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Abstract: Acute decompensated heart failure (ADHF) is a complex clinical event associated with excess morbidity and mortality. Managing ADHF patients is challenging because of the lack of effective treatments that both reduce symptoms and improve clinical outcomes. Existing guideline recommendations are largely based on expert opinion, but several recently published trials have yielded important data to inform both current clinical practice and future research directions. New insight has been gained regarding volume management, including dosing strategies for intravenous loop diuretics and the role of ultrafiltration in patients with heart failure and renal dysfunction. Although the largest ADHF trial to date (ASCEND-HF, using nesiritide) was neutral, promising results with other investigational agents have been reported. If these findings are confirmed in phase III trials, novel compounds, such as relaxin, omecamtiv mecarbil, and ularitide, among others, may become therapeutic options. Translation of research findings into quality clinical care can not be overemphasized. Although many gaps in knowledge exist, ongoing studies will address issues around delivery of evidence-based care to achieve the goal of improving the health status and clinical outcomes of patients with ADHF. [Copyright &y& Elsevier]

Aims There is little evidence of beta-blocker treatment benefit in patients with heart failure and reduced left ventricular ejection fraction (HFREF) and atrial fibrillation (AF). We investigated the effects of bucindolol in HFREF patients with AF enrolled in the Beta-blocker Evaluation of Survival Trial (BEST). Methods and results A post-hoc analysis of patients in BEST with and without AF was performed to estimate the effect of bucindolol on mortality and hospitalization. Patients were also evaluated for treatment effects on heart rate and the influence of beta1-adrenergic receptor position 389 (β1389) arginine (Arg) vs. glycine (Gly) genotypes. In the 303/2708 patients in AF, patients receiving bucindolol were more likely to achieve a resting heart rate ≤80 b.p.m. at 3 months (P < 0.005) in the absence of treatment-limiting bradycardia. In AF patients and sinus rhythm (SR) patients who achieved a resting heart rate ≤80 b.p.m., there were beneficial treatment effects on cardiovascular mortality/cardiovascular hospitalization [hazard ratio (HR) 0.61, P = 0.025, and 0.79, P = 0.002]. Without achieving a resting heart rate ≤80 b.p.m., there were no treatment effects on events in either group. β1389-Arg/Arg AF patients had nominally significant reductions in all-cause mortality/HF hospitalization and cardiovascular mortality/hospitalization with bucindolol (HR 0.23, P = 0.037 and 0.28, P = 0.039), whereas Gly carriers did not. There was no evidence of diminished heart rate response in β1389-Arg homozygotes. Conclusion In HFREF patients with AF, bucindolol was associated with reductions in composite HF endpoints in those who achieved a resting heart rate ≤80 b.p.m. and nominally in those with the β1389-Arg homozygous genotype. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a β-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (β1 adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α2C AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology. Methodology: In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of β1389 and α2C322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for β1389 AR variants was measured in human explanted left ventricles. Principal Findings: The combination of β1389 Arg+α2C322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in b1389 Arg homozygotes+α2C322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in b1389 Arg vs. Gly ARs, which converts α2CDel minor allele-associated NE lowering from a therapeutic liability to a benefit. Conclusions: On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (β1389 Arg homozygotes), intermediate (β1389 Gly carriers+α2C322-325 Wt homozygotes), and no (β1389 Gly carriers+α2C322-325 Del carriers) efficacy. [ABSTRACT FROM AUTHOR]

Abstract: Aldosterone antagonists (or mineralocorticoid receptor antagonists [MRAs]) are guideline-recommended therapy for patients with moderate to severe heart failure (HF) symptoms and reduced left ventricular ejection fraction (LVEF), and in postmyocardial infarction patients with HF. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial evaluated the MRA eplerenone in patients with mild HF symptoms. Eplerenone reduced the risk of the primary endpoint of cardiovascular death or HF hospitalization (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54–0.74, P < .001) and all-cause mortality (adjusted HR 0.76, 95% CI 0.62–0.93, P < .008) after a median of 21 months. Based on EMPHASIS-HF, an MRA is recommended for patients with New York Heart Association (NYHA) Class II–IV symptoms and reduced LVEF (<35%) on standard therapy (Strength of Evidence A). Patients with NYHA Class II symptoms should have another high-risk feature to be consistent with the EMPHASIS-HF population (age >55 years, QRS duration >130 msec [if LVEF between 31% and 35%], HF hospitalization within 6 months or elevated B-type natriuretic peptide level). Renal function and serum potassium should be closely monitored. Dose selection should consider renal function, baseline potassium, and concomitant drug interactions. The efficacy of eplerenone in patients with mild HF symptoms translates into a unique opportunity to reduce morbidity and mortality earlier in the course of the disease. [Copyright &y& Elsevier]

The article assesses effects of Irbesartan on heart failure (HF) with preserved ejection fraction (PEF) as measured by Minnesota Living with Heart Failure Questionnaire in the Irbesartan in HF with Preserved Systolic Function (I-PRESERVE) trial. It is noted that MLHFQ is a measure of HF as indicated by adverse effects on patients' lives used in clinical trials of HF with reduced ejection. Results showed that Irbesartan did not substantially improve MLHFQ scores over long follow-up period.

Abstract: Cardiac resynchronization therapy (CRT) improves survival, symptoms, quality of life, exercise capacity, and cardiac structure and function in patients with New York Heart Association (NYHA) functional class II or ambulatory class IV heart failure (HF) with wide QRS complex. The totality of evidence supports the use of CRT in patients with less severe HF symptoms. CRT is recommended for patients in sinus rhythm with a widened QRS interval (≥150 ms) not due to right bundle branch block (RBBB) who have severe left ventricular (LV) systolic dysfunction and persistent NYHA functional class II-III symptoms despite optimal medical therapy (strength of evidence A). CRT may be considered for several other patient groups for whom evidence of benefit is clinically significant but less substantial, including patients with a QRS interval of ≥120 to <150 ms and severe LV systolic dysfunction who have persistent mild to severe HF despite optimal medical therapy (strength of evidence B), some patients with atrial fibrillation, and some with ambulatory class IV HF. Several evidence gaps remain that need to be addressed, including the ideal threshold for QRS duration, QRS morphology, lead placement, degree of myocardial scarring, and the modality for evaluating dyssynchrony. Recommendations will evolve over time as additional data emerge from completed and ongoing clinical trials. [Copyright &y& Elsevier]

The article focuses on the benefits of irbesartan in the management of patients with heart failure and preserved ejection fraction. I-PRESERVE (Irbesartan in Heart Failure with Preserved Ejection Fraction Trial) patients' N-terminal pro-brain natriuretic peptide was measured by the authors for their study. They discovered that significant interaction was seen between irbesartan's effect and median split of baseline NT-proBNP, all-cause mortality and the heart failure composite outcome.

Abstract: Background: Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF ≤35% and narrow QRS randomized to optimal medical treatment (OMT) plus CCM (n = 215) versus OMT alone (n = 213) and found no significant effect on ventilatory anaerobic threshold (VAT), the study’s primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM. Methods and Results: The protocol specified that multiregression analysis would be used to determine if baseline EF, NYHA functional class, pVO2, or etiology of heart failure influenced the impact of CCM on AT. Etiology and baseline pVO2 did not affect efficacy. However, baseline NYHA functional class III and EF ≥25% were significant predictors of increased efficacy. In this subgroup (comprising 97 OMT and 109 CCM patients, ∼48% of the entire population) VAT increased by 0.10 ± 2.36 in CCM versus −0.54 ± 1.83 mL kg−1 min−1 in OMT (P = .03) and pVO2 increased by 0.34 ± 3.11 in CCM versus −0.97 ± 2.31 (P = .001) at 24 weeks compared with baseline; 44% of CCM versus 23% of OMT subjects showed improvement of ≥1 class in NYHA functional class (P = .002), and 59% of CCM versus 42% of OMT subjects showed a ≥10-point reduction in Minnesota Living with Heart Failure Questionnaire (P = .01). All of these findings were similar to those seen at 50 weeks. Conclusions: The results of this retrospective hypothesis-generating analysis indicate that CCM significantly improves objective parameters of exercise tolerance in a subgroup of patients characterized by normal QRS duration, NYHA functional class III symptoms, and EF >25%. [Copyright &y& Elsevier]

Background: Previous studies have not extensively examined the association of hyperuricemia and adverse outcomes in systolic heart failure (HF) in relation to xanthine oxidase inhibitor therapy. Methods: The Prospective Randomized Amlodipine Survival Evaluation study included New York Heart Association class IIIB or IV patients with left ventricular ejection fraction <30%. For analysis, the population was divided into uric acid quartiles among nonallopurinol users (2.2-7.1, >7.1-8.6, >8.6-10.4, >10.4 mg/dL) and those using allopurinol. Multivariate Cox regression modeling was performed to identify predictors of mortality. Uric acid quartile and allopurinol groups were referenced to the lowest uric acid quartile. Results: A total of 1,152 patients were included. In general, patients in the allopurinol group and in the highest uric acid quartile had indicators of more severe HF, including worse renal function and greater proportion of New York Heart Association class IV patients, and greater diuretic use. The allopurinol group and highest uric acid quartile had the highest total mortality (41.7 and 42.4 per 100 person-years, respectively) and combined morbidity/mortality (45.6 and 51.0 per 100 person-years, respectively). Allopurinol use and highest uric acid quartile were independently associated with mortality (hazard ratio [HR] 1.65, 95% CI 1.22-2.23, P = .001 and HR 1.35, 95% CI 1.07-1.72, P = .01, respectively) and combined morbidity/mortality (uric acid quartile 4 vs 1: HR 1.32, 95% CI 1.06-1.66, P = .02; allopurinol use: HR 1.48, 95% CI 1.11-1.99, P = .008). Conclusion: Elevated uric acid level was independently associated with mortality in patients with severe systolic HF, even when accounting for allopurinol use. [ABSTRACT FROM AUTHOR]

Background: End point committees are routinely used to adjudicate efficacy and safety end points in clinical trials. The 2,708-patient β-Blocker Evaluation of Survival Trial (BEST) originally determined hospitalization type via investigator case report forms (CRFs), which captured whether a hospitalization was due to worsening heart failure (HF). Recently, the BEST End Points Committee (EPC) completed a blinded adjudication of all hospitalizations, allowing a comparison of the CRF method to the EPC method of determining hospitalization type. We sought to compare the investigator-determined mode of hospitalizations with the adjudicated events, to quantify the degree of agreement, and to compare the clinical trial results by method of event classification. Methods: The BEST EPC reviewed all 5,086 hospitalizations that occurred in BEST. Events were identified using investigator-reported hospitalizations, as well as those documented by FDA Form 3500 (MedWatch) reports. Results: The investigators identified more HF hospitalization events than adjudication (2,466 vs 1,729, P < .0001, paired analysis). Eight hundred thirty-four (34%) HF hospitalizations identified in CRFs were not confirmed by adjudication. Ninety-seven (6%) adjudicated events were not identified by the investigator reported method. One thousand six hundred thirty-two events were similarly identified by both methods. Conclusions: The EPC adjudication identified fewer HF hospitalizations than did the investigator reported method with no change in the hazard ratio for this end point. Our findings suggest that independent end point committees may improve reliability through reduced variance, thus providing similar outcome results with fewer events and no increase in CIs. [ABSTRACT FROM AUTHOR]

Several retrospective studies have raised concerns regarding digoxin therapy in select subgroups of heart failure patients. To assess the impact of digoxin therapy on outcomes in the current era of heart failure therapy, the authors analyzed data representing 5010 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) to examine the relationship of baseline digoxin use and all-cause mortality, first morbid event, and heart failure hospitalizations. At baseline, 3374 patients (67%) were receiving digoxin therapy and 1636 (33%) were not. Patients receiving digoxin had features of worse heart failure with higher New York Heart Association class and lower blood pressure, ejection fraction, and b-blocker use (32.1% vs 40.8%). Digoxin use was associated with worse mortality (21.1 vs 15.0%, P<.001), first morbid event (34.6 vs 21.7, P<.001), and HF hospitalization rate (19.1 vs 10.1%, P<.001). After adjustment for baseline group differences including medical therapy and baseline rhythm, patients receiving digoxin remained at a higher risk for all-cause mortality (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.05-1.57), first morbid event (HR, 1.35; 95% CI, 1.15-1.59), and heart failure hospitalization (HR, 1.41; 95% CI, 1.12-1.78). These results remained materially unchanged with propensity matched analysis. No benefit with digoxin use was observed in this study, underscoring the need to reassess the role of digoxin in the contemporary management of heart failure. [ABSTRACT FROM AUTHOR]

Abstract: Background: To characterize the quality of life (QOL) in the African-American Heart Failure Trial (A-HeFT) for factors associated with baseline score, relation of score to prognosis, and response to therapy with a fixed-dose combination of isosorbide dinitrate/hydralazine (FDC I/H). Limited data exist on QOL scores in African-American heart failure patients or on the prognostic value of theses scores in any population. Finally, the effect of FDC I/H on QOL scores, particularly in A-HeFT, is not known. Methods and Results: A-HeFT randomized 1050 African-American patients with New York Heart Association (NYHA) Class III-IV heart failure and systolic dysfunction. QOL measurements using Minnesota Living with Heart Failure Questionnaire (MLHFQ) were done at baseline and 3-month intervals. At baseline, worse MLHFQ scores were associated with younger age, female sex, greater body mass index, nonischemic etiology, high heart rate and NYHA Class, low systolic blood pressure, and chronic obstructive pulmonary disease. Both baseline and change in MLHFQ score were associated with a higher risk for combined all-cause mortality or heart failure hospitalization (baseline P < .0001, change at 3 months P =.001, and at 6 months P =.0008), but not mortality. Treatment with FDC I/H significantly improved MLHFQ score compared with placebo. Conclusions: In A-HeFT, baseline QOL (MLHFQ) scores and change in score were predictive of combined HF morbidity and mortality outcomes. FDC I/H consistently improved QOL scores in A-HeFT compared with placebo. [Copyright &y& Elsevier]

It is unknown whether statin use improves survival in patients with advanced chronic heart failure (HF) receiving cardiac resynchronization therapy (CRT). The authors retrospectively assessed the effect of statin use on survival in patients with advanced chronic HF receiving CRT alone (CRT-P) or CRT with implantable cardioverter-defibrillator therapy (CRT-D) in 1520 patients with advanced chronic HF from the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial database. Six hundred three patients (40%) were taking statins at baseline. All-cause mortality was 18% in the statin group and 22% in the no statin group (hazard ratio [HR] 0.85; confidence interval (CI), 0.67–1.07; P=.15). In a multivariable analysis controlling for significant baseline characteristics and use of CRT-P/CRT-D, statin use was associated with a 23% relative risk reduction in mortality (HR, 0.77; CI, 0.61–0.97; P=.03). Statin use is associated with improved survival in patients with advanced chronic HF receiving CRT. No survival benefit was seen in patients receiving statins and optimal pharmacologic therapy without CRT. [ABSTRACT FROM AUTHOR]

The authors reply to letters written in response to the article "Irbesartan in Patients With Heart Failure and Preserved Ejection Fraction," published in the December 4, 2008 issue.

Background: Approximately 50% of patients with heart failure have a left ventricular ejection fraction of at least 45%, but no therapies have been shown to improve the outcome of these patients. Therefore, we studied the effects of irbesartan in patients with this syndrome. Methods: We enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II, III, or IV heart failure and an ejection fraction of at least 45% and randomly assigned them to receive 300 mg of irbesartan or placebo per day. The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). Secondary outcomes included death from heart failure or hospitalization for heart failure, death from any cause and from cardiovascular causes, and quality of life. Results: During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes. Conclusions: Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction. (ClinicalTrials.gov number, NCT00095238.) N Engl J Med 2008;359:2456-67. [ABSTRACT FROM AUTHOR]

Background: We determined whether low-dose oral enoximone could wean patients with ultra-advanced heart failure (UA-HF) from intravenous (IV) inotropic support. Chronic parenteral inotropic therapy in UA-HF is costly and requires an indwelling catheter. An effective and safe oral inotrope would have value. Methods: In this placebo-controlled study, 201 subjects with UA-HF requiring IV inotropic therapy were randomized to enoximone or placebo. Subjects receiving intermittent IV inotropes were administered study medication of 25 or 50 mg 3 times a day (tid). Subjects receiving continuous IV inotropes were administered 50 or 75 mg tid for 1 week, which was reduced to 25 or 50 mg tid. The ability of subjects to remain alive and free of inotropic therapy was assessed for up to 182 days. Results: Thirty days after weaning, 51 (51%) subjects on placebo and 62 (61.4%) subjects in the enoximone group were alive and free of IV inotropic therapy (unadjusted primary end point P = 0.14, adjusted for etiology P = .17). At 60 days, the wean rate was 30% in the placebo group and 46.5% in the enoximone group (unadjusted P = .016) Kaplan-Meier curves demonstrated a trend toward a decrease in the time to death or reinitiation of IV inotropic therapy over the 182-day study period (hazard ratio 0.76 [95% CI 0.55-1.04]) and a reduction at 60 days (0.62 [95% CI 0.43-0.89], P = .009) and 90 days (0.69 [95% CI 0.49-0.97], P = .031) after weaning in the enoximone group. Conclusions: Although there was no benefit over placebo in weaning patients from IV inotropes from 0 to 30 days, the EMOTE data suggest that low-dose oral enoximone can be used to wean a modest percentage of subjects from IV inotropic support for up to 90 days after initiation of therapy. [Copyright &y& Elsevier]

Abstract: Objectives: We performed a post hoc analysis to determine the influence of cardiac resynchronization therapy with a defibrillator (CRT-D) or without a defibrillator (CRT-P) on outcomes among diabetic patients with advanced heart failure (HF). Background: In patients with systolic HF, diabetes is an independent predictor of morbidity and mortality. No data are available on its impact on CRT-D or CRT-P in advanced HF. Methods: The database of the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure trial was examined to determine the influence of CRT (CRT-D and CRT-P) on outcomes among diabetic patients. All-cause mortality or hospitalization, all-cause mortality or cardiovascular hospitalization, all-cause mortality or HF hospitalization, and all-cause mortality were analyzed among diabetic patients (n = 622). A Cox proportional hazard model, adjusting for age, gender, New York Heart Association, ischemic status, body mass index, left ventricular ejection fraction, heart rate, QRS, left or right bundle branch block, blood pressure, comorbidities (renal failure, carotid artery disease, peripheral vascular disease, hypertension, coronary artery bypass grafting, and atrial fibrillation), medications, and device (with or without defibrillator), was used to estimate hazard ratios (HRs) and significance. Results: The overall outcome of diabetic patients was similar to that of nondiabetic patients in the optimal pharmacologic therapy arm. With CRT, diabetic patients experienced a substantial reduction in all-cause mortality or all-cause hospitalization (HR = 0.77, 95% confidence interval [CI] 62–0.97), all-cause mortality or cardiovascular hospitalization (HR = 0.67, 95% CI 0.53–0.85), all-cause mortality or HF hospitalization (HR = 0.52, 95% CI 0.40–0.69), and all-cause mortality (HR = 0.67, 95% CI 0.45–0.99) compared with optimal pharmacologic therapy. Procedure-related complications and length of stay were identical in diabetic and nondiabetic patients. Conclusion: In diabetic patients with advanced HF, there is a substantial benefit from device therapy with significant improvement in all end points. [Copyright &y& Elsevier]

Abstract: Background: Although 40% to 50% of patients with chronic heart failure (HF) have relatively preserved systolic function (PSF), few trials have been conducted in this population and treatment guidelines do not include evidence-based recommendations. Methods and Results: The Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) is enrolling 4100 subjects with HF-PSF to evaluate whether 300 mg irbesartan is superior to placebo in reducing mortality and prespecified categories of cardiovascular hospitalizations. The principal inclusion criteria are age ≥60 years, heart failure symptoms, an ejection fraction ≥45%, and either hospitalization for heart failure within 6 months or corroborative evidence of heart failure or the substrate for diastolic heart failure. Additional secondary end points include cardiovascular mortality, cause-specific mortality and morbidity, change in New York Heart Association functional class, quality of life, and N-terminal pro-BNP measurements. Follow-up will continue until 1440 patients experience a primary end point. Substudies will evaluate changes in echocardiographic measurements and serum collagen markers. Conclusion: I-PRESERVE is the largest trial in this understudied area and will provide crucial information on the characteristics and course of the syndrome, as well as the efficacy of the angiotensin receptor blocker irbesartan. [Copyright &y& Elsevier]

Background: Atrial fibrillation (AF) in heart failure (HF) is generally considered a negative prognostic factor. Recent studies indicate that the incidence of AF might be decreased by renin angiotensin aldosterone system inhibitors. The identification of a treatment to prevent its occurrence is likely to improve patients outcome. The aims of these subanalyses of Val-HeFT were to assess (a) the effects of valsartan in the prevention of AF, (b) the independent predictors of this event, and (c) the prognostic role of AF occurrence. Methods and Results: The occurrence of AF was evaluated based on adverse event reports in the patients with HF enrolled in Val-HeFT. Patients were randomized to valsartan or placebo on top of their prescribed treatments for HF. During the mean 23 months of follow-up, AF was reported in 287/4395 patients (6.53%) in sinus rhythm at baseline, of whom 113/2205 (5.12%) were allocated to valsartan and 174/2190 (7.95%) to placebo (P = .0002). Multivariable analysis showed that brain natriuretic peptide (BNP) levels at baseline above the median value (HR 2.28, 95% CI 1.75-2.98), age over 70 years (HR 1.51, 95% CI 1.17-1.95), male sex (HR 1.53, 95% CI 1.07-2.18), and the valsartan treatment (HR 0.63, 95% CI 0.49-0.81) were independently associated with AF occurrence. Cox multivariable regression analysis showed that occurrence of AF was independently associated with a worse prognosis, with the adjusted hazard risks for all-cause mortality and combined mortality/morbidity of 1.40 (95% CI 1.16-1.58) and 1.38 (95% CI 1.12-1.70), respectively. Conclusions: The results of the present study demonstrate that (a) adding valsartan to prescribed therapy for HF significantly reduces the incidence of AF by 37%; (b) BNP level and advanced age were the strongest independent predictors for AF occurrence; and (c) AF occurrence further worsens the outcome in patients with HF. [Copyright &y& Elsevier]

Presents a comparison on the effectiveness between hospital and home care for patients with coronary thrombosis in Great Britain. Information on mortality rates in home-treated cases; Indications for hospital treatment; Role of general practitioners in providing efficient care during the first two hours after infarction.

Cites information on the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial study which investigated the effect which amlodipine has on patients with advanced heart failure. Details on the PRAISE trial; Information on the participants in the study; Concern regarding calcium antagonists in heart disease patients; In-depth look at the results of the study.

Presents several letters to the editor published in the 'British Medical Journal' as of August 1989. Inquiries related to selection of surgeon as leader for the trauma team; Interrelations between the death at Lake Nyos and carbon dioxide emission; Scrutiny on the ethical practices involved in clinical research.

Focuses on medical-related issues in Great Britain. Agreement on HIV testing within the British Medical Association; Incidence of coronary disease in people taking strenuous exercise; Management of patients undergoing gastrointestinal operations.

Electrocardiograms were recorded from human patients using a bipolar chest lead together with simultaneous His-bundle electrograms. These were then subjected to the technique of signal averaging in an attempt to extract His-bundle activity from the surface record. This was successful in three out of 10 cases subjected to the truly non-invasive surface technique. Methods are discussed by which the technique could be improved. [ABSTRACT FROM PUBLISHER]

Presents several correspondents on medicine. Reduction in the incidence of clinical staphylococcal infection in the newborn; Comment on the 'critical' blood concentrations of hexachlorophene; Benefits of the computer system at Stoke-on-Trent to medical experiments.

Fifty-nine men with known coronary disease entered an exercise rehabilitation programme. Forty-nine had sustained recent myocardial infarctions, nine had had past myocardial infarcts, and one had had a recent internal mammary implant for severe angina. Each class lasted about 45 minutes and they were held twice weekly; the course for each patient was three months. Sixteen patients dropped out from the course, only three for reasons obviously medical. No deaths or cardiac arrests occurred during the programme. Extrasystoles and angina were detected in a minority of patients and did not constitute reasons for failure to complete the course. The main aim of the study was to show that such a programme is feasible in a district general hospital. Improvement in the morale of patients was impressive and the incidence of return to work high. [ABSTRACT FROM PUBLISHER]

Clinical endpoints are standard outcomes measures used to prove treatment effect in clinical trials. Differences in endpoint definitions and ascertainment of cause-specific clinical events influence the validity of heart failure (HF) trials. Cause-specific clinical events have become preferred endpoints because they separate signals of efficacy from noise (non-related events). Clinical endpoints could be ascertained through case report forms (CRFs) by investigators or through a central adjudication method by a Clinical Endpoint Committee (CEC). Investigator reporting is more efficient and inexpensive but is affected by inaccuracy, geographic variability, and complexity of endpoint definitions. CEC adjudication is a standardized, blind and independent ascertainment process but may be limited by high costs. To analyze cause-specific endpoints, and the need for CEC adjudication in HF trials, comparing HF with reduced versus preserved ejection fraction (EF). We analyzed 10 HF with reduced EF (HFrEF) trials and five HF with preserved EF (HFpEF) trials. For each trial we described and compared the prevalence of all-cause and cause-specific mortality. A comparison between all-cause mortality and cardiovascular mortality in 9 selected HFrEF and HFpEF clinical trials is presented in Figure 1. The relative proportion of CV death was significantly lower in HFpEF compared with HFrEF trials. Additionally, in HFrEF, the relative proportion of CV death was significantly lower in recent trials compared with early trials. CV specific endpoints were the primary cause of death in HF trials. There are more CV deaths in HFrEF trials, although it is the primary mode of death in both populations. CEC adjudication may be more beneficial in HFpEF vs. HFrEF trials, and in recent HFrEF trials due to the increase in non-CV events which may attenuate the treatment effect. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Prior studies of cardiac contractility modulation (CCM) employed a 3-lead Optimizer system. A new 2-lead system eliminated the need for an atrial lead. This study tested the safety and effectiveness of this 2-lead system compared with the 3-lead system. Methods: Patients with New York Heart Association III/IVa symptoms despite medical therapy, left ventricular ejection fraction 25% to 45%, and not eligible for cardiac resynchronization therapy could participate. All subjects received an Optimizer 2-lead implant. The primary end point was the estimated difference in the change of peak VO2 from baseline to 24 weeks between FIX-HF-5C2 (2-lead system) subjects relative to control subjects from the prior FIX-HF-5C (3-lead system) study. Changes in New York Heart Association were a secondary end point. The primary safety end point was a comparison of device-related adverse events between FIX-HF-5C2 and FIX-HF-5C subjects. Results: Sixty subjects, 88% male, 66±9 years old with left ventricular ejection fraction 34±6% were included. Baseline characteristics were similar between FIX-HF-5C and FIX-HF-5C2 subjects except that 15% of FIX-HF-5C2 subjects had permanent atrial fibrillation versus 0% in FIX-HF-5C. CCM delivery did not differ significantly between 2- and 3-lead systems (19 892±3472 versus 19 583±4998 CCM signals/day, CI of difference [−1228 to 1847]). The change of peak VO2 from baseline to 24 weeks was 1.72 (95% Bayesian credible interval, 1.02–2.42) mL/kg per minute greater in the 2-lead device group versus controls. 83.1% of 2-lead subjects compared with 42.7% of controls experienced ≥1 class New York Heart Association improvement (P <0.001). There were decreased Optimizer-related adverse events with the 2-lead system compared with the 3-lead system (0% versus 8%; P =0.03). Conclusions: The 2-lead system effectively delivers comparable amount of CCM signals (including in subjects with atrial fibrillation) as the 3-lead system, is equally safe and improves peak VO2 and New York Heart Association. Device-related adverse effects are less with the 2-lead system. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03339310 [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction. Methods: Baseline characteristics (including biomarkers and quality of life) and outcomes (primary outcome: composite of first heart failure hospitalization or cardiovascular death) were compared in 4458 women and 4010 men enrolled in CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) (EF≥45%), I-Preserve (Irbesartan in heart failure with Preserved ejection fraction), and TOPCAT-Americas (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial). Results: Women were older and more often obese and hypertensive but less likely to have coronary artery disease or atrial fibrillation. Women had more symptoms and signs of congestion and worse quality of life. Despite this, the risk of the primary outcome was lower in women (hazard ratio, 0.80 [95% CI, 0.73–0.88]), as was the risk of cardiovascular death (hazard ratio, 0.70 [95% CI, 0.62–0.80]), but there was no difference in the rate for first hospitalization for heart failure (hazard ratio, 0.92 [95% CI, 0.82–1.02]). The lower risk of cardiovascular death in women, compared with men, was in part explained by a substantially lower risk of sudden death (hazard ratio, 0.53 [0.43–0.65]; P <0.001). E/A ratio was lower in women (1.1 versus 1.2). Conclusions: There are significant differences between women and men with heart failure with preserved ejection fraction. Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men. Their risk of sudden death was half that of men. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00853658, NCT01035255. [ABSTRACT FROM AUTHOR]

Examines the outcome of the patients reported to have raised mean platelet volumes following myocardial infarction in Great Britain. Calculation on the platelet distribution of the patients; Impact of infarction on the changes in platelet volume; Duration of platelet survival on patients with ischemic heart disease.