We read with interest the study by Stolz et al. 1 reporting on the lack of improvement of exercise capacity caused by the dual endothelin-1 antagonist bosentan in patients with severe chronic obstructive pulmonary disease (COPD) and absence of severe pulmonary hypertension (PH) at rest. Pulmonary vasodilators, like bosentan or sildenafil, may not work in patients with COPD-related PH, a condition dominated by right ventricular diastolic dysfunction with normal cardiac output 2.
However, Stolz et al. 1 acknowledged that these results may not apply to uncommon cases of severe PH associated with COPD. Thus it was suggested that PH-specific treatment first be studied in the subgroup of patients identified by Chaouat et al. 3, with severe disproportionate PH 4, 5, arbitrarily defined by a mean pulmonary arterial pressure (P̄ pa) of >40 mmHg 3.
Herein, we report dramatic functional improvement with bosentan therapy in a patient with COPD and severe disproportionate PH. A 53-yr-old female with a history of obesity (body mass index 41 kg·m−2), type II diabetes, hypothyroidism and acute pulmonary embolism 3 yrs previously, was followed for severe COPD. She was a former smoker (30 pack-yrs) and her dyspnoea was functional class III. After two episodes of right cardiac failure 3 yrs previously she was receiving furosemide 80 mg·day−1. Obstructive sleep apnoea syndrome was ruled out. High-resolution computed tomography of the chest showed mild diffuse emphysema. Pulmonary function tests showed severe airflow obstruction with air trapping and hyperinflation: forced vital capacity (FVC) 2.3 L (76% predicted), total lung capacity 6.3 L (128% pred), forced expiratory volume in one second (FEV1) 0.84 L (34% pred), FEV1/FVC 37%, residual volume 4.0 L (226% pred) and carbon monoxide diffusion capacity was 87% pred. The patient had been on long-term oxygen therapy (2.5 L·min−1) for 3 yrs, with arterial oxygen tension (Pa,O2) on long-term oxygen therapy of 11.0 kPa, but elevated carbon dioxide arterial tension (Pa,CO2; table 1⇓).
Patient characteristics and outcome with bosentan
PH suggested by echocardiography was confirmed by right heart catheterisation, demonstrating a pulmonary artery pressure of 110/50 mmHg (mean 65 mmHg), with a transpulmonary gradient of 49 mmHg, cardiac index of 2.6 L·min−1·m−2 and pulmonary vascular resistance (PVR) of 739 dyn·s·cm−5 without response to inhaled NO. No chronic thromboembolic disease or other cause of PH was found. The patient had not taken anorexigens and left ventricular function was normal. Since the contribution of PH to exercise limitation was considered significant and dyspnoea gradually increased, therapy with oral bosentan was initiated at 62.5 mg b.i.d. for 4 weeks, then increased to 125 mg b.i.d. Oral anticoagulation was initiated and long-term oxygen therapy was kept unchanged.
Within 4 weeks of bosentan initiation, dyspnoea significantly decreased to functional class II. The patient was able to resume activities such as home cleaning, going shopping and going to the beach. She could climb one flight of stairs without stopping (as opposed to no more than 5–10 steps before treatment) and resumed indoor biking. However, arterial blood gas analysis showed increased Pa,CO2 (9.6 kPa), and nocturnal noninvasive nasal ventilation was initiated 1 yr after the diagnosis of PH. Clinical improvement persisted throughout follow-up. Bosentan was well tolerated.
The 6-min walk test distance had improved from 198 to 360 m 2 yrs after initiating bosentan therapy. Right heart cavities were no longer dilated at echocardiography, and right heart catheterisation showed that PVR decreased to 214 dyn·s·cm−5, cardiac index increased to 3.7 L·min−1·m−2 and P̄ pa was 34 mmHg. Pulmonary function tests were unchanged (table 1⇑).
Improvement of PH was not explained by weight loss 6, or by changes in Pa,O2. Interestingly, in the study by Stolz et al. 1, bosentan therapy was associated with a significant decrease in Pa,O2, presumably related to increased ventilation–perfusion mismatching, intrapulmonary right-to-left microshunting (itself due to quantitative perfusion augmentation or fluid retention) and/or the reduction of peripheral carotid body sensitivity with a decrease in hypoxic ventilatory response. Indeed, Pa,CO2 was further increased in our patient while on bosentan, leading to the initiation of noninvasive ventilation.
This observation suggests that clinical trials are warranted to evaluate the possible efficacy of pulmonary hypertension-specific therapy in patients with chronic obstructive pulmonary disease and disproportionate pulmonary hypertension and characterise possible responders 3–5. However, detrimental effects on gas exchange should be carefully monitored.
Statement of interest
Statements of interest for V. Cottin, R. Lazor and J-F. Cordier can be found at www.erj.ersjournals.com/misc/statements.shtml
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