Clinical Trials Using Vasodilators in Pulmonary Arterial Hypertension:Where Do We Go from Here? (original) (raw)
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American Heart Journal, 2010
Background In a previous metaanalysis on the approved treatments for pulmonary hypertension, we reported that all therapies caused small changes in 6-minute walk distance over a short period, with minimal effects on hemodynamics and no effect on survival. Since that last review, 10 new clinical trials with about 1,500 patients have been published, which has increased the statistical power of our observations. Methods A systematic review of all clinical trials in pulmonary arterial hypertension was done. Results The pooled effect of all treatments strategies (relative risk [95% CI], P) now shows a significant reduction of 39% (2%-62%, P = .041) in all-cause mortality. The benefits were confined only to patients with advanced disease for 16 weeks, regardless of which class of drug is used. When considering the effects within each drug family, no class of drug produced a statistically significant reduction in all-cause mortality. The improved survival bore no relationship with the change in 6-minute walk, the primary end point in most of the trials.
Journal of the American College of Cardiology, 2004
The numerous controlled clinical trials performed recently in pulmonary arterial hypertension (PAH) can allow us to abandon a clinical-based treatment strategy and adopt an evidencebased therapy. Both uncontrolled and controlled clinical trials with different compounds and procedures are reviewed and compared in order to define the efficacy-to-side-effect ratio of each treatment. A grading system for the level of evidence of treatments based on the number of favorable controlled clinical trials performed with a given compound is adopted; a treatment algorithm based on the evidence derived by clinical trials is proposed. It includes drugs approved by regulatory agencies for the treatment of patients with PAH and/or drugs available on the market for other indications. The algorithm is restricted to patients in New York Heart Association (NYHA) functional class III or IV because they represent the largest population included in controlled clinical trials. In addition, the different treatments have been evaluated mainly in sporadic, idiopathic PAH and in PAH associated with scleroderma or to anorexigen use. Extrapolation of these recommendations to the other PAH subgroups should be done with caution. Oral anticoagulation is proposed for all patients, whereas diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia, respectively. High doses of calcium channel blockers are indicated only in the minority of patients who are responders to acute vasoreactivity testing. Nonresponders to acute vasoreactivity testing, or responders who remain in NYHA functional class III, should be considered candidates for treatment with either an endothelin receptor antagonist or a prostanoid. Continuous intravenous administration of epoprostenol is proposed as rescue treatment in NYHA functional class IV patients. Phosphodiesterase-V inhibitors should be considered in patients who have failed or are not candidates to other therapies. Combination therapy can be attempted in selected cases. Both balloon atrial septostomy and lung transplantation are indicated for refractory patients or where medical treatment is unavailable. (J Am Coll Cardiol 2004;43:81S-88S) © 2004 by the American College of Cardiology Foundation
Clinical Pulmonary Medicine, 2017
Pulmonary artery hypertension (PAH) is rare, progressive, and difficult to treat. Earlier trials have found that active drug treatments improve hemodynamics, surrogate outcomes, and mortality compared with placebo. Few direct trials of active treatments exist and a mixed treatment comparison network meta-analysis allows comparisons of direct and indirect treatment effects. Randomized controlled trials of patients aged 10 to 80 years with idiopathic or secondary PAH treated with epoprostenol, treprostinil, iloprost, beraprost, bosentan, ambrisentan, macitentan, sildenafil, tadalafil, vardenafil, or riociguat monotherapy were reviewed using the Oxford scoring. Reviewers abstracted data on 6-minute walk distance, change in cardiac index, change in pulmonary artery pressure, change in pulmonary vascular resistance, clinical worsening, and death along with safety endpoints. A Bayesian mixed treatment comparison network meta-analysis using Markov chain Monte Carlo analysis was used to construct network geometry and evaluate treatments. Twenty trials met the criteria and were included, creating a star-shaped evidence network, with some diversity and limited cooccurrence. There were 4328 patients with a mean age of 51 years and idiopathic hypertension in World Health Organization functional class II (34%) or III (60%) PAH. Significant disease progression was observed in every treatment arm, and no individual treatment was consistently better than placebo (direct comparisons) or any other active treatment (indirect comparisons) for 6-minute walk distance, cardiac index, pulmonary artery pressure, pulmonary vascular resistance, clinical worsening, death, or any safety endpoint. No treatment was clearly preferred directly against placebo or indirectly for any endpoint. Providers should select PAH treatments on the basis of individualized treatment responses, preferences, and tolerability.
A Systematic Review of Novel Therapies of Pulmonary Arterial Hypertension
American Journal of Cardiovascular Drugs
Background Pulmonary arterial hypertension (PAH) is a progressive, cureless disease, characterized by increased pulmonary vascular resistance and remodeling, with subsequent ventricular dilatation and failure. New therapeutic targets are being investigated for their potential roles in improving PAH patients' symptoms and reversing pulmonary vascular pathology. Method We aimed to address the available knowledge from the published randomized controlled trials (RCTs) regarding the role of Rho-kinase (ROCK) inhibitors, bone morphogenetic protein 2 (BMP2) inhibitors, estrogen inhibitors, and AMPactivated protein kinase (AMPK) activators on the PAH evaluation parameters. This systematic review (SR) was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CDR42022340658) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Overall, 5092 records were screened from different database and registries; 8 RCTs that met our inclusion criteria were included. The marked difference in the study designs and the variability of the selected outcome measurement tools among the studies made performing a meta-analysis impossible. However, the main findings of this SR relate to the powerful potential of the AMPK activator and the imminent antidiabetic drug metformin, and the BMP2 inhibitor sotatercept as promising PAH-modifying therapies. There is a need for long-term studies to evaluate the effect of the ROCK inhibitor fasudil and the estrogen aromatase inhibitor anastrozole in PAH patients. The role of tacrolimus in PAH is questionable. The discrepancy in the hemodynamic and clinical parameters necessitates defining cut values to predict improvement. The differences in the PAH etiologies render the judgment of the therapeutic potential of the tested drugs challenging. Conclusion Metformin and sotatercept appear as promising therapeutic drugs for PAH. Clinical Trials Registration This work was registered in PROSPERO (CDR42022340658).
CHEST Journal, 2013
Background: Current treatments for pulmonary arterial hypertension (PAH) have been shown to improve dyspnea, 6-min walk distance (6MWD), and pulmonary hemodynamics, but few studies were designed to compare treatment regimens or assess the impact of treatment on mortality. Methods: We conducted a systematic review to evaluate the comparative effectiveness and safety of monotherapy or combination therapy for PAH using endothelin receptor antagonists, phosphodiesterase inhibitors, or prostanoids. We searched English-language publications of comparative studies that reported intermediate or long-term outcomes associated with drug therapy for PAH. Two investigators abstracted data and rated study quality and applicability. Results: We identifi ed 28 randomized controlled trials involving 3,613 patients. We found no studies that randomized treatment-naive patients to monotherapy vs combination therapy. There was insuffi cient statistical power to detect a mortality difference associated with treatment. All drug classes demonstrated increases in 6MWD when compared with placebo, and combination therapy showed improved 6MWD compared with monotherapy. For hospitalization, the OR was lower in patients taking endothelin receptor antagonists or phosphodiesterase-5 inhibitors compared with placebo (OR, 0.34 and 0.48, respectively). Conclusions: Although no studies were powered to detect a mortality reduction, monotherapy was associated with improved 6MWD and reduced hospitalization rates. Our fi ndings also suggest an improvement in 6MWD when a second drug is added to monotherapy.
Pulmonary Circulation, 2016
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 w...