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Update on Management of Pulmonary Hypertension in LVAD Patients

Melissa Smallfield, MD
Virginia Commonwealth University
Richmond, VA, USA

In the United States, there are 5.8 million people with heart failure, a small percentage of them with advanced heart failure requiring therapy with left ventricular assist devices (LVAD) and heart transplantation. A significant number of advanced heart failure patients will have secondary pulmonary hypertension due to the passive congestion of left heart disease. LVAD therapy is effective in decompressing the left ventricle, thus reducing left sided filling pressures and reducing pulmonary pressures. Unfortunately, patients may have combined pre- and post-capillary pulmonary hypertension (CpcPH) for which LVAD therapy does not entirely normalize PA pressures and pulmonary vascular resistance (PVR). CpcPH is defined as a mean pulmonary artery pressures (mPAP) > 25 mmHg, a pulmonary artery wedge pressure (PAWP) > 15 mmHg, a PVR ≥ 3 WU and a diastolic pressure gradient (DPG) ≥ 7 mmHg by hemodynamic testing. These persistently elevated PA pressures can lead to right ventricular dysfunction after LVAD placement and exclude heart transplantation if the PVR does not return to normal.

There has been a growing interest in using pulmonary vasodilators for the treatment of CpcPH after LVAD implantation. The 2013 ISHLT guidelines for mechanical circulatory support recommend using PDE5 inhibitors for the treatment of persistent pulmonary hypertension and right ventricular dysfunction although the benefits of such therapy have not been sufficiently proven. Tedford et al published one of the most cited studies on the use of PDE5 inhibitors to treat CpcPH after LVAD implantation. They evaluated 26 consecutive patients with persistent pulmonary hypertension (defined as PVR > 3) 7 to 14 days after LVAD implantation despite normal PAWP. They were started on sildenafil 20mg three times a day and compared to 32 LVAD control patients. The patients on sildenafil had a decrease in the mPAP and PVR within 2 to 4 weeks of therapy, and these results were maintained though 12 to 15 weeks. There was marked improvement in RV function. Sildenafil was well tolerated and did not elevate PAWP or decrease cardiac output [1].

While there are several studies using PDE5 inhibitors in the treatment of pulmonary hypertension due to left heart disease, the same cannot be said for endothelin receptor antagonists (ERA). Early studies performed with bosentan in patients with systolic dysfunction showed worsening edema and more frequent hospitalizations for heart failure. Macitentan is the newest ERA to be used for the treatment of pulmonary arterial hypertension. The SERAPHIN trial (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinic Outcomes) evaluated two doses of macitentan (3mg and 10mg) versus placebo with the primary endpoint of time from initiation of treatment to a composite endpoint of death, atrial septostomy, lung transplantation, initiation of prostanoids, or worsening PAH. There was significantly reduced morbidity and mortality seen in the macitentan arms with improvements in 6-minute walk distances, WHO functional class, pulmonary vascular resistance and cardiac index. The incidence of edema was similar among all three treatment groups ranging from 16-18%. Other side effects in the macitentan groups include nasopharyngitis, headache and anemia [2].

The MELODY-1 study (Macitentan in subjects with combined prE- and post-capiLlary pulmOnary hypertension due to left ventricular DYsfunction) was the first study to evaluate macitentan for pulmonary hypertension due to left heart disease in patients with CpcPH. Patients were required to have a LVEF > 30% with evidence of CpcPH on RHC. The primary endpoint assessed was a composite of significant fluid retention or a worsening in NYHA functional class. More patients in the macitentan group experienced significant fluid retention or worsening in NYHA functional class. There was no difference in PVR, mRAP, or PAWP after treatment with macitentan. There was a nonsignificant decrease in pro-BNP levels and 6-minute walk distances in the treatment groups. Of note, 76% of the patients had a LVEF ≥ 50% (3).

The SOPRANO trial (Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients with Pulmonary Hypertension after Left Ventricular Assist Device Implantation) is an ongoing study enrolling patients with CpcPH after LVAD implantation. The aim is to assess the effect of macitentan on PVR at week 12 versus baseline. It is the first randomized, placebo-controlled study of ERAs in this patient population. Secondary objectives include effect of macitentan on cardio-pulmonary hemodynamics, disease severity, right ventricular function, renal function, and pro-BNP levels [4].

CpcPH can be common in patients with advanced heart failure and can persist even after LVAD implantation. This can lead to persistently elevated PVRs and RV dysfunction which increases morbidity and mortality after LVAD implantation and heart transplantation. Studies using pulmonary vasodilators for the treatment of CpcPH after LVAD implantation have included short term follow up. More research is needed to understand the long term outcomes of these patients after heart transplantation. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


  1. Tedford RJ, Hemnes AR, Russell SD, et al. PDE5A Inhibitor Treatment of Persistent Pulmonary Hypertension After Mechanical Circulatory Support. Circ Heart Fail. 2008;1:213-219.
  2. Pulido T, Adzerikho I, Chennick RN, et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med. 2013;369:809-818.
  3. Vachiery JL, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J 2018;51:1701886.
  4. Clinical trials.gov NCT02554903

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