Christian Hassager

Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest

BACKGROUND Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. METHODS In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. RESULTS In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. CONCLUSIONS In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.).

The association between low bone mass at the menopause and cardiovascular mortality

BACKGROUND Low bone mineral density in late postmenopausal women has been associated with increased nontrauma mortality. We investigated whether bone mass in women soon after menopause was also associated with the risk of mortality in later life. METHODS Between 1977 and 1988, two samples of healthy women were enrolled; one group soon after the menopause (age 50 +/- 2 years [mean +/- SD], n = 309) and another later after menopause (age 70 +/- 2 years, n = 754). The baseline visit included a medical examination and a measurement of bone mineral content in the distal forearm. In 1994, vital status was checked. All causes of death were registered, excluding those that were due to trauma or suicide. Multivariate relative risks (RR) and 95% confidence intervals (CI) were determined. RESULTS In the early postmenopausal group, each decrease of one SD (0.4 g/cm) in bone mineral content was associated with a 43% increase in mortality (RR = 1.4; 95% CI 1.0 to 2.0; P < 0.05). When only cardiovascular death was considered, the relative risk of dying within 17 years of the menopause was increased 2.3-fold (95% CI 1.0 to 5.3; P < 0.05). Correspondingly, a 70-year-old woman with a bone mineral content 1 SD below the mean for her age had a 1.8-fold increased risk of dying from cardiovascular disease (95% CI 1.0 to 3.2; P = 0.06). Expressed as quartiles, women with bone mass in the lowest quartile had twice the risk of cardiovascular death compared with those in the highest quartile. A prevalent vertebral compression fracture in the late postmenopausal group was independently associated with cardiovascular death (RR = 2.0; 95% CI 1.4 to 3.3; P = 0.004). CONCLUSION Low bone mineral content at the menopause is a risk factor for increased mortality in later life, especially from cardiovascular disease.

Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure

BACKGROUND The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT). METHODS In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. RESULTS After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29). CONCLUSIONS In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).

Prevention of Disease Progression by Cardiac Resynchronization Therapy in Patients With Asymptomatic or Mildly Symptomatic Left Ventricular Dysfunction: Insights From the European Cohort of the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) Trial

OBJECTIVES The aim of this study was to determine the long-term effects of cardiac resynchronization therapy (CRT) in the European cohort of patients enrolled in the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial. BACKGROUND Previous data suggest that CRT slows disease progression and improves the outcomes of asymptomatic or mildly symptomatic patients with left ventricular (LV) dysfunction and a wide QRS complex. METHODS We randomly assigned 262 recipients of CRT pacemakers or defibrillators, with QRS > or =120 ms and LV ejection fraction < or =40% to active (CRT ON; n = 180) versus control (CRT OFF; n = 82) treatment, for 24 months. Mean baseline LV ejection fraction was 28.0%. All patients were in sinus rhythm and receiving optimal medical therapy. The primary study end point was the proportion worsened by the heart failure (HF) clinical composite response. The main secondary study end point was left ventricular end-systolic volume index (LVESVi). RESULTS In the CRT ON group, 19% of patients were worsened versus 34% in the CRT OFF group (p = 0.01). The LVESVi decreased by a mean of 27.5 +/- 31.8 ml/m(2) in the CRT ON group versus 2.7 +/- 25.8 ml/m(2) in the CRT OFF group (p < 0.0001). Time to first HF hospital stay or death (hazard ratio: 0.38; p = 0.003) was significantly delayed by CRT. CONCLUSIONS After 24 months of CRT, and compared with those of control subjects, clinical outcomes and LV function were improved and LV dimensions were decreased in this patient population in New York Heart Association functional classes I or II. These observations suggest that CRT prevents the progression of disease in patients with asymptomatic or mildly symptomatic LV dysfunction. (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction [REVERSE]; NCT00271154).

Effect of an energy-restrictive diet, with or without exercise, on lean tissue mass, resting metabolic rate, cardiovascular risk factors, and bone in overweight postmenopausal women

PURPOSE To study the effect of exercise added to an energy-restrictive diet in overweight postmenopausal women. SUBJECTS AND METHODS In a longitudinal clinical study, 121 healthy, overweight postmenopausal women (age 53.8 +/- 2.5 years, body mass index: 29.7 +/- 3.1 kg/m2) were randomly assigned to 3 groups: controls, a 4,200 kJ/d diet, or a 4,200 kJ/d diet with combined aerobic and anaerobic exercise. Body composition (measured by dual-energy x-ray absorptiometry), fat distribution, resting metabolic rate, blood pressure, serum lipids and lipoproteins, bone mineral densities, and markers of collagen and bone turnover were measured before and after 12 weeks of intervention. RESULTS One hundred eighteen women completed the study. The mean loss of body weight (9.5 kg versus 10.3 kg, NS) was similar in the intervention groups, but compared with the diet-only group, the diet-plus-exercise group lost more fat (7.8 kg versus 9.6 kg, p < 0.001) and no lean tissue mass (1.2 kg versus -0.0 kg, p < 0.001). The resting metabolic rate (per kg wt) was increased in the diet-plus-exercise group compared with the control group (11% versus 4%, p < 0.009). The levels of serum triglycerides, total cholesterol, low-density lipoprotein, and very-low-density lipoprotein decreased, and the ratio of high-density lipoprotein to low-density lipoprotein increased by 20% to 30% in both intervention groups compared with the control group (p < 0.001). The systolic blood pressure dropped, and the waist-to-hip circumference ratio and abdominal-to-total body fat decreased in both intervention groups compared with the control group (10%, p < 0.003, and 3.5%, p < 0.0001). There were no consistent, major differences between the groups in terms of changes in total body, spinal, or forearm bone mineral densities, or in markers of collagen and bone turnover. CONCLUSION Overweight postmenopausal women benefit from addition of combined aerobic and anaerobic exercise to an energy-restrictive diet. The diet itself has a positive effect on cardiovascular risk factors.

Age- and menopause-associated variations in body composition and fat distribution in healthy women as measured by dual-energy x-ray absorptiometry

To assess the variation with age and menopause, 407 healthy normal women aged 18 to 75 years had body composition and fat distribution measured by dual-energy x-ray absorptiometry (DEXA). The mean +/- SD are given for different age decades. Postmenopausal women had significantly more fat, a more central fat distribution, and less lean tissue mass (LTM) than premenopausal women. In premenopausal and postmenopausal women, age only correlated with the abdominal to total-body fat tissue ratio (r approximately .24, P < .05), whereas the years since onset of menopause correlated with fat tissue mass (FTM), fat%, abdominal fat%, and the abdominal to total-body fat tissue ratio (r approximately .2, P < .05). To assess the independent impact of age, menopausal status, and years since menopause, multiple linear regressions were performed. FTM, fat%, and abdominal fat% were significantly related to menopausal status and years since menopause independently of age. The abdominal to total-body fat tissue ratio was statistically significantly related to age, but tended also to be independently related to years since menopause. LTM was statistically significantly related to menopausal status independently of age and years since menopause. In summary, we suggest that in healthy women total-body and abdominal fat may increase and LTM may decrease in the years after menopause, primarily in the perimenopausal years, without significant changes before menopause.

Cardiac Resynchronization Induces Major Structural and Functional Reverse Remodeling in Patients With New York Heart Association Class I/II Heart Failure

Background— Cardiac resynchronization therapy (CRT) improves LV structure, function, and clinical outcomes in New York Heart Association class III/IV heart failure with prolonged QRS. It is not known whether patients with New York Heart Association class I/II systolic heart failure exhibit left ventricular (LV) reverse remodeling with CRT or whether reverse remodeling is modified by the cause of heart failure. Methods and Results— Six hundred ten patients with New York Heart Association class I/II heart failure, QRS duration ≥120 ms, LV end-diastolic dimension ≥55 mm, and LV ejection fraction ≤40% were randomized to active therapy (CRT on; n=419) or control (CRT off; n=191) for 12 months. Doppler echocardiograms were recorded at baseline, before hospital discharge, and at 6 and 12 months. When CRT was turned on initially, immediate changes occurred in LV volumes and ejection fraction; however, these changes did not correlate with the long-term changes (12 months) in LV end-systolic (r=0.11, P=0.31) or end-diastolic (r=0.10, P=0.38) volume indexes or LV ejection fraction (r=0.07, P=0.72). LV end-diastolic and end-systolic volume indexes decreased in patients with CRT turned on (both P<0.001 compared with CRT off), whereas LV ejection fraction in CRT-on patients increased (P<0.0001 compared with CRT off) from baseline through 12 months. LV mass, mitral regurgitation, and LV diastolic function did not change in either group by 12 months; however, there was a 3-fold greater reduction in LV end-diastolic and end-systolic volume indexes and a 3-fold greater increase in LV ejection fraction in patients with nonischemic causes of heart failure. Conclusions— CRT in patients with New York Heart Association I/II resulted in major structural and functional reverse remodeling at 1 year, with the greatest changes occurring in patients with a nonischemic cause of heart failure. CRT may interrupt the natural disease progression in these patients. Clinical Trial Registration— Clinicaltrials.gov Identifier: NCT00271154.

Right ventricular dysfunction as an independent predictor of short‐ and long‐term mortality in patients with heart failure

The prognostic importance of right ventricular (RV) dysfunction in heart failure (HF) has been suggested in patients with severe systolic heart failure. Tricuspid annular plane systolic excursion (TAPSE) is a simple echocardiographic measure of RV ejection fraction, but may be affected by co‐existing chronic obstructive pulmonary disease (COPD).

Supported High-Risk Percutaneous Coronary Intervention With the Impella 2.5 Device: The Europella Registry

OBJECTIVES This retrospective multicenter registry evaluated the safety and feasibility of left ventricular (LV) support with the Impella 2.5 (Abiomed Europe GmbH, Aachen, Germany) during high-risk percutaneous coronary intervention (PCI). BACKGROUND Patients with complex or high-risk coronary lesions, such as last remaining vessel or left main lesions, are increasingly being treated with PCI. Because periprocedural hemodynamic compromise and complications might occur rapidly, many of these high-risk procedures are being performed with mechanical cardiac assistance, particularly in patients with poor LV function. The Impella 2.5, a percutaneous implantable LV assist device, might be a superior alternative to the traditionally used intra-aortic balloon pump. METHODS The Europella registry included 144 consecutive patients who underwent a high-risk PCI. Safety and feasibility end points included incidence of 30-day adverse events and successful device function. RESULTS Patients were older (62% >70 years of age), 54% had an LV ejection fraction < or = 30%, and the prevalence of comorbid conditions was high. Mean European System for Cardiac Operative Risk Evaluation score was 8.2 (SD 3.4), and 43% of the patients were refused for coronary artery bypass grafting. A PCI was considered high-risk due to left main disease, last remaining vessel disease, multivessel coronary artery disease, and low LV function in 53%, 17%, 81%, and 35% of the cases, respectively. Mortality at 30 days was 5.5%. Rates of myocardial infarction, stroke, bleeding requiring transfusion/surgery, and vascular complications at 30 days were 0%, 0.7%, 6.2%, and 4.0%, respectively. CONCLUSIONS This large multicenter registry supports the safety, feasibility, and potential usefulness of hemodynamic support with Impella 2.5 in high-risk PCI.

NT-proBNP: a new diagnostic screening tool to differentiate between patients with normal and reduced left ventricular systolic function

Objective: To evaluate whether measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) can be used to differentiate patients with normal and reduced left ventricular ejection fraction (LVEF) in an unselected consecutive group of hospital inpatients. Setting: City general hospital, Copenhagen, Denmark. Patients and design: During a 10 month period 2230 admissions to a city general hospital (80% of targeted patients) had an echocardiographic evaluation of left ventricular function, a comprehensive clinical evaluation, and blood analysis of N-terminal-pro-brain natriuretic peptide (NT-proBNP) within 24 hours of admission. Exclusions resulted from lack of informed consent or failure to obtain the required evaluations before death or discharge from hospital. Echocardiography was unsatisfactory in 37 patients, so the final number studied was 2193. Results: A raised NT-proBNP (≥ 357 pmol/l) identified patients with an LVEF of ≤ 40% (n = 157) with a sensitivity of 73% and a specificity of 82%. The negative predictive value of having an NT-proBNP concentration below 357 pmol/l was 98%. Concentrations of NT-proBNP increased with increasing age and with decreasing LVEF (p < 0.05). A predicted concentration of NT-proBNP (corrected for age, sex, and serum creatinine) was determined for each patient. In patients with an NT-proBNP value less than predicted, the probability of having an LVEF of > 40% was more than 97%. This probability rapidly decreased to 70% as the measured NT-proBNP increased to 150% of the predicted value. Conclusions: A single measurement of NT-proBNP at the time of hospital admission provides important information about LVEF in unselected patients.