Effects of Sildenafil on Haemodynamics and Exercise in HF
Between October 2011 and September 2014, 52 patients with HFpEF and pulmonary hypertension were randomized to receive sildenafil or placebo (Figure 1). Baseline characteristics are summarized in Table 1. We observed some imbalances between the two treatment arms based on standardized differences, as can be expected in small studies (see Supplementary material online, Table S1http://eurheartj.oxfordjournals.org/content/suppl/2015/07/16/ehv336.DC1). The proportion of patients with a pre-capillary component of pulmonary hypertension is summarized in Table 2. Using the definitions transpulmonary gradient (TPG) >12 mmHg, diastolic pulmonary gradient (DPG) ≥7 mmHg and PVR >240 dynes/s/cm, 52, 12, and 35%, respectively, of patients had a pre-capillary component of pulmonary hypertension. In these subgroups, median TPG was 18 (15–20) mmHg, median DPG was 9 (9–13) mmHg, and median PVR was 321 (269–387) dynes/s/cm (Table 2).
Primarily, 13 patients could not be taken into account in the efficacy analysis (Figure 1). One patient died due to heart failure, and was considered as a potential 'treatment failure'. Prior unblinding, missing data of this patient were imputed with the highest increase for the variable of interest.
After 12 weeks of therapy, mean change in PAP from baseline to Week 12 was −2.4 (95% CI −4.5 to −0.3) mmHg in the sildenafil group, whereas change in mean change in PAP from baseline to Week 12 was −4.7 (95% CI −7.1 to −2.3) mmHg in the placebo group (P = 0.14, Figure 2, Table 3). The mean PAP trajectories of each individual patient are visualized in Supplementary material online, Figure S2http://eurheartj.oxfordjournals.org/content/suppl/2015/07/16/ehv336.DC1. In the subgroup >240 dynes/s/cm, treatment effect of sildenafil (n = 7) vs. placebo (n = 8) after 12 weeks was −4.6 (95% −10.3 to 1.2) mmHg vs. −5.1 (95% −10.8 to 0.6) mmHg. In the subgroup ≤240 dynes/s/cm, treatment effect of sildenafil (n = 13) vs. placebo (n = 14) was −1.4 (95% −3.5 to 0.7) mmHg vs. −4.4 (95% −7.1 to −1.7) mmHg (P for interaction = 0.958). After 12 weeks of treatment, mean PCPW was reduced by 3.5 (95% CI −5.2 to −1.8) mmHg in the placebo group, compared with 0.5 (95% CI −1.9 to 1.0) mmHg in the sildenafil group (P = 0.008, Table 3). The Pearson's correlation between left ventricular end-diastolic pressure and PAWP was 0.848 (P < 0.001). In the sildenafil group, mean change in cardiac output from baseline to Week 12 was −0.4 (95% CI −0.9 to 0.1) L/min. In the placebo group, mean change in cardiac output from baseline to Week 12 was −0.2 (95% CI −0.5 to 0.1) L/min (P = 0.37, Table 3). Table 4 summarizes haemodynamic data of the cardiac catheterization at baseline and 12 weeks. In the sildenafil group, mean change in peak VO2 from baseline to Week 12 was 0.2 (95% CI −0.9 to 1.4) mL/min/kg. In the placebo group, mean change in peak VO2 from baseline to Week 12 was 0.7 (95% CI −0.3 to 1.6) mL/min/kg (P = 0.51, Table 3). At baseline and 12 weeks 22 and 16 patients, respectively, reached an RQ ≥1.0. Supplementary material online, Table S2http://eurheartj.oxfordjournals.org/content/suppl/2015/07/16/ehv336.DC1, summarizes measurements of the exercise test at baseline and Week 12. At baseline, mean KCCQ clinical summary was 51.08 ± 24.93 points in the sildenafil group and 47.31 ± 29.28 points in the placebo group. After 12 weeks of treatment, mean KCCQ clinical summary was 64.05 ± 34.29 points in the sildenafil group and 68.33 ± 32.16 points in the placebo group. The mean change in the KCCQ clinical summary score from baseline to 12 weeks was 12.05 (95% CI 1.14–22.96) points in the sildenafil group and 19.83 (95% CI 8.23–31.44) points in the placebo group (P = 0.32). Supplementary material online, Table S3http://eurheartj.oxfordjournals.org/content/suppl/2015/07/16/ehv336.DC1, summarizes detailed information regarding concomitant medication, physical examination, laboratory values, and echocardiographic measurements.
(Enlarge Image)
Figure 2.
Change in mean pulmonary artery pressure after 12 weeks of treatment with sildenafil of placebo.
During follow-up, one patient receiving sildenafil died due to heart failure (4%), and one patient receiving placebo died due to intestinal ischaemia (4%). Adverse events occurred in 22 patients (85%) who received sildenafil and 21 (81%) patients who received placebo (P = 1.00). Prevalence of known adverse effects of sildenafil, such as headache, dyspepsia, (orthostatic) hypotension, increased erection and respiratory tract infection, was higher in the sildenafil group. No major NYHA reclassifications were observed during follow-up (Figure 3). Detailed adverse events are listed in Supplementary material online, Table S4http://eurheartj.oxfordjournals.org/content/suppl/2015/07/16/ehv336.DC1.
(Enlarge Image)
Figure 3.
New York Heart Association classification at baseline, and at Week 2, 4, and 12.
Results
Baseline Characteristics
Between October 2011 and September 2014, 52 patients with HFpEF and pulmonary hypertension were randomized to receive sildenafil or placebo (Figure 1). Baseline characteristics are summarized in Table 1. We observed some imbalances between the two treatment arms based on standardized differences, as can be expected in small studies (see Supplementary material online, Table S1http://eurheartj.oxfordjournals.org/content/suppl/2015/07/16/ehv336.DC1). The proportion of patients with a pre-capillary component of pulmonary hypertension is summarized in Table 2. Using the definitions transpulmonary gradient (TPG) >12 mmHg, diastolic pulmonary gradient (DPG) ≥7 mmHg and PVR >240 dynes/s/cm, 52, 12, and 35%, respectively, of patients had a pre-capillary component of pulmonary hypertension. In these subgroups, median TPG was 18 (15–20) mmHg, median DPG was 9 (9–13) mmHg, and median PVR was 321 (269–387) dynes/s/cm (Table 2).
Primarily, 13 patients could not be taken into account in the efficacy analysis (Figure 1). One patient died due to heart failure, and was considered as a potential 'treatment failure'. Prior unblinding, missing data of this patient were imputed with the highest increase for the variable of interest.
Study Outcomes
After 12 weeks of therapy, mean change in PAP from baseline to Week 12 was −2.4 (95% CI −4.5 to −0.3) mmHg in the sildenafil group, whereas change in mean change in PAP from baseline to Week 12 was −4.7 (95% CI −7.1 to −2.3) mmHg in the placebo group (P = 0.14, Figure 2, Table 3). The mean PAP trajectories of each individual patient are visualized in Supplementary material online, Figure S2http://eurheartj.oxfordjournals.org/content/suppl/2015/07/16/ehv336.DC1. In the subgroup >240 dynes/s/cm, treatment effect of sildenafil (n = 7) vs. placebo (n = 8) after 12 weeks was −4.6 (95% −10.3 to 1.2) mmHg vs. −5.1 (95% −10.8 to 0.6) mmHg. In the subgroup ≤240 dynes/s/cm, treatment effect of sildenafil (n = 13) vs. placebo (n = 14) was −1.4 (95% −3.5 to 0.7) mmHg vs. −4.4 (95% −7.1 to −1.7) mmHg (P for interaction = 0.958). After 12 weeks of treatment, mean PCPW was reduced by 3.5 (95% CI −5.2 to −1.8) mmHg in the placebo group, compared with 0.5 (95% CI −1.9 to 1.0) mmHg in the sildenafil group (P = 0.008, Table 3). The Pearson's correlation between left ventricular end-diastolic pressure and PAWP was 0.848 (P < 0.001). In the sildenafil group, mean change in cardiac output from baseline to Week 12 was −0.4 (95% CI −0.9 to 0.1) L/min. In the placebo group, mean change in cardiac output from baseline to Week 12 was −0.2 (95% CI −0.5 to 0.1) L/min (P = 0.37, Table 3). Table 4 summarizes haemodynamic data of the cardiac catheterization at baseline and 12 weeks. In the sildenafil group, mean change in peak VO2 from baseline to Week 12 was 0.2 (95% CI −0.9 to 1.4) mL/min/kg. In the placebo group, mean change in peak VO2 from baseline to Week 12 was 0.7 (95% CI −0.3 to 1.6) mL/min/kg (P = 0.51, Table 3). At baseline and 12 weeks 22 and 16 patients, respectively, reached an RQ ≥1.0. Supplementary material online, Table S2http://eurheartj.oxfordjournals.org/content/suppl/2015/07/16/ehv336.DC1, summarizes measurements of the exercise test at baseline and Week 12. At baseline, mean KCCQ clinical summary was 51.08 ± 24.93 points in the sildenafil group and 47.31 ± 29.28 points in the placebo group. After 12 weeks of treatment, mean KCCQ clinical summary was 64.05 ± 34.29 points in the sildenafil group and 68.33 ± 32.16 points in the placebo group. The mean change in the KCCQ clinical summary score from baseline to 12 weeks was 12.05 (95% CI 1.14–22.96) points in the sildenafil group and 19.83 (95% CI 8.23–31.44) points in the placebo group (P = 0.32). Supplementary material online, Table S3http://eurheartj.oxfordjournals.org/content/suppl/2015/07/16/ehv336.DC1, summarizes detailed information regarding concomitant medication, physical examination, laboratory values, and echocardiographic measurements.
(Enlarge Image)
Figure 2.
Change in mean pulmonary artery pressure after 12 weeks of treatment with sildenafil of placebo.
Safety Analysis
During follow-up, one patient receiving sildenafil died due to heart failure (4%), and one patient receiving placebo died due to intestinal ischaemia (4%). Adverse events occurred in 22 patients (85%) who received sildenafil and 21 (81%) patients who received placebo (P = 1.00). Prevalence of known adverse effects of sildenafil, such as headache, dyspepsia, (orthostatic) hypotension, increased erection and respiratory tract infection, was higher in the sildenafil group. No major NYHA reclassifications were observed during follow-up (Figure 3). Detailed adverse events are listed in Supplementary material online, Table S4http://eurheartj.oxfordjournals.org/content/suppl/2015/07/16/ehv336.DC1.
(Enlarge Image)
Figure 3.
New York Heart Association classification at baseline, and at Week 2, 4, and 12.
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