A 69-year-old male patient with a non-ischemic cardiomyopathy and severe biventricular failure experienced multiple recurrent admissions on home inotrope therapy. His pulmonary artery pressure precluded listing for heart transplantation. The patient had severe mitral regurgitation. He underwent repair of the mitral valve with a 31 mm ring and HVAD (Heartware Inc.; Framingham, MA) implant as destination therapy.
He was transferred to the intensive care unit post-procedure with epoprostenol inhaled, milrinone, and epinephrine. On post-operative day 3, the patient's hemodynamics had not improved significantly, and he remains on dobutamine 2.5 mcg/Kg/min and milrinone 0.375 mcg/Kg/min (Table 1).
Table 1
Right Heart Catheterization
Medications
Right Atrial Pressure
Pulmonary Capillary Wedge Pressure
Pulmonary Artery Pressure
Cardiac Output /Cardiac Index
Blood Pressure
Heart Rate
Pre-operation
Milrinone
6
22
73/30 ~ 46
4.6/2.3
98/68
69
Post-operative Day 3
Milrinone, dobutamine
18
Could not wedge catheter
58/27 ~ 36
5.5/2.7
109/77
110
When the critical care physician asks your opinion on starting the patient on sildenafil, what is your response?
Show Answer
The correct answer is: D. The level of evidence to recommend sildenafil in this setting is not strong.
Based on the data presented in Table 1, it appears that the patient does have evidence of acute RV failure based on the elevated right atrial pressure >16 and the persistent requirement of inotropic support and inhaled pulmonary vasodilators 3 days post-surgery. Sildenafil is an oral pulmonary vasodilator, classified as a type 5 phosphodiesterase inhibitor (PDE5i). It maintains or augments cGMP action, which in turn relaxes vascular smooth muscle and causes vasodilation. There have been some studies looking at sildenafil because of its mechanism of action in the setting of "fixed" pulmonary hypertension pre and post left ventricular assist device (LVAD) implantation looking at improving hemodynamics or mitigating RV failure post-LVAD implantation. However, these studies were small. A prospective open-label study with a historical control involving 26 patients in 2008 showed favorable hemodynamics in patients receiving sildenafil. The other studies have been small retrospective case series looking at hemodynamics and RV failure. These studies demonstrated benefit in mean pulmonary artery pressure, pulmonary vascular resistance, and incidence of acute RV failure. But given the small number patients and the nature of the studies, the confidence in this evidence is weak. The total number of patients in all the studies combined was 40. No consistency was noted in the dosing of the medication, and right atrial pressure lowering was not consistently seen.
On the contrary, a study published in 2019 looking at the use of sildenafil preoperatively in the INTERMACS Registry (Interagency Registry for Mechanically Assisted Circulatory Support) (looking at patients enrolled from 2012 to 2017) found a higher incidence of acute early RV failure in a propensity-matched analysis. This appeared to be driven primarily by prolonged use of inotropes in patients receiving PDE5i compared with matched controls. This also led to an increase in total length of hospital stay by 3 days in patients receiving PDE5i. There were no differences in the requirement of right ventricular assist device support, although there was a statistically significant higher incidence of mild acute RV failure, based on prolonged inotropic support, in patients on PDE5 inhibitors. The incidence of right ventricular assist device implantation for RV failure was similar between both groups, and the time to implantation was similar. Survival at 6 months was also similar. So, there did not appear to be a signal of benefit for the use of PDE5i. There was also an increase in the incidence of acute bleeding in first 7-day post-operative period, the mechanism of which was not well understood. Although this is not a randomized controlled trial, it is an observational study of the largest registry of patients with LVAD. It raises concern about the lack of benefit in clinical outcomes for patients taking PDE5i because the incidence of late RV failure, mortality, and multiorgan failure were no different in the two groups.
The RELAX (Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure) study looked at sildenafil in patients with heart failure with preserved ejection fraction and would not apply to this patient.
References
Klodell CT Jr, Morey TE, Lobato EB, et al. Effect of sildenafil on pulmonary artery pressure, systemic pressure, and nitric oxide utilization in patients with left ventricular assist devices. Ann Thorac Surg 2007;83:68-71.
Sahay S, Khirfan G, Tonelli AR. Management of combined pre- and post-capillary pulmonary hypertension in advanced heart failure with reduced ejection fraction. Respir Med 2017;131:94-100.
Tedford RJ, Hemnes AR, Russell SD, et al. PDE5A inhibitor treatment of persistent pulmonary hypertension after mechanical circulatory support. Circ Heart Fail 2008;1:213-9.
Hamdan R, Mansour H, Nassar P, Saab M. Prevention of right heart failure after left ventricular assist device implantation by phosphodiesterase 5 inhibitor. Artif Organs 2014;38:963-7.
Critoph C, Green G, Hayes H, et al. Clinical Outcomes of Patients Treated With Pulmonary Vasodilators Early and in High Dose After Left Ventricular Assist Device Implantation. Artif Organs 2016;40:106-14.
Baker WL, Radojevic J, Gluck JA. Systematic Review of Phosphodiesterase-5 Inhibitor Use in Right Ventricular Failure Following Left Ventricular Assist Device Implantation. Artif Organs 2016;40:123-8.
Gulati G, Grandin EW, Kennedy K, et al. Preimplant Phosphodiesterase-5 Inhibitor Use Is Associated With Higher Rates of Severe Early Right Heart Failure After Left Ventricular Assist Device Implantation. Circ Heart Fail 2019;12:e005537.
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;309:1268-77.
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