[HTML][HTML] Treatment of group I pulmonary arterial hypertension with carvedilol is safe

D Grinnan, HJ Bogaard, J Grizzard… - American journal of …, 2014 - atsjournals.org
D Grinnan, HJ Bogaard, J Grizzard, B Van Tassell, A Abbate, C DeWilde, A Priday
American journal of respiratory and critical care medicine, 2014atsjournals.org
The principal treatment strategy for patients with pulmonary artery hypertension (PAH) is the
use of medications targeting the pulmonary vasculature (1, 2). Despite several classes of
available therapy for the treatment of PAH, some of which can improve cardiac function,
patients continue to die of right heart failure (RHF)(3) and additional therapies are needed.
We have previously proposed that the dysfunctional right ventricle (RV) should be a
treatment target in patients with PAH (3, 4). b-Adrenergic receptor (BAR) blockade has been …
The principal treatment strategy for patients with pulmonary artery hypertension (PAH) is the use of medications targeting the pulmonary vasculature (1, 2). Despite several classes of available therapy for the treatment of PAH, some of which can improve cardiac function, patients continue to die of right heart failure (RHF)(3) and additional therapies are needed. We have previously proposed that the dysfunctional right ventricle (RV) should be a treatment target in patients with PAH (3, 4). b-Adrenergic receptor (BAR) blockade has been a mainstay of congestive left heart failure treatment for years and yet, despite some initial prospective safety data (5), BAR blockers are infrequently used in patients with PAH and RV dysfunction. On the basis of experimental data obtained in an animal model of severe angio-obliterative PAH and RHF (6, 7) we designed a single-arm open-label pilot study (clinicaltrials. gov; NCT00964678) to evaluate the feasibility and safety of add-on treatment with carvedilol in patients with stable PAH and RV dysfunction (functional classes II and III) in a prospective study using cardiac magnetic resonance (CMR) to measure interval changes in RV dimensions and systolic function, using a threedimensional reconstruction of the RV cavity (CVI 42 software; Circle Cardiovascular Imaging, Calgary, AB, Canada). Carvedilol was chosen because it is the preferred BAR in congestive left heart failure, and was found to improve RV ejection fraction (RVEF) in patients with biventricular failure (8). Here we report our findings from this pilot study. The study was initially registered at clinicaltrials. gov in August 2009; however, enrollment was delayed by needed changes in principal investigator and study design, leading to initiation in March 2011. Ten consecutive patients signed an institutional review board-approved consent form and enrolled in the study. Of these, four were excluded (two unable to tolerate CMR, one required titration of PAH therapy before initiation, and one had pulmonary hypertension other than PAH). After the screening CMR study, the remaining six patients were started on carvedilol at a dose of 3.25 mg twice daily, and up-titrated every 2 weeks as tolerated, based on evaluation of vital signs, electrocardiogram, and symptoms (including dizziness, fatigue, diarrhea, palpitations, edema, or change in breathlessness). A second CMR was completed after 6 months. Baseline characteristics and changes over time of the study for the six patients are presented in Table 1 and Figure 1. All patients were stable on PAH therapy for 3 months before study entry and throughout the study. All patients had normal left ventricular function assessed by echocardiogram and CMR on study entry. The titration rate differed among patients, but no patient required cessation or downtitration. Reasons for slow titration included asymptomatic bradycardia (n= 1), asymptomatic hypotension (n= 1), and mild fatigue (n= 1). None of the patients experienced worsening dyspnea. Carvedilol add-on treatment (median tolerated dose, 18.75 mg twice daily; with three patients reaching 25 mg twice daily) led to a statistically significant improvement in RVEF and RV stroke volume, due to a reduction in RV end-systolic volume and without changes in RV end-diastolic volume. There was a significant increase in brain natriuretic peptide (BNP) levels (P= 0.046), which correlated with the improvement in RVEF (R=+ 0.83, P= 0.042). There was a nonsignificant trend (P= 0.22) toward increase in 6-minute walk distance (6MWD). One patient could not complete 6MWD testing at study completion because of an orthopedic injury, and one patient could not be scheduled for …
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