Tadalafil therapy for pulmonary arterial hypertension.

BACKGROUND: Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway. METHODS AND RESULTS: In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (P<0.01). Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95% confidence interval, -2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to clinical worsening (P=0.041), incidence of clinical worsening (68% relative risk reduction; P=0.038), and health-related quality of life. The changes in World Health Organization functional class were not statistically significant. The most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing. CONCLUSIONS: In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening.

Ethnic differences in coronary atherosclerosis.

OBJECTIVES: The study was done to evaluate whether ethnic differences exist in the prevalence of coronary artery calcification (CAC), and to determine whether differences in calcification correlate with the degree of coronary obstruction. BACKGROUND: Electron beam tomography (EBT) can be used to quantitate the amount of CAC and assist in prognostication of future cardiac events. It is unclear whether ethnic differences in coronary mortality are related to differences in the prevalence of coronary obstruction and CAC. METHODS: A total of 782 symptomatic subjects underwent both EBT and angiography. A 50% luminal narrowing defined an angiographic obstruction. RESULTS: We observed substantial ethnic differences in prevalence of both CAC and angiographic stenosis. In whites (n = 453), prevalence of CAC (score >0) was 84%, and significant obstruction on angiogram was 71%. Compared with whites, blacks (n = 108) had a significantly lower prevalence of CAC (62%, p < 0.001) and angiographic disease (49%, p < 0.01). Hispanics (n = 177) also had a lower prevalence of CAC (71%, p < 0.001) and angiographic obstruction (58%, p < 0.01). Asians (n = 44) were not significantly different in regard to CAC (73%, p = 0.06) or angiographic stenosis (64%, p = 0.30). These ethnic differences remained after simultaneously controlling (by use of multiple logistic regression) for age, gender and cardiac risk factors. CONCLUSIONS: As compared with whites, blacks and Hispanics had significantly lower prevalence of CAC and obstructive coronary disease. Ethnic differences in risk-factor profiles do not explain these differences. This study demonstrated that whites have a higher atherosclerotic burden than blacks and Hispanics, independent of risk-factor differences among symptomatic patients referred for angiography.

Coronary calcium scanning adds incremental value to patients with positive stress tests.

BACKGROUND: The sensitivity of coronary calcification by electron beam tomography (EBT) for the detection of coronary atherosclerosis is well-established. Combining the anatomic information of EBT with the functional information of stress testing might reduce the high false-positive result rate seen with treadmill stress test (TMST) alone. No studies have reported the additive value of a negative EBT result (no coronary calcium) for excluding obstructive coronary artery disease (OCAD) in patients with a positive TMST result. This study evaluated the negative predictive value and potential clinical utility of EBT to identify patients with a falsely abnormal TMST. METHODS: A coronary calcium score was determined by EBT for 153 symptomatic patients who underwent coronary angiography because of a positive TMST. The sensitivity, specificity, and predictive values of EBT were determined. A multiple logistic regression analysis compared conventional cardiac risk factors with coronary calcification by EBT for predicting OCAD. A receiver operating characteristic curve was generated plotting sensitivity versus false-positive rate. RESULTS: The false-positive rate of the TMST compared with angiography was 27% (41 of 153). The sensitivity of a nonzero coronary calcium score for OCAD was 98% (110 of 112), with a negative predictive value of 93%. According to multiple logistic regression, coronary calcification by EBT was a stronger predictor of OCAD than any conventional cardiac risk factor. EBT calcium added incremental value to the results of the TMST. Receiver operating characteristic curve analysis found an area under the curve of 0.91 (P <.001). CONCLUSIONS: The absence of coronary calcification by EBT reliably identified patients with a false-positive TMST result. The combination of EBT with TMST is a potentially useful diagnostic strategy to reduce the number of false-positive test results.

Micrococcus-associated central venous catheter infection in patients with pulmonary arterial hypertension.

STUDY OBJECTIVES: To determine the incidence of catheter-related infection in patients with pulmonary arterial hypertension (PAH) receiving epoprostenol (EPO), and to note an etiologic role for Micrococcus spp, which is rarely reported as a pathogen in the medical literature. DESIGN: Observational study. SETTING: Two PAH specialty treatment centers, Harbor-UCLA Medical Center (Torrance, CA), and the College of Physicians and Surgeons, Columbia University (New York, NY). PATIENTS: A total of 192 patients with PAH receiving continuous therapy with IV EPO. INTERVENTIONS: From 1987 to 2000, 192 patients with PAH received infusions of EPO via central venous catheter. Catheter care included regular dressing changes with dry gauze using a sterile procedure, without the use of flushes. Patients were asked to report on known infections and treatments, and symptoms. All infections were verified by a telephone call to the patient, care provider, and microbiology laboratory whenever possible. MEASUREMENTS AND RESULTS: There were 335,285 catheter days (mean +/- SD, 1,325 +/- 974 catheter days). There were 88 clinical catheter infections with 51 blood culture-positive infections, necessitating catheter removal in 38 instances. The following pathogens were isolated: Staphylococcus aureus (25); Micrococcus spp (14); mixed flora (3); coagulase-negative Staphylococcus spp (2); Corynebacterium spp (2); Serratia marcessens (1); Enterobacter spp (1); Pseudomonas aeruginosa (1); enterococci (1); and unidentified Gram-positive cocci (1). The catheter infection rate was 0.26 per 1,000 catheter days. CONCLUSIONS: The use of long-term therapy with continuous EPO appears to be associated with a low incidence of catheter-related infections. Micrococcus spp were the second most common etiologic agent. Caregivers managing patients with PAH must be aware of the risk of catheter infection, as it may contribute to the morbidity and mortality associated with the use of EPO. When isolated, Micrococcus spp should not be viewed as a contaminant, but rather as a true pathogen that may require therapeutic intervention.

[Clinical study on long-term treatment of primary pulmonary hypertension with continuous intravenous epoprostenol infusion].

OBJECTIVE: To observe the effects of treatment with long-term continuous epoprostenol (Epo) infusion on the survival and pulmonary artery pressure in patients with primary pulmonary hypertension (PPH). METHODS: Sixty nine patients with PPH and congestive heart failure of stage III or IV (classification by New York Heart Association) treated with Epo of initial dose of 2 - 62 ng x kg(-1) x min(-1) (the dosage was enhanced by 1 - 2 ng x kg(-1) x min(-1) every 2 months according to patient's response). All patients underwent right heart catheterization and Doppler echocardiography to measure the systolic pressure gradient between the right ventricle and right atrium (DeltaP) and the cardiac output (CO). Doppler echocardiography and catheterization data were compared. Patients were followed up with echocardiography once every 4 months. RESULTS: Of 69 patients treated with Epo 17 were followed up for > 330 days. During this period, DeltaP decreased from (84.1 +/- 24.1) mm Hg to (62.7 +/- 18.2) mm Hg (P < 0.01), CO increased from (4.00 +/- 1.22) L/min to (4.70 +/- 1.27) L/min (P < 0.02), DeltaP/CO decreased from 22.8 +/- 9.4 to 14.9 +/- 6.5 (P < 0.01). The patient survival was improved. CONCLUSIONS: Patients with PPH treated with continuous infusion of Epo experienced a decrease in pulmonary artery pressure and an increase in cardiac output. Long-term follow-up of some patients of the group demonstrated improved survival during the period of Epo therapy.

Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study.

OBJECTIVES: The aim of this study was to evaluate the long-term safety and durability of efficacy of tadalafil for pulmonary arterial hypertension. BACKGROUND: Tadalafil is an oral phosphodiesterase-5 inhibitor approved for PAH treatment. In the multicenter, placebo-controlled, randomized, 16-week PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study, tadalafil 40 mg improved exercise capacity and delayed clinical worsening. METHODS: Eligible patients from PHIRST received once-daily tadalafil 20 mg (T20 mg) or 40 mg (T40 mg) (n = 357) in the double-blind, 52-week, uncontrolled extension study (PHIRST-2); 293 patients completed PHIRST-2. Durability of efficacy was explored using the 6-min walk distance (6MWD) test. Clinical worsening and changes in World Health Organization functional class were evaluated. RESULTS: The safety profile of tadalafil in PHIRST-2 was similar to that in PHIRST, with typical phosphodiesterase-5 inhibitor adverse events. The 6MWDs achieved in PHIRST for the subset of patients receiving T20 mg and T40 mg in both PHIRST and PHIRST-2 (406 ± 67 m [n = 52] and 413 ± 81 m [n = 59] at PHIRST-2 enrollment, respectively) were maintained at PHIRST-2 completion (415 ± 80 m [n = 51] and 410 ± 78 m [n = 59], respectively). Numerically fewer patients who were on T40 mg in PHIRST and PHIRST-2 experienced World Health Organization functional class deterioration (6% [n = 5]) compared with those randomized to T20 mg (9% [n = 7]) across both studies. Post hoc analyses showed that background bosentan use and higher 6MWD at PHIRST baseline were associated with fewer clinical worsening events. CONCLUSIONS: Long-term treatment with tadalafil was well tolerated in patients with pulmonary arterial hypertension. In patients receiving either T20 mg or T40 mg, the improvements in 6MWD demonstrated in the 16-week PHIRST study appeared sustained for up to 52 additional weeks of treatment in PHIRST-2. (Pulmonary Arterial Hypertension and Response to Tadalafil Study; NCT00549302).

Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension.

BACKGROUND: Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background bosentan. Analyses of tadalafil in treatment-naive patients and as add-on to bosentan were pre-specified. Objectives were to provide safety and efficacy data for both groups. METHODS: Groups analyzed included: treatment-naive + PBO; treatment-naive + tadalafil; background bosentan + PBO; and background bosentan + tadalafil. Patients randomized to tadalafil or PBO (N = 405) were analyzed by bosentan use (yes = 216, no = 189). Treatment differences in 6-minute walk distance (6MWD, PBO-adjusted), functional class (FC), clinical worsening (CW) and adverse events were assessed. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for FC and CW. RESULTS: At Week 16, PBO-adjusted 6MWD increases were 44 m (CI: 20 to 69 m; n = 37) for tadalafil 40 mg in treatment-naive patients and 23 m (CI: -2 to 48 m; n = 42) for tadalafil 40 mg add-on to bosentan. The 6MWD for treatment-naive and background bosentan PBO patients decreased by 3 m and increased by 19 m, respectively, at Week 16 compared with baseline. Two (5%) treatment-naive patients had CW with tadalafil 40 mg vs 8 (22%) with PBO (HR = 3.3, CI: 1.1 to 10.0). Two (5%) background bosentan patients had CW with tadalafil 40 mg add-on vs 5 (11%) for PBO add-on (HR = 1.9, CI: 0.4 to 10.2). Adverse events for tadalafil monotherapy and as add-on were similar. CONCLUSION: Tadalafil 40 mg was well-tolerated and provided clinical benefit in patients as monotherapy. It was also well-tolerated when added to background bosentan, but data are insufficient to conclude additional benefit.