Alain Romero

Five-Year Outcomes of Patients Enrolled in the REVEAL Registry

BACKGROUND Pulmonary arterial hypertension (PAH) is a rare, severe disease characterized by worsening right-sided heart failure, decreasing functional status, and poor survival. The present study characterizes the 5-year survival in the United States of a new and previous diagnosis of PAH in patients stratified by baseline functional class (FC). The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) is a 55-center observational US registry of the demographics, disease course, and management of patients with World Health Organization (WHO) group 1 PAH. METHODS The REVEAL Registry enrolled newly and previously diagnosed patients aged ≥ 3 months with WHO group 1 PAH consecutively from March 2006 to December 2009. Demographics, disease characteristics, and hemodynamic data were collected at enrollment. Survival analysis was conducted by FC and other subgroups in patients aged ≥ 18 years. RESULTS Survival differences between previously diagnosed and newly diagnosed patients at 1 year (90.4% vs 86.3%) were maintained to 5 years; 5-year survival for previously diagnosed patients was 65.4% compared with 61.2% for newly diagnosed patients. Previously diagnosed patients in FC I, II, III, and IV had an estimated 5-year survival rate of 88.0%, 75.6%, 57.0%, and 27.2%, respectively, compared with 72.2%, 71.7%, 60.0%, and 43.8% for newly diagnosed patients in FC I, II, III, and IV, respectively. CONCLUSIONS Patient survival of advanced PAH remains poor at 5 years despite treatment advances. New York Heart Association FC remains one of the most important predictors of future survival. These observations reinforce the importance of continuous monitoring of FC in patients with PAH. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Characterization of First-Time Hospitalizations in Patients With Newly Diagnosed Pulmonary Arterial Hypertension in the REVEAL Registry

BACKGROUND: Hospitalization is an important outcome in pulmonary arterial hypertension (PAH), shown previously to correlate with survival. Using the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry), we sought to characterize first-time hospitalizations and their effect on subsequent hospitalization and survival in patients with newly diagnosed disease. METHODS: Patients with newly diagnosed PAH (n = 862, World Health Organization group 1) were evaluated for first-time hospitalization. The hospitalizations were categorized as PAH related or PAH unrelated based on the case report form. Categories for PAH-related and PAH-unrelated hospitalization were defined before independent review. Patient demographics and disease characteristics are described as well as freedom from hospitalization and survival. RESULTS: Of 862 patients, 490 (56.8%) had one or more hospitalizations postenrollment: 257 (52.4%) PAH related, 214 (43.7%) PAH unrelated, and 19 (3.9%) of undetermined causes. The most common causes of PAH-related hospitalization were congestive heart failure and placement/removal of a central venous catheter. Patients with PAH-related hospitalizations were more likely to receive parenteral therapy, be in functional class III/IV, and have higher risk scores before hospitalization at enrollment. Following discharge, 25.4% ± 3.2% and 31.0% ± 4.0% of patients with PAH-related and PAH-unrelated first hospitalization, respectively, remained hospitalization-free for 3 years (P = .11). Survival estimates at 3 years postdischarge were 56.8% ± 3.5% and 67.8% ± 3.6% (P = .037) for patients with PAH-related and PAH-unrelated hospitalization, respectively. CONCLUSIONS: In the REVEAL Registry, PAH-related hospitalization was associated with relatively more rehospitalizations and worse survival at 3 years. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov

Evaluation of the Potential for Drug Interactions With Patiromer in Healthy Volunteers

Introduction: Patiromer is a potassium-binding polymer that is not systemically absorbed; however, it may bind coadministered oral drugs in the gastrointestinal tract, potentially reducing their absorption. Methods: Twelve randomized, open-label, 3-period, 3-sequence crossover studies were conducted in healthy volunteers to evaluate the effect of patiromer (perpetrator drug) on absorption and single-dose pharmacokinetics (PK) of drugs (victims) that might be commonly used with patiromer. Subjects received victim drug alone, victim drug administered together with patiromer 25.2 g (highest approved dose), and victim drug administered 3 hours before patiromer 25.2 g. The primary PK endpoints were area under the curve (AUC), extrapolated to infinity (AUC0-∞), and maximum concentration (C max). Results were reported as 90% confidence intervals (CIs) about the geometric mean AUC0-∞ and C max ratios with prespecified equivalence limits of 80% to 125%. Results: Overall, 370 subjects were enrolled, with 365 receiving ≥1 dose of patiromer; 351 subjects completed the studies and all required treatments. When coadministered with patiromer, the 90% CIs for AUC0-∞ remained within 80% to 125% for 9 drugs (amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil, and warfarin). The AUC0-∞ point estimate ratios for levothyroxine and metformin with patiromer coadministration were ≥80%, with the lower bounds of the 90% CIs at 76.8% and 72.8%, respectively. For ciprofloxacin, the point estimate for AUC0-∞ was 71.5% (90% CI: 65.3-78.4). For 8 of 12 drugs, point estimates for C max were ≥80% with patiromer coadministration; for ciprofloxacin, clopidogrel, metformin, and metoprolol, the point estimates were <80%. When patiromer was administered 3 hours after each victim drug, the 90% CIs for AUC0-∞ and C max for each drug were within the prespecified 80% to 125% limits. Conclusion: For 9 of the 12 drugs coadministered with patiromer, there were no clinically significant drug–drug interactions. For 3 drugs (ciprofloxacin, levothyroxine, and metformin), a 3-hour separation between patiromer and their administration resulted in no clinically significant drug–drug interactions.

Development of macitentan for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a serious, chronic condition that, without early recognition and treatment, leads to progressive right heart failure and death. The dual endothelin receptor antagonist macitentan was designed through a deliberate discovery process to maximize endothelin‐axis blockade while improving adverse‐effect profiles compared with previous compounds. Macitentans efficacy was demonstrated in an event‐driven morbidity and mortality study of treatment‐naive and background PAH therapy–treated symptomatic patients. Compared to placebo, 10 mg of macitentan significantly reduced the relative risk of morbidity and mortality by 45%, primarily by delaying PAH worsening, most prominently in World Health Organization (WHO) functional class II and III PAH patients. Macitentan reduced the incidence of the composite end point of PAH‐related hospitalizations and mortality and improved WHO FC and exercise capacity (6‐min walk distance). Furthermore, it significantly improved cardiopulmonary hemodynamics and quality of life, and had a favorable safety and tolerability profile. To date, this was the largest and longest prospective trial for PAH. Macitentan, currently the only approved oral PAH treatment shown to be safe and effective in delaying long‐term progression and reducing PAH‐related hospitalizations, has changed treatment paradigms from goal‐directed to long‐term outcome–oriented therapy.

Patiromer to Enable Spironolactone Use in the Treatment of Patients with Resistant Hypertension and Chronic Kidney Disease: Rationale and Design of the AMBER Study

Background: While chronic kidney disease (CKD) is common in resistant hypertension (RHTN), prior studies evaluating mineralocorticoid receptor antagonists excluded patients with reduced kidney function due to risk of hyperkalemia. AMBER (ClinicalTrials.gov identifier NCT03071263) will evaluate if the potassium-binding polymer patiromer used concomitantly with spironolactone in patients with RHTN and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management. Methods: Randomized, double-blind, placebo-controlled parallel group 12-week study of patiromer and spironolactone versus placebo and spironolactone in patients with uncontrolled RHTN and CKD. RHTN is defined as unattended systolic automated office blood pressure (AOBP) of 135–160 mm Hg during screening despite taking ≥3 antihypertensives, including a diuretic, and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker (unless not tolerated or contraindicated). The CKD inclusion criterion is an estimated glomerular filtration rate (eGFR) of 25 to ≤45 mL/min/1.73 m2. Screening serum potassium must be 4.3–5.1 mEq/L. The primary efficacy endpoint is the between-group difference (spironolactone plus patiromer versus spironolactone plus placebo) in the proportion of patients remaining on spironolactone at Week 12. Results: Baseline characteristics have been analyzed as of March 2018 for 146 (of a targeted 290) patients. Mean (SD) baseline age is 69.3 (10.9) years; 52.1% are male, 99.3% White, and 47.3% have diabetes. Mean (SD) baseline serum potassium is 4.68 (0.25) mEq/L, systolic AOBP is 144.3 (6.8) mm Hg, eGFR is 35.7 (7.7) mL/min/1.73 m2. Conclusion: AMBER will define the ability of patiromer to facilitate the use of spironolactone, an effective antihypertensive therapy for patients with RHTN and CKD.