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Treatment of Pulmonary Hypertension Complicating Sarcoidosis
Treatment of SAPH remains controversial due to the limited available data mostly from case reports and small nonrandomized series ( Table 1 ). In theory, anti-inflammatory and immunomodulatory agents have the potential to attenuate PH caused by active granulomatous inflammation in sarcoidosis. A nonrandomized study evaluated 12 months of corticosteroid use in 24 patients with radiographic stage II and stage III sarcoidosis. At baseline, RHC demonstrated PH at rest in three patients; 18 had exercise-induced PH. At 12 months, chest radiographs and pulmonary function tests (PFTs) improved in 92%, while hemodynamics improved in 50%. Another retrospective study evaluated 10 patients with SAPH [stage 0 (n = 1); stage II (n = 4); stage IV (n = 5)] after treatment with high dose prednisone (0.5–1 mg/kg). After 3–6 months of treatment, all 5 patients with stage IV disease had unchanged or increased sPAP, whereas 3 of 5 patients with less advanced disease showed mild improvement. Thus, corticosteroids or immunosuppressive agents may be effective in sarcoid patients with active granulomatous inflammation, but may have little benefit in those with severe cystic or fibrotic disease.
The use of PH-specific therapies in SAPH has been extrapolated from studies in Group I PAH. However, there are inherent differences in the pathophysiology of PH between these diseases, and the use PH-targeted therapy in SAPH is controversial. PH-targeted therapy may be ineffective for SAPH as areas of fibrotic or "fixed" remodeling may not respond to pulmonary artery vasodilators. PH-targeted therapy may worsen oxygenation by reversing physiologic hypoxemic vasoconstriction and increasing blood flow to areas with poor ventilation, causing increased shunt or ventilation/perfusion (V/Q) inequality. In addition, PH-targeted therapy may also cause acute pulmonary edema and hypoxemia through preferential vasodilation of the pulmonary arteries in the setting of downstream venular obliteration by granulomas.
One non-randomized study treated 8 patients with advanced sarcoidosis (stage III or IV) and concurrent PH (mPAP 55 mm Hg) with vasodilators [i.e., iNO, intravenous epoprostenol (EPO), or calcium channel blockers (CCB)]. Short term responses (>20% decrease in PVR) were noted in 7 of 8 receiving iNO, 4 of 6 receiving EPO, and 2 of 5 receiving CCB. Long term iNO was associated with improved 6 MWD in all five treated patients; however, five of the eight patients died within 1.5 years of study enrollment. One death was due to catheter-related sepsis but no other significant treatment complications were reported. Another retrospective review evaluated treatment with EPO in 7 patients with sarcoidosis [radiologic stages: I (n = 1), II (n = 1), III (n = 1), and IV (n = 4)] and PH. These patients had severe diffusion impairment (mean DLCO 30% predicted) but only moderate restrictive physiology (mean FVC 59% predicted). Although six of seven patients responded favorably to EPO, defined as >25% reduction in PVR, there were significant adverse events due to EPO initiation. One patient died from a cardiac arrest 4 hours after initiation of EPO; two others developed acute respiratory failure due to pulmonary edema (one required mechanical ventilation and the other high flow oxygen supplementation). Both subjects improved with aggressive diuresis and temporary reduction in the EPO dose. Other adverse reactions included systemic hypotension, jaw pain, headache and flushing. After a mean follow-up of 29 months, the five remaining patients were alive on chronic EPO therapy and all had functional improvement by 1 or 2 WHO functional classes.
Inhaled prostanoids (e.g., iloprost or treprostinil) have the theoretical advantage of drug delivery directly to areas with good ventilation and may provide pulmonary vasodilatation with less shunting compared with parenteral prostanoids. However, data utilizing inhaled prostanoids in SAPH are scant. An open-label study of 22 patients with SAPH, mostly stage IV sarcoidosis (68%) and moderate PH (mPAP = 33 mm Hg), reported a mild improvement in hemodynamics and quality of life with inhaled iloprost. Fifteen patients completed 16 weeks of inhaled iloprost therapy with the following hemodynamic changes: PVR declined by > 20% in 6 patients (40%); mPAP declined > 5 mm Hg in 5 patients (33%). Three patients (20%) improved their 6MW distance by > 30 m; however, only 1 of these 3 patients showed hemodynamic improvement. Oxygen requirements increased in 2 patients after initiation of therapy and 7 patients withdrew from the study due to intractable cough and difficulty with compliance, but no other significant adverse events were noted. Inhaled prostanoids are exceedingly expensive, and given the lack of proven efficacy, have no role as therapy for SAPH.
Oral agents (e.g., ET-1 receptor antagonists and phosphodiesterase inhibitors) have been used in small trials, with anecdotal success. A retrospective study of end-stage sarcoidosis patients referred for LT evaluated the use of the phosphodiesterase inhibitor sildenafil (daily oral dose 75 to 225 mg) in 12 patients with SAPH. After a median treatment duration of 4 months (range 1 to 12 months), mPAP decreased by 8 mm Hg; PVR decreased by 5 Wood units; cardiac index increased by 0.6 L/min/m; 6 MWD was unchanged.
Bosentan (an ET-1 receptor inhibitor) has been studied in several small series of SAPH, case reports, and a recent small randomized controlled trial. Barnett et al retrospectively evaluated the use of three PH-specific therapies among 22 patients with SAPH at two referral centers where patients received either sildenafil (n = 9), bosentan (n = 12), or epoprostenol (n = 1). After a median of 11 months, WHO functional class had improved by at least one class in 9 (41%), and mean 6 MWD increased by 59 m from baseline (p = 0.03). Patients with higher FVC and FEV1 had greater improvement in 6 MWD. Among 12 patients who had repeat RHC, mPAP decreased from 49 to 39 mm Hg (p = 0.008). Transplant-free survival rates at 1- and 3-years were 90 and 64%, respectively, with no adverse events reported.
Most recently, Baughman et al evaluated bosentan in a small randomized, double-blind, placebo-controlled trial. Thirty-five SAPH patients from five sites were randomized 2:1 to bosentan (n = 23) or placebo (n = 12), for 16 weeks. Patients were excluded for severe airway obstruction (FEV1/FVC < 35% predicted), NYHA functional class IV status, left ventricular ejection fraction < 35%, cardiac index < 2.0 L/min/m, and/or right atrial pressure > 15 mm Hg. Approximately half of the patients randomized to both groups had FVC < 60% predicted with Scadding Stage IV chest radiographs. After 16-weeks of therapy, there was a significant decrease in mPAP for those treated with bosentan [mean decrease 4 mm Hg (from 36 to 32 mm Hg)] compared with placebo [mean increase 1 mm Hg (from 30 to 31 mm Hg)], p < 0.05. PVR decreased by 1.7 Wood units (from 6.1 to 4.4 Wood units) in the bosentan group compared with a 0.2 Wood unit increase (from 4.0 to 4.2 Wood units) in the placebo group, p > 0.05. However, there was no improvement in functional class, quality of life, or 6 MWD associated with bosentan therapy. No significant adverse events were reported.
Ambrisentan (an ET-1 receptor antagonist) was evaluated in an open label prospective trial of 21 patients with SAPH recruited from two outpatient clinics. Patients received ambrisentan 5 mg per day for 4 weeks, then 10 mg per day for 20 weeks. Exclusion criteria included: FVC < 40% predicted, 6 MWD < 150 m, WHO functional class IV, and left ventricular systolic dysfunction. The mean FVC, FEV1, and DLCO of those enrolled were 62, 59, and 33% (% predicted), respectively. After 24 weeks of treatment, there was no significant change in 6 MWD, DLCO, quality of life, or dyspnea scores. However, this study was poorly powered with 11 (52%) patients discontinuing the study. Eight patients discontinued ambrisentan due to medical reasons (increased edema or dyspnea), and 3 discontinued for social reasons. Only 10 patients completed 24 weeks of therapy.
In a recent retrospective review of 24 patients with SAPH, median survival without LT was 5.3 years. Eleven patients were treated with pulmonary vasodilators. More patients who died or underwent LT had moderate or severe pulmonary fibrosis (67 vs. 15%) and RV dysfunction (80 vs. 8%), and were in WHO class IV (67 vs. 31%). Mortality rates were not statistically different between patients treated with pulmonary vasodilators (54.5%) compared with untreated patients (38%, p = 0.44). By Cox regression survival model, lower body surface area, RV dysfunction, and presence of moderate or severe fibrosis were predictors of worse outcomes, but treatment with pulmonary vasodilators was not predictive of mortality. Among 11 patients treated with pulmonary vasodilators, 6 MWT improved and BNP improved during follow-up; there was a trend toward improvement in hemodynamics.
In summary, the role of PH-targeted therapy for SAPH remains controversial. Data from available studies are confounded by small sample size, lack of suitable controls, differences in the study methodology, heterogeneous patient populations, duration of treatment, and follow-up. Furthermore, the multifactorial nature of PH in sarcoidosis is problematic since PH may be caused by parenchymal fibrosis, granulomatous obliteration, and/or angitis of small vessels, hypoxic vasoconstriction, extrinsic compression of pulmonary vasculature, PVOD, and left heart failure. Inclusion of these diverse patients into a single study may add significant variability to the treatment response. We believe that a subset of patients with PH-sarcoidosis may benefit from PH-targeted therapy, but additional studies are required to determine optimal agents, appropriate recipients, and indications for therapy in this patient population.
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