease; however, the quality of data were reported to be low due to imprecision and inconsistency across trials. There were reduced odds of an improvement in the WHO functional class for those using PDE5 inhibitors compared with placebo. The PDE5 treatment group were reported to walk further than those in the control group, while no difference in mortality between the groups was noted.

There were five trials that compared PDE5 inhibitors with placebo in patients with pulmonary hypertension secondary to lung disease/hypoxia; however, data were reported to be of low quality. A small improvement was noted in the intervention group for 6MWD and no evidence of worsening hypoxia was noted in those treated with PDE5 inhibitors.

Conclusion

There were a number of positive clinical benefits identified for the use of PDE5 inhibitors in patients with Group 1 PAH compared with placebo, in a finding that was statistically significant and based on high-quality evidence. These benefits included improvements in mortality, WHO functional class, time to clinical worsening, haemodynamic, 6MWD and quality of life, including dyspnoea. The use of PDE5 inhibitors was associated with side effects reported, including headaches, flushing, gastrointestinal upset and muscle and joint pains.

Implications for practice

The evidence from this review supports the use of PDE5 inhibitors for the treatment of patients with Group 1 PAH. Clinicians should consider the potential side effects of the specific PDE5 inhibitor medications for each patient, as part of the decision-making process around treatment.

Acknowledgements

Conflicts of interest

The author reports no conflicts of interest.

References