Sildenafil in severe pulmonary hypertension associated with chronic obstructive pulmonary disease: A randomized controlled multicenter clinical trial

Pulmonary hypertension (PH) complicating chronic obstructive pulmonary disease (COPD-PH) and interstitial lung disease (ILD-PH) (World Health Organization [WHO] Group III PH) increases medical costs and reduces survival. Despite limited data, many clinicians are using pulmonary arterial hypertension (PAH)-specific therapy to treat WHO Group III PH patients. To further investigate the utility of PAH-specific therapy in WHO Group III PH, we performed a systematic review and meta-analysis. Relevant studies from January 2000 through May 2016 were identified in the MEDLINE, EMBASE, and COCHRANE electronic databases and www.clinicaltrials.gov. Change in six-minute walk distance (6MWD) was estimated using random effects meta-analysis techniques. Five randomized controlled trials (RCTs) in COPD-PH (128 placebo or standard treatment and 129 PAH-medication treated patients), two RCTs in ILD-PH (23 placebo and 46 treated patients), and four single-arm clinical trials (50 patients) in ILD-PH were identified. Treatment in both COPD-PH and ILD-PH did not worsen hypoxemia. Symptomatic burden was not consistently reduced but there were trends for reduced pulmonary artery pressures and pulmonary vascular resistance with PAH-specific therapy. As compared to placebo, 6MWD was not significantly improved with PAH-specific therapy in the five COPD-PH RCTs (42.7 m; 95% confidence interval [CI], –1.0 – 86.3). In the four single-arm studies in ILD-PH patients, there was a significant improvement in 6MWD after PAH-specific treatment (46.2 m; 95% CI, 27.9–64.4), but in the two ILD-PH RCTs there was not an improvement (21.6 m; 95% CI, –17.8 – 61.0) in exercise capacity when compared to placebo. Due to the small numbers of patients evaluated and inconsistent beneficial effects, the utility of PAH-specific therapy in WHO Group III PH remains unproven. A future clinical trial that is appropriately powered is needed to definitively determine the efficacy of this widely implemented treatment approach.

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“…showed no difference in oxygenation with treatment (Table 2). 12,20,21 In the ILD-PH, Corte et al. 2014 showed no change in oxygen levels.…”

Section: Resultsmentioning

confidence: 99%

Chronic use of PAH‐specific therapy in World Health Organization Group III Pulmonary Hypertension: a systematic review and meta‐analysis

et al. 2017

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“…The reduction in DLCO following a reduction in mPAP is in contrast to previous studies demonstrating that, in clinical conditions where pulmonary vascular pressures are increased, sildenafil actually improves DLCO (Guazzi et al 2004a,b;Bussotti et al 2008;Vitulo et al 2017). Theoretically, this may be evidence of a 'sweet spot' for mPAP.…”

Section: Importance Of Tpg In Pulmonary Capillary Recruitmentmentioning

confidence: 65%

The influence of pulmonary vascular pressures on lung diffusing capacity during incremental exercise in healthy aging

et al. 2018

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Alveolar‐capillary surface area for pulmonary gas exchange falls with aging, causing a reduction in lung diffusing capacity for carbon monoxide (DLCO). However, during exercise additional factors may influence DLCO, including pulmonary blood flow and pulmonary vascular pressures. First, we sought to determine the age‐dependent effect of incremental exercise on pulmonary vascular pressures and DLCO. We also aimed to investigate the dependence of DLCO on pulmonary vascular pressures during exercise via sildenafil administration to reduce pulmonary smooth muscle tone. Nine younger (27 ± 4 years) and nine older (70 ± 3 years) healthy subjects performed seven 5‐min exercise stages at rest, 0 (unloaded), 10, 15, 30, 50, and 70% of peak workload before and after sildenafil. DLCO, cardiac output (Q), and pulmonary artery and wedge pressure (mPAP and mPCWP; subset of participants) were collected at each stage. mPAP was higher (P = 0.029) and DLCO was lower (P = 0.009) throughout exercise in older adults; however, the rate of rise in mPAP and DLCO with increasing Q was not different. A reduction in pulmonary smooth muscle tone via sildenafil administration reduced mPAP, mPCWP, and the transpulmonary gradient (TPG = mPAP–mPCWP) in younger and older subjects (P < 0.001). DLCO was reduced following the reduction in mPAP and TPG, regardless of age (P < 0.001). In conclusion, older adults successfully adapt to age‐dependent alterations in mPAP and DLCO. Furthermore, DLCO is dependent on pulmonary vascular pressures, likely to maintain adequate pulmonary capillary recruitment. The rise in pulmonary artery pressure with aging may be required to combat pulmonary vascular remodeling and maintain lung diffusing capacity, particularly during exercise.

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“…However, the combined treatment of LTOT with sildenafil or sildenafil associated with simvastatin was more efficacy in the reduction of PAP measured by transthoracic echocardiography (EET) (Tables 2 and 3). The role of sildenafil in treatment of PAH has been described previously but its role in COPD patients with PAH has not been well demonstrated [22,24]. In general, PDE-5 inhibitors could reduce PAP by the effect on vasodilation.…”

Section: Discussionmentioning

confidence: 99%

“…Until now, the exact mechanism of sildenafil or other phosphodiesterase-5 (PDE-5) inhibitors on dyspnea status of patients with COPD has not been well demonstrated [21,22]. However, its role in amelioration of dyspnea status in patients with other cardio-respiratory diseases has been described by previous studies [23,24].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Long Term Oxygen-Therapy (LTOT) and LTOT Combined with Sildenafil and Simvastatin in the Treatment of Severe Chronic Obstructive Pulmonary (COPD) with Hypoxia at Rest and Severe Pulmonary Arterial Hypertension

Tran-Van¹,

Vo-Thi-Kim²,

Tran-Ngoc³

et al. 2017

Vasc Med Surg

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Sildenafil in severe pulmonary hypertension associated with chronic obstructive pulmonary disease: A randomized controlled multicenter clinical trial

Abstract: This pilot study found that treatment with sildenafil reduced pulmonary vascular resistance and improved the BODE index and quality of life, without a significant effect on gas exchange.

Cited by 103 publications

References 24 publications

Chronic use of PAH‐specific therapy in World Health Organization Group III Pulmonary Hypertension: a systematic review and meta‐analysis

Chronic use of PAH‐specific therapy in World Health Organization Group III Pulmonary Hypertension: a systematic review and meta‐analysis

The influence of pulmonary vascular pressures on lung diffusing capacity during incremental exercise in healthy aging

Comparison of Long Term Oxygen-Therapy (LTOT) and LTOT Combined with Sildenafil and Simvastatin in the Treatment of Severe Chronic Obstructive Pulmonary (COPD) with Hypoxia at Rest and Severe Pulmonary Arterial Hypertension

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