Pulmonary vasodilation by sildenafil in acute intermediate-high risk pulmonary embolism: a randomized explorative trial

Patients with acute pulmonary embolism confirmed by contrast enhanced computed tomography (CT) were eligible for inclusion if they had symptom duration of less than 14 days, were older than 18 years and had a right ventricular/left ventricular ratio (RV/LV) > 1 measured by trans-thoracic echocardiography (TTE, 1 cm above the atrio-ventricular valves in the four-chamber view at end-diastole). Patients were excluded if they were pregnant, had cardiac arrest that required cardiopulmonary resuscitation, a life expectancy < 120 days, systolic blood pressure < 90 mmHg, metal implants, obesity or claustrophobia that excluded the patient from cardiac magnetic resonance (CMR), altered mental status making the patient unable to provide informed consent, recent use of drugs with influence on the NO-cGMP pathway, known or suspected chronic thromboembolic pulmonary hypertension, inability to perform study protocol < 72 h after conventional PE treatment was instituted or active bleeding after thrombolysis. Patients were screened for inclusion at hospitals in the Central Region of Denmark.

The study was designed as a single centre, prospective, randomized, placebo-controlled, double-blind, explorative trial. If eligible for inclusion, the patient was transferred to Aarhus University Hospital to complete the study protocol. To characterize the patients, RV/LV ratio was calculated from the CT scan and by TTE performed at the local institution on the day of diagnosis. Cardiac biomarkers [troponin T/I, N-terminal pro-brain natriuretic peptide (NT-proBNP)], height, weight, respiratory frequency, peripheral saturation, and pulse were measured at the local institution on the day of screening and by the study site on the day of inclusion. A detailed medical history was collected including duration of symptoms, known active cancer, recent surgery/trauma, chronic obstructive pulmonary disease, diabetes mellitus, oestrogen therapy, and/or immobilisation.

During the study protocol (Fig. 1), right ventricular function was evaluated on the same day before and shortly after (0.5–1.5 h) randomization to sildenafil 50 (n = 10) mg or placebo (n = 10) with CMR, TTE and RHC. Primary efficacy endpoint was cardiac index (CI) evaluated by CMR. Blood pressure was evaluated at 30, 45, 120 and 180 min after randomization as a safety measure. Other hemodynamic parameters were analysed as exploratory endpoints. Exploratory endpoints evaluated by TTE were RV/LV ratio, fractional area change (FAC), tricuspid annular plane excursion (TAPSE), pulmonary artery acceleration time (PAAT) and tricuspid regurgitation gradient (TI). Exploratory endpoints evaluated by CMR were heart rate (HR), RV stroke volume (SV), RV end-diastolic volume (EDV), RV end-systolic volume (ESV), right ventricular ejection fraction (EF), mean peak longitudinal strain (MPLS). Exploratory endpoints evaluated by right heart catheterization were mean pulmonary capillary wedge pressure (mPCWP), diastolic-, systolic- and mean pulmonary artery pressure (dPAP, sPAP, mPAP), mixed venous oxygen saturation (SvO₂) and pulmonary vascular resistance (PVR). Detailed protocols for TTE, CMR and RHC are available in the Additional file 1. Study drugs (sildenafil or placebo) were prepared in quickly absorbable gelatinous caps by the institutional pharmacy to blind both patients and the physicians to treatment. The dose of 50 mg sildenafil was chosen based on previous case reports [16, 17] where sildenafil improved hemodynamics in patients with acute PE and a study investigating acute hemodynamic effects of sildenafil in patients with pulmonary hypertension where an i.v. dose equivalent to 50 mg sildenafil effectively lowered MPAP and PVR without any hemodynamic compromise [18]. Patients were randomized in blocks of 10 with sequentially randomly numbered containers. The randomization key was disclosed by the institutional pharmacy after data analysis was complete. All analyses were performed with the observer blinded to treatment. The study was performed and data collected at Aarhus University Hospital, Denmark. The study adheres to CONSORT guidelines.

Sample size was calculated to be 10 patients in each treatment group. The calculation was based on the assumptions of a power of 0.9 and α of 0.05 to detect a paired difference of 29 mL/kg/min change in cardiac index with standard deviation of the difference to be 25 mL. Normality testing was performed with the Shapiro–Wilk test. Within-group comparison of continuous data was performed using the two-sided paired t-test. Between-group continuous data and baseline patient characteristics were compared using the two-sided unpaired Students t-test as an explorative analysis. Two-way ANOVA testing was performed to test differences in systemic blood pressure between groups. If data was not normally distributed, non-parametric tests were used (Wilcoxon matched pairs signed-rank or rank sum test) accordingly. All data are presented as mean ± standard deviation (SD). P ≤ 0.05 was considered statistically significant.

We enrolled 21 patients from the 1st of march 2015 through 10th of September 2017 and randomly assigned 20 patients to a single 50 mg dose of sildenafil (n = 10) or placebo (n = 10). All patients randomized to treatment had acute PE verified by CT pulmonary angiography, increased RV/LV ratio measured on CT and TTE and increased cardiac biomarkers measured by troponin T/I and/or NT-proBNP. More patients had previous deep venous thromboses in the placebo group. None of the patients were treated with thrombolysis. Other baseline characteristics were similar in both groups (Table 1). Time from hospital admission and initiation of conventional therapy to study inclusion were 2.3 ± 0.7 days. Mean CI for all patients included was 2.3 ± 0.6 l/min/m². CMR was performed in all patients. Inclusion rate was low initially as several patients wanted to avoid right heart catheterization (RHC). To improve inclusion rate, RHC was made optional 4 months after initiation of the study. RHC was performed in 16 patients (sildenafil n = 8 and placebo n = 8). TTE were performed in all patients, but the results from 2 patients were excluded before unblinding due to poor image quality (placebo n = 2). One patient did not have RV/LV > 1 on TTE on the day of inclusion and was excluded as screening failure before randomization.

Primary and explorative endpoints are summarized in Fig. 2a and Table 2. Time from administration of study drug to right ventricular evaluation were 32 ± 5 min for RHC, 74 ± 17 min for CMR, and 84 ± 40 min for TTE. Sildenafil did not improve cardiac index (primary endpoint) measured by CMR (Placebo baseline vs. follow up 2.28 ± 0.40 vs. 2.29 ± 0.54, p = 0.97; sildenafil baseline vs. follow-up 2.37 ± 0.70 vs. 2.38 ± 0.61, p = 0.89). Exploratory endpoints measured by CMR revealed that sildenafil significantly reduced end-diastolic and end-systolic RV volume. mPCWP increased with placebo but was unaltered by sildenafil. PAAT was shortened after placebo treatment but was unaltered by sildenafil. Other exploratory endpoints were unaltered both by sildenafil and placebo.

None of the patients reported adverse events. Blood pressure was lower in sildenafil treated patients compared to placebo (Fig. 2b). The maximal drop in blood pressure was observed 120 min after administration of study drug (sildenafil: -19 ± 10, placebo: 0 ± 9 mmHg, p = 0.0007) to a MAP of 91 ± 14 mmHg in the sildenafil and 104 ± 10 in the placebo treated patients. The largest drop in systemic blood pressure in a single patient was from 146/95 to 94/64 mmHg observed 180 min after sildenafil treatment.