We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in ...such patients.
In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.
The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval CI, 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.
LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
The angiotensin-receptor-neprilysin inhibitor (ARNI) LCZ696 reduced cardiovascular deaths and all-cause mortality compared with enalapril in patients with chronic heart failure in the prospective ...comparison of ARNI with an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. To more completely understand the components of this mortality benefit, we examined the effect of LCZ696 on mode of death.
PARADIGM-HF was a prospective, double-blind, randomized trial in 8399 patients with chronic heart failure, New York Heart Association Class II-IV symptoms, and left ventricular ejection fraction ≤40% receiving guideline-recommended medical therapy and followed for a median of 27 months. Mode of death was adjudicated by a blinded clinical endpoints committee. The majority of deaths were cardiovascular (80.9%), and the risk of cardiovascular death was significantly reduced by treatment with LCZ (hazard ratio, HR 0.80, 95% CI 0.72-0.89, P < 0.001). Among cardiovascular deaths, both sudden cardiac death (HR 0.80, 95% CI 0.68-0.94, P = 0.008) and death due to worsening heart failure (HR 0.79, 95% CI 0.64-0.98, P = 0.034) were reduced by treatment with LCZ696 compared with enalapril. Deaths attributed to other cardiovascular causes, including myocardial infarction and stroke, were infrequent and distributed evenly between treatment groups, as were non-cardiovascular deaths.
LCZ696 was superior to enalapril in reducing both sudden cardiac deaths and deaths from worsening heart failure, which accounted for the majority of cardiovascular deaths.
https://clinicaltrials.gov/, NCT01035255.
High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo.
To investigate the ...effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA).
A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion.
Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively.
Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001.
The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints.
The nominal change in the total atheroma volume (adjusted means) was -2.71, -3.13, -1.50, and -3.05 mm(3) with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, -0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was -0.022, -0.036, -0.022, and -0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was -0.51, 2.65, 0.71, and -0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups.
CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2;
NCT01201837.
We aimed to assess the impact of eplerenone on cardiovascular (CV) outcomes in STEMI without known heart failure, when initiated within 24 h of symptom onset.
In this randomized, placebo-controlled, ...double-blind trial, we assigned 1012 patients with acute STEMI and without a history of heart failure to receive either eplerenone (25-50 mg once daily) or placebo in addition to standard therapy. The primary endpoint was the composite of CV mortality, re-hospitalization, or, extended initial hospital stay, due to diagnosis of HF, sustained ventricular tachycardia or fibrillation, ejection fraction ≤40%, or elevated BNP/NT-proBNP at 1 month or more after randomization. BNP elevation was defined as BNP levels or values above 200 pg/mL or NT-proBNP values above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or above 1800 pg/mL (patients older than 75). After a mean follow-up of 10.5 months, the primary endpoint occurred in 92 patients (18.2%) in the eplerenone group and in 149 patients (29.4%) in the placebo group adjusted hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45-0.76; P < 0.0001. The primary endpoint was driven by a high BNP/NT-proBNP level (adjusted HR, 0.60; 95% CI, 0.45-0.79; P < 0.0003). Adverse event rates were similar in both groups. Serum potassium levels exceeded 5.5 mmol/L in 5.6 vs. 3.2% (P = 0.09) and were below 3.5 mmol/L in 1.4 vs. 5.6% of patients (P = 0.0002), in the eplerenone and placebo groups, respectively.
The addition of eplerenone during the acute phase of STEMI was safe and well tolerated. It reduced the primary endpoint over a mean 13 months follow-up mostly because of significantly lower BNP/NT-proBNP levels. Additional studies are needed to clarify the role of early use of MRAs in STEMI patients without heart failure.
NCT01176968.
Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, but little is known about their effects in severe heart failure.
We evaluated 2289 ...patients who had symptoms of heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less than 25 percent. In a double-blind fashion, we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for heart failure was continued. Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs were excluded.
There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.00013, unadjusted; P=0.0014, adjusted for interim analyses). A total of 507 patients died or were hospitalized in the placebo group, as compared with 425 in the carvedilol group. This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol (95 percent confidence interval, 13 to 33 percent; P<0.001). The favorable effects on both end points were seen consistently in all the subgroups we examined, including patients with a history of recent or recurrent cardiac decompensation. Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons (P=0.02).
The previously reported benefits of carvedilol with regard to morbidity and mortality in patients with mild-to-moderate heart failure were also apparent in the patients with severe heart failure who were evaluated in this trial.
Objective
Concerns about differences in registration practices across countries have limited the use of routine data for international very preterm birth (VPT) rate comparisons.
Design
...Population‐based study.
Setting
Twenty‐seven European countries, the United States, Canada and Japan in 2010.
Population
A total of 9 376 252 singleton births.
Method
We requested aggregated gestational age data on live births, stillbirths and terminations of pregnancy (TOP) before 32 weeks of gestation, and information on registration practices for these births. We compared VPT rates and assessed the impact of births at 22–23 weeks of gestation, and different criteria for inclusion of stillbirths and TOP on country rates and rankings.
Main outcome measures
Singleton very preterm birth rate, defined as singleton stillbirths and live births before 32 completed weeks of gestation per 1000 total births, excluding TOP if identifiable in the data source.
Results
Rates varied from 5.7 to 15.7 per 1000 total births and 4.0 to 11.9 per 1000 live births. Country registration practices were related to percentage of births at 22–23 weeks of gestation (between 1% and 23% of very preterm births) and stillbirths (between 6% and 40% of very preterm births). After excluding births at 22–23 weeks, rate variations remained high and with a few exceptions, country rankings were unchanged.
Conclusions
International comparisons of very preterm birth rates using routine data should exclude births at 22–23 weeks of gestation and terminations of pregnancy. The persistent large rate variations after these exclusions warrant continued surveillance of VPT rates at 24 weeks and over in high‐income countries.
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International comparisons of VPT rates should exclude births at 22–23 weeks of gestation and terminations of pregnancy.
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International comparisons of VPT rates should exclude births at 22–23 weeks of gestation and terminations of pregnancy.
Congestive heart failure is an important cause of patient morbidity and mortality. Although several randomized clinical trials have compared beta-blockers with placebo for treatment of congestive ...heart failure, a meta-analysis quantifying the effect on mortality and morbidity has not been performed recently.
The MEDLINE, Cochrane, and Web of Science electronic databases were searched from 1966 to July 2000. References were also identified from bibliographies of pertinent articles.
All randomized clinical trials of beta-blockers versus placebo in chronic stable congestive heart failure were included.
A specified protocol was followed to extract data on patient characteristics, beta-blocker used, overall mortality, hospitalizations for congestive heart failure, and study quality.
A hierarchical random-effects model was used to synthesize the results. A total of 22 trials involving 10 135 patients were identified. There were 624 deaths among 4862 patients randomly assigned to placebo and 444 deaths among 5273 patients assigned to beta-blocker therapy. In these groups, 754 and 540 patients, respectively, required hospitalization for congestive heart failure. The probability that beta-blocker therapy reduced total mortality and hospitalizations for congestive heart failure was almost 100%. The best estimates of these advantages are 3.8 lives saved and 4 fewer hospitalizations per 100 patients treated in the first year after therapy. The probability that these benefits are clinically significant (>2 lives saved or >2 fewer hospitalizations per 100 patients treated) is 99%. Both selective and nonselective agents produced these salutary effects. The results are robust to any reasonable publication bias.
beta-Blocker therapy is associated with clinically meaningful reductions in mortality and morbidity in patients with stable congestive heart failure and should be routinely offered to all patients similar to those included in trials.
Please cite this paper as: Kramer M, Rouleau J, Liu S, Bartholomew S, Joseph K for the Maternal Health Study Group of the Canadian Perinatal Surveillance System. Amniotic fluid embolism: incidence, ...risk factors, and impact on perinatal outcome. BJOG 2012;119:874–879.
Objective To extend our previous work on AFE in Canada by including stricter criteria for case identification and by examining risks for stillbirth, neonatal mortality and serious maternal and neonatal morbidity.
Design Population‐based cohort study.
Setting Canada.
Population or sample In all, 4 508 462 hospital deliveries from fiscal year 1991/92 to 2008/09.
Methods To reduce false‐positive diagnoses, we restricted our analysis to AFE cases with cardiac arrest, shock or severe hypertension, respiratory distress, mechanical ventilation, coma, seizure, or coagulation disorder. Linkage of maternal and neonatal records, available since 2001/02, enabled us to examine the effects of AFE on neonatal outcomes. Detailed demographic and clinical data facilitated control for a broad array of potential confounding variables.
Main outcome measures Amniotic fluid embolism, in‐hospital neonatal death, asphyxia, mechanical ventilation, bacterial sepsis, seizure, nonimmune haemolytic or traumatic jaundice and length of hospital stay.
Results A total of 292 AFE cases were identified, of which only 120 (40%) were confirmed after applying our additional diagnostic criteria, yielding an AFE incidence of 2.5 per 100 000 deliveries. Of the 120 confirmed cases, 33 (27%) were fatal. Significant modifiable risk factors included medical induction, caesarean delivery, instrumental vaginal delivery, and uterine or cervical trauma. Amniotic fluid embolism was associated with significantly increased risks of stillbirth and neonatal asphyxia, mechanical ventilation, sepsis, seizures and prolonged length of hospital stay.
Conclusions Amniotic fluid embolism remains a rare but serious obstetric outcome, with several important modifiable risk factors and major implications for maternal, fetal and neonatal health.
Objective To investigate the cause of a recent increase in hysterectomies for postpartum haemorrhage in Canada.
Design Retrospective cohort study.
Setting Canada between 1991 and 2004.
Population ...All hospital deliveries in Canada as documented in the database of the Canadian Institute for Health Information (excluding incomplete data from Quebec, Manitoba and Nova Scotia).
Methods Deliveries with postpartum haemorrhage by subtype were identified using International Classification of Diseases codes, while hysterectomies were identified using procedure codes. Changes in determinants of postpartum haemorrhage (all postpartum haemorrhage and that requiring hysterectomy) were examined, and crude and adjusted period changes were assessed using logistic models.
Main outcome measures Postpartum haemorrhage, postpartum haemorrhage with hysterectomy, postpartum haemorrhage with blood transfusion and postpartum haemorrhage by subtype.
Results Rates of postpartum haemorrhage increased from 4.1% in 1991 to 5.1% in 2004 (23% increase, 95% CI 20–26%), while rates of postpartum haemorrhage with hysterectomy increased from 24.0 in 1991 to 41.7 per 100 000 deliveries in 2004 (73% increase, 95% CI 27–137%). These increases were because of an increase in atonic postpartum haemorrhage, from 29.4 per 1000 deliveries in 1991 to 39.5 per 1000 deliveries in 2004 (34% increase, 95% CI 31–38%). Adjustment for temporal changes in risk factors did not explain the increase in atonic postpartum haemorrhage but attenuated the increase in atonic postpartum haemorrhage with hysterectomy.
Conclusions There has been a recent, unexplained increase in the frequency, and possibly the severity, of atonic postpartum haemorrhage in Canada.
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