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Pulmonary Hypertension Drugs Were Never Properly Tested in Heart FailurePulmonary Hypertension Drugs in Heart Failure FREE TO VIEW

Maya Guglin, MD, PhD
Author and Funding Information

From the Department of Cardiology, University of South Florida.

Correspondence to: Maya Guglin, MD, PhD, University of South Florida, 2A Columbia Dr, Ste 5074, Tampa, FL 33618; e-mail: mguglin@gmail.com


Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(2):420. doi:10.1378/chest.13-2121
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To the Editor:

I read with interest the review on pulmonary hypertension (PH) due to left-sided heart disease by Hansdottir et al1 in a recent issue of CHEST (August 2013). It is a thorough and comprehensive review.

Unfortunately, the authors repeated a widespread belief that clinical trials of pulmonary arterial hypertension-specific therapies in heart failure (HF) have been largely disappointing. Specifically, they refer to the Flolan International Randomized Survival Trial (FIRST), which was prematurely stopped because of increased mortality in the epoprostenol arm.2

Although technically this statement is correct, it is worth mentioning that the presence of PH was not required for patients enrolled in this trial. Inclusion criteria for the FIRST trial were New York Heart Association class IIIB or IV, left ventricular ejection fraction of < 25%, low cardiac output and increased wedge pressure, proof of inotrope dependency for patients on inotropes, ineligibility for cardiac transplantation, and eligibility for anticoagulation.2

Elevated pulmonary arterial pressure was not among the inclusion criteria, and normal pulmonary pressure was not among the exclusion criteria. In other words, epoprostenol in HF was tested in patients who did not necessarily have a target for pharmacologic effects of the drug. When there is no substrate for therapeutic effects, the drug can cause only side effects, and this is exactly what occurred. I doubt anyone could design a trial for a PH drug in the setting of idiopathic pulmonary arterial hypertension without selecting patients with PH. Meanwhile, the FIRST trial did exactly this, in an HF population, and essentially blocked the use of prostacyclin in patients with HF with secondary PH.

Another trial testing sildenafil in HF with preserved ejection fraction (the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure [RELAX] trial)3 had the same flaw in the design. Patients were not required to have PH to enter the study. It is naive to expect the drug to demonstrate its therapeutic effect if you do not select patients who have the target abnormality that the drug is supposed to correct. Predictably, the trial was negative, with no effect of sildenafil on functional capacity. However, we cannot conclude that sildenafil is useless in HF until we specifically test it in patients with PH due to HF.

Drugs for PH should be tested in patients with PH. If this condition is not met, the results of such trials are inconclusive, and the trials themselves are useless.

References

Hansdottir S, Groskreutz DJ, Gehlbach BK. WHO’s in second? A practical review of World Health Organization group 2 pulmonary hypertension. Chest. 2013;144(2):638-650. [CrossRef] [PubMed]
 
Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1997;134(1):44-54. [CrossRef] [PubMed]
 
Redfield MM, Chen HH, Borlaug BA, et al; RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268-1277. [CrossRef] [PubMed]
 

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References

Hansdottir S, Groskreutz DJ, Gehlbach BK. WHO’s in second? A practical review of World Health Organization group 2 pulmonary hypertension. Chest. 2013;144(2):638-650. [CrossRef] [PubMed]
 
Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1997;134(1):44-54. [CrossRef] [PubMed]
 
Redfield MM, Chen HH, Borlaug BA, et al; RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309(12):1268-1277. [CrossRef] [PubMed]
 
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