Abstract
Only a small percentage of patients with chronic thromboembolic pulmonary hypertension are eligible for pulmonary thrombendarterectomy. We investigated the effects of oral sildenafil on hemodynamics and exercise capacity in 12 nonoperable chronic thromboembolic pulmonary hypertension patients. All patients were in disease progression despite sufficient long-term anticoagulation and the best supportive care and suffered from severe pulmonary hypertension (pulmonary vascular resistance index 1,935 ± 228 dyn · s · cm−5 · m2, cardiac index 2.0 l · min−1 · m−2, 6-minute walking distance 312 ± 30 m). After approximately 6 months of sildenafil treatment, pulmonary hemodynamics and exercise capacity improved significantly (pulmonary vascular resistance index 1,361 ± 177 L · min−1 · m2 , p = 0.004, cardiac index 2.4 ± 0.2 L · min−1 · m−2, p = 0.009, 6-minute walking distance 366 ± 28 m, p = 0.02). Therefore, oral sildenafil may offer a new option for medical treatment of this devastating disease.
Only a percentage of patients with severe chronic thromboembolic pulmonary hypertension (CTEPH) can be treated by pulmonary thrombendarterectomy (1). Once substantial embolization has occurred, vascular remodeling in the nonoccluded vascular bed may ensue. This accounts for a progressive increase in lung vascular resistance, resembling the pathologic features in primary pulmonary hypertension (2–4).
In patients with CTEPH, inhaled nitric oxide and aerosolized iloprost cause acute pulmonary vasodilation (5). A recent controlled multicenter study in long-term inhaled iloprost for treatment of severe pulmonary hypertension demonstrated significant improvement of exercise capacity, pulmonary hemodynamics, and event-free survival. This study included also patients with CTEPH, further supporting the notion that vasodilator/antiremodeling therapy may also be effective in this type of pulmonary hypertension (6).
Oral sildenafil was recently noted to be a more potent acute pulmonary vasodilator than inhaled nitric oxide in pulmonary hypertension (5). Approved for the treatment of erectile dysfunction, sildenafil is an inhibitor of the phosphodiesterase type 5. This enzyme is abundantly expressed in the lung tissue (7) and thereby stabilizes the second messenger cGMP. In this study, we investigated the long-term effect of oral sildenafil in nonoperable CTEPH patients.
Twelve patients (5 females and 7 males) who were referred to our center because of severe pulmonary hypertension were selected. In all cases, they had undergone extensive diagnostic procedures that strongly suggested CTEPH. These procedures included lung function testing, echocardiography, high-resolution computed tomography scan, ventilation/perfusion scintigraphy, spiral computed tomography, and pulmonary angiography. Spiral computed tomography findings were considered as CTEPH typical if most of the following nine criteria were met: (1) the absence of central intraluminal filling defects outlined by contrast medium which are confident signs of acute pulmonary embolism, (2) thromboembolic wall thickening, (3) irregular vessel margins, (4) intraluminal webs, (5) dilation of the central pulmonary arteries, (6) mosaic perfusion in high-resolution computed tomography, (7) enlargement of the right ventricle, (8) pleural or pericardial effusion, and (9) dilation and serpentiguous course of the bronchial arteries. Pulmonary angiography was performed by selective catheterization of the right and left pulmonary artery in at least two views. Imaging of peripheral vessels was performed by balloon-occlusion angiography. All were evaluated for surgical desobliteration but were excluded from this procedure because of predominant or exclusive peripheral localization of the thrombotic material. At the beginning of the study, all patients were on controlled oral anticoagulant treatment with phenprocoumon for at least 6 months (mean 10.8 ± 2.4 months). Patients were suggested to enter this study when at least two of the following criteria of deterioration were fulfilled over a 3-month observation period: (1) subjective clinical worsening, (2) deterioration in 6-minute walk distance of more than 20%, (3) signs of increased right heart load despite ongoing therapy and optimization of diuretics (e.g., edema refractory to diuretic therapy, ascites or pleural effusion refractory to diuretic therapy, increased liver enzymes attributable to venous congestion, central venous pressure of 17 mm Hg or higher), and (4) syncope.
The study was approved by the Justus-Liebig-University Giessen Ethics Committee, and each patient gave written informed consent. Exercise capacity was quantified by the unencouraged 6-minute walking test, in accordance with the guidelines of the American Thoracic Society (8). The test was initially repeated at least twice for familiarization. Oxygen supply continued during the test procedure whenever patients were on chronic oxygen therapy. The technician who assisted the test carried the transportable oxygen delivery system. At the beginning of the study, six patients were on chronic oxygen therapy. At the time of the second catheterization, only four patients still required long-term oxygen therapy. Hemodynamics were assessed by pulmonary artery catheterization, including acute vasodilator testing with inhaled nitric oxide (10–20 parts per million) and, after hemodynamic parameters had returned to baseline, donation of a single oral dose of 50 mg of sildenafil with subsequent measurements being made 60 minutes after drug intake. After baseline testing, patients received oral sildenafil (50 mg three times daily; dosage increased over the first 4–5 days). The addition of new (or a significant increase in the dosage of the ongoing) diuretics (i.e., doubling of the dose), changes in calcium channel antagonists (as far as applied), or the addition of other vasodilators was not performed in any of the patients during the observation period. However, changes in unspecific therapy (e.g., antibiotics, corticosteroids) were made whenever appropriate. Retesting was performed after a mean of 6.5 ± 1.1 months of treatment.
All data presented here are means ± SEM. The Wilcoxon test was used to test for significant differences between presildenafil and postsildenafil values (StatExact-4 version 4.0.1; Cytel Software Corporation, Cambridge, MA).
The patients suffered from severe pulmonary hypertension with a mean pulmonary artery pressure of 52.6 ± 3.6 mm Hg, an increased pulmonary vascular resistance index of 1,935 ± 228 dyn · s · cm−5 · m2, a low cardiac index of 2.0 l · min−1 · m−2, and an elevated central venous pressure of 11.0 ± 1.4 mm Hg (Table 1
HR (L/min) | mSAP (mm Hg) | mPAP (mm Hg) | CVP (mm Hg) | CI (L · min−1 · m−2) | PVRI (dyn · s · cm−5 · m2) | 6 mw (m) | PaO2 (mm Hg) | |||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient Number | Pre-sil | Sil | Pre-sil | Sil | Pre-sil | Sil | Pre-sil | Sil | Pre-sil | Sil | Pre-sil | Sil | Pre-sil | Sil | Pre-sil | Sil | ||||||||
| 1 | 77 | 86 | 85 | 69 | 50 | 52 | 10 | 13 | 1.3 | 2.6 | 2909 | 1348 | 330 | 335 | 64 | 56 | ||||||||
| 2 | 82 | 81 | 95 | 78 | 81 | 64 | 9 | −3 | 1.9 | 1.9 | 3061 | 2596 | 292 | 364 | 57 | 89 | ||||||||
| 3 | 79 | 69 | 98 | 80 | 50 | 48 | 13 | 5 | 1.4 | 1.7 | 2077 | 2008 | 386 | 513 | 65 | 55 | ||||||||
| 4 | 65 | 65 | 111 | 103 | 40 | 28 | 2 | −2 | 2.2 | 2.5 | 1153 | 442 | 358 | 422 | 74 | 75 | ||||||||
| 5 | 76 | 68 | 123 | 95 | 53 | 37 | 11 | 3 | 2.5 | 2.3 | 1201 | 991 | 474 | 414 | 80 | 63 | ||||||||
| 6 | 86 | 74 | 90 | 108 | 46 | 30 | 11 | 3 | 1.1 | 2.0 | 3111 | 1023 | 144 | 200 | 71 | 104 | ||||||||
| 7 | 77 | 71 | 125 | 130 | 55 | 47 | 13 | 8 | 2.2 | 2.6 | 1544 | 1096 | 161 | 320 | 67 | 80 | ||||||||
| 8 | 77 | 70 | 87 | 76 | 48 | 47 | 14 | 10 | 1.7 | 1.9 | 1923 | 1647 | 270 | 332 | 73 | 88 | ||||||||
| 9 | 73 | 63 | 113 | 100 | 67 | 60 | 12 | 6 | 2.4 | 2.3 | 1725 | 1780 | 260 | 280 | 59 | 60 | ||||||||
| 10 | 62 | 72 | 118 | 93 | 34 | 33 | 5 | −2 | 1.7 | 1.8 | 1297 | 1385 | 278 | 250 | 63 | 87 | ||||||||
| 11 | 90 | 75 | 90 | 74 | 48 | 41 | 22 | 15 | 3.8 | 4.7 | 805 | 491 | 315 | 460 | 66 | 67 | ||||||||
| 12 | 75 | 62 | 107 | 106 | 59 | 52 | 10 | 2 | 1.7 | 2.2 | 2412 | 1522 | 480 | 502 | 82 | 76 | ||||||||
| Mean | 76.6 | 71.3 | 103.5 | 92.7 | 52.6 | 44.9 | 11.0 | 4.8 | 2.0 | 2.4 | 1935 | 1361 | 312 | 366 | 68 | 75 | ||||||||
| SEM | 2.2 | 2.0 | 4.2 | 5.2 | 3.6 | 3.3 | 1.4 | 1.7 | 0.2 | 0.2 | 228 | 177 | 30 | 28 | 2 | 4 | ||||||||
| Wilcoxon Test | NS | p = 0.03 | p = 0.03 | p = 0.001 | p = 0.009 | p = 0.004 | p = 0.02 | NS | ||||||||||||||||
Figure 1. Pulmonary vascular resistance index (PVRI) and 6-minute walking distance before (pre-sil baseline; hatched bars) and during sildenafil therapy (sil; black bars ). Baseline values were assessed before the start of any sildenafil treatment, and reassessment was undertaken after 6.5 ± 1.1 months of therapy (2–3 hours after oral intake of the regular morning dose of sildenafil). Data presented are means ± SEM (n = 12, each). Significant differences (two-sided p value given) are indicated.
[More] [Minimize]After 6.5 ± 1.1 months, a significant reduction of mean pulmonary artery pressure, pulmonary vascular resistance index, and central venous pressure and a significant increase in cardiac index was noted (Table 1). Arterial oxygenation improved some. There was also an increase (though nonsignificant) in mixed venous oxygen saturation (58.2 ± 2.5% versus 61.4 ± 1.5%). The 6-minute walking distance significantly increased to 366 ± 28 m (p = 0.02).
No serious, sildenafil-related adverse events were reported, including headache, dyspepsia, or unwanted erections. Ophthalmologic examinations did not reveal abnormal vision. There was some decrease in systemic arterial pressure noted, although there was no syncope in any patient during sildenafil treatment and no complaints of dizziness. No patient had to be hospitalized due to clinical deterioration, and no death occurred.
The patients included in this study were not candidates for surgical desobliteration and were diagnosed with severe CTEPH using state of the art techniques. All complained of the deterioration of their clinical state despite controlled long-term anticoagulation, suggesting secondary remodeling mechanisms (2). Two recent studies addressing the issue of prognostic factors in medically treated patients with CTEPH found that mean pulmonary arterial pressure values above 30 mm Hg were among the strongest risk factors predictive of a poor survival and rapid disease progression (9, 10). Therefore, the average value of mean pulmonary artery pressure of 52.6 mm Hg in this patient population strongly suggested poor prognosis. Furthermore, elevated central venous pressure values, along with significantly restricted cardiac output, indicated commencing right heart failure. As all patients deteriorated during the preceding period of well-documented anticoagulation, spontaneous improvement was not to be expected in this group (10).
Long-term treatment with sildenafil markedly improved hemodynamics and exercise capacity. The consistency of the sildenafil effect is obvious because all of the relevant parameters changed significantly (mean pulmonary artery pressure, pulmonary vascular resistance index, cardiac index, central venous pressure, 6-minute walk distance). The 6-minute walking distance increased by 54 m, which is similar to the changes seen with prostanoids in primary pulmonary hypertension patients (6).
The marked effect of sildenafil in the pulmonary circulation, both when assessing acute hemodynamic effects (5, 11) and on chronic use (this study), reflects the fact that the lung is rich in phosphodiesterase-5 (7). This could even be upregulated in pulmonary hypertension. This may also explain the preferential pulmonary vasodilatory action of oral sildenafil and the fact that this agent appears to show higher efficacy than prostanoids, as far as hitherto being assessed in CTEPH patients (6, 12). It will be of interest to see in future studies whether the impressive effects seen with sildenafil could be obtained also with other vasodilators. Notably, because arterial oxygenation did not deteriorate, we refute the expectation that systemic vasodilators will worsen ventilation/perfusion matching.
In conclusion, although limited by the lack of a control group, long-term treatment with the oral phosphodiesterase-5 inhibitor sildenafil caused a significant improvement of pulmonary hemodynamics and exercise capacity in patients with severe nonoperable CTEPH. These findings must be confirmed by a randomized placebo-controlled multicenter study.
The authors thank Jenny and Michael Yeager for thorough linguistic editing of the manuscript.
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