Phase I safety study of ranolazine in pulmonary arterial hypertension.

UNLABELLED: Pulmonary arterial hypertension (PAH) causes right ventricular ischemia, dysfunction, and failure. PAH patients may benefit from antianginal agents based on a shared pathophysiology with left ventricular ischemia. A single-center, randomized, placebo-controlled trial (1∶1) to assess the acute vasoreactivity and safety of ranolazine in PAH was conducted. Plasma samples for pharmacokinetic (PK) studies were drawn during hemodynamic measurements at 0, 60, 90, 120, 240, and 360 minutes from a Swan-Ganz catheter. All patients received 500-mg doses, uptitrated to 1,000 mg at week 4, monthly evaluations, and a complete objective assessment after 12 weeks, followed by an open-label extension. Thirteen patients were randomized and 12 enrolled (6 ranolazine, 6 placebo). All patients completed the acute phase; 10 completed the 12-week study. There were no acute changes in invasive hemodynamics. At 12 weeks ranolazine was well tolerated. Only 1 of the 5 patients on ranolazine had a serum concentration considered to be in the therapeutic range. Two serious adverse events required early withdrawal (both in the ranolazine group); gastrointestinal complaints were the most common adverse event. Efficacy measures did not demonstrate any differences between treatment groups. During the open-label trial, 2 additional patients reached a therapeutic concentration. Ranolazine in PAH appears safe, without acute hemodynamic effects after a 500-mg dose. Ranolazine administrated to PAH patients receiving background PAH therapies did not consistently reach therapeutic levels. Future studies should first perform PK analysis in PAH patients receiving PAH therapies and explore the safety and tolerability of the higher doses perhaps necessary to achieve therapeutic levels in PAH patients. ( TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01757808.).

Risk assessment in pulmonary hypertension associated with heart failure and preserved ejection fraction.

BACKGROUND: Pulmonary hypertension (PH) is common in patients with left heart failure (HF), especially those with HF and preserved ejection fraction (HFpEF). However, there is limited data on risk stratification in these patients. METHODS: Baseline clinical and hemodynamic variables of 339 patients with World Health Organization (WHO) Group 2 PH, 90% of whom had HFpEF, were studied to derive a multivariate Cox proportional hazards model. A simplified prognostic risk score was created based on the outcome of all-cause mortality. Nine predictors, significant after stepwise multivariable regression (p < 0.05), were used to create the risk score. Components of the risk score were functional class, diastolic blood pressure, pulmonary artery saturation, interstitial lung disease, hypotension on initial presentation, right ventricular hypertrophy, diffusion capacity of the lung for carbon monoxide, and 2 serum creatinine variables (≤ 0.9 mg/dl and ≥ 1.4 mg/dl). RESULTS: Overall 2-year survival was 73.8% ± 2.4% in the derivation cohort, and 87.5% ± 2.3%, 66.4% ± 4.9%, and 24.4% ± 6.7% for risk scores of 0 to 2, 3 to 4, and 5+, respectively (p < 0.0001 for the trend), with a C-index of 0.76 (95% confidence interval [CI], 0.71-0.81). The risk score was validated in 2 independent PH-HFpEF cohorts: 179 patients with a C-index of 0.68 (95% CI, 0.55-0.80) and 117 patients with a C-index of 0.68 (95% CI, 0.53-0.83). For the 3 cohorts combined (N = 635), the overall C-index was 0.72 (95% CI 0.68-0.76). In all 3 cohorts individually and in the 3 cohorts combined, the risk score predicted death (hazard ratio, 1.4-1.6; p < 0.01). CONCLUSIONS: Several clinical factors independently predict death in PH-HFpEF confirmed by validation. A novel risk score composed of these factors can be used to determine prognosis and may be useful in making therapeutic decisions.

The effect of diluent pH on bloodstream infection rates in patients receiving IV treprostinil for pulmonary arterial hypertension.

BACKGROUND: Recent studies have reported an increase in catheter-related bloodstream infections (BSIs) and gram-negative BSIs among patients with pulmonary arterial hypertension treated with IV treprostinil. One possible explanation is the neutral pH of the treprostinil diluent compared with the basic pH of epoprostenol. We hypothesized that administering IV treprostinil with epoprostenol diluent will lower the rate of gram-negative BSI. METHODS: We prospectively enrolled patients treated with IV treprostinil and changed the diluent from native diluent to epoprostenol diluent. We compared the incidence of BSI and gram-negative BSI between those receiving IV treprostinil with epoprostenol diluent (n = 25) and those actively receiving IV epoprostenol (n = 61), as well as with a cohort of patients who received IV treprostinil in native diluent (n = 34). Incidence rates of BSI were expressed as a fraction of 1,000 medicine treatment days. RESULTS: There were similar rates of BSI in those treated with treprostinil with epoprostenol diluent and those treated with epoprostenol (0.32 of 1,000 vs 0.40 of 1,000; P = .79). Also, there were similar rates of gram-negative BSI in these two cohorts (0.08 of 1,000 vs 0.20 of 1,000; P = .46). BSI rates were not statistically different between those treated with treprostinil with epoprostenol diluent and those treated with treprostinil (0.32 of 1,000 vs 0.90 of 1,000; P = .06). However, gram-negative BSIs were significantly lower in patients treated with treprostinil with epoprostenol diluent than in those treated with treprostinil (0.08 of 1,000 vs 0.71 of 1,000, respectively; P = .01). CONCLUSIONS: Patients treated with treprostinil with epoprostenol diluent have a lower incidence of gram-negative BSI than do those treated with treprostinil and a similar rate to those treated with epoprostenol. Changing the diluent of treprostinil to epoprostenol diluent, in combination with the use of water-tight seals throughout the delivery system, appears to be an effective safety measure.

Relative adrenal insufficiency in severe congestive heart failure with preserved systolic function: a case report.

Relative adrenal insufficiency in critically ill patients is an important syndrome in septic shock. The insufficient stress response of the hypothalamic-pituitary-adrenal axis in acute illness contributes to hemodynamic instability. Treatment of this state in septic shock improves patient outcomes. In this report, we describe the case of a patient with severe diastolic dysfunction who presented in cardiogenic shock associated with relative adrenal insufficiency and had a complete recovery with corticosteroid replacement. Alteration of the hypothalamic-pituitary-adrenal axis may be more prevalent than suspected in end-stage heart failure, and the diagnosis and treatment of this syndrome may ultimately improve outcomes in a subgroup of heart failure patients.