Reports

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PRIORITY PRESS - 30th Annual Meeting of the International Society of Heart and Lung Transplantation

Chicago, Illinois / April 21-24, 2010

Among the complications that can occur following heart transplantation is early right ventricular dysfunction (RVD), especially among patients with pulmonary arterial hypertension (PAH) prior to receiving the transplant. Usually, either sodium nitroprusside or inhaled nitric oxide is used to try and reverse secondary PAH but there are patients with irreversible disorders of the pulmonary vascular bed in whom conventional therapy is not consistently useful.

When PAH proves unresponsive to conventional vasodilators, potential heart transplant recipients may be deemed ineligible for transplantation. However, several speakers here at the ISHLT meeting suggested that this might be unnecessary and even inappropriate because lack of response to sodium nitroprusside does not mean that pulmonary pressures might not respond to other vasodilators. Growing experience with the oral phosphodiesterase type-5 (PDE-5) inhibitor sildenafil in the setting of PAH suggests that much of so-called irreversible PAH due to left heart disease may in fact be reversible on adequate dosing and duration of treatment with sildenafil.

As discussed by Dr. Hikmet Al-Hiti, Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic, most patients with advanced heart failure who are heart transplant candidates have PAH and it is necessary to test the reversibility of PAH in order to ensure patients are in fact appropriate candidates for transplantation.

In this particular study, researchers compared the acute administration of the prostaglandin E1 (PGE1), alprostadil with sildenafil in patients with chronic heart failure and severe PAH. “From January 2007 through to December 2007, we performed a total of 263 right heart catheterizations,” Dr. Al-Hiti told delegates. In 16 of those patients, pulmonary hemodynamics were such that they mandated testing of the reversibility of PAH, defined as patients who had a transpulmonary gradient (TPG) >15 mm Hg and/or pulmonary vascular resistance =3 woods units (Wu) in euvolemia.

“Hemodynamic parameters were measured at baseline prior to right heart catheterization, after five minutes of continuous infusion with the PGE1 alprostadil 200 ug/kg/min and 1 hour after the administration of a single dose of sildenafil 40 mg.

Table 1.

Dr. Al-Hiti reported, “Results show that sildenafil citrate has higher pulmonary selectivity than PGE1 and improves hemodynamic parameters in pulmonary circulation of patients with PAH and heart failure.” In commenting further on their findings, Dr. Al-Hiti noted that the whole concept of “unmasking” reversible PAH due to left heart disease might have to be re-assessed because the newer agents such as sildenafil can decrease PAH in most patients, such that some of them can be taken off the waiting list: with therapy, pulmonary pressures return to normal and functional class improves. “If there is no response to PGE1, we give sildenafil chronically to these patients and then repeat right heart catheterization after two to three months to see if there is still some contraindication to heart transplantation; we may uptitrate the dose or if the [pulmonary pressures] are still too high, we give them a ventricular assist device,” he explained.

Dr. Al-Hiti also remarked that perhaps in contrast to North American practice, their institute uses sildenafil at a dose of between 20 and 40 mg t.i.d. and that treatment is well tolerated in this patient population.

Right Ventricular Dysfunction Following Transplantation

Right ventricular dysfunction (RVD) is a complication that arises in approximately 10% to 15% of patients following heart transplantation, typically within the first few hours or days following surgery. When RVD occurs, it has a negative impact on both long-term prognosis and survival and PAH is the most important contributor to the development of RVD after heart transplantation. Another study was discussed in a poster submitted by Dr. Marek Orban, Center of Cardiovascular and Transplant Surgery, Brno, Czech Republic, and fellow researchers. Between November 2007 and December 2009, 13 patients out of 51 who had developed RVD after undergoing heart transplantation in their centre were treated with sildenafil.

Pre-operative diagnoses were ischemic cardiomyopathy in eight patients, dilated cardiomyopathy in four patients and congenital abnormalities in one patient. “In selected graft recipients with PAH and significant tricuspid regurgitation, in addition to conventional inodilator support and alprostadil, we administered 1 to 2 mg/kg of sildenafil,” investigators observed, “and hemodynamic measurements were obtained before transplantation and d
ion.”

Table 2.

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On day 1 following transplantation, right ventricular ejection fraction (RVEF) was 40%, the authors reported; one month later, RVEF was 55%. Tricuspid regurgitation decreased from an average grade of 2.8 on day 1 after the surgery to a grade of 1.2 one month later and was “trivial” at the time of discharge, as the authors noted.

“Sildenafil treatment was discontinued within three days after significant regression of tricuspid regurgitation using stepwise dose reduction,” investigators noted. They concluded, “sildenafil may be effectively used for the treatment of acute RVD in heart transplantation recipients with PAH.”

Pediatric Population

Dr. Rakesh Singh, Instructor in Clinical Pediatrics, Columbia University Medical Center, New York, discussed the development of RVD due to high pulmonary vascular resistance indexed (PVRI) following heart transplantation in a pediatric population. Between September 2007 and September 2009, 13 children, median age 6.4 years, with RVD and high PVRI on either echocardiogram or right heart catheterization received sildenafil following heart transplantation. “Three patients had early (<72 hours) discontinuation of sildenafil due to pulmonary edema,” Dr. Singh reported. Hemodynamic data from right heart catheterization carried out before and after starting sildenafil were available in eight patients and was collected prior to transplantation; post-transplantation but before sildenafil treatment; post-transplantation on treatment; and post-transplantation off treatment. Sildenafil significantly decreased three hemodynamic parameters: systolic pulmonary artery pressure (SPAP), TPG and PVRI (Table 3). Furthermore, right vent
ved in all patients on follow-up echocardiograms.

Table 3.

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Summary

“One of the advantages of using sildenafil is that it allows us to transition patients out of the hospital more quickly as we can give it to them orally rather than intravenously or via an inhaler,” Dr. Singh observed. “Within the limitations of our study, their numbers do improve, they tend to do well and it suggests that this medication offers a lot of hope for these children.”