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The low-density lipoprotein (LDL) cholesterol goal of <70 mg/dl, recommended for patients with acute coronary syndrome, typically requires intensive therapy with high-dose statins. The secondary goals of nonLhigh-density lipoprotein (non-HDL) cholesterol <100 mg/dl and apolipoprotein B (ApoB) <80 mg/dl have been recommended to reduce excess cardiovascular risk not captured by LDL cholesterol. The present post hoc analysis from the Limiting UNdertreatment of lipids in Acute coronary syndrome with Rosuvastatin (LUNAR) study examined the relation of ApoB with LDL cholesterol and non-HDL cholesterol at baseline and during treatment with intensive statin therapy. The LUNAR participants had acute coronary syndrome and received rosuvastatin 40 mg/day or 20 mg/day or atorvastatin 80 mg/day for 12 weeks. Linear regression analyses were used to compare ApoB, direct LDL cholesterol, and non-HDL cholesterol at baseline and during therapy. Of the 682 patients included in the analysis, 220 had triglycerides ≥200 mg/dl. Linear regression analysis showed that correlation of ApoB and non-HDL cholesterol was stronger than that of ApoB and LDL cholesterol and stronger with statin therapy than at baseline (R² = 0.93 for ApoB vs non-HDL cholesterol with statins). The target of ApoB of 80 mg/dl correlated with LDL cholesterol of 90 mg/dl and non-HDL cholesterol of 110 mg/dl at baseline and with LDL cholesterol of 74 mg/dl and non-HDL cholesterol of 92 mg/dl with statin therapy. For high-triglyceride patients, the corresponding on-treatment targets were LDL cholesterol of 68 mg/dl and non-HDL cholesterol of 92 mg/dl. In conclusion, non-HDL cholesterol is an adequate surrogate of ApoB during statin therapy, independent of triglyceride status. However, to match LDL cholesterol and ApoB treatment goals in the very-high-risk category, the current non-HDL cholesterol goal should be lowered by 8 to 10 mg/dl. [ABSTRACT FROM AUTHOR]

Patients with acute coronary syndrome are recommended for early aggressive low-density lipoprotein (LDL) cholesterol–lowering therapy. The LUNAR study compared the efficacy of rosuvastatin with that of atorvastatin in decreasing LDL cholesterol in patients with acute coronary syndrome. Adult patients with coronary artery disease who were hospitalized for an acute coronary syndrome within 48 hours of first symptoms were randomized (n = 825) to an open-label, once-daily treatment with rosuvastatin 20 mg (RSV20), rosuvastatin 40 mg (RSV40), or atorvastatin 80 mg (ATV80) for 12 weeks. Patients were evaluated at weeks 2, 6, and 12. The primary end point was treatment efficacy in lowering LDL cholesterol averaged over 6 to 12 weeks. Changes in other lipoproteins, including high-density lipoprotein (HDL) cholesterol, and safety were evaluated. Analysis of covariance was used to compare least squares mean differences between each rosuvastatin treatment arm and the atorvastatin arm. The efficacy of RSV40 in lowering LDL cholesterol was significantly greater than that of ATV80 (46.8% vs 42.7% decrease, p = 0.02). LDL cholesterol lowering by RSV20 was similar to that by ATV80. Increases in HDL cholesterol were significantly greater with RSV40 (11.9%, p <0.001) and RSV20 (9.7%, p <0.01) than with ATV80 (5.6%). RSV40 was also significantly more effective than ATV80 in improving most other secondary efficacy variables, whereas the effects of RSV20 on these parameters were generally similar to those of ATV80. All 3 treatments were generally well tolerated over 12 weeks. In conclusion, results from the LUNAR study show that RSV40 more effectively decreased LDL cholesterol, increased HDL cholesterol, and improved other blood lipid parameters than ATV80 in patients with acute coronary syndrome. [ABSTRACT FROM AUTHOR]

The associations of a history of hypertension with subsequent outcomes after acute myocardial infarction have not been examined in propensity-matched studies. Of the 6,632 patients with acute myocardial infarctions and left ventricular systolic dysfunction in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), 4,407 had histories of hypertension. Propensity scores for a history of hypertension, estimated for each patient using 64 baseline characteristics, were used to match 1,990 pairs of patients with and without hypertension. Matched Cox regression models were used to estimate associations between hypertension and outcomes during a mean of 16 months of follow-up. Heart failure (HF) hospitalization occurred in 11.9% and 8.8% of patients, respectively, with and without hypertension (hazard ratio [HR] for hypertension vs no hypertension 1.36, 95% confidence interval [CI] 1.10 to 1.68, p = 0.004). The association between a history of hypertension and HF hospitalization was significant only in patients without previous HF (n = 3,495, HR 1.48, 95% CI 1.18 to 1.84, p = 0.001), but not in those with previous HF (n = 485, HR 1.09, 95% CI 0.73 to 1.62, p = 0.688, p for interaction = 0.179). A history of hypertension was not associated with all-cause mortality (HR 1.02, 95% CI 0.86 to 1.22, p = 0.790) or cardiovascular hospitalization (HR 1.08, 95% CI 0.92 to 1.27, p = 0.339). In conclusion, a history of hypertension was associated with subsequent HF hospitalization after acute myocardial infarction, especially in patients without histories of HF, suggesting that hypertension increased the risk for hospitalization with incident HF but did not affect hospitalization for worsening HF symptoms in those with prevalent HF. [Copyright &y& Elsevier]

Although angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and β-blockers have been proved to reduce mortality in patients with heart failure post–acute myocardial infarction (AMI), studies show that these agents are consistently underused in this population. Further, morbidity and mortality remain high even when standard-of-care therapies are applied. Thus, new strategies have been sought to better counteract the maladaptive effects of neurohormonal stimulation in post-AMI heart failure. The Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone, when used in addition to standard therapy, results in significant incremental improvements in survival and morbidity and is safe and well tolerated in this setting. Based on this, major therapeutic guidelines in the United States and Europe now strongly recommend that all eligible patients with concomitant heart failure post-AMI be treated with an aldosterone blocker in addition to an ACE inhibitor (or an ARB) and a β-blocker. To achieve needed improvements in outcomes in this population, early and consistent initiation of these evidence-based, guideline-recommended therapies in all eligible patients is crucial. [Copyright &y& Elsevier]

Angiotensin-converting enzyme inhibitors improve endothelial function, inhibit experimental atherogenesis, and decrease ischemic events. The Quinapril Ischemic Event Trial was designed to test the hypothesis that quinapril 20 mg/day would reduce ischemic events (the occurrence of cardiac death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary artery bypass grafting, coronary angioplasty, or hospitalization for angina pectoris) and the angiographic progression of coronary artery disease in patients without systolic left ventricular dysfunction. A total of 1,750 patients were randomized to quinapril 20 mg/day or placebo and followed a mean of 27 +/- 0.3 months. The 38% incidence of ischemic events was similar for both groups (RR 1.04; 95% confidence interval 0.89 to 1.22; p = 0.6). There was also no significant difference in the incidence of patients having angiographic progression of coronary disease (p = 0.71). The rate of development of new coronary lesions was also similar in both groups (p = 0.35). However, there was a difference in the incidence of angioplasty for new (previously unintervened) vessels (p = 0.018). Quinapril was well tolerated in patients after angioplasty with normal left ventricular function. Quinapril 20 mg did not significantly affect the overall frequency of clinical outcomes or the progression of coronary atherosclerosis. However, the absence of the demonstrable effect of quinapril may be due to several limitations in study design. [ABSTRACT FROM AUTHOR]

Studies the clinical and angiographic characteristics of patients undergoing a Quinapril Ischemic Event Trial (QUIET). Purpose of QUIET; Therapeutic effects of quinapril; Utilization of angiotensin-converting enzyme inhibition in the treatment of left ventricular systolic dysfunction.

The article focuses on a study on impact of angiotensin II-receptor blockers (ARBs) on hypertension and heart failure treatment. Topics discussed include angiotensin-converting enzyme (ACE) inhibitors' impact on renin-angiotensin system, angiotensin II type 1 (AT1) receptors activation by ARBs, bradykinin degradation regulated by angiotensin II and ARBs, blood pressure-lowering effect associated with ARBs and the ACE inhibitor Enalapril and angiotensin II effect blocked by the AT1 receptor.

Post hoc analyses of the Digitalis Investigation Group (DIG) trial indicate that digoxin at low (0.5 to 0.9 ng/ml) serum digoxin concentration (SDC) reduces mortality, which is eliminated at higher (≥1 ng/ml) SDC, and that low-dose digoxin (≤0.125 mg/day) predicts low SDC. In the DIG trial, patients with ambulatory chronic systolic and diastolic heart failure (HF) (n = 7,788) in normal sinus rhythm receiving angiotensin-converting enzyme inhibitors and diuretics were randomized to receive placebo (n = 3,899) or digoxin (n = 3,889). The median dose of digoxin (0.25 mg/day) and the target SDC (0.8 to 2.5 ng/ml) were higher than what are currently recommended, which in part may explain the lack of long-term mortality benefit of digoxin in the DIG trial. To test this hypothesis, we examined the effect of digoxin on short-term outcomes; 1-year all-cause mortality occurred in 392 and 448 patients respectively in the digoxin and placebo groups (hazard ratio for digoxin 0.87, 95% confidence interval [CI] 0.76 to 0.995, p = 0.043). Respective hazard ratios for cardiovascular and HF deaths were 0.87 (95% CI 0.76 to 1.01, p = 0.072) and 0.66 (95% CI 0.52 to 0.85, p = 0.001). All-cause hospitalization occurred in 1,411 and 1,529 patients receiving digoxin and placebo respectively (hazard ratio 0.89, 95% CI 0.83 to 0.96, p = 0.002). Respective hazard ratios for cardiovascular and HF hospitalizations were 0.82 (95% CI 0.75 to 0.89, p <0.0001) and 0.59 (95% CI 0.52 to 0.66, p <0.0001). In conclusion, digoxin reduced 1-year mortality and hospitalization in patients with chronic HF receiving angiotensin-converting enzyme inhibitors and diuretics. Randomized clinical trials are needed to determine the effect of low-dose digoxin in contemporary patients with chronic HF. [Copyright &y& Elsevier]

Heart failure continues to significantly impact morbidity and mortality after acute myocardial infarction (AMI), especially when associated with left ventricular systolic dysfunction (LVSD). Therefore, routine use of optimal therapy for patients with heart failure after AMI is needed in the future. Data from the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) has demonstrated that addition of eplerenone to standard therapy in patients with LVSD and clinical heart failure post-AMI significantly improves outcomes in these patients, providing the basis for acceptance of aldosterone blockade as an integral component of therapy. However, further studies are needed to more broadly explore the usefulness of aldosterone blockade in heart failure therapy. As research clarifies the many complex pathophysiologic processes involved in post-AMI remodeling, treatment should continue to move beyond symptom-targeted therapies to disease- and mechanism-targeted therapies that will further improve outcomes in the setting of heart failure post-AMI and beyond. [Copyright &y& Elsevier]

The aim of our study is to investigate the effect of spironolactone on 30-day outcomes in patients with acute heart failure (AHF) and the association between treatment and outcomes stratified by biomarkers. We conducted a secondary analysis of the biomarker substudy of the multicenter COACH (Co-ordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure) trial involving 534 AHF patients for 30-day mortality and HF rehospitalizations. Spironolactone therapy was initiated and terminated at the discretion of the treating physician; 30-day outcomes were compared between patients who were treated with spironolactone and those who were not. Outcomes with spironolactone therapy were explored based on N-terminal proeB-type natriuretic peptide, ST2, galectin-3, and creatinine levels. Spironolactone was prescribed to 297 (55.6%) patients at discharge (158 new and 139 continued). There were 19 deaths and 30 HF rehospitalizations among 46 patients by 30 days. Patients discharged on spironolactone had significantly less 30-day event (hazard ratio 0.538, p[0.039) after adjustment for multiple risk factors. Initiation of spironolactone in patients who were not on spironolactone before admission was associated with a significant reduction in event rate (hazard ratio 0.362, p[0.027). The survival benefit of spironolactone was more prominent in patient groups with elevations of creatinine, N-terminal proeB-type natriuretic peptide, ST2, or galectin-3. In conclusion, AHF patients who received spironolactone during hospitalization had significantly fewer 30-day mortality and HF rehospitalizations, especially in high-risk patients. [ABSTRACT FROM AUTHOR]

Combination therapy with benazepril 40 mg and amlodipine 10 mg (BDA) has been shown to be more effective than benazepril 40 mg and hydrochlorothiazide (HCTZ) 25 mg (BDH) in reducing cardiovascular (CV) events in high-risk patients with stage 2 hypertension with similar blood pressure reductions. In the present post hoc analysis, we evaluated whether BDA is more effective than BDH for reducing CV events in patients with known coronary artery disease (CAD) at baseline in a subgroup analysis of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) study. The main trial randomized 11,506 patients. Of those, 5,744 received BDA and 5,762 received BDH. Of the 11,506 patients, 5,314 (46%) were classified as having CAD at baseline. The mean patient follow-up period was 35.7 months for the BDA group and 35.6 months for the BDH group. The primary end point was the interval to the first event of composite CV morbidity and mortality. At baseline, significant differences were present between the 5,314 with CAD and the 6,192 without CAD. The patients with CAD had a lower systolic blood pressure and heart rate, a lower incidence of diabetes, and greater incidence of dyslipidemia. However, no baseline differences were found between the randomized BDA and BDH groups. In the patients with CAD, an 18% reduction occurred in the hazard ratio for CV events (primary end point) with BDA versus BDH (p [ 0.0016). In a prespecified secondary analysis of the composite end point, including only CV death, myocardial infarction, and stroke, the hazard ratio in the patients with CAD was reduced by 25% (p[0.0033) in the BDA group compared with the BDH group. BDA was more effective than BDH at comparable blood pressure reductions for reducing CV events in patients, regardless of the presence of CAD. In conclusion, our findings suggest that the combination of BDA should be preferentially used for older patients with high-risk, stage 2 hypertension. [ABSTRACT FROM AUTHOR]

Angiotensin receptor blockers have been hypothesized to have synergistic effects with statins. We evaluated the effects of valsartan alone or combined with simvastatin on blood pressure (BP) and indexes of inflammation and oxidant stress in hypertensive patients with hyperlipidemia. In this double-blind trial, 404 patients were randomized to 12 weeks valsartan 160 mg (V) or valsartan 160 mg plus simvastatin 20 mg (V/S20) or 80 mg (V/S80). Twenty-four–hour mean ambulatory BP and biochemical marker measurements were recorded at baseline and study end. There were no statistically significant between-treatment differences for least-square mean reductions from baseline in systolic BP (V, −9.22; V/S20, −9.25; V/S80, −9.58 mm Hg; p <0.0001 for all within-treatment changes vs baseline). Plasma high-sensitivity C-reactive protein decreased with the combinations but not with V alone (least-square mean median change from baseline, −0.16, −0.20, −0.70 mg/L; p = 0.0001 for V/S80 vs baseline; p = 0.045 for V/S20 vs baseline; p = 0.0023 for V/S80 vs V/S20; p = 0.0045 for V/S80 vs V). Monocyte chemoattractant protein–1 was reduced by V, with no evidence for additional lowering with V/S combinations. In conclusion, addition of simvastatin to valsartan did not incrementally lower BP. However, V/S80 was superior to V and V/S20 in reducing high-sensitivity C-reactive protein. [Copyright &y& Elsevier]

The myocardial contractile protein myosin light chain 1 isoform (MLC-1) is released into the circulation during myocyte necrosis and could thus be a marker of low-grade myocardial damage and of poor prognosis in patients with heart failure. Two hundred eighteen patients with stable heart failure (ejection fraction [EF] <35%) and in New York Heart Association (NYHA) class III to IV had MLC-1 measured at baseline and 1 month after being randomized to the direct vasodilator flosequinan or placebo. Patients were followed a mean of 302 ± 142 days. The prognostic value of an increase in MLC-1 above the 98th percentile of normal controls was compared with that of conventional prognostic variables in heart failure. MLC-1 was increased in over half of patients at baseline and 1 month, and this was associated with increased age, NYHA class IV, and renal insufficiency. By Kaplan-Meier survival analysis, patients with a baseline increase in MLC-1 had a greater mortality (26%) than those without an increase (15%) (p = 0.043). A significant interaction among MLC-1, survival, and treatment was found (p = 0.043). In the placebo group, MLC-1 was associated with increased mortality (29% vs 12%, p = 0.025), whereas there was no significant difference among patients receiving flosequinan. In a multivariate logistic regression model including age, treatment, and left ventricular (LV) ejection fraction, the MLC-1 chain was most predictive of mortality (p = 0.049). Thus, circulating MLC-1 is elevated in over half of patients with stable severe heart failure, and this increase is associated with a poor prognosis. Flosequinan treatment eliminates this association, highlighting the complexity of the relation between cardiac myocyte damage, drug treatment, and mortality. [Copyright &y& Elsevier]

Aging is associated with progressive deterioration in endothelial function. We hypothesized that losartan may represent a useful therapeutic strategy to ameliorate endothelial function in aged subjects. Eighteen healthy older subjects (mean age 75 ± 3 years) were prospectively randomized in a double-blind, crossover fashion to receive either losartan 50 mg/day or placebo for 6 weeks. Subjects were switched to the opposite arm after a 2- week washout period. Flow-mediated dilation (FMD) in the brachial artery and plasma levels of vascular cell adhesion molecule-1, intercellular adhesion molecule (ICAM), moncocyte chemoattractant 1 protein, and E-selectin were measured in both arms at the beginning and end of the 6-week period. Losartan resulted in a 6-mm Hg decrease in systolic blood pressure (from 130 ± 12 to 124 ± 13 mm Hg), which was no different from placebo (132 ± 12 to 127 ± 13 mm Hg). FMD increased from 3.1 ± 0.6% to 3.9 ± 0.6% after losartan, and decreased from 3.3 ± 0.3% to 2.4 ± 0.6% after placebo (p = NS for both). In contrast, losartan reduced circulating concentrations of vascular cell adhesion molecule 1 (750 ± 73 to 572 ± 39), ICAM (405 ± 26 to 196 ± 10), and moncocyte chemoattractant 1 protein (560 ± 56 to 423 ± 35) (p <0.01 for all by analysis of variance), but not E-selectin. On univariate analyses, the strongest predictor of baseline endothelial function and change in FMD with losartan was low-density lipoprotein. There was a negative correlation between baseline endothelial function and change in FMD in response to losartan (r2 = −0.75, p = 0.0003). Baseline ICAM levels alone significantly correlated with low-density lipoprotein cholesterol (r2 = 0.54, p = 0.02) and weakly correlated with total cholesterol (r2 = 0.47, p = 0.05). Thus, administration of losartan for a duration of 6 weeks has favorable effects on inflammatory markers in healthy older subjects, but does not alter peripheral conduit endothelial function. [Copyright &y& Elsevier]

Depressive illness in patients without traditional risk factors for coronary artery disease is associated with striking abnormalities of endothelial function and elevation of circulating markers of atherosclerosis propensity. Further studies are needed to define the mechanisms that underlie these observations. [ABSTRACT FROM AUTHOR]

Arterial stiffness, as evidenced by increased pulse pressure (PP), is associated with adverse cardiovascular events. However, the prognostic importance of PP in patients who have undergone revascularization is unknown. We examined the prognostic importance of PP and predictors of increased PP in patients entered into the Balloon Angioplasty Revascularization Investigation (BARI). Estimated correlation and standardized regression coefficients were reported, indicating the relative magnitude of independent effects of baseline characteristics on PP. The independent association of PP and outcome over 5 years was determined. Baseline characteristics independently associated with PP were higher mean arterial pressure, older age, female sex, noncoronary vascular disease, history of diabetes mellitus, and history of hypertension (p <0.001 for all). Cox regression covariates significantly associated with time to death were age, smoking, male gender, diabetes history, congestive heart failure, and baseline use of angiotensin-converting enzyme inhibitors, diuretic, or digitalis. When PP was added to the model, it was found to be an independent predictor of time to death (p = 0.008). When PP and mean arterial pressure were added to the model, PP remained significantly associated with time to death (p = 0.033). When renal disease and noncoronary vascular disease were added to the model, the relative risk declined from 1.07 to 1.04 and the association was no longer statistically significant. Thus, increased PP is directly and independently associated with mean arterial pressure, hypertension, age > or =65 years, diabetes mellitus, and the presence of noncoronary vascular disease, and inversely associated with a history of myocardial infarction. After coronary revascularization, PP, reflecting arterial stiffness, is independently associated with total mortality. [ABSTRACT FROM AUTHOR]

The Survival With ORal D-sotalol (SWORD) trial tested the hypothesis that the prophylactic administration of oral d-sotalol would reduce total mortality in patients surviving myocardial infarction (MI) with a left ventricular ejection fraction (LVEF) of < or = 40%. Two index MI groups were included: recent (6 to 42 days) and remote (> 42 days) with clinical heart failure (n = 915 and 2,206, respectively). The trial was discontinued when the statistical boundary for harm was crossed (RR = 1.65; p = 0.006). All baseline variables known to be associated with mortality risk (e.g., LVEF, heart failure class, age) as well as variables related to torsades de pointes (e.g., time from beginning of therapy, QTc, gender, potassium, renal function, dose of d-sotalol) were assessed for interaction of each variable with treatment assignment, computing RR and 95% confidence interval (CI) from Cox regression models. The d-sotalol-associated mortality was greatest in the group with remote MI and LVEFs of 31% to 40% (RR = 7.9; 95% CI 2.4 to 26.2). Most variables known to be associated with torsades de pointes were not differentially predictive of d-sotalol-associated risk, except female gender (RR = 4.7; 95% CI 1.4 to 16.5). These findings suggest that (1) most of the d-sotalol-associated risk was in patients remote from MI with a LVEF of 31% to 40%; comparable placebo patients had a very low mortality (0.5%); and (2) very little objective data supports torsades de pointes or any specific proarrhythmic mechanism as an explanation for d-sotalol-associated mortality risk. [ABSTRACT FROM AUTHOR]