Controversies in pulmonary hypertension due to left heart disease

Should pulmonary hypertension due to left heart disease be treated?

Besides the controversies in definition and diagnosis of PH-LHD, the general agreement is that treatment of PH-LHD should start with aggressive management of the underlying cardiac disease and of any other potential confounding factor, such as respiratory tract infections, sleep apnea syndrome, arrhythmias, or pulmonary embolism. Aggressive control of cardiovascular risk factors is also recommended.

There is no specific treatment for PH-LHD, though. Diuretics are the mainstay of medical treatment for fluid control and relief of congestion, whereas angiotensin-converting enzyme inhibitors and β-blockers are indicated to improve morbidity and long-term survival in HF. Some subsets of patients may benefit from invasive monitoring and cyclic inotropic support to optimize volume status, alleviate symptoms, or reduce hospitalizations (or a combination of these), although the long-term benefit of this strategy remains uncertain. When appropriate, corrective/palliative surgery for valvular heart disease should be considered, along with the implantation of cardiac resynchronization therapy or implantable cardiac defibrillators for those with QRS of more than 120 ms and ejection fraction of less than 35%. If clinically indicated, younger patients unresponsive to medical treatment should be evaluated for heart transplantation or implantation of ventricular assist devices to support cardiac output, either as a bridge to transplant or as destination therapy. For this indication, the pre-transplant assessment of reversibility of PH-LHD is particularly relevant.

The appealing hypothesis of targeting PH-LHD with drugs approved for PAH has been supported by affinities in the increase of endothelin-1 levels and in the impairment of nitric oxide-mediated vasodilation; small single-center therapeutic trials have reported improvement of exercise capacity and hemodynamic parameters [16-18]. However, the results of randomized trials have been largely unsatisfactory, if not detrimental, with most of the compounds. In our opinion, this has several reasons. First, patients were generally not stratified on the basis of PH, nor was hemodynamic evaluation systematically performed. Second, with the exception of phosphodiesterase-5 inhibitors, mostly patients with HFrEF were enrolled and patients with valvular heart disease were excluded. Third, preliminary optimization of volume status was not required for inclusion. Lastly, high dosages of compounds were used in order to attain systemic effects.

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As a result, data coming from multicenter randomized trials are scarce. In fact, only two of these trials are available in the literature. In a multicentric placebo-controlled trial [19], riociguat (a soluble guanylate cyclase stimulator approved for PAH and chronic thromboembolic pulmonary hypertension) was compared with placebo in 201 patients with PH due to HF-rEF during 16 weeks. No effect on the primary endpoint (a change in PAPm after 16 weeks) was observed at any dose of riociguat compared with placebo. A proof-of-concept study to test the acute effects of riociguat in patients with PH associated with diastolic dysfunction ({“type”:”clinical-trial”,”attrs”:{“text”:”NCT01172756″,”term_id”:”NCT01172756″}}NCT01172756) has recently been published, with similar negative results [20].

Two multicenter clinical trials in PH-LHD are currently under way with the phosphodiesterase 5 inhibitors sildenafil ({“type”:”clinical-trial”,”attrs”:{“text”:”NCT01616381″,”term_id”:”NCT01616381″}}NCT01616381) and tadalafil ({“type”:”clinical-trial”,”attrs”:{“text”:”NCT01910389″,”term_id”:”NCT01910389″}}NCT01910389). Although these trials plan to include a well-defined population with PH due to systolic HF, the absence of right heart catheterization validation of PH might represent a significant limitation.

Finally, a pilot phase II study with the endothelin receptor antagonist macitentan (MELODY-1) ({“type”:”clinical-trial”,”attrs”:{“text”:”NCT02070991″,”term_id”:”NCT02070991″}}NCT02070991) is the only trial including patients falling in the new definition of CpcPH. Until results from large trials are available, PH-LHD should not be treated with drugs approved to treat PAH.


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About the Author: Tung Chi