Multicentre, randomized, double-blind, prospective study on the effects of ImmunoAdSorptiOn on cardiac function in patients with Dilated CardioMyopathy (IASO-DCM): Rationale and design.

AIMS: Pilot studies indicate that immunoadsorption with subsequent IgG substitution (IA/IgG) induces beneficial effects in patients with dilated cardiomyopathy (DCM) and heart failure. This placebo-controlled study investigates whether IA/IgG treatment enhances left ventricular (LV) systolic function as compared to a control group receiving pseudo-treatment. METHODS: This multicentre, randomized, double-blind, parallel-group trial aims to include 200 patients with heart failure due to DCM (LV ejection fraction [LVEF] <40%) on optimized guideline-directed heart failure medication. Participants are randomly assigned in a 1:1 ratio to IA/IgG using protein-A columns, or to pseudo-immunoadsorption followed by an intravenous infusion without IgG. Follow-up visits take place by telephone after 1 and 3 months and at the study centres after 6, 12 and 24 months. The primary efficacy endpoint is the change in LVEF from baseline to 6 months determined by contrast echocardiography, analysed at a core lab. In addition, LV end-diastolic and end-systolic volumes will be analysed as secondary endpoints over the entire study period to assess whether IA/IgG affects LV remodelling. As main secondary outcome, a composite of all-cause death, cardiac resuscitation, hospitalization for heart failure, and need for cardiac surgery to improve myocardial pump function will be evaluated after 24 months. In addition, exploratory outcomes as well as safety endpoints related to the treatment will be assessed throughout the whole study period. CONCLUSION: IASO-DCM is a randomized study which will provide comprehensive insights into the effects of immunoadsorption with subsequent IgG substitution in patients with DCM.

In Ischemic Heart Disease, Reduced Sensitivity to Pressure at the Sternum Accompanies Lower Mortality after Five Years: Evidence from a Randomized Controlled Trial.

Background: Autonomic nervous system dysfunction (ANSD) is associated with negative prognosis of ischemic heart disease (IHD). Elevated periosteal pressure sensitivity (PPS) at the sternum relates to ANSD and sympathetic hyperactivity. Two previous observational case-control studies of the effect of reduction of PPS suggested lower all-cause mortality from IHD and stroke. We now used a specific daily, adjunct, non-pharmacological program of reduction of elevated PPS to test the hypothetical association between the intervention and reduced all-cause mortality in patients with stable IHD in a randomized controlled trial (RCT). Methods: We completed active (n = 106) and passive interventions (n = 107) and compared the five-year mortalities. We also compared the five-year individual all-cause mortality of each participant to approximately 35.000 members of the general population of Denmark. Pooling the mortality data from the active group of the RCT with the two preliminary studies, we registered the mortality following active intervention of 1.168 person-years, compared to 40 million person-years of the pooled general population. Results: We recorded fewer deaths of the active RCT intervention group than of the corresponding control group from the general population (p = 0.01), as well as of the passive RCT intervention group (p = 0.035). The meta-analysis of the three studies together demonstrated reduced 4.2-year all-cause mortality of 60% (p = 0.007). Conclusions: The test of the hypothetical effect of an intervention aimed at the attenuation of ANSD accompanied by a lowered PPS revealed reduced all-cause mortality in patients with stable IHD.

Effect of growth hormone treatment on circulating levels of NT-proBNP in patients with ischemic heart failure.

AIMS: Growth hormone (GH) therapy in heart failure (HF) is controversial. We investigated the cardiovascular effects of GH in patients with chronic HF due to ischemic heart disease. METHODS: In a double-blind, placebo-controlled trial, we randomly assigned 37 patients (mean age 66 years; 95% male) with ischemic HF (ejection fraction [EF] < 40%) to a 9-month treatment with either recombinant human GH (1.4 mg every other day) or placebo, with subsequent 3-month treatment-free follow-up. The primary outcome was change in left ventricular (LV) end-systolic volume measured by cardiac magnetic resonance (CMR). Secondary outcomes comprised changes in cardiac structure and EF. Prespecified tertiary outcomes included changes in New York Heat Association (NYHA) functional class and quality of life (QoL), as well as levels of insulin-like growth factor-1 (IGF-1) and N-terminal pro-brain natriuretic peptide (NT-proBNP). RESULTS: No changes in cardiac structure or systolic function were identified in either treatment group; nor did GH treatment affect QoL or functional class. In the GH group, circulating levels of IGF-1 doubled from baseline (+105%; p < 0.001) and NT-proBNP levels halved (-48%; p < 0.001) during the treatment period, with subsequently a partial return of both towards baseline levels. No changes in IGF-1 or NT-proBNP were observed in the placebo group at any time during the study. CONCLUSION: In patients with chronic ischemic HF, nine months of GH treatment was associated with significant increases in levels of IGF-1 and reductions in levels of NT-proBNP, but did not affect cardiac structure, systolic function or functional capacity.

Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials.

Aims: Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results: Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis. Conclusion: Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40-49%.

Chronic psychological stress seems associated with elements of the metabolic syndrome in patients with ischaemic heart disease.

BACKGROUND AND OBJECTIVES: Chronic psychological stress, the metabolic syndrome (MS) and ischaemic heart disease (IHD) seem closely connected. In this study, we evaluate the association between chronic stress and elements of MS in patients with stable IHD. DESIGN: Cross-sectional cohort study. METHODS: Three hundred and fifty patients with stable IHD were included. Chronic stress was evaluated by the two questionnaires, Major Depression Inventory (MDI) and the psychological wellbeing index WHO-5, as well as by Pressure Pain Sensitivity (PPS), a physiological measure of hyperalgesia at the sternum known to be associated to elements of the chronic stress syndrome. Elements of MS were evaluated by dual-energy X-ray absorptiometry, body weight, HOMA-IR and blood lipids. RESULTS: Depressive symptoms were associated with a high percentage of body fat (ß = 0.179, p = .001), and high level of triglycerides (ß = 0.150, p = .007). Low psychological wellbeing was associated with a high percentage of body fat (ß = -0.165, p = .002) and low level of HDL cholesterol (ß = 0.128, p = .024). Chronic stress measured by PPS was associated with a high percentage body fat (ß = 0.327, p < .001), low body weight (ß = -0.218, p < .001) and low HDL-cholesterol (ß = -0.137, p = .013). Adjusting for several life style factors did not change these results. CONCLUSIONS: In patients with stable IHD, different measures of chronic psychological stress seem associated with a high percentage of body fat and adverse blood lipids independent of several lifestyle factors.

Heart Rate and Rhythm and the Benefit of Beta-Blockers in Patients With Heart Failure.

BACKGROUND: The relationship between mortality and heart rate remains unclear for patients with heart failure with reduced ejection fraction in either sinus rhythm or atrial fibrillation (AF). OBJECTIVES: This analysis explored the prognostic importance of heart rate in patients with heart failure with reduced ejection fraction in randomized controlled trials comparing beta-blockers and placebo. METHODS: The Beta-Blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual patient data from 11 double-blind randomized controlled trials. The primary outcome was all-cause mortality, analyzed with Cox proportional hazard ratios (HR) modeling heart rate measured at baseline and approximately 6 months post-randomization. RESULTS: A higher heart rate at baseline was associated with greater all-cause mortality for patients in sinus rhythm (n = 14,166; adjusted HR: 1.11 per 10 beats/min; 95% confidence interval [CI]: 1.07 to 1.15; p < 0.0001) but not in AF (n = 3,034; HR: 1.03 per 10 beats/min; 95% CI: 0.97 to 1.08; p = 0.38). Beta-blockers reduced ventricular rate by 12 beats/min in both sinus rhythm and AF. Mortality was lower for patients in sinus rhythm randomized to beta-blockers (HR: 0.73 vs. placebo; 95% CI: 0.67 to 0.79; p < 0.001), regardless of baseline heart rate (interaction p = 0.35). Beta-blockers had no effect on mortality in patients with AF (HR: 0.96, 95% CI: 0.81 to 1.12; p = 0.58) at any heart rate (interaction p = 0.48). A lower achieved resting heart rate, irrespective of treatment, was associated with better prognosis only for patients in sinus rhythm (HR: 1.16 per 10 beats/min increase, 95% CI: 1.11 to 1.22; p < 0.0001). CONCLUSIONS: Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with heart failure with reduced ejection fraction in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm.

Association between pressure pain sensitivity and autonomic function as assessed by a tilt table test.

BACKGROUND: We tested the hypothesis that pressure sensitivity of the sternum (PPS) is associated with autonomic nervous system (ANS) function as assessed by tilt table test (TTT). in patients with stable ischemic heart disease. OBJECTIVES: (1) To evaluate an association between PPS and systolic blood pressure (SBP) and heart rate (HR) responses to TTT; and (2) to test the hypothesis that a reduction of resting PPS raises the PPS, SBP and HR responses to TTT response and lowers risk factors for ANS dysfunction (ANSD). METHODS: Cross-sectional study: In 361 patients with stable ischemic heart disease we measured PPS, SBP, and HR during TTT. Intervention study: We reassessed subjects with persistent stress who concluded a stress intervention trial by a second TTT. RESULTS: Cross-sectional study: Resting PPS and the PPS response to TTT were correlated (r = - 0.37). The PPS response to TTT was correlated with that of SBP (r = 0.44) and HR (r = 0.49), and with the number of risk factors for ANSD (r = - 0.21) (all p < 0.0001). Intervention study: A reduction in resting PPS was associated with an increment in PPS response to TTT (r = - 0.52, p < 0.0001). The greater this increment, the greater was the reduction in ANSD risk factors (r = - 0.23; p = 0.003). CONCLUSION: The results are consistent with the hypothesis that PPS at rest and in response to TTT reflects ANS function.

Diabetes and ischemic heart disease: double jeopardy with regard to depressive mood and reduced quality of life.

The aim of this study was to test i) whether patients having diabetes and ischemic heart disease (IHD), i.e., patients suffering from two chronic diseases, demonstrate a higher degree of chronic stress when compared with patients suffering from IHD alone, and ii) whether suffering from the two chronic diseases results in an elevation in specific elements of the chronic stress concept. A total of 361 participants with IHD were included, of whom 47 suffered from concomitant diabetes. Stress was measured by pressure pain sensitivity (PPS) and by the following questionnaires: the Major Depression Inventory (MDI), the SF-36 Quality of Life questionnaire (SF-36 QOL), the WHO-5 Well-being Index, and the clinical stress signs (CSSs) scale. Participants with diabetes and IHD had a higher MDI score, a lower SF-36 physical component summary score, and a lower score of several sub-measurements of the SF-36 mental component score when compared with patients with IHD without diabetes. No significant differences were observed regarding stress measured by the PPS measure, the WHO-5 Well-being Index, or the number of CSSs. In conclusion, the combination of diabetes and IHD seems to be associated with increased depressive symptoms, lower overall physical QOL, and reduced mental QOL on several sub-elements of the questionnaire. This should be recognized in the management of patients with double diagnoses.

The effect of daily self-measurement of pressure pain sensitivity followed by acupressure on depression and quality of life versus treatment as usual in ischemic heart disease: a randomized clinical trial.

BACKGROUND: Depressive symptoms and reduced quality of life (QOL) are parts of the chronic stress syndrome and predictive of adverse outcome in patients with ischemic heart disease (IHD). Chronic stress is associated with increased sensitivity for pain, which can be measured by algometry as Pressure Pain Sensitivity (PPS) on the sternum. AIM: To evaluate if stress focus by self-measurement of PPS, followed by stress reducing actions including acupressure, can decrease depressive symptoms and increase psychological well-being in people with stable IHD. DESIGN: Observer blinded randomized clinical trial over 3 months of either intervention or treatment as usual (TAU). STATISTICAL ANALYSIS: Intention to treat. METHODS: Two hundred and thirteen participants with IHD were included: 106 to active treatment and 107 to TAU. Drop-out: 20 and 12, respectively. The active intervention included self-measurement of PPS twice daily followed by acupressure as mandatory action, aiming at a reduction in PPS. Primary endpoint: change in depressive symptoms as measured by Major depression inventory (MDI). Other endpoints: changes in PPS, Well-being (WHO-5) and mental and physical QOL (SF-36). RESULTS: At 3 months PPS decreased 28%, to 58, in active and 11%, to 72, in TAU, p<0.001. MDI decreased 22%, to 6.5, in active group vs. 12%, to 8.3 in TAU, p = 0.040. WHO-5 increased to 71.0 and 64.8, active group and TAU, p = 0.015. SF-36 mental score sum increased to 55.3 and 53.3, active and TAU, p = 0.08. CONCLUSIONS: PPS measurements followed by acupressure reduce PPS, depressive symptoms and increase QOL in patients with stable IHD. TRIAL REGISTRATION: ClinicalTrials.gov NCT01513824.

Pressure pain sensitivity: a new method of stress measurement in patients with ischemic heart disease.

BACKGROUND: Chronic stress is prevalent in patients with ischemic heart disease (IHD) and worsens the long-term prognosis. Chronic stress is vaguely defined, but is associated with depressive symptoms, reduced psychological wellbeing, and reduced quality of life (QOL). Stress seems to induce hyperalgesia.The aim of the present study was to evaluate hyperalgesia by pressure pain sensitivity (PPS) in patients with IHD, and compare PPS to questionnaires measuring depressive symptoms, reduced psychological wellbeing, and QOL as markers of stress. Design. A cross-sectional study of 361 subjects with IHD. METHODS: PPS was measured on the sternum, and compared to the questionnaires: Clinical stress symptoms score (CSS), Major Depression Inventory (MDI), WHO-5 Wellbeing Index, and SF-36 QOL score. RESULTS: PPS correlated to CSS (r = 0.20, p < 0.001), MDI (r = 0.14, p = 0.02), SF-36 mental component summary score (MCS) (r = - 0.10, p = 0.049), SF-36 physical component summary score (PCS) (r = - 0.17, p = 0.001), and self-perceived stress level (r = 0.15, p = 0.006). CSS correlated similarly (r = 0.5-0.7, all p < 0.001). Comparing subjects within the lowest vs. highest tertiles of PPS and CSS, the mean MDI score was 4 vs. 15, WHO-5 was 77 vs. 53, SF-36 PCS was 53 vs. 43, and SF-36 MCS was 58 vs. 46; all p < 0.001. CONCLUSIONS: PPS reflected to a modest degree markers of chronic stress in IHD. PPS and CSS together might be useful as easy-to use tools for evaluating these markers in IHD patients.

Coenzyme Q10, rosuvastatin, and clinical outcomes in heart failure: a pre-specified substudy of CORONA (controlled rosuvastatin multinational study in heart failure).

OBJECTIVES: The purpose of this study was to determine whether coenzyme Q10 is an independent predictor of prognosis in heart failure. BACKGROUND: Blood and tissue concentrations of the essential cofactor coenzyme Q10 are decreased by statins, and this could be harmful in patients with heart failure. METHODS: We measured serum coenzyme Q10 in 1,191 patients with ischemic systolic heart failure enrolled in CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure) and related this to clinical outcomes. RESULTS: Patients with lower coenzyme Q10 concentrations were older and had more advanced heart failure. Mortality was significantly higher among patients in the lowest compared to the highest coenzyme Q10 tertile in a univariate analysis (hazard ratio: 1.50, 95% confidence interval: 1.04 to 2.6, p = 0.03) but not in a multivariable analysis. Coenzyme Q10 was not an independent predictor of any other clinical outcome. Rosuvastatin reduced coenzyme Q10 but there was no interaction between coenzyme Q10 and the effect of rosuvastatin. CONCLUSIONS: Coenzyme Q10 is not an independent prognostic variable in heart failure. Rosuvastatin reduced coenzyme Q10, but even in patients with a low baseline coenzyme Q10, rosuvastatin treatment was not associated with a significantly worse outcome. (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA]; NCT00206310).

Intermittent claudication as a predictor of outcome in patients with ischaemic systolic heart failure: analysis of the Controlled Rosuvastatin Multinational Trial in Heart Failure trial (CORONA).

AIMS: To examine the relationship between baseline intermittent claudication and outcomes in patients enrolled in the Controlled Rosuvastatin Multinational Trial in Heart Failure trial (CORONA). Intermittent claudication is an independent predictor of worse outcome in coronary heart disease, but its prognostic importance in heart failure (HF) is unknown. Patients aged >or=60 years with NYHA class II-IV, low ejection fraction HF of ischaemic aetiology were enrolled in CORONA. Rosuvastatin did not reduce the primary outcome or all-cause mortality. METHODS AND RESULTS: To determine whether intermittent claudication was an independent predictor of clinical outcomes, a three-step multivariable model was built: (i) demographic/clinical variables, (ii) biochemical measures added, (iii) high-sensitivity C-reactive protein and N-terminal pro B-type natriuretic-peptide added. Of the 5011 patients, 637 (12.7%) had intermittent claudication at baseline. Patients with intermittent claudication were more likely to be male (83 vs. 75%), be a current smoker (19 vs. 9%), and have diabetes mellitus (36 vs. 29%) relative to those without intermittent claudication. Over a median 33-month follow-up, 2168 patients died or were hospitalized for HF. Patients with intermittent claudication had an increased risk of death (any cause) (adjusted hazard ratio 1.36, 95% CI 1.19-1.56, P < 0.0001), death from worsening HF (1.35, 1.03-1.77, P = 0.028), sudden death (1.24, 1.00-1.54, P = 0.05), and risk of non-fatal or fatal myocardial infarction (time to first event 1.67, 1.24-2.27, P < 0.001). In the full multivariable model, intermittent claudication remained an independent predictor of most outcomes evaluated. CONCLUSION: Intermittent claudication is a relatively common symptom in ischaemic HF and an independent predictor of worse outcome. CLINICAL TRIAL REGISTRATION INFORMATION: NCT00206310-http://clinicaltrials.gov/ct2/show/NCT00206310?term=corona&rank=2.

An economic evaluation of rosuvastatin treatment in systolic heart failure: evidence from the CORONA trial.

AIMS: To estimate the cost-effectiveness of 10 mg rosuvastatin daily for older patients with systolic heart failure in the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA) trial. METHODS AND RESULTS: This within trial analysis of CORONA used major cardiovascular (CV) events as the outcome measure. Resource use was valued and the costs of hospitalizations, procedures, and statin use compared. Cost-effectiveness was estimated as cost per major CV event avoided. There were significantly fewer major CV events in the rosuvastatin group compared with the placebo group (1.04 vs. 1.20 per patient; difference 0.164; 95% CI: 0.075-0.254, P < 0.001). The average cost of CV hospitalizations and procedures was significantly lower for those receiving rosuvastatin ( pound1531 vs. pound1769; difference pound238; 95% CI: pound73-403, P = 0.005); the additional cost of the statin resulted in significantly higher total costs for the rosuvastatin group ( pound1769 vs. pound2072; difference pound303; 95% CI: pound138-468, P < 0.001). Overall, rosuvastatin was found to cost pound1840 (95% CI: pound562-6028) per major CV event avoided. CONCLUSION: This economic analysis showed that a significant reduction in major CV events with rosuvastatin led to significantly reduced costs of CV hospitalizations and procedures. The reduction in associated costs for major CV events was found to offset partially (by 44%) the cost of rosuvastatin treatment in patients with systolic heart failure.

Plasma concentration of amino-terminal pro-brain natriuretic peptide in chronic heart failure: prediction of cardiovascular events and interaction with the effects of rosuvastatin: a report from CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure).

OBJECTIVES: We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective. BACKGROUND: Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile. METHODS: In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke. RESULTS: Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin. CONCLUSIONS: Patients with heart failure due to ischemic heart disease who have NT-proBNP values <103 pmol/l (868 pg/ml) may benefit from rosuvastatin.

Effects of statin therapy according to plasma high-sensitivity C-reactive protein concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): a retrospective analysis.

BACKGROUND: We examined whether the antiinflammatory action of statins may be of benefit in heart failure, a state characterized by inflammation in which low cholesterol is associated with worse outcomes. METHODS AND RESULTS: We compared 10 mg rosuvastatin daily with placebo in patients with ischemic systolic heart failure according to baseline high sensitivity-C reactive protein (hs-CRP) <2.0 mg/L (placebo, n=779; rosuvastatin, n=777) or > or = 2.0 mg/L (placebo, n=1694; rosuvastatin, n=1711). The primary outcome was cardiovascular death, myocardial infarction, or stroke. Baseline low-density lipoprotein was the same, and rosuvastatin reduced low-density lipoprotein by 47% in both hs-CRP groups. Median hs-CRP was 1.10 mg/L in the lower and 5.60 mg/L in the higher hs-CRP group, with higher hs-CRP associated with worse outcomes. The change in hs-CRP with rosuvastatin from baseline to 3 months was -6% in the low hs-CRP group (27% with placebo) and -33.3% in the high hs-CRP group (-11.1% with placebo). In the high hs-CRP group, 548 placebo-treated (14.0 per 100 patient-years of follow-up) and 498 rosuvastatin-treated (12.2 per 100 patient-years of follow-up) patients had a primary end point (hazard ratio of placebo to rosuvastatin, 0.87; 95% confidence interval, 0.77 to 0.98; P=0.024). In the low hs-CRP group, 175 placebo-treated (8.9 per 100 patient-years of follow-up) and 188 rosuvastatin-treated (9.8 per 100 patient-years of follow-up) patients experienced this outcome (hazard ratio, 1.09; 95% confidence interval, 0.89 to 1.34; P>0.2; P for interaction=0.062). The numbers of deaths were as follows: 581 placebo-treated (14.1 per 100 patient-years of follow-up) and 532 rosuvastatin-treated (12.6 per 100 patient-years) patients in the high hs-CRP group (hazard ratio, 0.89; 95% confidence interval, 0.79 to 1.00; P=0.050) and 170 placebo-treated (8.3 per 100 patient-years) and 192 rosuvastatin-treated (9.7 per 100 patient-years) patients in the low hs-CRP group (hazard ratio, 1.17; 95% confidence interval, 0.95 to 1.43; P=0.14; P for interaction=0.026). CONCLUSIONS: In this retrospective hypothesis-generating study, we found a significant interaction between hs-CRP and the effect of rosuvastatin for most end points whereby rosuvastatin treatment was associated with better outcomes in patients with hs-CRP > or = 2.0 mg/L. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

The influence of renal function on clinical outcome and response to beta-blockade in systolic heart failure: insights from Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF).

BACKGROUND: Limited information is available on the risk and impact of renal dysfunction on the response to beta-blockade and mode of death in systolic heart failure (HF). METHODS AND RESULTS: Renal function was estimated with glomerular filtration rate (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) equation. Patients from the Metoprolol CR/XL Controlled Randomized Intervention Trial in Chronic HF (MERIT-HF) were divided into 3 renal function subgroups (MDRD formula): eGFR(MDRD) > 60 (n = 2496), eGFR(MDRD) 45 to 60 (n = 976), and eGFR(MDRD) < 45 mL/min per 1.73 m(2) body surface area (n = 493). Hazard ratio (HR) was estimated with Cox proportional hazards models adjusted for prespecified risk factors. Placebo patients with eGFR < 45 had significantly higher risk than those with eGFR > 60: HR for all-cause mortality, 1.90 (95% confidence interval [CI], 1.28 to 2.81) comparing placebo patients with eGFR < 45 and eGFR > 60, and for the combined end point of all-cause mortality/hospitalization for worsening HF (time to first event): HR, 1.91 (95% CI, 1.44 to 2.53). No significant increase in risk with deceased renal function was observed for those randomized to metoprolol controlled release (CR)/extended release (XL) due to a highly significant decrease in risk on metoprolol CR/XL in those with eGFR < 45. For total mortality, metoprolol CR/XL vs placebo: HR, 0.41 (95% CI. 0.25 to 0.68; P < .001) in those with eGFR < 45 compared with HR, 0.71 (95% CI, 0.54 to 0.95; P < .021) for those with eGFR > 60; corresponding data for the combined end point was HR, 0.44 (95% CI, 0.31 to 0.63; P < .0001) and HR, 0.75 (0.62 to 0.92; P = .005, respectively; P = .095 for interaction by treatment for total mortality; P = .011 for combined end point). Metoprolol CR/XL was well tolerated in all 3 renal function subgroups. CONCLUSIONS: Renal function as estimated by eGFR was a powerful predictor of death and hospitalizations from worsening HF. Metoprolol CR/XL was at least as effective in reducing death and hospitalizations for worsening HF in patients with eGFR < 45 as in those with eGFR > 60.

Predictors of fatal and non-fatal outcomes in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): incremental value of apolipoprotein A-1, high-sensitivity C-reactive peptide and N-terminal pro B-type natriuretic peptide.

AIMS: Few prognostic models in heart failure have been developed in typically elderly patients treated with modern pharmacological therapy and even fewer included simple biochemical tests (such as creatinine), new biomarkers (such as natriuretic peptides), or, especially, both. In addition, most models have been developed for the single outcome of all-cause mortality. METHODS AND RESULTS: We built a series of models for nine different fatal and non-fatal outcomes. For each outcome, a model was first built using demographic and clinical variables (Step 1), then with the addition of biochemical measures (serum creatinine, alanine aminotransferase, creatine kinase, thyrotrophin, apolipoproteins A-1 and B, and triglycerides) (Step 2) and finally with the incorporation of high-sensitivity C-reactive protein (hsCRP) and N-terminal pro B-type natriuretic peptide (NT-proBNP). Ranked according to the Wald chi(2) value, age (56), ejection fraction (44), and body mass index (42) were most predictive of all-cause mortality in Step 1 (total model chi(2) 343). Creatinine was the most powerful predictor at Step 2 (48) and ApoA-1 ranked fifth (25), with the overall chi(2) increasing to 440. Log NT-proBNP (167) was the most powerful of the 14 independently predictive variables identified at Step 3 and the overall chi(2) increased to 600. NT-proBNP was the most powerful predictor of each other outcome. hsCRP was not a predictor of all-cause mortality but did predict the composite atherothrombotic outcome. CONCLUSION: Of the two new biomarkers studied in prognostic models in heart failure, NT-proBNP, but not hsCRP, added substantial and independent predictive information, for a range of clinical outcomes, to that provided by simple demographic, clinical, and biochemical measures. ApoA-1 was more predictive than LDL or HDL.

Rosuvastatin in older patients with systolic heart failure.

BACKGROUND: Patients with systolic heart failure have generally been excluded from statin trials. Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients. METHODS: A total of 5011 patients at least 60 years of age with New York Heart Association class II, III, or IV ischemic, systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per day. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included death from any cause, any coronary event, death from cardiovascular causes, and the number of hospitalizations. RESULTS: As compared with the placebo group, patients in the rosuvastatin group had decreased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P<0.001) and of high-sensitivity C-reactive protein (difference between groups, 37.1%; P<0.001). During a median follow-up of 32.8 months, the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.83 to 1.02; P=0.12), and 728 patients and 759 patients, respectively, died (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.31). There were no significant differences between the two groups in the coronary outcome or death from cardiovascular causes. In a prespecified secondary analysis, there were fewer hospitalizations for cardiovascular causes in the rosuvastatin group (2193) than in the placebo group (2564) (P<0.001). No excessive episodes of muscle-related or other adverse events occurred in the rosuvastatin group. CONCLUSIONS: Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. The drug did not cause safety problems. (ClinicalTrials.gov number, NCT00206310.)

Economic implications of extended-release metoprolol succinate for heart failure in the MERIT-HF trial: a US perspective of the MERIT-HF trial.

BACKGROUND: The MERIT-HF trial demonstrated improved survival and fewer hospitalizations for worsening heart failure with extended-release (ER) metoprolol succinate in patients with heart failure. This study sought to estimate the economic implications of this trial from a US perspective. METHODS AND RESULTS: A discrete event simulation was developed to examine the course of patients with heart failure. Characteristics of the population modeled, probabilities of hospitalization and death with standard therapy, and risk reductions with ER metoprolol succinate were obtained from Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) and evaluated in weekly cycles. Direct medical costs were estimated from US databases in 2001 US dollars. Uncertainty in inputs was incorporated and analyses were carried out to estimate events prevented total and net costs. The model predicts that ER metoprolol succinate will prevent approximately 7 deaths and 15 hospitalizations from heart failure per 100 patients over 2 years. Compared with standard therapy alone, this translates to a cost reduction between $395 and $1112 per patient, depending on whether the costs of hospitalizations for other causes are included. Savings were maintained in 90% of the simulations. CONCLUSION: This analysis predicts that the positive effect of ER metoprolol succinate on mortality and morbidity demonstrated in MERIT-HF leads to substantial savings.