Effect of 5 weeks of oral acetazolamide on patients with pulmonary vascular disease: A randomized, doubleblind, cross-over trial

Background: The carbonic anhydrase inhibitor acetazolamide stimulates ventilation through metabolic acidosis mediated by renal bicarbonate excretion. In animal models, acetazolamide attenuates acute hypoxia-induced pulmonary hypertension (PH), but its efficacy in treating patients with PH due to pulmonary vascular disease (PVD) is unknown. Methods: 28 PVD patients (15 pulmonary arterial hypertension, 13 distal chronic thromboembolic PH), 13 women, mean +/- SD age 61.6 +/- 15.0 years stable on PVD medications, were randomised in a double-blind crossover protocol to 5 weeks acetazolamide (250mg b.i.d) or placebo separated by a >= 2 week washout period. Primary endpoint was the change in 6-minute walk distance (6MWD) at 5 weeks. Additional endpoints included safety, tolerability, WHO functional class, quality of life, arterial blood gases, and hemodynamics (by echocardiography). Results: Acetazolamide had no effect on 6MWD compared to placebo (treatment effect: mean change [95%CI] -18 [-40 to 4]m, p=0.102) but increased arterial blood oxygenation through hyperventilation induced by metabolic acidosis. Other measures including pulmonary hemodynamics were unchanged. No severe adverse effects occurred, side effects that occurred significantly more frequently with acetazolamide vs. placebo were change in taste (22/0%), paraesthesia (37/4%) and mild dyspnea (26/4%). Conclusions: In patients with PVD, acetazolamide did not change 6MWD compared to placebo despite improved blood oxygenation. Some patients reported a tolerable increase in dyspnoea during acetazolamide treatment, related to hyperventilation, induced by the mild drug-induced metabolic acidosis. Our findings do not support the use of acetazolamide to improve exercise in patients with PVD at this dosing. ClinicalTrials.gov Identifier: NCT02755298 (c) 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier Espa & ntilde;a, S.L.U. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/bync-nd/4.0/).