Are beta-blockers needed in patients receiving spironolactone for severe chronic heart failure? An analysis of the COPERNICUS study

BACKGROUND: The beneficial effects of beta-blockers and aldosterone receptor antagonists are now well established in patients with severe systolic chronic heart failure (CHF). However, it is unclear whether beta-blockers are able to provide additional benefit in patients already receiving aldosterone antagonists. We therefore examined this question in the COPERNICUS study of 2289 patients with severe CHF receiving the beta1-beta2/alpha1 blocker carvedilol compared with placebo. METHODS: Patients were divided post hoc into subgroups according to whether they were receiving spironolactone (n = 445) or not (n = 1844) at baseline. Consistency of the effect of carvedilol versus placebo was examined for these subgroups with respect to the predefined end points of all-cause mortality, death or CHF-related hospitalizations, death or cardiovascular hospitalizations, and death or all-cause hospitalizations. RESULTS: The beneficial effect of carvedilol was similar among patients who were or were not receiving spironolactone for each of the 4 efficacy measures. For all-cause mortality, the Cox model hazard ratio for carvedilol compared with placebo was 0.65 (95% CI 0.36-1.15) in patients receiving spironolactone and 0.65 (0.51-0.83) in patients not receiving spironolactone. Hazard ratios for death or all-cause hospitalization were 0.76 (0.55-1.05) versus 0.76 (0.66-0.88); for death or cardiovascular hospitalization, 0.61 (0.42-0.89) versus 0.75 (0.64-0.88); and for death or CHF hospitalization, 0.63 (0.43-0.94) versus 0.70 (0.59-0.84), in patients receiving and not receiving spironolactone, respectively. The safety and tolerability of treatment with carvedilol were also similar, regardless of background spironolactone. CONCLUSION: Carvedilol remained clinically efficacious in the COPERNICUS study of patients with severe CHF when added to background spironolactone in patients who were practically all receiving angiotensin-converting enzyme inhibitor (or angiotensin II antagonist) therapy. Therefore, the use of spironolactone in patients with severe CHF does not obviate the necessity of additional treatment that interferes with the adverse effects of sympathetic activation, specifically beta-blockade.

Family satisfaction in the intensive care unit: cross-cultural adaptation of a questionnaire

PURPOSE: Family needs and expectations are often unmet in the intensive care unit (ICU), leading to dissatisfaction. This study assesses cross-cultural adaptability of an instrument evaluating family satisfaction in the ICU. MATERIALS AND METHODS: A Canadian instrument on family satisfaction was adapted for German language and central European culture and then validated for feasibility, validity, internal consistency, reliability, and sensitivity. RESULTS: Content validity of a preliminary translated version was assessed by staff, patients, and next of kin. After adaptation, content and comprehensibility were considered good. The adapted translation was then distributed to 160 family members. The return rate was 71.8%, and 94.4% of questions in returned forms were clearly answered. In comparison with a Visual Analogue Scale, construct validity was good for overall satisfaction with care (Spearman rho = 0.60) and overall satisfaction with decision making (rho = 0.65). Cronbach alpha was .95 for satisfaction with care and .87 for decision-making. Only minor differences on repeated measurements were found for interrater and intrarater reliability. There was no floor or ceiling effect. CONCLUSIONS: A cross-cultural adaptation of a questionnaire on family satisfaction in the ICU can be feasible, valid, internally consistent, reliable, and sensitive.

Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study

BACKGROUND: A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. METHODS: We compared treatment-naive patients or patients with treatment interruptions > or = 12 months starting either a TDF-based combination antiretroviral therapy (cART) (n = 363) or a TDF-sparing regime (n = 715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. RESULTS: Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58-0.72) and 0.80 (95% CI 0.76-0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR] = 2.34 [95% CI 1.24-4.42]), higher baseline cGFR (HR = 1.03 [95% CI 1.02-1.04] by 10 ml/min), TDF use (HR = 1.84 [95% CI 1.35-2.51]) and boosted protease inhibitor use (HR = 1.71 [95% CI 1.30-2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. CONCLUSION: There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.

Clinical end points in coronary stent trials: a case for standardized definitions

BACKGROUND: Although most clinical trials of coronary stents have measured nominally identical safety and effectiveness end points, differences in definitions and timing of assessment have created confusion in interpretation. METHODS AND RESULTS: The Academic Research Consortium is an informal collaboration between academic research organizations in the United States and Europe. Two meetings, in Washington, DC, in January 2006 and in Dublin, Ireland, in June 2006, sponsored by the Academic Research Consortium and including representatives of the US Food and Drug Administration and all device manufacturers who were working with the Food and Drug Administration on drug-eluting stent clinical trial programs, were focused on consensus end point definitions for drug-eluting stent evaluations. The effort was pursued with the objective to establish consistency among end point definitions and provide consensus recommendations. On the basis of considerations from historical legacy to key pathophysiological mechanisms and relevance to clinical interpretability, criteria for assessment of death, myocardial infarction, repeat revascularization, and stent thrombosis were developed. The broadly based consensus end point definitions in this document may be usefully applied or recognized for regulatory and clinical trial purposes. CONCLUSION: Although consensus criteria will inevitably include certain arbitrary features, consensus criteria for clinical end points provide consistency across studies that can facilitate the evaluation of safety and effectiveness of these devices.

Clinical endpoints in peripheral endovascular revascularization trials: a case for standardized definitions

BACKGROUND: Endovascular therapy is a rapidly expanding option for the treatment of patients with peripheral arterial disease (PAD), leading to a myriad of published studies reporting on various revascularization strategies. However, these reports are often difficult to interpret and compare because they do not utilize uniform clinical endpoint definitions. Moreover, few of these studies describe clinical outcomes from a patients' perspective. METHODS AND RESULTS: The DEFINE Group is a collaborative effort of an ad-hoc multidisciplinary team from various specialties involved in peripheral arterial disease therapy in Europe and the United States. DEFINE's goal was to arrive at a broad based consensus for baseline and endpoint definitions in peripheral endovascular revascularization trials for chronic lower limb ischemia. In this project, which started in 2006, the individual team members reviewed the existing pertinent literature. Following this, a series of telephone conferences and face-to-face meetings were held to agree upon definitions. Input was also obtained from regulatory (United States Food and Drug Administration) and industry (device manufacturers with an interest in peripheral endovascular revascularization) stakeholders, respectively. The efforts resulted in the current document containing proposed baseline and endpoint definitions in chronic lower limb PAD. Although the consensus has inevitably included certain arbitrary choices and compromises, adherence to these proposed standard definitions would provide consistency across future trials, thereby facilitating evaluation of clinical effectiveness and safety of various endovascular revascularization techniques. CONCLUSION: This current document is based on a broad based consensus involving relevant stakeholders from the medical community, industry and regulatory bodies. It is proposed that the consensus document may have value for study design of future clinical trials in chronic lower limb ischemia as well as for regulatory purposes.

Psychometric properties of the MacNew heart disease health-related quality of life instrument in patients with heart failure

RATIONALE, AIMS AND OBJECTIVES: Heart failure (HF) is a severe chronic disease and impairs health-related quality of life (HRQL). While validated specific HRQL instruments are required for evaluation of treatment and rehabilitation in patients with HF, a single validated measure to document changes in HRQL for patients with different heart disease diagnoses would be invaluable. The purpose of this analysis was the psychometric analysis of the German MacNew Heart Disease Questionnaire (MacNew) in HF patients, which has previously been shown to be reliable and valid in patients with myocardial infarction, angina pectoris and arrhythmia. METHODS: We recruited 89 patients (61.7+/-11.5 years; 84.3% male) in two Austrian and one Swiss cardiology department with documented HF (effect sizes 28.9+/-10.1%). The self-administered MacNew, the Short Form-36 (SF-36) and the Hospital Anxiety and Depression Scale were completed. Internal consistency reliability (Cronbach's alpha), discriminative and evaluative validity were assessed. RESULTS: Cronbach's alpha exceeded 0.80. Each MacNew scale differentiated between patients with and without anxiety (3.9+/-1.0 vs. 5.3+/-0.8, all P<0.001), with and without depression (4.2+/-1.2 vs. 5.2+/-0.9 all P<0.03) and by the SF-36 health transition item (deteriorate=4.39, no change=4.95, improve=5.45, all P<0.02). Evaluative validity was demonstrated with effect sizes >0.70 for a subsample attending a 12-week outpatient rehabilitation programme. CONCLUSIONS: The German language version of the MacNew demonstrates consistently acceptable psychometric properties of reliability, validity and responsiveness in patients with documented HF. Together with previous documentation of reliability, validity and responsive, these findings strengthen the argument for the MacNew as a potential 'core' HRQL measure, at least in the German language.

Variability in pain response to a non-pharmacological intervention across repeated routine pain exposure in preterm infants: a feasibility study

AIM: To explore the variability in pain response in preterm infants across time who received sucrose during routine heel stick. METHOD: Single group, exploratory repeated measures design. SETTING: Two tertiary level neonatal intensive care units (NICU) in Switzerland. SUBJECTS: Nine preterm infants born between 28 2/7 and 31 4/7 weeks of gestation during their first 14 days of life. MEASUREMENTS: Pain was assessed by the Bernese Pain Scale for Neonates (BPSN), the Premature Infant Pain Profile (PIPP) and the Visual Analogue Scale (VAS). Salivary cortisol was analysed. RESULTS: 72-94% of the variability was within-subject variability, indicating inconsistency of pain responses across the 5 heel sticks. Interrater agreement was highest during heel sticks 1-3 and decreased during heel stick 4 and 5, indicating a possible alteration of pain patterns. No significant differences in the amount of cortisol could be detected before and after the heel sticks (p = 0.55), indicating no stress-induced peak after the painful intervention. However, a general gradual decrease of cortisol levels across time could be detected. CONCLUSION: A high variability in pain response among preterm neonates across time could be described. Consistency of cortisol levels before and after the heel sticks could indicate the effectiveness of sucrose across time.