Sean van Diepen

How evidence-based are the recommendations in evidence-based guidelines?

Background Treatment recommendations for the same condition from different guideline bodies often disagree, even when the same randomized controlled trial (RCT) evidence is cited. Guideline appraisal tools focus on methodology and quality of reporting, but not on the nature of the supporting evidence. This study was done to evaluate the quality of the evidence (based on consideration of its internal validity, clinical relevance, and applicability) underlying therapy recommendations in evidence-based clinical practice guidelines. Methods and Findings A cross-sectional analysis of cardiovascular risk management recommendations was performed for three different conditions (diabetes mellitus, dyslipidemia, and hypertension) from three pan-national guideline panels (from the United States, Canada, and Europe). Of the 338 treatment recommendations in these nine guidelines, 231 (68%) cited RCT evidence but only 105 (45%) of these RCT-based recommendations were based on high-quality evidence. RCT-based evidence was downgraded most often because of reservations about the applicability of the RCT to the populations specified in the guideline recommendation (64/126 cases, 51%) or because the RCT reported surrogate outcomes (59/126 cases, 47%). Conclusions The results of internally valid RCTs may not be applicable to the populations, interventions, or outcomes specified in a guideline recommendation and therefore should not always be assumed to provide high-quality evidence for therapy recommendations.

Heart Failure Is a Risk Factor for Orthopedic Fracture A Population-Based Analysis of 16 294 Patients

Background— Heart failure (HF) is associated with factors that may contribute to accelerated bone loss and subsequent fractures. Whether it leads to an increased fracture risk is unknown. Methods and Results— A population-based cohort of consecutive patients ≥65 years of age with cardiovascular disease presenting to all emergency rooms between 1998 and 2001 in Alberta, Canada (n=16294 patients), was used. The 2041 patients with a new diagnosis of HF were compared with a control group of 14 253 patients with non-HF cardiovascular diagnoses. The primary outcome was any orthopedic fracture requiring hospital admission in the year after the emergency room visit. Patients with HF had a median age of 78 years (interquartile range, 72 to 84 years), and 51.9% were female; control subjects had a median age of 73 years (interquartile range, 68 to 79 years), and 53.2% were female. In the first year after the emergency room visit, 4.6% of the HF cohort (n=93) and 1.0% of patients without HF (n=147) sustained an orthopedic fracture (P<0.001). Hip fractures occurred in 26 HF patients (1.3%) and 18 patients (0.1%) without HF (P<0.001). After multivariable adjustment, HF was independently associated with a greater risk of any orthopedic fracture (adjusted odds ratio, 4.0; 95% CI, 2.9 to 5.3) or hip fracture (adjusted odds ratio, 6.3; 95% CI, 3.4 to 11.8). Conclusions— HF is associated with an increased risk of subsequent orthopedic fracture, particularly hip fracture. This suggests that screening for and treatment of osteoporosis to reduce fracture risk need to be considered in those with HF.

Mortality and Readmission of Patients With Heart Failure, Atrial Fibrillation, or Coronary Artery Disease Undergoing Noncardiac Surgery An Analysis of 38 047 Patients

Background— The postoperative risks for patients with coronary artery disease (CAD) undergoing noncardiac surgery are well described. However, the risks of noncardiac surgery in patients with heart failure (HF) and atrial fibrillation (AF) are less well known. The purpose of this study is to compare the postoperative mortality of patients with HF, AF, or CAD undergoing major and minor noncardiac surgery. Methods and Results— Population-based data were used to create 4 cohorts of consecutive patients with either nonischemic HF (NIHF; n=7700), ischemic HF (IHF; n=12 249), CAD (n=13 786), or AF (n=4312) who underwent noncardiac surgery between April 1, 1999, and September 31, 2006, in Alberta, Canada. The main outcome was 30-day postoperative mortality. The unadjusted 30-day postoperative mortality was 9.3% in NIHF, 9.2% in IHF, 2.9% in CAD, and 6.4% in AF (each versus CAD, P<0.0001). Among patients undergoing minor surgical procedures, the 30-day postoperative mortality was 8.5% in NIHF, 8.1% in IHF, 2.3% in CAD, and 5.7% in AF (P<0.0001). After multivariable adjustment, postoperative mortality remained higher in NIHF, IHF, and AF patients than in those with CAD (NIHF versus CAD: odds ratio 2.92; 95% confidence interval 2.44 to 3.48; IHF versus CAD: odds ratio 1.98; 95% confidence interval 1.70 to 2.31; AF versus CAD: odds ratio 1.69; 95% confidence interval 1.34 to 2.14). Conclusions— Although current perioperative risk prediction models place greater emphasis on CAD than HF or AF, patients with HF or AF have a significantly higher risk of postoperative mortality than patients with CAD, and even minor procedures carry a risk higher than previously appreciated.

Left Ventricular Systolic Dysfunction, Heart Failure and the Risk of Stroke and Systemic Embolism in Patients with Atrial Fibrillation: Insights from the ARISTOTLE Trial

Background—We examined the risk of stroke or systemic embolism (SSE) conferred by heart failure (HF) and left ventricular systolic dysfunction (LVSD) in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation Trial (ARISTOTLE), as well as the effect of apixaban versus warfarin. Methods and Results—The risk of a number of outcomes, including the composite of SSE or death (to take account of competing risks) and composite of SSE, major bleeding, or death (net clinical benefit) were calculated in 3 patient groups: (1) no HF/no LVSD (n=8728), (2) HF/no LVSD (n=3207), and (3) LVSD with/without symptomatic HF (n=2736). The rate of both outcomes was highest in patients with LVSD (SSE or death 8.06; SSE, major bleeding, or death 10.46 per 100 patient-years), intermediate for HF but preserved LV systolic function (5.32; 7.24), and lowest in patients without HF or LVSD (1.54; 5.27); each comparison P<0.0001. Each outcome was less frequent in patients treated with apixaban: in all ARISTOTLE patients, the apixaban/warfarin hazard ratio for SSE or death was 0.89 (95% confidence interval, 0.81–0.98; P=0.02); for SSE, major bleed, or death it was 0.85 (0.78–0.92; P<0.001). There was no heterogeneity of treatment effect across the 3 groups. Conclusions—Patients with LVSD (with/without HF) had a higher risk of SSE or death (but similar rate of SSE) compared with patients with HF but preserved LV systolic function; both had a greater risk than patients without either HF or LVSD. Apixaban reduced the risk of both outcomes more than warfarin in all 3 patient groups. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

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.)

Efficacy and Safety of Rivaroxaban in Patients With Heart Failure and Nonvalvular Atrial Fibrillation Insights From ROCKET AF

Background—In Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), rivaroxaban was noninferior to warfarin for the prevention of stroke and systemic embolic events and significantly reduced intracranial bleeding in patients with nonvalvular atrial fibrillation. We explore the safety and efficacy of rivaroxaban in patients with heart failure (HF). Methods and Results—A total of 9033 (63.7%) patients had HF. The primary efficacy analysis was rates of stroke or systemic embolism (per 100 patient-years) by intention to treat. The safety outcomes were major or nonmajor clinically relevant bleeding and hemorrhagic stroke during treatment. Patients with HF were younger (72 versus 74 years), more likely to have persistent atrial fibrillation (83.0% versus 77.6%), and had higher mean CHADS2 scores (3.7 versus 3.1). The efficacy of rivaroxaban compared with warfarin was similar in patients with HF (1.90 versus 2.09) and without HF (2.10 versus 2.54; P-interaction=0.62). The risk of major or nonmajor clinically relevant bleeding with rivaroxaban was similar to warfarin in patients with HF (14.22 versus 14.02) and without HF (16.12 versus 15.35; P-interaction=0.99). A reduction in hemorrhagic stroke was observed with rivaroxaban in patients with HF as in the overall trial (adjusted hazard ratio, 0.38; 95% confidence interval, 0.19–0.76; P-interaction=0.067). Among patients with HF, the efficacy of rivaroxaban was similar, irrespective of ejection fraction <40 or ≥40% (P-interaction=0.38), New York Heart Association class I-II versus III-IV (P-interaction=0.68), HF preserved or reduced ejection fraction (P-interaction=0.35), or CHADS2 score 2 versus ≥3 (P-interaction=0.48). Conclusions—Treatment-related outcomes were similar in patients with and without HF and across HF subgroups. These findings support the use of rivaroxaban as an alternative to warfarin in patients with atrial fibrillation and HF. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

Regional Variation in Out-of-Hospital Cardiac Arrest Survival in the United States

Background— Although previous studies have shown marked variation in out-of-hospital cardiac arrest survival across US regions, factors underlying this survival variation remain incompletely explained. Methods and Results— Using data from the Cardiac Arrest Registry to Enhance Survival, we identified 96 662 adult patients with out-of-hospital cardiac arrest in 132 US counties. We used hierarchical regression models to examine county-level variation in rates of survival and survival with functional recovery (defined as Cerebral Performance Category score of 1 or 2) and examined the contribution of demographics, cardiac arrest characteristics, bystander cardiopulmonary resuscitation, automated external defibrillator use, and county-level sociodemographic factors in survival variation across counties. A total of 9317 (9.6%) patients survived to discharge, and 7176 (7.4%) achieved functional recovery. At a county level, there was marked variation in rates of survival to discharge (range, 3.4%–22.0%; median odds ratio, 1.40; 95% confidence interval, 1.32–1.46) and survival with functional recovery (range, 0.8%–21.0%; median odds ratio, 1.53; 95% confidence interval, 1.43–1.62). County-level rates of bystander cardiopulmonary resuscitation and automated external defibrillator use were positively correlated with both outcomes (P<0.0001 for all). Patient demographic and cardiac arrest characteristics explained 4.8% and 27.7% of the county-level variation in survival, respectively. Additional adjustment of bystander cardiopulmonary resuscitation and automated external defibrillator explained 41% of the survival variation, and this increased to 50.4% after adjustment of county-level sociodemographic factors. Similar findings were noted in analyses of survival with functional recovery. Conclusions— Although out-of-hospital cardiac arrest survival varies significantly across US counties, a substantial proportion of the variation is attributable to differences in bystander response across communities.

Efficacy and Safety of Rivaroxaban in Patients With Heart Failure and Nonvalvular Atrial FibrillationClinical Perspective

Background—In Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), rivaroxaban was noninferior to warfarin for the prevention of stroke and systemic embolic events and significantly reduced intracranial bleeding in patients with nonvalvular atrial fibrillation. We explore the safety and efficacy of rivaroxaban in patients with heart failure (HF). Methods and Results—A total of 9033 (63.7%) patients had HF. The primary efficacy analysis was rates of stroke or systemic embolism (per 100 patient-years) by intention to treat. The safety outcomes were major or nonmajor clinically relevant bleeding and hemorrhagic stroke during treatment. Patients with HF were younger (72 versus 74 years), more likely to have persistent atrial fibrillation (83.0% versus 77.6%), and had higher mean CHADS2 scores (3.7 versus 3.1). The efficacy of rivaroxaban compared with warfarin was similar in patients with HF (1.90 versus 2.09) and without HF (2.10 versus 2.54; P-interaction=0.62). The risk of major or nonmajor clinically relevant bleeding with rivaroxaban was similar to warfarin in patients with HF (14.22 versus 14.02) and without HF (16.12 versus 15.35; P-interaction=0.99). A reduction in hemorrhagic stroke was observed with rivaroxaban in patients with HF as in the overall trial (adjusted hazard ratio, 0.38; 95% confidence interval, 0.19–0.76; P-interaction=0.067). Among patients with HF, the efficacy of rivaroxaban was similar, irrespective of ejection fraction <40 or ≥40% (P-interaction=0.38), New York Heart Association class I-II versus III-IV (P-interaction=0.68), HF preserved or reduced ejection fraction (P-interaction=0.35), or CHADS2 score 2 versus ≥3 (P-interaction=0.48). Conclusions—Treatment-related outcomes were similar in patients with and without HF and across HF subgroups. These findings support the use of rivaroxaban as an alternative to warfarin in patients with atrial fibrillation and HF. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association

Cardiogenic shock is a high-acuity, potentially complex, and hemodynamically diverse state of end-organ hypoperfusion that is frequently associated with multisystem organ failure. Despite improving survival in recent years, patient morbidity and mortality remain high, and there are few evidence-based therapeutic interventions known to clearly improve patient outcomes. This scientific statement on cardiogenic shock summarizes the epidemiology, pathophysiology, causes, and outcomes of cardiogenic shock; reviews contemporary best medical, surgical, mechanical circulatory support, and palliative care practices; advocates for the development of regionalized systems of care; and outlines future research priorities.

Temporal Differences in Out-of-Hospital Cardiac Arrest Incidence and Survival

Background— Understanding temporal differences in the incidence and outcomes of out-of-hospital cardiac arrest (OHCA) has important implications for developing preventative strategies and optimizing systems for OHCA care. Methods and Results— We studied 18 588 OHCAs of presumed cardiac origin in patients aged ≥18 years who received resuscitative efforts by emergency medical services (EMS) and were enrolled in the Cardiac Arrest Registry to Enhance Survival (CARES) from October 1, 2005, to December 31, 2010. We evaluated temporal variability in OHCA incidence and survival to hospital discharge. There was significant variability in the frequency of OHCA by hour of the day (P<0.001), day of the week (P<0.001), and month of the year (P<0.001), with the highest incidence occurring during the daytime, from Friday to Monday, in December. Survival to hospital discharge was lowest for OHCA that occurred overnight (from 11:01 PM to 7 AM; 7.1%) versus daytime (7:01 AM to 3 PM; 10.8%) or evening (3:01 PM to 11 PM; 11.3%; P<0.001) and during the winter (8.8%) versus spring (11.1%), summer (11.0%), or fall (10.0%; P<0.001). There was no difference in survival to hospital discharge between OHCAs that occurred on weekends and weekdays (9.5% versus 10.4%, P=0.06). After multivariable adjustment for age, sex, race, witness status, layperson resuscitation, first monitored cardiac rhythm, and emergency medical services response time, compared with daytime and spring, survival to hospital discharge remained lowest for OHCA that occurred overnight (odds ratio, 0.81; 95% confidence interval, 0.70–0.95; P=0.008) and during the winter (odds ratio, 0.81; 95% confidence interval, 0.70–0.94; P=0.006), respectively. Conclusions— There is significant temporal variability in the incidence of and survival after OHCA. The relative contribution of patient pathophysiology, likelihood of the OHCA being observed, and prehospital and hospital-based resuscitative factors deserves further exploration.