Tolterodine and tamsulosin for treatment of men with lower urinary tract symptoms and overactive bladder: a randomized controlled trial

Context  Men with overactive bladder and other lower urinary tract symptoms may not respond to monotherapy with antimuscarinic agents or -receptor antagonists. Objective  To evaluate the efficacy and safety of tolterodine extended release (ER), tamsulosin, or both in men who met research criteria for both overactive bladder and benign prostatic hyperplasia. Design, Setting, and Participants  Randomized, double-blind, placebo-controlled trial conducted at 95 urology clinics in the United States involving men 40 years or older who had a total International Prostate Symptom Score of 12 or higher and, an International Prostate Symptom Score quality-of-life (QOL) item score of 3 or higher, a self-rated bladder condition of at least moderate bother, and a bladder diary documenting micturition frequency (8 micturitions per 24 hours) and urgency (3 episodes per 24 hours), with or without urgency urinary incontinence. Patients were recruited between November 2004 and February 2006, and the study was completed May 2006. Interventions  Patients were randomly assigned to receive placebo (n = 222), 4 mg of tolterodine ER (n = 217), 0.4 mg of tamsulosin (n = 215), or both tolterodine ER plus tamsulosin (n = 225) for 12 weeks. Main Outcome Measures  Patient perception of treatment benefit, bladder diary variables, International Prostate Symptom Scores, and safety and tolerability were assessed. Results  A total of 172 men (80%) receiving tolterodine ER plus tamsulosin reported treatment benefit by week 12 compared with 132 patients (62%) receiving placebo (P<.001), 146 (71%) receiving tamsulosin (P=.06 vs placebo), or 135 (65%) receiving tolterodine ER (P=.48 vs placebo). Patients receiving tolterodine ER plus tamsulosin compared with placebo experienced significant reductions in urgency urinary incontinence (–0.88 vs –0.31, P=.005), urgency episodes without incontinence (–3.33 vs –2.54, P=.03), micturitions per 24 hours (–2.54 vs –1.41, P<.001), and micturitions per night (–0.59 vs –0.39, P.02). Patients receiving tolterodine ER plus tamsulosin demonstrated significant improvements on the total International Prostate Symptom Score (–8.02 vs placebo, –6.19, P=.003) and QOL item (–1.61 vs –1.17, P=.003). All interventions were well tolerated. The incidence of acute urinary retention requiring catheterization was low (tolterodine ER plus tamsulosin, 0.4%; tolterodine ER, 0.5%; tamsulosin, 0%; and placebo, 0%). Conclusions  These results suggest that treatment with tolterodine ER plus tamsulosin for 12 weeks provides benefit for men with moderate to severe lower urinary tract symptoms including overactive bladder. Clinical Trials Registration  clinicaltrials.gov Identifier: NCT00147654      

Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial

Context  Treatment strategies for cystic fibrosis (CF) lung disease include antibiotics, mucolytics, and anti-inflammatory therapies. Increasing evidence suggests that macrolide antibiotics might be beneficial in patients with CF. Objective  To determine if an association between azithromycin use and pulmonary function exists in patients with CF. Design and Setting  A multicenter, randomized, double-blind, placebo-controlled trial conducted from December 15, 2000, to May 2, 2002, at 23 CF care centers in the United States. Participants  Of the 251 screened participants with a diagnosis of CF, 185 (74%) were randomized. Eligibility criteria included age 6 years or older, infection with Pseudomonas aeruginosa for 1 or more years, and a forced expiratory volume in 1 second (FEV₁) of 30% or more. Participants were stratified by FEV₁ (=" BORDER="0">60% predicted vs <60% predicted), weight of less than 40 kg vs 40 kg or more, and CF center. Intervention  The active group (n = 87) received 250 mg (weight <40 kg) or 500 mg (weight =" BORDER="0">40 kg) of oral azithromycin 3 days a week for 168 days; placebo group (n = 98) received identically packaged tablets. Main Outcome Measures  Change in FEV₁ from day 0 to completion of therapy at day 168 and determination of safety. Secondary outcomes included pulmonary exacerbations and weight gain. Results  The azithromycin group had a mean 0.097-L (SD, 0.26) increase in FEV₁ at day 168 compared with 0.003 L (SD, 0.23) in the placebo group (mean difference, 0.094 L; 95% confidence interval [CI], 0.023-0.165; P = .009). Nausea occurred in 17% more participatns in the azithromycin group (P = .01), diarrhea in 15% more (P = .009), and wheezing in 13% more (P = .007). Participants in the azithromycin group had less risk of experiencing an exacerbation than participants in the placebo group (hazard ratio, 0.65; 95% CI, 0.44-0.95; P = .03) and weighed at the end of the study an average 0.7 kg more than participants receiving placebo (95% CI, 0.1-1.4 kg; P = .02). Conclusion  Azithromycin treatment was associated with improvement in clinically relevant end points and should be considered for patients with CF who are 6 years or older and chronically infected with P aeruginosa.      

Sumatriptan-naproxen for acute treatment of migraine: a randomized trial

Context  Multiple pathogenic mechanisms may be involved in generating the migraine symptom complex, and multimechanism-targeted therapy may confer advantages over monotherapy. Objective  To evaluate the efficacy and safety of a fixed-dose tablet containing sumatriptan succinate and naproxen sodium relative to efficacy and safety of each monotherapy and placebo for the acute treatment of migraine. Design, Setting, and Participants  Two replicate, randomized, double-blind, single-attack, parallel-group studies conducted among 1461 (study 1) and 1495 (study 2) patients at 118 US clinical centers who were diagnosed as having migraine and received study treatment for a moderate or severe migraine attack. Interventions  Patients were randomized in a 1:1:1:1 ratio to receive a single tablet containing sumatriptan, 85 mg, and naproxen sodium, 500 mg; sumatriptan, 85 mg (monotherapy); naproxen sodium, 500 mg (monotherapy); or placebo, to be used after onset of a migraine with moderate to severe pain. Main Outcome Measures  Primary outcome measures included the percentages of patients with headache relief 2 hours after dosing, absence of photophobia, absence of phonophobia, and absence of nausea for the comparison between sumatriptan–naproxen sodium and placebo, and the percentages of patients with sustained pain-free response for the comparison between sumatriptan–naproxen sodium and each monotherapy. Results  Sumatriptan–naproxen sodium was more effective than placebo for headache relief at 2 hours after dosing (study 1, 65% vs 28%; P<.001 and study 2, 57% vs 29%; P<.001), absence of photophobia at 2 hours (58% vs 26%; P<.001 and 50% vs 32%; P<.001), and absence of phonophobia at 2 hours (61% vs 38%; P<.001 and 56% vs 34%; P<.001). The absence of nausea 2 hours after dosing was higher with sumatriptan–naproxen sodium than placebo in study 1 (71% vs 65%; P = .007), but in study 2 rates of absence of nausea did not differ between sumatriptan–naproxen sodium and placebo (65% vs 64%; P = .71). For 2- to 24-hour sustained pain-free response, sumatriptan–naproxen sodium was superior at P<.01 (25% and 23% in studies 1 and 2, respectively) to sumatriptan monotherapy (16% and 14% in studies 1 and 2), naproxen sodium monotherapy (10% and 10% in studies 1 and 2), and placebo (8% and 7% in studies 1 and 2). The incidence of adverse events was similar between sumatriptan–naproxen sodium and sumatriptan monotherapy. Conclusion  Sumatriptan, 85 mg, plus naproxen sodium, 500 mg, as a single tablet for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well-tolerated adverse effect profile. Trial Registration  clinicaltrials.gov Identifiers: NCT00434083 (study 1); NCT00433732 (study 2)      

Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial

Context  Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B₁₂ can lower plasma total homocysteine levels. Objective  To assess the effect of treatment with folic acid and vitamin B₁₂ and the effect of treatment with vitamin B₆ as secondary prevention in patients with coronary artery disease or aortic valve stenosis. Design, Setting, and Participants  Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3% had double- or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes. Interventions  Using a 2 x 2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B₁₂, 0.4 mg, plus vitamin B₆, 40 mg (n = 772); folic acid plus vitamin B₁₂ (n = 772); vitamin B₆ alone (n = 772); or placebo (n = 780). Main Outcome Measures  The primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke. Results  Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B₁₂. The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B₁₂ vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P = .36) and 200 participants (13.0%) receiving vitamin B₆ vs 222 (14.3%) not receiving vitamin B₆ (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P = .28). Conclusions  This trial did not find an effect of treatment with folic acid/vitamin B₁₂ or vitamin B₆ on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease. Trial Registration  clinicaltrials.gov Identifier: NCT00354081      

Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial

Context  Inhaled nitric oxide has been shown to improve oxygenation in acute lung injury. Objective  To evaluate the clinical efficacy of low-dose (5-ppm) inhaled nitric oxide in patients with acute lung injury. Design and Setting  Multicenter, randomized, placebo-controlled study, with blinding of patients, caregivers, data collectors, assessors of outcomes, and data analysts (triple blind), conducted in the intensive care units of 46 hospitals in the United States. Patients were enrolled between March 1996 and September 1999. Patients  Patients (n = 385) with moderately severe acute lung injury, a modification of the American-European Consensus Conference definition of acute respiratory distress syndrome (ARDS) using a ratio of PaO₂ to FiO₂ of 250, were enrolled if the onset was within 72 hours of randomization, sepsis was not the cause of the lung injury, and the patient had no significant nonpulmonary organ system dysfunction at randomization. Interventions  Patients were randomly assigned to placebo (nitrogen gas) or inhaled nitric oxide at 5 ppm until 28 days, discontinuation of assisted breathing, or death. Main Outcome Measures  The primary end point was days alive and off assisted breathing. Secondary outcomes included mortality, days alive and meeting oxygenation criteria for extubation, and days patients were alive following a successful unassisted ventilation test. Results  An intent-to-treat analysis revealed that inhaled nitric oxide at 5 ppm did not increase the number of days patients were alive and off assisted breathing (mean [SD], 10.6 [9.8] days in the placebo group and 10.7 [9.7] days in the inhaled nitric oxide group; P = .97; difference, –0.1 day [95% confidence interval, –2.0 to 1.9 days]). This lack of effect on clinical outcomes was seen despite a statistically significant increase in PaO₂ that resolved by 48 hours. Mortality was similar between groups (20% placebo vs 23% nitric oxide; P = .54). Days patients were alive following a successful 2-hour unassisted ventilation trial were a mean (SD) of 11.9 (9.9) for placebo and 11.4 (9.8) for nitric oxide patients (P = .54). Days alive and meeting criteria for extubation were also similar: 17.0 placebo vs 16.7 nitric oxide (P = .89). Conclusion  Inhaled nitric oxide at a dose of 5 ppm in patients with acute lung injury not due to sepsis and without evidence of nonpulmonary organ system dysfunction results in short-term oxygenation improvements but has no substantial impact on the duration of ventilatory support or mortality.      

Inhaled Budesonide in Addition to Oral Corticosteroids to Prevent Asthma Relapse Following Discharge From the Emergency Department: A Randomized Controlled Trial

Context  Relapses of acute asthma following emergency department (ED) discharge can be reduced with systemic corticosteroid treatment. However, whether inhaled corticosteroids (ICSs) provide additional benefit is not known. Objective  To determine whether the addition of ICSs to oral corticosteroid treatment would reduce relapses in patients with acute asthma discharged from the ED. Design and Setting  Placebo-controlled, double-blind, randomized clinical trial conducted in a community teaching hospital ED in Canada between November 1995 and September 1997, with a 21-day follow-up. Participants  A total of 1006 consecutive patients aged 16 to 60 years presented to the ED with acute asthma; after excluding those using oral and/or inhaled corticosteroids as well as those meeting other exclusion criteria, 188 were included in the study. Interventions  Patients were discharged with a nontapering course of oral prednisone (50 mg/d) for 7 days. In a double-blind fashion, patients were randomly assigned to 1600 µg/d of inhaled budesonide (n=94) or identical placebo (n=94) for 21 days. Main Outcome Measures  Incidence of relapse, defined as an unscheduled visit for worsening asthma symptoms, in budesonide vs placebo groups. Secondary outcomes included response to the Asthma Quality of Life Questionnaire, ₂-agonist use, symptom score, global asthma improvement assessment, and pulmonary function. Results  Five patients in the budesonide group and 3 in the placebo group either dropped out or were lost to follow-up but were included in primary analyses. After 21 days, 12 (12.8%) of 94 patients in the budesonide group experienced a relapse compared with 23 (24.5%) of 94 in the placebo group, a 48% relapse reduction (P=.049). Asthma Quality of Life Questionnaire scores were higher (better quality) in the budesonide group (P=.001), as well as for all domain scores (P=.001 to .01). Fewer ₂-agonist activations were used at the end of the trial by patients receiving budesonide (2.4/d vs 4.2/d; P=.01). Symptom scores (P=.001 to .004) and self-assessed asthma improvement scores (based on a 7-point Likert scale) (6.2 vs 5.2; P<.001) were higher (indicating fewer symptoms) for budesonide vs placebo. There were no differences in pulmonary function between the groups (peak expiratory flow rate: budesonide, 437 vs placebo, 453 L/min; P=.39) at 21 days. Using this approach, as few as 9 patients would require budesonide to prevent 1 relapse. Conclusions  Patients discharged from the ED following treatment for acute asthma benefit from added treatment with high-dose inhaled budesonide for 21 days compared with oral corticosteroids alone.      

Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model

Context  Recent studies have suggested a link between inhaled particulate matter exposure in urban areas and susceptibility to cardiovascular events; however, the precise mechanisms remain to be determined. Objective  To test the hypothesis that subchronic exposure to environmentally relevant particulate matter, even at low concentrations, potentiates atherosclerosis and alters vasomotor tone in a susceptible disease model. Design, Setting, and Participants  Between July 21, 2004, and January 12, 2005, 28 apolipoprotein E^–/– (apoE^–/–) mice were, based on randomized assignments, fed with normal chow or high-fat chow and exposed to concentrated ambient particles of less than 2.5 µm (PM_2.5) or filtered air (FA) in Tuxedo, NY, for 6 hours per day, 5 days per week for a total of 6 months. Main Outcome Measures  Composite atherosclerotic plaque in the thoracic and abdominal aorta and vasomotor tone changes. Results  In the high-fat chow group, the mean (SD) composite plaque area of PM_2.5 vs FA was 41.5% (9.8%) vs 26.2% (8.6%), respectively (P<.001); and in the normal chow group, the composite plaque area was 19.2% (13.1%) vs 13.2% (8.1%), respectively (P = .15). Lipid content in the aortic arch measured by oil red-O staining revealed a 1.5-fold increase in mice fed the high-fat chow and exposed to PM_2.5 vs FA (30.0 [8.2] vs 20.0 [7.0]; 95% confidence interval [CI], 1.21-1.83; P = .02). Vasoconstrictor responses to phenylephrine and serotonin challenge in the thoracic aorta of mice fed high-fat chow and exposed to PM_2.5 were exaggerated compared with exposure to FA (mean [SE], 134.2% [5.2%] vs 100.9% [2.9%], for phenylephrine, and 156.0% [5.6%] vs 125.1% [7.5%], for serotonin; both P = .03); relaxation to the endothelium-dependent agonist acetylcholine was attenuated (mean [SE] of half-maximal dose for dilation, 8.9 [0.2] x 10^-8 vs 4.3 [0.1] x 10^-8, respectively; P = .04). Mice fed high-fat chow and exposed to PM_2.5 demonstrated marked increases in macrophage infiltration, expression of the inducible isoform of nitric oxide synthase, increased generation of reactive oxygen species, and greater immunostaining for the protein nitration product 3-nitrotyrosine (all P<.001). Conclusion  In an apoE^–/– mouse model, long-term exposure to low concentration of PM_2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis.      

Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial

Context  -Blockers have been shown to decrease cardiovascular risk in patients with hypertension and type 2 diabetes mellitus (DM); however, some components of the metabolic syndrome are worsened by some -blockers. Objective  To compare the effects of -blockers with different pharmacological profiles on glycemic and metabolic control in participants with DM and hypertension receiving renin-angiotensin system (RAS) blockade, in the context of cardiovascular risk factors. Design, Setting, and Participants  A randomized, double-blind, parallel-group trial (The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives [GEMINI]) conducted between June 1, 2001, and April 6, 2004, at 205 US sites that compared the effects of carvedilol and metoprolol tartrate on glycemic control. The 1235 participants were aged 36 to 85 years with hypertension (>130/80 mm Hg) and type 2 DM (glycosylated hemoglobin [HbA_1c], 6.5%-8.5%) and were receiving RAS blockers. Participants were followed up for 35 weeks. Interventions  Participants were randomized to receive a 6.25- to 25-mg dose of carvedilol (n = 498) or 50- to 200-mg dose of metoprolol tartrate (n = 737), each twice daily. Open-label hydrochlorothiazide and a dihydropyridine calcium antagonist were added, if needed, to achieve blood pressure target. Main Outcome Measures  Difference between groups in mean change from baseline HbA_1c following 5 months of maintenance therapy. Additional prespecified comparisons included change from baseline HbA_1c in individual treatment groups, treatment effect on insulin sensitivity, and microalbuminuria. Results  The 2 groups differed in mean change in HbA_1c from baseline (0.13%; 95% confidence interval [CI], –0.22% to –0.04%; P = .004; modified intention-to-treat analysis). The mean (SD) HbA_1c increased with metoprolol (0.15% [0.04%]; P<.001) but not carvedilol (0.02% [0.04%]; P = .65). Insulin sensitivity improved with carvedilol (–9.1%; P = .004) but not metoprolol (–2.0%; P = .48); the between-group difference was –7.2% (95% CI, –13.8% to –0.2%; P = .004). Blood pressure was similar between groups. Progression to microalbuminuria was less frequent with carvedilol than with metoprolol (6.4% vs 10.3%; odds ratio, 0.60; 95% CI, 0.36-0.97; P = .04). Conclusions  Both -blockers were well tolerated; use of carvedilol in the presence of RAS blockade did not affect glycemic control and improved some components of the metabolic syndrome relative to metoprolol in participants with DM and hypertension. The effects of the 2 -blockers on clinical outcomes need to be compared in long-term clinical trials.      

Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial

Context  Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. Objective  To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. Design and Setting  Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. Participants  Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. Interventions  Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. Main Outcome Measures  Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. Results  On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was –9.20 (0.67) (95% confidence interval [CI], –10.51 to –7.89) for placebo vs –8.68 (0.68) (95% CI, –10.01 to –7.35) for H perforatum (P = .59) and –10.53 (0.72) (95% CI, –11.94 to –9.12) for sertraline (P = .18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum–treated patients (P = .21) and 24.8% of sertraline-treated patients (P = .26). Sertraline was better than placebo on the CGI improvement scale (P = .02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo. Conclusion  This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.      

Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials

Context  Heart failure causes more than 1 million US hospitalizations yearly, mostly related to congestion. Tolvaptan, an oral, nonpeptide, selective vasopressin V₂-receptor antagonist, shows promise in this condition. Objective  To evaluate short-term effects of tolvaptan when added to standard therapy in patients hospitalized with heart failure. Design, Setting, and Patients  Two identical prospective, randomized, double-blind, placebo-controlled trials at 359 sites in North America, South America, and Europe were conducted during the inpatient period of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) between October 7, 2003, and February 3, 2006. A total of 2048 (trial A) and 2085 (trial B) patients hospitalized with heart failure and congestion were studied. Intervention  Patients were randomized to receive either tolvaptan (30 mg/d) or matching placebo, within 48 hours of admission. Main Outcome Measures  Primary end point was a composite of changes in global clinical status based on a visual analog scale and body weight at day 7 or discharge if earlier. Secondary end points included dyspnea (day 1), global clinical status (day 7 or discharge), body weight (days 1 and 7 or discharge), and peripheral edema (day 7 or discharge). Results  Rank sum analysis of the composite primary end point showed greater improvement with tolvaptan vs placebo (trial A, mean [SD], 1.06 [0.43] vs 0.99 [0.44]; and trial B, 1.07 [0.42] vs 0.97 [0.43]; both trials P<.001). Mean (SD) body weight reduction was greater with tolvaptan on day 1 (trial A, 1.71 [1.80] vs 0.99 [1.83] kg; P<.001; and trial B, 1.82 [2.01] vs 0.95 [1.85] kg; P<.001) and day 7 or discharge (trial A, 3.35 [3.27] vs 2.73 [3.34] kg; P<.001; and trial B, 3.77 [3.59] vs 2.79 [3.46] kg; P<.001), whereas improvements in global clinical status were not different between groups. More patients receiving tolvaptan (684 [76.7%] and 678 [72.1%] for trial A and trial B, respectively) vs patients receiving placebo (646 [70.6%] and 597 [65.3%], respectively) reported improvement in dyspnea at day 1 (both trials P<.001). Edema at day 7 or discharge improved significantly with tolvaptan in trial B (P = .02) but did not reach significance in trial A (P = .07). Serious adverse event frequencies were similar between groups, without excess renal failure or hypotension. Conclusion  In patients hospitalized with heart failure, oral tolvaptan in addition to standard therapy including diuretics improved many, though not all, heart failure signs and symptoms, without serious adverse events. Trial Registration  clinicaltrials.gov Identifier: NCT00071331