BARCELONA, SPAIN — Patients with residual pulmonary hypertension (PH) following successful valvular surgery should not be treated with sildenafil, suggest results of the first randomized controlled trial to test the drug's effects in this population.
The researchers tested sildenafil, which is more commonly known as a treatment for erectile dysfunction but is also effective in treating pulmonary arterial hypertension, against placebo in 200 patients who had undergone valve repair or replacement.
Presenting their data as a late-breaking clinical trial at the European Society of Cardiology (ESC) 2017 Congress, they showed that the drug doubled the risk of clinical events, with few patients showing improvements in their clinical status.
During a press conference that featured the study, Dr Javier Bermejo (Hospital General Universitario Gregorio Marañón, Madrid, Spain) told theheart.org | Medscape Cardiology that he cannot say at this stage why sildenafil is worsening outcomes in these patients.
"We will need to go into all of this to try to understand why this is happening . . . but we do believe it must have to do with rising pulmonary pressures in the long term," he said.
Bermejo added that it is known that these patients "have a number of issues," and previous studies have shown that patients who have undergone valvular procedures have an increase in cardiac output and a lowering of pulmonary resistance, which "may have an impact."
He said that this "is something we definitely need to look at the specific subgroups of hemodynamic data we have."
However, Dr Jacob Thorsted Sorensen (Aarhus University Hospital, Skejby, Denmark), who was not involved in the study, told theheart.org | Medscape Cardiology that, to him, the results "are not so surprising, because the mechanism behind pulmonary hypertension in these patients is completely different" from that seen in other PH patients.
"But, of course, I think that most cardiologists would think that this wouldn't do any harm, and in that sense this is something that has led us to think about off-label use in general," he added.
"We have to make sure that we're not doing any harm, and that's why this is such an important study, showing very elegantly and very simply that we can't just take results from one area and then apply them on another without doing the science," Sorensen said.
The only established treatment for valvular heart disease is the repair or replacement of the valve, either surgically or percutaneously. However, patients can experience ongoing or reemergent symptoms over the long term, with residual PH an important risk factor for death and disability, even after a successful procedure.
Bermejo explained that, while there is currently no treatment for residual PH following a valvular repair or replacement, sildenafil has been shown to be effective in treating other forms of PH.
He nevertheless said that the evidence in support of the drug when used to treat pulmonary hypertension related to left heart disease is "discordant," and sildenafil has never previously been tested for PH related to valvular heart disease.
To examine whether the drug improves outcomes in patients with successfully corrected valvular heart disease but residual PH, the team conducted the Sildenafil for Improving Outcomes after Valvular Correction (SIOVAC) study, a multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial.
They performed right cardiac catheterization to confirm the presence of residual moderate or severe PH following a successful valve procedure performed at least 1 year previously in 200 patients treated at 18 tertiary-care hospitals in Spain. They were randomized in a 1:1 fashion to either sildenafil 40 mg three times daily (n=104) or placebo (n=96) for 6 months.
The two groups were well balanced in terms of their baseline demographic and clinical characteristics.
The patients underwent clinical, laboratory, and imaging follow-up at 3 and 6 months, and their composite clinical score, which is a commonly used tool in heart-failure clinical trials, was calculated to assess their outcomes.
Using this tool, each patient was classified as having worsened, improved, or remained unchanged.
Patients were deemed to have worsened if they had died; were readmitted to the hospital due to heart failure and required intravenous diuretic therapy; had worsening World Health Organization functional class as determined by the investigating physician; or had markedly worsening self-reported patient global assessment scores.
Patients were classified as having improved if they improved in their functional class or reported significant improvements on their self-assessment scores, while those who were deemed unchanged were those who fulfilled the requirements of neither of the two other categories.
The raw data indicated that 33 of the patients given sildenafil experienced a worsening of their clinical status during follow-up, compared with 14 patients in the placebo group. This compared with 37 sildenafil patients and 32 placebo patients who remained unchanged, and 27 sildenafil and 44 placebo patients whose clinical status improved.
Further analysis revealed that the use of sildenafil was associated with a significantly reduced the likelihood of having an improvement in their composite clinical score, at an odds ratio compared with placebo of 0.39 (95% CI 0.22–0.67, P<0.001).
Furthermore, the drug was associated with a significant increase in the risk of major clinical events vs placebo, at a hazard ratio of 2.0 (95% CI 1.0–4.0, log-rank P=0.044), which was driven primarily by a doubling in readmissions to the hospital due to heart failure.
There was no difference in mortality rates during the study, at three deaths in the sildenafil arm and two among those given placebo (P=0.63).
Bermejo concluded that, based on these findings, treating residual PH after successful correction of valvular heart disease with sildenafil is associated with unfavorable results and that off-label use of the drug in these patients "should be discouraged."
The study was funded by the Spanish Government and coordinated by the Spanish Network Center for Cardiovascular Research. The authors declare no relevant financial relationships.
Medscape Medical News © 2017
Cite this: Sildenafil Warning in Pulmonary Hypertension After Valve Surgery - Medscape - Aug 28, 2017.