PDE5A inhibitor treatment of persistent pulmonary hypertension after mechanical circulatory support

Abstract

Background: Pulmonary hypertension (PH) secondary to left heart failure portends a poor prognosis and is a relative contraindication to heart transplantation at many centers. We tested the hypothesis that when PH persists after adequate left ventricle unloading via recent left ventricular assist device (LVAD) therapy, phosphodiesterase type 5A inhibition would decrease PH in this population.

Methods and results: We performed an open-label clinical trial using control patients not receiving therapy. Between 1999 and 2007, 138 consecutive patients undergoing cardiac transplantation evaluation with advanced left ventricular dysfunction, an elevated pulmonary capillary wedge pressure, and PH (defined by a pulmonary vascular resistance (PVR) >3 Woods Units), were treated with LVAD therapy. Fifty-eight of these patients reduced their pulmonary capillary wedge pressure to a value <15 mm Hg (11.8+/-2.0 mm Hg from baseline 23.2+/-6.2 mm Hg) 1 to 2 weeks after LVAD implantation, but despite this improvement, the PVR of these patients was only minimally affected (5.65+/-3.00 to 5.39+/-1.78 Wood Units). Twenty-six consecutive patients from this group with persistently elevated PVR were started on oral phosphodiesterase type 5A inhibition with sildenafil and titrated to an average of dose of 51.9 mg by mouth 3 times per day. The average PVR in the sildenafil-treated group fell from 5.87+/-1.93 to 2.96+/-0.92 Wood Units (P<0.001) and the mean pulmonary artery pressure fell from 36.5+/-8.6 to 24.3+/-3.6 mm Hg (P<0.0001) and was significantly lower when compared with the 32 LVAD recipients not receiving sildenafil at weeks 12 to 15 after the initial post-LVAD hemodynamic measurements (13 to 17 weeks post-LVAD implantation). In addition, hemodynamic measurements of right ventricular function in sildenafil-treated patients was also improved compared with patients not receiving sildenafil.

Conclusions: In patients with persistent PH after recent LVAD placement, phosphodiesterase type 5A inhibition in this open-label trial resulted in a significant decrease in PVR when compared with control patients.

Figure 1

Effects of LVAD on cardiac output (CO), mean pulmonary arterial pressure (mPAP), Pulmonary Capillary Wedge Pressure (PCWP), and Pulmonary Vascular Resistance (PVR) in 58 consecutive patients with persistently elevated PVR 7–14 days post LVAD implantation. N indicates number of patients. Comparisons made with paired t-test.

Figure 2

Effect of Sildenafil on cardiac output (CO), mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR) on patients treated with LVAD and with persistent pulmonary hypertension. N indicates number of patients. * P<0.05 vs. pre-sildenafil. Comparisons made with paired t-test.

Figure 3

Influence of sildenafil treatment on pulmonary vascular resistance (PVR) and contractility index (dP/dt_max/IP) compared with consecutive LVAD control patients at pre-left ventricular assist device (pre-LVAD), Post-LVAD, and 2–4, 6–9, and 12–15 weeks post treatment with sildenafil or with no treatment. Data are presented as Mean +/− SD. Post-LVAD measurement is time of first right heart catherization and also when patients were initiated on sildenafil. n indicates number of patients. * P<0.05 vs control patients at 12–15 week right heart catheterization. Comparisons for the week 12–15 time point were made with un-paired Student’s t-test.

Figure 4

Effect of Sildenafil on RV contractility index (dP/dt_max/IP), isovolumic relaxation time constant (Tau), augmentation index (RV ΔP/PP), and tricuspid annular plane systolic excursion (TAPSE). n indicates number of patients. * P<0.05 vs pre sildenafil. Comparisons made with paired t-test.