To the Editor:
We thank Dr Guglin for her comments on our recent article1 regarding the use of pulmonary hypertension (PH)-specific therapies in patients with World Health Organization (WHO) group 2 PH due to left-side heart disease (LHD). As Dr Guglin points out, elevated pulmonary arterial pressures were not required for enrollment in the Flolan International Randomized Survival Trial (FIRST).2 However, all patients underwent right-sided heart catheterization, and most subjects (> 75%) did, in fact, have PH as defined by mean pulmonary arterial pressure > 25 mm Hg. This makes it unlikely that epoprostenol is of significant benefit in patients with systolic heart failure and PH. The same is true for the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial. The rationale behind the RELAX trial was to target the pleiotropic (cardiac, vascular, and neurohormonal) effects of phosphodiesterase-5 inhibition on cardiovascular function in patients with heart failure with reduced ejection fraction regardless of the pulmonary pressures.3 Based on echocardiographic estimates (which are admittedly imprecise), approximately two-thirds of subjects in this trial also had elevated pulmonary arterial systolic pressure (> 35 mm Hg).
Recently, Bonderman and colleagues4 reported the results of the Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial (LEPHT). Riociguat, a guanylate cyclase stimulator, is efficacious in the treatment of pulmonary arterial hypertension and in PH due to chronic thromboembolic disease; it received US Food and Drug Administration approval for these indications in October 2013. LEPHT was a phase 2 trial that examined the hemodynamic effects of riociguat in patients with hemodynamically confirmed PH due to heart failure with reduced ejection fraction. In this study, riociguat failed to reduce mean pulmonary arterial pressure, and there was no significant improvement in N-terminal pro-brain natriuretic peptide or 6-min walk test distance after 16 weeks of treatment. On a more positive note, subjects receiving riociguat had significantly increased cardiac index and a decrease in the Minnesota Living With Heart Failure score.
To conclude, the clinical trials to date have been disappointing, and the use of PH-specific therapies for PH due to LHD should be discouraged outside of the context of clinical trials. We do agree with Dr Guglin that additional, adequately powered, trials looking at subgroups of patients with LHD and a fixed component of PH are needed.
Acknowledgments
Role of sponsors: The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute.
Footnotes
Funding/Support: Dr Gehlbach receives support from the National Heart, Lung and Blood Institute [K23HL088020].
Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Hansdottir is the principal investigator at the University of Iowa for multicenter studies on pulmonary arterial hypertension sponsored by Actelion Pharmaceuticals US, Inc; Bayer AG; Gilead; INO Therapeutics LLC; and United Therapeutics Corporation. Dr Gehlbach has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
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References
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