The Chronic Kidney Disease Epidemiology Collaboration equation outperforms the Modification of Diet in Renal Disease equation for estimating glomerular filtration rate in chronic systolic heart failure.

AIMS: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula estimates glomerular filtration rate (GFR) better than the simplified Modification of Diet in Renal Disease (sMDRD) formula in numerous populations. It has not previously been validated in heart failure patients. METHODS AND RESULTS: The GFR was measured in 120 patients with chronic systolic heart failure (CHF) using [(125)I]iothalamate clearance (GFR(IOTH)) and estimated using the sMDRD and CKD-EPI equations. Accuracy, bias, and prognostic performance were compared. Cockcroft-Gault, CKD-EPI serum cystatin C, and CKD-EPI creatinine-serum cystatin C equations were compared in secondary analyses. Mean age was 59 ± 12 years, 80% were male. Mean LVEF was 29 ± 10%. Mean GFR(IOTH) was 74 ± 27 mL/min/1.73 m(2), and mean estimated GFR was 66 ± 23 mL/min/1.73 m(2) (CKD-EPI) and 63 ± 21 mL/min/1.73m(2) (sMDRD). CKD-EPI showed less bias than sMDRD (-8 ± 15 vs. -11 ± 16 mL/min/1.73 m(2), P < 0.001). Both equations underestimate at higher and overestimate at lower GFR(IOTH). Eleven patients (9%) were accurately reclassified into lower CKD classes with CKD-EPI. Cockcroft-Gault showed lower bias (-3 ± 16 mL/min/1.73 m(2)) but worse precision and accuracy. Cystatin C-based estimation showed the lowest bias (-3 ± 14 mL/min/1.73 m(2)) and the best precision and accuracy. Prognostic value did not differ between all GFR estimates CONCLUSION: The CKD-EPI equation more accurately estimates measured GFR than the sMDRD equation in CHF patients, with less bias and greater accuracy and precision. The prognostic power of all GFR assessments was equivalent. Based on better performance and equal risk prediction, we believe the CKI-EPI equation should be the preferred creatinine-based GFR estimation method in heart failure patients, particularly those with preserved or moderately impaired renal function.

Urinary proteins in heart failure.

Renal insufficiency is common in patients with heart failure (HF), with both acute kidney injury and worsening renal function being associated with poor prognosis. The interplay between cardiac and renal failure has been termed the cardiorenal syndrome and is currently the subject of intense investigation. Urinary biochemistry has several advantages over blood or serum analyses, including lower costs, better patient comfort, and higher sensitivity to renal injury. However, urinalysis is currently not part of routine daily practice in cardiology. Recent advances in proteomics have allowed identification of numerous novel urinary biomarkers, many of which show promise in HF populations. In this review, we aim to provide an overview of both traditional and novel urinary biomarkers, examining evidence for diagnostic and prognostic value in HF as well as potential clinical utility.

Long-term impact of secondary preventive treatments in patients with stable angina.

We assessed the independent effects of beta blockers, calcium antagonists, lipid-lowering drugs, angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), anti-platelet drugs, vitamin K antagonists, percutaneous coronary intervention (PCI) and coronary artery by-pass grafting (CABG) on mortality and on the composite endpoint of death, myocardial infarction, stroke or heart failure in patients with stable angina pectoris. We estimated the effects of the interventions used at baseline by multivariate Cox regression and during follow-up by G-estimation in 7,665 patients followed for a mean of 5 years in the ACTION trial. Adjusted hazard ratios (95% confidence intervals) comparing all cause mortality among users during follow-up to non-users were 1.01 (0.91, 1.09) for beta blockade, 0.82 (0.75, 0.89) for ACEIs or ARBs, 0.93 (0.87, 0.98) for calcium antagonists, 0.54 (0.49, 0.62) for lipid-lowering drugs, 0.49 (0.42, 0.53) for anti-platelet drugs, 0.74 (0.69, 0.78) for PCI, and 0.91 (0.82, 0.98) for CABG. Effects on the composite endpoint were less marked. This observational study confirms that ACEIs or ARBs, lipid-lowering and anti-platelet drugs as used in the everyday management of stable angina have independent secondary preventive effects. Calcium antagonists, PCI and CABG also appear to improve outcome.

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.

Effects of rosuvastatin on coronary flow reserve and metabolic mismatch in patients with heart failure (from the CORONA Study).

In patients with heart failure (HF), statin treatment might improve myocardial perfusion, but could also have detrimental effects on myocardial metabolism. A predefined substudy of the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) trial sought to determine the effects of statin treatment on myocardial blood flow reserve and cardiac metabolism. Sixteen patients with HF (New York Heart Association class II or III) were randomized to rosuvastatin 10 mg/day (n = 8) or placebo treatment (n = 8). At baseline and after 6 months of treatment, nitrogen-13 ammonia at rest and after dipyridamole stress and 18-fluorodeoxyglucose positron emission tomography were performed. Rosuvastatin treatment significantly lowered total (-36%, p <0.01) and low-density lipoprotein (-47%, p <0.001) cholesterol and C-reactive protein levels (-36%, p <0.05). Myocardial perfusion reserve (ratio) changed from 1.64 +/- 0.90 to 1.30 +/- 0.37 in placebo-treated and from 1.51 +/- 0.18 to 1.55 +/- 0.34 in rosuvastatin-treated patients (p = NS). Metabolic mismatch changed from 4.25 +/- 2.37% to 4.38 +/- 3.81% in placebo-treated and from 5.13 +/- 2.75% to 3.50 +/- 2.73% in rosuvastatin-treated patients (p = NS). In conclusion, changes regarding myocardial perfusion and metabolic mismatch after 6 months of rosuvastatin treatment in patients with HF did not suggest any beneficial or adverse effects in this pilot study, although due to the small numbers of patients small effects might have been missed.

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.

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.

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.

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.

Effect of moderate or intensive disease management program on outcome in patients with heart failure: Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH).

BACKGROUND: Heart failure (HF) disease management programs are widely implemented, but data about their effect on outcome have been inconsistent. METHODS: The Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) was a multicenter, randomized, controlled trial in which 1023 patients were enrolled after hospitalization because of HF. Patients were assigned to 1 of 3 groups: a control group (follow-up by a cardiologist) and 2 intervention groups with additional basic or intensive support by a nurse specializing in management of patients with HF. Patients were studied for 18 months. Primary end points were time to death or rehospitalization because of HF and the number of days lost to death or hospitalization. RESULTS: Mean patient age was 71 years; 38% were women; and 50% of patients had mild HF and 50% had moderate to severe HF. During the study, 411 patients (40%) were readmitted because of HF or died from any cause: 42% in the control group, and 41% and 38% in the basic and intensive support groups, respectively (hazard ratio, 0.96 and 0.93, respectively; P = .73 and P = .52, respectively). The number of days lost to death or hospitalization was 39 960 in the control group, 33 731 days for the basic intervention group (P = .81), and 34 268 for the intensive support group (P = .49). All-cause mortality occurred in 29% of patients in the control group, and there was a trend toward lower mortality in the intervention groups combined (hazard ratio, 0.85; 95% confidence interval, 0.66-1.08; P = .18). There were slightly more hospitalizations in the 2 intervention groups (basic intervention group, P = .89; and intensive support group, P = .60). CONCLUSIONS: Neither moderate nor intensive disease management by a nurse specializing in management of patients with HF reduced the combined end points of death and hospitalization because of HF compared with standard follow-up. There was a nonsignificant, potentially relevant reduction in mortality, accompanied by a slight increase in the number of short hospitalizations in both intervention groups. Clinical Trial Registry http://trialregister.nl Identifier: NCT 98675639.

The efficacy of statin monotherapy uptitration versus switching to ezetimibe/simvastatin: results of the EASEGO study.

OBJECTIVE: To assess the incremental low-density lipoprotein-cholesterol (LDL-C) lowering efficacy of doubling the statin dose or switching to the ezetimibe/simvastatin 10/20 mg combination tablet (EZE/SIMVA) in patients on simvastatin 20 mg or atorvastatin 10 mg not at LDL-C target < 2.5 mmol/L. STUDY DESIGN AND METHODS: Patients with documented coronary heart disease (CHD) and/or type 2 diabetes (DM2) with LDL-C > or = 2.5 and < 5.0 mmol/L despite treatment with atorvastatin 10 mg or simvastatin 20 mg were randomized to (1) double statin dose or (2) switch to ezetimibe/simvastatin 10/20, according to a PROBE study design. LDL-C, lipoprotein subfractions and safety data were assessed during the study. RESULTS: 119 of 178 (67%) patients in the EZE/SIMVA group and 49 of 189 (26%) in the doubling statin group reached target LDL-C < 2.5 mmol/L. The odds ratio of success for EZE/SIMVA versus doubling statin treatment in reaching the LDL-C target of < 2.5 mmol/L was 5.7 (95% CI: 3.7-9.0, p < 0.0001). A reduction in total cholesterol (TC), total/high density lipoprotein (HDL) cholesterol ratio and apolipoprotein B was observed in both groups, but this reduction was significantly more pronounced in the EZE/SIMVA group as compared with the doubling statin dose group. Treatment was well tolerated and no difference was observed between the two groups with regard to adverse effects. CONCLUSIONS: In CHD/DM2 patients treated with simvastatin or atorvastatin with LDL-C persistently > or = 2.5 mmol/L, switching to the EZE/SIMVA was more effective in attaining the LDL-C target of < 2.5 mmol/L than doubling the statin dose.

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.)

Nifedipine Gastrointestinal Therapeutic System (GITS) in the treatment of coronary heart disease and hypertension.

Since the 1960s, calcium antagonists have been available for the treatment of angina pectoris and hypertension. The first of this class, nifedipine, was introduced and readily accepted as the third treatment option for angina, alongside beta-blockers and nitrates. However, the short-acting formulations of nifedipine had pharmacokinetic properties that were far from ideal and in 1995, several studies involving various dosing regimens reported possible dangerous effects in secondary prevention. Since then, large-scale, randomized controlled trials with new controlled-released formulations of nifedipine have demonstrated the effectiveness and safety of this drug. As a consequence of these results, guidelines for both hypertension and angina pectoris have been recently reconsidered, and have put the modern formulations of calcium channel blockers in a pole position. Within this group of therapeutics, nifedipine gastrointestinal therapeutic system has a unique position and it cannot be replaced by other controlled-release formulations of nifedipine, the pharmaceutical properties of which have yet to be tested in large-scale outcome trials.

Resource utilization implications of treatment were able to be assessed from appropriately reported clinical trial data.

BACKGROUND AND OBJECTIVE: Published clinical trial data rarely allow assessment of the health care resource utilization implications of treatment. We give an example of how these can be assessed given appropriate tabulation of data. METHODS: Data from a trial comparing long-acting nifedipine gastrointestinal therapeutic system to placebo in 7,665 patients with stable angina pectoris was analyzed. RESULTS: Relative to placebo, nifedipine significantly increased mean cardiovascular (CV) event-free survival by 41 days but had no effect on mean survival. Per 100 years of follow-up, 78.1 patient-years of double-blind nifedipine administration reduced use of another calcium antagonist, an angiotensin converting enzyme inhibitor, an angiotensin receptor blocker, a diuretic and a cardiac glycoside by 1.54, 3.73, 2.63, 2.23, and 0.64 years, respectively, whereas 0.21 less hospitalization for overt heart failure, 0.47 less hospitalization for any stroke or transient ischemic attack, 0.8 less coronary angiogram, 0.38 less coronary bypass procedure, and 0.13 additional orthopedic procedure was required. Combining resource utilization with cost data for one particular hospital showed that one additional year of CV event-free survival costs an average additional euro 3,036 in the setting considered. CONCLUSION: Appropriately tabulated clinical trial data allows clinicians to judge the resource utilization implications and economic effect of treatment decisions.

Clinical course of isolated stable angina due to coronary heart disease.

AIMS: To describe the clinical course of patients with stable angina due to coronary heart disease without a history of cardiovascular (CV) events or revascularization (isolated angina). METHODS AND RESULTS: Of 7,665 patients in a trial comparing long-acting nifedipine with placebo, 2170 (28%) had isolated angina. During a mean follow-up of 4.9 years, 147 of these died (1.4/100 patient-years), while 761 (8.7/100 patient-years) either died, or had a cardiac event or procedure. The first event was death in 82, myocardial infarction or heart failure in 112, coronary revascularization in 171, and chest pain requiring hospitalization in 396. Six hundred and twelve patients (6.8/100 patient-years) underwent coronary angiography (CAG), followed by revascularization in 371. Sixty-eight of 262 deaths or major cardiac events were preceded by chest pain requiring hospitalization or revascularization. Event-rates after CAG were higher than before. The stroke rate was 0.7/100 patient-years (75 patients). CONCLUSION: Patients with stable isolated angina have low rates of death and major cardiac events, but relatively high rates of chest pain requiring hospitalization despite contemporary management. Since the majority of deaths and major CV clinical events are not preceded by clear warning symptoms, the main clinical implication is that measures to prevent such events must target all patients.

Diagnostic criteria and adjudication process both determine published event-rates: the ACTION trial experience.

OBJECTIVE: Few trials report event-adjudication procedures in detail. Using data from the ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS) study, we compared the impact on event-rates of an adjudication strategy based on systematic screening of all reported serious adverse events (SAEs) with a strategy based on investigator diagnoses. The final diagnosis was always made by a critical events committee (CEC) using standard criteria. METHODS: ACTION randomized 7665 patients with stable angina to either nifedipine or placebo. Pre-specified events included acute or procedural myocardial infarction (MI), refractory angina, heart failure and debilitating stroke. Clinically related SAEs including in-hospital procedures were combined into episodes independent from the investigator diagnoses entered on SAE reports. All fatal episodes and those episodes suggestive of pre-specified events were adjudicated by the CEC. RESULTS: During follow-up, 17,081 episodes were reported in 5312 patients. The SAE descriptions ruled out the occurrence of a pre-specified event in 28%. The remaining 72% were adjudicated by the CEC and 616 cases of MI, 361 of refractory angina, 275 of heart failure and 190 of debilitating stroke were diagnosed (total=1442). Had adjudication by the CEC been limited to the 3924 episodes (2397 patients) that were fatal or for which the investigator had reported any of the diagnoses mentioned, 98 cases of MI, 35 of refractory angina, 81 of heart failure and 14 of debilitating stroke would have been missed (total=228). CONCLUSION: Both the diagnostic criteria used and the adjudication process determine event-rates and conclusions about treatment effects in clinical trials. Published trial reports should always state if event-adjudication was independent of the diagnoses of investigators, and if all events of interest were adjudicated or only the first one.

Presence and development of atrial fibrillation in chronic heart failure. Experiences from the MERIT-HF Study.

BACKGROUND: Atrial fibrillation is common in heart failure, but data regarding beta-blockade in these patients and its ability to prevent new occurrence of atrial fibrillation are scarce. METHODS: Baseline ECGs in MERIT-HF were coded regarding baseline rhythm, and outcome was analyzed in relation to rhythm. Occurrence of atrial fibrillation during follow-up was also analyzed. RESULTS: At baseline atrial fibrillation was diagnosed in 556 patients (13.9%). Mean metoprolol CR/XL dose in patients in atrial fibrillation (154 mg) and sinus rhythm (158 mg) was similar, as well as decrease in heart rate (14.8 and 13.7 bpm, respectively). Only 61 (total of 362) deaths occurred in those in atrial fibrillation at baseline, 31 on placebo and 30 on metoprolol (RR 1.0; 95% CI 0.61-1.65). During follow-up, new atrial fibrillation was observed in 85 patients on placebo and 47 patients on metoprolol (RR 0.53; 95% CI 0.37-0.76; p=0.0005). CONCLUSION: First, given the wide confidence interval, it was impossible to detect an interaction between metoprolol and mortality in patients with atrial fibrillation and heart failure. Second, in patients with sinus rhythm at baseline, metoprolol reduced the incidence of atrial fibrillation during follow-up. However, we must be extremely cautious in over-interpreting effects in these subgroups.

LDL-C/HDL-C ratio in subjects with cardiovascular disease and a low HDL-C: results of the RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study.

BACKGROUND: The ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (LDL-C/HDL-C) is a reliable predictor of cardiovascular risk. Low HDL-C levels in patients with coronary artery disease are associated with a high risk for cardiovascular events. OBJECTIVES: This study compared the effects of rosuvastatin and atorvastatin on the LDL-C/HDL-C. METHODS: Patients aged 40-80 years with established cardiovascular disease and HDL-C < 1.0 mmol/L (< 40 mg/dL) entered as a 6-week dietary run-in period, before randomisation to open-label treatment with rosuvastatin 10 mg (n = 230) or atorvastatin 20 mg (n = 231) for 6 weeks. Doses were increased after 6 weeks to rosuvastatin 20 mg or atorvastatin 40 mg, and after 12 weeks to rosuvastatin 40 mg or atorvastatin 80 mg. Serum lipid parameters were measured at baseline and 6, 12 and 18 weeks. RESULTS: After 6 weeks of treatment, mean percentage change from baseline in LDL-C/HDL-C ratio was -47.0% in the rosuvastatin group and -41.9% in the atorvastatin group (p < 0.05 for between-group comparison). After 12 and 18 weeks of treatment, change from baseline was -53.0% and -57.3%, respectively, for rosucastatin, compared with -47.9% and -49.6%, respectively, for atorvastatin (p < 0.01 and p < 0.001, respectively, for between-group comparison). Rosuvastatin also reduced LDL-C, total cholesterol/HDL-C significantly more than atorvastatin at all three time points, and significantly improved total cholesterol/HDL-C and apolipoprotein B/A-I ratios. CONCLUSIONS: Rosuvastatin 10, 20 and 40 mg is significantly more effective than atorvastatin 20, 40 and 80 mg, respectively, in improving the LDL-C/HDL-C ratio in patients with cardiovascular disease and low HDL-C. Further studies are required to clarify the benefits of rosuvastatin for reduction of cardiovascular risk.