Plasma Microbial Cell-Free DNA Sequencing in Immunocompromised Patients With Pneumonia: A Prospective Observational Study.

BACKGROUND: Pneumonia is a common cause of morbidity and mortality, yet a causative pathogen is identified in a minority of cases. Plasma microbial cell-free DNA sequencing may improve diagnostic yield in immunocompromised patients with pneumonia. METHODS: In this prospective, multicenter, observational study of immunocompromised adults undergoing bronchoscopy to establish a pneumonia etiology, plasma microbial cell-free DNA sequencing was compared to standardized usual care testing. Pneumonia etiology was adjudicated by a blinded independent committee. The primary outcome, additive diagnostic value, was assessed in the Per Protocol population (patients with complete testing results and no major protocol deviations) and defined as the percent of patients with an etiology of pneumonia exclusively identified by plasma microbial cell-free DNA sequencing. Clinical additive diagnostic value was assessed in the Per Protocol subgroup with negative usual care testing. RESULTS: Of 257 patients, 173 met Per Protocol criteria. A pneumonia etiology was identified by usual care in 52/173 (30.1%), plasma microbial cell-free DNA sequencing in 49/173 (28.3%) and the combination of both in 73/173 (42.2%) patients. Plasma microbial cell-free DNA sequencing exclusively identified an etiology of pneumonia in 21/173 patients (additive diagnostic value 12.1%, 95% confidence interval [CI], 7.7% to 18.0%, P < .001). In the Per Protocol subgroup with negative usual care testing, plasma microbial cell-free DNA sequencing identified a pneumonia etiology in 21/121 patients (clinical additive diagnostic value 17.4%, 95% CI, 11.1% to 25.3%). CONCLUSIONS: Non-invasive plasma microbial cell-free DNA sequencing significantly increased diagnostic yield in immunocompromised patients with pneumonia undergoing bronchoscopy and extensive microbiologic and molecular testing. CLINICAL TRIALS REGISTRATION: NCT04047719.

Fitness of real-world data for clinical trial data collection: Results and lessons from a HARMONY Outcomes ancillary study.

BACKGROUND: Despite the extensive use of real-world data for retrospective, observational clinical research, our understanding of how real-world data might increase the efficiency of data collection in patient-level randomized clinical trials is largely unknown. The structure of real-world data is inherently heterogeneous, with each source electronic health record and claims database different from the next. Their fitness-for-use as data sources for multisite trials in the United States has not been established. METHODS: For a subset of participants in the HARMONY Outcomes Trial, we obtained electronic health record data from recruiting sites or Medicare claims data from the Centers for Medicare & Medicaid Services. For baseline characteristics and follow-up events, we assessed the level of agreement between these real-world data and data documented in the trial database. RESULTS: Real-world data-derived demographic information tended to agree with trial-reported demographic information, although real-world data were less accurate in identifying medical history. The ability of real-world data to identify baseline medication usage differed by real-world data source, with claims data demonstrating substantially better performance than electronic health record data. The limited number of lab results in the collected electronic health record data matched closely with values in the trial database. There were not enough follow-up events in the ancillary study population to draw meaningful conclusions about the performance of real-world data for identification of events. Based on the conduct of this ancillary study, the challenges and opportunities of using real-world data within clinical trials are discussed. CONCLUSION: Based on a subset of participants from the HARMONY Outcomes Trial, our results suggest that electronic health record or claims data, as currently available, are unlikely to be a complete substitute for trial data collection of medical history or baseline lab results, but that Medicare claims were able to identify most medications. The limited size of the study population prevents us from drawing strong conclusions based on these results, and other studies are clearly needed to confirm or refute these findings.

Levosimendan in patients with reduced left ventricular function undergoing isolated coronary or valve surgery.

OBJECTIVE: In the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial, no differences in clinical outcomes were observed between levosimendan and placebo in a broad population of patients undergoing cardiac surgery. In previous studies, the benefits of levosimendan were most clearly evident in patients undergoing isolated coronary artery bypass grafting (CABG) surgery. In a prespecified analysis of LEVO-CTS, we compared treatment-related outcomes and costs across types of cardiac surgical procedures. METHODS: Overall, 563 (66.4%) patients underwent isolated CABG, 97 (11.4%) isolated valve, and 188 (22.2%) combined CABG/valve surgery. Outcomes included the co-primary 4-component composite (30-day mortality, 30-day renal replacement, 5-day myocardial infarction, or 5-day mechanical circulatory support), the 2-component composite (30-day mortality or 5-day mechanical circulatory support), 90-day mortality, low cardiac output syndrome (LCOS), and 30-day medical costs. RESULTS: The 4- and 2-component outcomes were not significantly different with levosimendan and placebo in patients undergoing CABG (15.2% vs 19.3% and 7.8% vs 10.4%), valve (49.0% vs 33.3% and 22.4% vs 2.1%), or combined procedures (39.6% vs 35.9% and 24.0% vs 19.6%). Ninety-day mortality was lower with levosimendan in isolated CABG (2.1% vs 7.9%; hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.11-0.64), but not significantly different in valve (8.3% vs 2.0%; HR, 4.10; 95% CI, 0.46-36.72) or combined procedures (10.4% vs 7.6%; HR, 1.39; 95% CI, 0.53-3.64; interaction P = .011). LCOS (12.0% vs 22.1%; odds ratio, 0.48; 95% CI, 0.30-0.76; interaction P = .118) was significantly lower in levosimendan-treated patients undergoing isolated CABG. Excluding study drug costs, median and mean 30-day costs were $53,707 and $65,852 for levosimendan and $54,636 and $67,122 for placebo, with a 30-day mean difference (levosimendan - placebo) of -$1270 (bootstrap 95% CI, -$8722 to $6165). CONCLUSIONS: Levosimendan was associated with lower 90-day mortality and LCOS in patients undergoing isolated CABG, but not in those undergoing isolated valve or combined CABG/valve procedures.

Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery.

BACKGROUND: Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery. METHODS: In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 µg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 µg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5. RESULTS: A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups. CONCLUSIONS: Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO-CTS ClinicalTrials.gov number, NCT02025621 .).

Levosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery on cardiopulmonary bypass: Rationale and study design of the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial.

BACKGROUND: Low cardiac output syndrome is associated with increased mortality and occurs in 3% to 14% of patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Levosimendan, a novel calcium sensitizer and KATP channel activator with inotropic, vasodilatory, and cardioprotective properties, has shown significant promise in reducing the incidence of low cardiac output syndrome and related adverse outcomes in patients undergoing cardiac surgery on CPB. METHODS: LEVO-CTS is a phase 3 randomized, controlled, multicenter study evaluating the efficacy, safety, and cost-effectiveness of levosimendan in reducing morbidity and mortality in high-risk patients with reduced left ventricular ejection fraction (≤35%) undergoing cardiac surgery on CPB. Patients will be randomly assigned to receive either intravenous levosimendan (0.2 µg kg-1 min-1 for the first hour followed by 0.1 µg/kg for 23hours) or matching placebo initiated within 8hours of surgery. The co-primary end points are (1) the composite of death or renal replacement therapy through day 30 or perioperative myocardial infarction, or mechanical assist device use through day 5 (quad end point tested at α<.01), and (2) the composite of death through postoperative day 30 or mechanical assist device use through day 5 (dual end point tested at α<.04). Safety end points include new atrial fibrillation and death through 90days. In addition, an economic analysis will address the cost-effectiveness of levosimendan compared with placebo in high-risk patients undergoing cardiac surgery on CPB. Approximately 880 patients will be enrolled at approximately 60 sites in the United States and Canada between July 2014 and September 2016, with results anticipated in January 2017. CONCLUSION: LEVO-CTS, a large randomized multicenter clinical trial, will evaluate the efficacy, safety, and cost-effectiveness of levosimendan in reducing adverse outcomes in high-risk patients undergoing cardiac surgery on CPB. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT02025621).

Predicting Outcomes Over Time in Patients With Heart Failure, Left Ventricular Systolic Dysfunction, or Both Following Acute Myocardial Infarction.

BACKGROUND: Most studies of risk assessment or stratification in patients with myocardial infarction (MI) have been static and fail to account for the evolving nature of clinical events and care processes. We sought to identify predictors of mortality, cardiovascular death or nonfatal MI, and cardiovascular death or nonfatal heart failure (HF) over time in patients with HF, left ventricular systolic dysfunction, or both post-MI. METHODS AND RESULTS: Using data from the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial, we developed models to estimate the association between patient characteristics and the likelihood of experiencing an event from the time of a follow-up visit until the next visit. The intervals are: hospital arrival to discharge or 14 days, whichever occurs first; hospital discharge to 30 days; 30 days to 6 months; and 6 months to 3 years. Models were also developed to predict the entire 3-year follow-up period using baseline information. Multivariable Cox proportional hazards modeling was used throughout with Wald chi-squares as the comparator of strength for each predictor. For the baseline model of overall mortality, the 3 strongest predictors were age (adjusted hazard ratio [HR], 1.35; 95% CI, 1.28-1.42; P<0.0001), baseline heart rate (adjusted HR, 1.17; 95% CI, 1.14-1.21; P<0.0001), and creatinine clearance (≤100 mL/min; adjusted HR, 0.86; 95% CI, 0.84-0.89; P<0.0001). According to the integrated discrimination improvement (IDI) and net reclassification improvement (NRI) indices, the updated model had significant improvement over the model with baseline covariates only in all follow-up periods and with all outcomes. CONCLUSIONS: Patient information assessed closest to the time of the outcome was more valuable in predicting death when compared with information obtained at the time of the index hospitalization. Using updated patient information improves prognosis over using only the information available at the time of the index event.

Clinical characteristics and outcomes after unplanned intraaortic balloon counterpulsation in the Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction trial.

BACKGROUND: Despite advances in primary percutaneous coronary intervention (pPCI) and regional systems of care, the development of cardiogenic shock is associated with poor clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). We sought to better characterize the baseline characteristics and clinical outcomes of patients who underwent crossover to intraaortic balloon counterpulsation (IABC) in the CRISP AMI trial. METHODS: Patients with anterior STEMI were randomized to IABC before pPCI or pPCI alone. Infarct size and 6-month clinical outcomes were evaluated in patients both in the pPCI-alone group who did undergo crossover to IABC and those who did not undergo crossover to IABC. RESULTS: Among 176 patients randomized to pPCI alone, 161 patients did not later receive IABC during the index hospitalization, and 15 patients (8.5%) underwent crossover and did receive unplanned IABC. Hypotension and/or cardiogenic shock precipitated crossover to IABC in 12 patients (80%). Patients who underwent crossover to IABC demonstrated lower systolic and diastolic blood pressures on admission. At 6 months, rates of death (26.7% vs 3.1%, P = .003), readmission for severe hypotension (53.3% vs 3.7%, P < .001), resuscitated cardiac arrest, and ventricular arrhythmia were higher in the group that did crossover to IABC. Crossover to IABC was not associated with increased infarct size. CONCLUSIONS: The most significant predictor of crossover to IABC in the setting of anterior STEMI was relative hypotension at the time of hospital admission, and crossover to IABC in CRISP AMI was associated with significantly worse clinical outcomes.

Randomized controlled trial of osmotic-release methylphenidate with cognitive-behavioral therapy in adolescents with attention-deficit/hyperactivity disorder and substance use disorders.

OBJECTIVE: To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD). METHOD: This was a 16-week, randomized, controlled, multi-site trial of OROS-MPH + CBT versus placebo + CBT in 303 adolescents (aged 13 through 18 years) meeting DSM-IV diagnostic criteria for ADHD and SUD. Primary outcome measures included the following: for ADHD, clinician-administered ADHD Rating Scale (ADHD-RS), adolescent informant; for substance use, adolescent-reported days of use in the past 28 days. Secondary outcome measures included parent ADHD-RS and weekly urine drug screens (UDS). RESULTS: There were no group differences on reduction in ADHD-RS scores (OROS-MPH: -19.2, 95% confidence interval [CI], -17.1 to -21.2; placebo, -21.2, 95% CI, -19.1 to -23.2) or reduction in days of substance use (OROS-MPH: -5.7 days, 95% CI, 4.0-7.4; placebo: -5.2 days, 95% CI, 3.5-7.0). Some secondary outcomes favored OROS-MPH, including lower parent ADHD-RS scores at 8 (mean difference = 4.4, 95% CI, 0.8-7.9) and 16 weeks (mean difference =6.9; 95% CI, 2.9-10.9) and more negative UDS in OROS-MPH (mean = 3.8) compared with placebo (mean = 2.8; p = .04). CONCLUSIONS: OROS-MPH did not show greater efficacy than placebo for ADHD or on reduction in substance use in adolescents concurrently receiving individual CBT for co-occurring SUD. However, OROS-MPH was relatively well tolerated and was associated with modestly greater clinical improvement on some secondary ADHD and substance outcome measures. Clinical Trial Registration Information-Attention Deficit Hyperactivity Disorder (ADHD) in Adolescents with Substance Use Disorders (SUD); http://www.clinicaltrials.gov; NCT00264797.

Impact of attention-deficit/hyperactivity disorder (ADHD) treatment on smoking cessation intervention in ADHD smokers: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: High smoking rates in adults with attention-deficit/hyperactivity disorder (ADHD) and nicotine's amelioration of ADHD suggest that effective ADHD treatment might facilitate abstinence in smokers with ADHD. The present study evaluated if using osmotic-release oral system methylphenidate (OROS-MPH) to treat ADHD enhances response to smoking cessation treatment in smokers with ADHD. METHOD: A randomized, double-blind, placebo-controlled, 11-week trial with a 1-month follow-up was conducted at 6 clinical sites between December 2005 and January 2008. Adults (aged 18-55 years) meeting DSM-IV criteria for ADHD and interested in quitting smoking were randomly assigned to OROS-MPH titrated to 72 mg/d (n = 127) or placebo (n = 128). All participants received brief weekly individual smoking cessation counseling for 11 weeks and 21 mg/d nicotine patches starting on the smoking quit day (day 27) through study week 11. Outcome measures included prolonged smoking abstinence and DSM-IV ADHD Rating Scale (ADHD-RS) score. RESULTS: Of 255 randomly assigned participants, 204 (80%) completed the trial. Prolonged abstinence rates, 43.3% and 42.2%, for the OROS-MPH and placebo groups, respectively, did not differ significantly (OR = 1.1; 95% CI, 0.63-1.79; P = .81). Relative to placebo, OROS-MPH evidenced a greater reduction in DSM-IV ADHD-RS score (P < .0001) and in cigarettes per day during the post-quit phase (P = .016). Relative to placebo, OROS-MPH increased blood pressure and heart rate to a statistically, but not clinically, significant degree (P < .05); medication discontinuation did not differ significantly between treatments. CONCLUSIONS: Treatment for ADHD did not improve smoking cessation success; OROS-MPH, relative to placebo, effectively treated ADHD and was safe and generally well tolerated in this healthy sample of adult ADHD smokers. TRIAL REGISTRATION: clinical trials.gov Identifier: NCT00253747.

Usefulness of beta blockers in high-risk patients after myocardial infarction in conjunction with captopril and/or valsartan (from the VALsartan In Acute Myocardial Infarction [VALIANT] trial).

Concern has been raised about combining beta blockers with angiotensin-receptor blockers in patients with heart failure. The VALsartan In Acute myocardial infarction (VALIANT) trial enrolled 14,703 patients with myocardial infarction complicated by heart failure or documented left ventricular systolic dysfunction. These patients were randomly allocated to treatment with valsartan, captopril, or both. Physicians were also encouraged to prescribe beta blockers because of previous evidence of benefit. The baseline characteristics, treatments, and outcomes were compared among 4 groups: patients taking beta blockers at admission only, at discharge only, at both admission and discharge, and neither. Patients treated with beta blockers were at lower risk than those not treated at any period. Those treated with beta blockers at both intervals had a lower 3-year mortality rate (17.7%) than those treated only at randomization (30.7%) or only at discharge (25.9%). The greatest mortality (35.1%) occurred in patients not treated at either point. No statistically significant interaction with prognosis was observed between beta-blocker use and treatment with valsartan or valsartan plus captopril. Patients discharged with a beta blocker had a significant survival advantage after adjustment for differences in baseline characteristics and intervening complications (hazard ratio 0.89, 95% confidence interval 0.81 to 0.98, p = 0.02). This association was most pronounced in patients prescribed consistent beta blockers at randomization and discharge and was present in both patients with impaired and those with preserved systolic left ventricular function. These results have further confirmed that beta blockers reduce the risk of death and nonfatal cardiovascular events in patients with heart failure or systolic left ventricular dysfunction after myocardial infarction. In conclusion, no evidence was found of adverse interactions between the angiotensin-receptor blocker valsartan and beta blockers or of a negative effect of the combination of valsartan, captopril, and beta blockers.

Admission or changes in renal function during hospitalization for worsening heart failure predict postdischarge survival: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF).

BACKGROUND: Admission measures of renal function (blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR]) in patients hospitalized for worsening heart failure are predictors of in-hospital outcomes. Less is known about the changes and relationships among these variables and the postdischarge survival rate. METHODS AND RESULTS: In a retrospective analysis of 949 patients from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure, we investigated the relation between admission values and changes in BUN and eGFR and rate of death by 60 days after discharge. On admission, median eGFR was 51 mL min(-1) 1.73 m(-2) (interquartile range, 37 to 70 mL min(-1) 1.73 m(-2)), and BUN was 25 mg/dL (interquartile range, 17 to 41 mg/dL). On average, there was a 1.1-mL min(-1) 1.73 m(-2) decrease in eGFR and a 4.7-mg/dL increase in BUN from admission to discharge. By discharge, 12% of patients had a >25% decrease in eGFR, and 39% had a >25% increase in BUN. Although both lower admission eGFR and higher admission BUN were associated with higher risk of death by 60 days after discharge, multivariable-adjusted Cox proportional-hazards analysis showed that BUN was a stronger predictor of death by 60 days than was eGFR (chi(2), 11.6 and 0.6 for BUN and eGFR, respectively). Independently of admission values, an increase of >or=10 mg/dL in BUN during hospitalization was associated with worse 60-day survival rate: BUN (per 5-mg/dL increase) had a hazard ratio of 1.08 (95% CI, 1.01 to 1.16). Although milrinone treatment led to a minor improvement in renal function by discharge, the 60-day death and readmission rates were similar between the milrinone and placebo groups. CONCLUSIONS: A substantial number of patients admitted with heart failure have worsening renal function during hospitalization. Higher admission BUN and increasing BUN during hospitalization, independently of admission values, are associated with a worse survival rate. Use of milrinone in these high-risk patients does not improve outcomes despite minor improvements in the renal function.

Telephone enhancement of long-term engagement (TELE) in continuing care for substance abuse treatment: a NIDA clinical trials network (CTN) study.

The TELE study examined the feasibility and potential efficacy of phone calls to patients after discharge from short- term inpatient and residential substance abuse treatment programs to encourage compliance with continuing care plans. After review of their continuing care plans, 339 patients from four programs were randomized either to receive calls or to have no planned contact. Ninety-two percent of patients randomized to receive calls received at least one call. No difference was found between groups in self-reported attendance at one or more outpatient counseling sessions after discharge (p = .89). When program records of all participants were examined, those receiving calls had a greater likelihood of documented attendance (48%) than those not called (37%). Results were not statistically significant (p < .003) because of the Hochberg correction for multiple tests. While the phone calls were feasible, the lack of clear evidence of efficacy of the calls suggests the need for further investigation of the role of telephone intervention to encourage compliance and improve outcomes.

Previously known and newly diagnosed atrial fibrillation: a major risk indicator after a myocardial infarction complicated by heart failure or left ventricular dysfunction.

AIMS: To characterize the relationship between known and newly diagnosed atrial fibrillation (AF) and the risk of death and major cardiovascular (CV) events in patients with acute myocardial infarction (MI) complicated by heart failure (HF) and/or left ventricular systolic dysfunction (LVSD). METHODS: The VALIANT trial enrolled 14,703 individuals with acute MI complicated by HF and/or LVSD. AF was assessed at presentation and at randomization (median 4.9 days after symptom onset). Primary outcomes were risk of death and major CV events 3 years following acute MI. RESULTS: A total of 1812 with current AF (AF between presentation and randomization), 339 patients with prior AF (history of AF without current AF), and 12,509 without AF were enrolled. Patients with AF were older; had more prior HF, angina, and MI, and received beta-blockers and thrombolytics less often than those without AF. Three-year mortality estimates were 20% in those without AF, 37% with current AF, and 38% with prior AF. Compared with patients without AF, the multivariable adjusted HR of death was 1.25 (1.03-1.52; p=0.03) for prior AF and 1.32 (1.20-1.45; p<0.0001) for current AF. HR for major CV events was 1.15 (0.98-1.35; p=0.08) and 1.21 (1.12-1.31; p<0.0001). CONCLUSION: AF is associated with greater long-term mortality and adverse CV events with acute MI complicated by HF or LVSD.

Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study.

BACKGROUND: The prognostic value of serum sodium in patients hospitalized for worsening heart failure has not been well defined. METHODS AND RESULTS: The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study randomized 949 patients with systolic dysfunction hospitalized for worsening heart failure to receive 48 to 72 hours of intravenous milrinone or placebo in addition to standard therapy. In a retrospective analysis, we investigated the relationship between admission serum sodium and the primary end point of days hospitalized for cardiovascular causes within 60 days of randomization, as well as the secondary end points of in-hospital mortality, 60-day mortality, and 60-day mortality/rehospitalization. The number of days hospitalized for cardiovascular causes was higher in the lowest sodium quartile: 8.0 (4.5, 18.5) versus 6 (4, 13) versus 6 (4, 11.5) versus 6 (4, 12) days (P<0.015 for comparison with the lowest quartile). Lower serum sodium was associated with higher in-hospital and 60-day mortality: 5.9% versus 1% versus 2.3% versus 2.3% (P<0.015) and 15.9% versus 6.4% versus 7.8% versus 7% (P=0.002), respectively. There was a trend toward higher mortality/rehospitalization for patients who were in the lowest sodium quartile. Multivariable-adjusted Cox proportional hazards analysis showed that serum sodium on admission, when modeled linearly, predicted increased 60-day mortality: sodium (per 3-mEq/L decrease) had a hazard ratio of 1.18 with a 95% CI of 1.03 to 1.36 (P=0.018). CONCLUSIONS: In patients hospitalized for worsening heart failure, admission serum sodium is an independent predictor of increased number of days hospitalized for cardiovascular causes and increased mortality within 60 days of discharge.

Risk stratification after hospitalization for decompensated heart failure.

BACKGROUND: Decompensated heart failure (HF) is among the most common indications for hospitalization in the United States, but little is known about features on admission that predict adverse events. We used data from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study to develop a model that would predict outcomes in patients with decompensated HF. METHODS AND RESULTS: OPTIME-CHF randomized 949 patients hospitalized with decompensated HF for 48 to 72 hours of infusion of either milrinone or placebo. We used multivariable modeling to evaluate variables on admission that would be predictive of 60-day mortality or the composite of death or rehospitalization at 60 days. Variables at presentation that predicted death at 60 days were increased age, lower systolic blood pressure, New York Heart Association class IV symptoms, elevated blood urea nitrogen (BUN), and decreased sodium. Predictors of the composite of death or rehospitalization within 60 days were the number of HF hospitalizations in the preceding 12 months, elevated BUN, lower systolic blood pressure, decreased hemoglobin, and a history of percutaneous coronary intervention (PCI). The discriminatory power of the model was substantial for the mortality model (c-index .77) but less for the composite endpoint (c-index .69). CONCLUSIONS: Risk stratification of patients with decompensated HF may be accomplished using easily assessed clinical variables. Further research into the validity of this model in independent samples will potentially aid in the development of risk stratification strategies.

Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial.

BACKGROUND: A prior diagnosis of diabetes mellitus is associated with adverse outcomes after acute myocardial infarction (MI), but the risk associated with a new diagnosis of diabetes in this setting has not been well defined. METHODS AND RESULTS: We assessed the risk of death and major cardiovascular events associated with previously known and newly diagnosed diabetes by studying 14,703 patients with acute MI enrolled in the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Patients were grouped by diabetic status: previously known diabetes (insulin use or diagnosis of diabetes before MI, n=3400, 23%); newly diagnosed diabetes (use of diabetic therapy or diabetes diagnosed at randomization [median 4.9 d after infarction], but no known diabetes at presentation, n=580, 4%); or no diabetes (n=10,719). Patients with newly diagnosed diabetes were younger and had fewer comorbid conditions than did patients with previously known diabetes. At 1 year after enrollment, patients with previously known and newly diagnosed diabetes had similarly increased adjusted risks of mortality (hazard ratio [HR] 1.43; 95% confidence interval [CI], 1.29 to 1.59 and HR, 1.50; 95% CI, 1.21 to 1.85, respectively) and cardiovascular events (HR, 1.37; 95% CI, 1.27 to 1.48 and HR, 1.34; 95% CI, 1.14 to 1.56). CONCLUSIONS: Diabetes mellitus, whether newly diagnosed or previously known, is associated with poorer long-term outcomes after MI in high-risk patients. The poor prognosis of patients with newly diagnosed diabetes, despite having baseline characteristics similar to those of patients without diabetes, supports the idea that metabolic abnormalities contribute to their adverse outcomes.

Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction.

BACKGROUND: The presence of coexisting conditions has a substantial effect on the outcome of acute myocardial infarction. Renal failure is associated with one of the highest risks, but the influence of milder degrees of renal impairment is less well defined. METHODS: As part of the Valsartan in Acute Myocardial Infarction Trial (VALIANT), we identified 14,527 patients with acute myocardial infarction complicated by clinical or radiologic signs of heart failure, left ventricular dysfunction, or both, and a documented serum creatinine measurement. Patients were randomly assigned to receive captopril, valsartan, or both. The glomerular filtration rate (GFR) was estimated by means of the four-component Modification of Diet in Renal Disease equation, and the patients were grouped according to their estimated GFR. We used a 70-candidate variable model to adjust and compare overall mortality and composite cardiovascular events among four GFR groups. RESULTS: The distribution of estimated GFR was wide and normally shaped, with a mean (+/-SD) value of 70+/-21 ml per minute per 1.73 m2 of body-surface area. The prevalence of coexisting risk factors, prior cardiovascular disease, and a Killip class of more than I was greatest among patients with a reduced estimated GFR (less than 45.0 ml per minute per 1.73 m2), and the use of aspirin, beta-blockers, statins, or coronary-revascularization procedures was lowest in this group. The risk of death or the composite end point of death from cardiovascular causes, reinfarction, congestive heart failure, stroke, or resuscitation after cardiac arrest increased with declining estimated GFRs. Although the rate of renal events increased with declining estimated GFRs, the adverse outcomes were predominantly cardiovascular. Below 81.0 ml per minute per 1.73 m2, each reduction of the estimated GFR by 10 units was associated with a hazard ratio for death and nonfatal cardiovascular outcomes of 1.10 (95 percent confidence interval, 1.08 to 1.12), which was independent of the treatment assignment. CONCLUSIONS: Even mild renal disease, as assessed by the estimated GFR, should be considered a major risk factor for cardiovascular complications after a myocardial infarction.

The impact of arrhythmias in acute heart failure.

BACKGROUND: Arrhythmias are common in chronic heart failure and affect outcomes. The incidence and significance of new arrhythmias in acute heart failure, however, are largely unknown. METHODS AND RESULTS: The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations study randomized 949 patients with decompensated heart failure to receive intravenous milrinone or placebo. In the study, patients were divided into 2 groups based on the occurrence of a new arrhythmic event during their index hospitalization and analyzed for outcome. There were 59 new arrhythmic events occurring in 6% of the population. Of these, 49% were atrial fibrillation/flutter. The primary endpoint of days hospitalized for cardiovascular causes within 60 days after randomization was 30.9+/-22.7 for those in the arrhythmia group and 11.3+/-12.7 days for those with no arrhythmias (P=.0001). Mortality during index hospitalization was 26% in the arrhythmia group and 1.8% in the no arrhythmia group (P=.001). Death or hospitalization at 60 days was also worse in the arrhythmia group (35 versus 8.2%, P=.0001; 57 versus 34%, P=.001, respectively). Cox proportional hazard analysis identified new arrhythmias as an independent risk factor for the primary endpoint and death at 60 days. CONCLUSION: New arrhythmia during an exacerbation of heart failure identifies a high-risk group with higher intrahospital and 60-day morbidity and mortality.

Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both.

BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitors such as captopril reduce mortality and cardiovascular morbidity among patients with myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both. In a double-blind trial, we compared the effect of the angiotensin-receptor blocker valsartan, the ACE inhibitor captopril, and the combination of the two on mortality in this population of patients. METHODS: Patients receiving conventional therapy were randomly assigned, 0.5 to 10 days after acute myocardial infarction, to additional therapy with valsartan (4909 patients), valsartan plus captopril (4885 patients), or captopril (4909 patients). The primary end point was death from any cause. RESULTS: During a median follow-up of 24.7 months, 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group (hazard ratio in the valsartan group as compared with the captopril group, 1.00; 97.5 percent confidence interval, 0.90 to 1.11; P=0.98; hazard ratio in the valsartan-and-captopril group as compared with the captopril group, 0.98; 97.5 percent confidence interval, 0.89 to 1.09; P=0.73). The upper limit of the one-sided 97.5 percent confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality (P=0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (P<0.001). The valsartan-and-captopril group had the most drug-related adverse events. With monotherapy, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group. CONCLUSIONS: Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival.

VALsartan In Acute myocardial iNfarcTion (VALIANT) trial: baseline characteristics in context.

BACKGROUND: The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial compared outcomes with: (1) angiotensin-converting enzyme inhibition (ACEI) with the reference agent captopril; (2) angiotensin-receptor blockade (ARB) with valsartan; or (3) both in patients with heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) after myocardial infarction (MI). AIMS: a goal of this active-control trial was to simulate conditions that would lead current practitioners to use ACEIs. Thus, we compared characteristics of VALIANT patients with those of patients in placebo-controlled trials that established ACEIs as standard treatment. METHODS AND RESULTS: We collected demographic, clinical, medication and imaging information from 14703 patients in 24 countries. This high-risk population was a median 65.8 years old, and 31.1% were female. Most (51.8%) showed imaging evidence of LVSD at enrollment. Most (72%) had Killip class>/=II HF. Patients received evidence-based therapies at rates similar to those of contemporary MI trials and at an improved rate compared with prior placebo-controlled ACEI trials. CONCLUSION: VALIANT represents the largest globally representative cohort enrolled with HF and/or LVSD after MI. Patients were similar to those in placebo-controlled ACEI trials while reflecting improvements in evidence-based care. With enrollment complete, VALIANT is poised to define the optimal strategy for renin-angiotensin system blockade after MI to improve cardiovascular outcomes.