Usefulness of Low-Dose Statin Plus Ezetimibe and/or Nutraceuticals in Patients With Coronary Artery Disease Intolerant to High-Dose Statin Treatment.

High-dose statin (HDS) therapy is recommended to reduce low-density lipoprotein cholesterol (LDL-C); however, some patients are unable to tolerate the associated side effects. Nutraceuticals have shown efficacy in lowering LDL-C. The aim of this study was to evaluate whether the combination of low-dose statin (LDS) plus ezetimibe (EZE) or LDS plus nutraceutical (Armolipid Plus [ALP] containing red yeast rice, policosanol, and berberine) can lead to a higher proportion of high-risk patients achieving target LDL-C. A secondary objective was to assess the efficacy of triple combination LDS + EZE + ALP in resistant patients (LDL-C >70 mg/dl). A randomized, prospective, parallel-group, single-blind study was conducted in patients with coronary artery disease (n = 100) who had undergone percutaneous coronary intervention in the preceding 12 months, were HDS-intolerant, and were not at LDL-C target (<70 mg/dl) with LDS alone. Patients received either LDS + EZE or LDS + ALP. Of the 100 patients, 33 patients (66%) treated with LDS + EZE and 31 patients (62%) treated with LDS + ALP achieved target LDL-C after 3 months, which was maintained at 6 months. Patients who did not achieve the therapeutic goal received a triple combination of LDS + EZE + ALP for a further 3 months. At 6 months, 28 of 36 patients (78%) achieved LDL-C target. Overall, 92% of patients enrolled in this study were at target LDL-C at 6 months. No patients in any group experienced major side effects. In conclusion, in HDS-intolerant coronary artery disease patients, the combination of LDS plus EZE and/or ALP represents a valuable therapeutic option allowing most patients to reach target LDL-C within 3 to 6 months.

Comparison of Low-Dose Statin Versus Low-Dose Statin + Armolipid Plus in High-Intensity Statin-Intolerant Patients With a Previous Coronary Event and Percutaneous Coronary Intervention (ADHERENCE Trial).

Low-density lipoprotein cholesterol (LDL-C) reduction is associated with a significant decrease in mortality, and statins represent the most effective drugs to achieve this. However, side effects of statins are very common and may lead to treatment discontinuation. Nutraceuticals are a combination of natural components that have shown efficacy in lowering LDL-C concentration when used alone or in association with other agents in patients who are intolerant to high-dose statins. Our aim was to compare the efficacy and tolerability of low-dose statin (LDS) therapy versus combined therapy of LDS plus a nutraceutical combination containing red yeast rice, policosanol, berberine, folic acid, coenzyme Q10 and astaxanthin (Armolipid Plus) in high-risk patients. We performed a randomized (1:1), prospective, parallel group, single-blind trial in which participants had coronary artery disease (n = 100), had undergone percutaneous coronary intervention in the preceding 12 months, were high-dose statin intolerant, and did not achieve ≥50% reduction in LDL-C with LDS treatment alone. After 3 months, patients in the LDS + Armolipid Plus (n = 50) group presented with a significantly greater reduction of LDL-C and total cholesterol (p <0.0001), and 70% of patients in this group achieved the therapeutic target (LDL-C <70 mg/dl), whereas patients in the LDS group did not. Six patients (3 from each group) dropped out due to myalgia. In conclusion, in patients with coronary artery disease and high-dose statin intolerance, the combination of LDS and nutraceuticals represents a valuable therapeutic option.

Greater cardiovascular risk reduction with once-daily fixed combination of three antihypertensive agents and statin versus free-drug combination: The ALL-IN-ONE trial.

BACKGROUND: The ultimate goal of antihypertensive therapy is cardiovascular risk (CVR) reduction. The aim of this study was to compare the efficacy and safety of once-daily fixed combination (ODFC) versus free-drug combination (FDC) of 3antihypertensive agents and statin. METHODS: The ALL-IN-ONE trial was a 12-week randomized, prospective, multicenter trial. A total of 305 hypertensive patients were randomized 1:1. The "fixed group" was given an ODFC of perindropil 10mg plus indapamide 2.5mg plus amlodipine 5 or 10mg plus atorvastatin 20mg. The "free group" was given a FDC of the 3antihypertensive agents plus atorvastatin 20mg. Primary end-points were the differences in clinic BP, cholesterol levels and CVR risk between the 2 groups after treatments. Secondary end-points included intragroup differences in clinic BP. Safety and compliance were also assessed. RESULTS: At 12-weeks, the fixed group had lower systolic BP and similar diastolic BP compared to the free group. BP targets at week 12 were more commonly reached with fixed than free combination (89% and 80% respectively, p=0.048). For cholesterol serum in both groups there was a significant reduction of values. Also CVR reduction was greater in those taking ODF. Safety was not significantly different between the 2 groups. Conversely, compliance was significantly greater in the fixed-group vs. the free-group. CONCLUSION: This randomized trial shows that ODF combination of perindropil, indapamide and amlodipine is as safe as free combination of the 3 drugs, but is associated with a greater efficacy in BP control, compliance and, associated with statin, in cholesterol reduction. A better cardiovascular risk control is achieved with ODF combination than with a free administration. ClinicalTrials.gov ID: NCT02710539.

Ranolazine improves insulin resistance in non-diabetic patients with coronary heart disease. A pilot study.

BACKGROUND: The aim of this pilot study was to evaluate if ranolazine (R) could improve insulin resistance (IR) in obese/overweight non-diabetic patients with coronary heart disease (CHD). METHODS: The study enrolled 40 patients with already diagnosed CHD, previous revascularization, residual ischemia at ergometric test and IR. Mean age was 62.4±9years, M/F=31/9. Patients were randomly assigned to one of the two following groups: group 1 (20 patients) started R at dose of 500mg/bid; group 2 (20 patients) increased the dose of beta/blockers or calcium-channel blockers without introducing R. IR was defined as having HOMA-IR>2.5. At baseline and after 12weeks, all subjects performed an ergometric test and 12h fasting blood sample collection for determining glucose and insulin levels. RESULTS: At 12weeks follow-up visit HOMA-IR significantly decreased in group 1 (from 3.1±1.7 to 2.3±0.9; p=0.02) while it remained unchanged in group 2 (from 3.0±1.4 to 2.8±1.2; p=0.14) (between groups p=0.009). At 12weeks follow-up visit patients of both groups obtained a significant increase of ischemic threshold at ergometric test, compared to baseline, (group 1 from 308.4±45s to 423.9±57s, p=0.0004); (group 1 from 315.7±63s to 441.2±51s, p=0.0001); without between groups difference (p=0.25). CONCLUSIONS: Our data suggest that starting R, instead of increasing the dose of beta-blockers/calcium-channel blockers, could be a preferable choice in obese/overweight CHD subjects with residual ischemia after revascularization.

Tai chi enhances the effects of endurance training in the rehabilitation of elderly patients with chronic heart failure.

Purpose. To assess if Tai Chi added to endurance training (ET) is more effective than ET alone in improving exercise tolerance and quality of life (QOL) of elderly patients with chronic heart failure (CHF). Design. Sixty CHF patients, age 73.8 ± 6 years, M/F 51/9, were enlisted. Thirty pts were randomized to combined training (CT) performing Tai Chi +ET and 30 patients to ET (ET only). Methods. At baseline and after 12 weeks all patients underwent 6-minute walking test (6MWT), assessment of amino terminal probrain natriuretic peptide (NT-pro BNP), quadriceps maximal voluntary contraction (MVC) and peak torque (PT), QOL questionnaire (MacNewQLMI), blood pressure (BP), and heart rate (HR). All patients performed 4 sessions of exercise/week. Results. Distance at 6mwt improved in both groups with significant between-groups differences (P = .031). Systolic BP and NT-proBNP decreased significant in the CT group compared to ET (P = .025) and P = .015), resp.). CT group had a greater significant improvement in physical perception (P = .026) and a significant increase of PT compared to ET group. Conclusions. The association of Tai Chi and ET improves exercise tolerance and QOL of patients with CHF more efficiently than ET.

Long-term effects of nutraceuticals (berberine, red yeast rice, policosanol) in elderly hypercholesterolemic patients.

INTRODUCTION: Statins are at the forefront of strategies to manage dyslipidemia, although they are not always well tolerated. At 6-7 months after the drug was supplied, discontinuation rates averaged 30%. Alternate agents to statins have been studied. Some nutraceuticals demonstrated an efficacy in reducing cholesterol concentrations. However, there are no data regarding the use of nutraceuticals in elderly dyslipidemic patients. The purpose of this study was to examine the efficacy, safety, and tolerability of a nutraceutical-based protocol in elderly hypercholesterolemic patients previously intolerant to statins. METHODS: This study was performed as a randomized, prospective, parallel group, single-blind study. Patients were included in the study if they had high total cholesterolemia, high low-density lipoprotein cholesterol (LDL-C), >75 years of age, statin-intolerant, and were refusing other pharmaceutical treatments for hypercholesterolemia. At the baseline visit, eligible patients were randomized to either nutraceutical-combined pill (containing berberine 500 mg, policosanol 10 mg, red yeast rice 200 mg, folic acid 0.2 mg, coenzyme Q10 2.0 mg, and astaxanthin 0.5 mg) or placebo, and the first dose was dispensed. The efficacy, safety, and tolerability of the proposed treatment were fully assessed after 3, 6, and 12 months of treatment. RESULTS: Out of 106 consecutive patients screened, 80 eligible patients were randomized to receive either nutraceutical-combined pill (40 patients) or placebo (40 patients). No patients were lost and no deaths occurred during the follow-up. There was a statistically significant reduction in total cholesterolemia (-20%), LDL-C (-31%), and insulin resistance (-10%) with nutraceutical treatment. No significant changes were detected for plasma high-density lipoprotein cholesterol (HDL-C). Furthermore, no statistical differences were found between baseline and end-study safety parameters. Medication compliance and tolerability were high. CONCLUSION: In this study the authors have demonstrated that combined nutraceuticals significantly reduce cholesterolemia and achieved acceptable plasma LDL-C levels in elderly hypercholesterolemic patients who were previously statin-intolerant. Combined nutraceuticals is also safe and well tolerated in these patients.

Comparative long term effects of nebivolol and carvedilol in hypertensive heart failure patients.

BACKGROUND: Beta-blockers improve left ventricular (LV) systolic function and prognosis in patients with chronic heart failure (CHF), but their different pleiotropic properties may influence their cardiovascular effects. This open-label study compared the effects of long-term treatment with nebivolol versus carvedilol on LV ejection fraction (LVEF), in hypertensive CHF patients. Secondary end points were to assess the effect of the 2 beta-blockers on exercise capacity and clinical outcome. METHODS AND RESULTS: A total of 160 hypertensive CHF patients, with LVEF <40% and in New York Heart Association (NYHA) functional class I, II, or III, were randomly assigned to receive nebivolol or carvedilol for 24 months. At baseline and at the end of treatment, all patients underwent clinical evaluation, echocardiography, and 6-minute walking test. The target doses were 10 mg/d for nebivolol and 50 mg/d for carvedilol. Compared with baseline values, LVEF increased by a similar extent in the carvedilol (C) and nebivolol (N) groups (C from 36.1% (SD 1.5%) to 40.9% (SD 1.9%), P < .001; N from 34.1% (SD 1.8%) to 38.5% (SF 2.2%), P < .001). Heart rate and NYHA functional class decreased significantly in both groups, and the 6-minute walking distance increased (C from 420 m (SD 104 m) to 490 m (SD 115 m), P < .001; N from 421 m (SD 118 m) to 487 m (SD 138 m), P < .001). During 24 months, 21 carvedilol recipients (26%) and 18 nebivolol recipients (22%) had cardiac events, including 3 and 4 deaths, respectively. CONCLUSION: In the long term, nebivolol and carvedilol appear to be similarly effective in the treatment of hypertensive patients with CHF.

Hydrotherapy added to endurance training versus endurance training alone in elderly patients with chronic heart failure: a randomized pilot study.

PURPOSE: To assess if Hydrotherapy (HT) added to endurance training (ET) is more effective than ET alone in order to improve exercise tolerance of elderly male patients with chronic heart failure (CHF). METHODS: Twenty-one male CHF patients, age 68+/-7 (mean+/-DS) years; ejection fraction 32+/-9. NYHA II-III were enrolled. Eleven pts were randomized to combined training (CT) group performing HT+ET and 10 patients to ET group (ET only). At baseline and after 24 weeks all patients underwent: 6-minute walking test (6MWT), assessment of quadriceps maximal voluntary contraction (MVC) and peak torque (PT), blood pressure and heart rate (HR), echocardiography and non-invasive hemodynamic evaluation. HT was performed 3 times/week in upright position at up to the xyphoid process at a temperature of 31°C. ET was performed 3 times/week. RESULTS: Exercise was well tolerated. No patients had adverse events. Distance at 6MWT improved in both groups (CT group: 150+/-32 m; ET group:105+/-28 m) with significant intergroup differences (p 0.001). On land diastolic BP and HR significantly decreased in the CT group while remained unchanged in the ET group (-11 mmHg+/-2, p 0.04; e - 12 bpm, p 0.03; respectively) CO and SV had a relative despite no significant increase in CT group TPR on land significantly decreased in CT group (-23+/-3 mmHg/l/m; p 0.01) while remained unchanged in ET group. Patients of CT group had no significant higher increase of both MVC and PT than ET group. CONCLUSIONS: CT training, significantly improves exercise tolerance and hemodynamic profile of patients with CHF.

Comparison of effectiveness of carvedilol versus bisoprolol for prevention of postdischarge atrial fibrillation after coronary artery bypass grafting in patients with heart failure.

Atrial fibrillation (AF) occurs frequently soon after coronary artery bypass grafting (CABG) and often results in increased mortality and morbidity, particularly in patients with heart failure. New-onset AF is also a common event in the early period after discharge from a cardiac surgery clinic. Current guidelines recommend ß blockers as first-line medication for the prevention of AF after CABG. In this prospective study, we investigated the effectiveness of the highly selective ß1 receptor antagonist bisoprolol compared to the less selective ß blocker carvedilol in preventing postdischarge AF after CABG in patients with decreased left ventricular function. Three hundred twenty patients (231 men, 89 women, mean age 66 ± 10 years) with ejection fraction <40% who underwent CABG and were then referred to an in-hospital cardiac rehabilitation program were randomized to receive bisoprolol (n = 160) or carvedilol (n = 160) starting 4 to 5 days after surgery. Bisoprolol was started at 1.25 mg 1 time/day and carvedilol was started 3.125 mg 2 times/day. All patients underwent continuous telemetric electrocardiographic monitoring for 5 days after entry in the study and thereafter 2 times/day routinely up to hospital discharge. During follow-up, 23 patients (14.6%) in the bisoprolol group and 37 patients (23%) in the carvedilol group developed AF (relative risk 0.6, confidence interval 0.4 to 0.9, p = 0.032). Twenty-six percent of all AF episodes were asymptomatic. At the 4-week outpatient visit, those in the bisoprolol group showed a significantly greater decrease in heart rate, being in sinus rhythm or AF (-15.6 ± 3 vs -9.4 ± 3 beats/min, p = 0.021), whereas changes in systolic and diastolic blood pressures did not differ significantly. In conclusion, bisoprolol is more effective than carvedilol in decreasing the incidence of postdischarge AF after CABG in patients with decreased left ventricular function.

Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study.

OBJECTIVES: The primary objective of this study was to assess the effect of a 6-month testosterone supplementation therapy on functional capacity and insulin resistance in female patients with chronic heart failure (CHF). BACKGROUND: Patients with CHF show decreased exercise capacity and insulin sensitivity. Testosterone supplementation improves these variables in men with CHF. No study has evaluated the effects of testosterone supplementation on female patients with CHF. METHODS: Thirty-six elderly female patients with stable CHF, (ejection fraction 32.9 ± 6) were randomly assigned (2:1 ratio) to receive testosterone transdermal patch (T group, n = 24) or placebo (P group, n = 12), both on top of optimal medical therapy. At baseline and after 6 months, patients underwent 6-min walking test (6MWT), cardiopulmonary exercise test, echocardiogram, quadriceps maximal isometric voluntary contraction, dynamic quadriceps isokinetic strength (peak torque), and insulin resistance assessment by homeostasis model. RESULTS: Distance walked at 6MWT as well as peak oxygen consumption significantly improved in the T group, whereas they were unchanged in the P group (p < 0.05 for all comparisons). The homeostasis model was significantly reduced in the T group in comparison with the P group (-16.5% vs. +5%, respectively; p < 0.05). Maximal voluntary contraction and peak torque increased significantly in the T group but did not change in the P group. Increase in distance walked at 6MWT was related to the increase in free testosterone levels (r = 0.593, p = 0.01). No significant changes in echocardiographic parameters were observed in either group. No side effects requiring discontinuation of T were detected. CONCLUSIONS: Testosterone supplementation improves functional capacity, insulin resistance, and muscle strength in women with advanced CHF. Testosterone seems to be an effective and safe therapy for elderly women with CHF.

Effectiveness of nebivolol and hydrochlorothiazide association on blood pressure, glucose, and lipid metabolism in hypertensive patients.

INTRODUCTION: Only 50% of hypertensive patients receive an appropriate treatment to normalize blood pressure (BP). Although monotherapy is often adequate in normalizing BP, it is sometimes necessary to start with combination therapy. The aim of the study was to evaluate the efficacy of nebivolol alone and in association with hydrochlorothiazide (HCT) in reducing BP in hypertensive patients with new-onset, mild-to-moderate hypertension, and to assess the effect of combination therapy on glucose and lipid metabolism. METHODS: At enrollment, patients underwent a full cardiovascular and metabolic evaluation. Patients were then prescribed nebivolol (5 mg/day). After 1 month, in those patients whose BP was not normalized, HCT 12.5 mg was added and increased further to 25 mg after 1 month in those whose BP still was not normalized. All patients were assessed at monthly intervals for a further 5 months. RESULTS: We enrolled 233 treatment-naive patients. After the first month of treatment with nebivolol, 70% of patients had normalized BP. The addition of HCT increased responder rates to 94%. An improvement in glucose metabolism was noted with nebivolol alone (at 1 month, the reduction in Homeostasis Model Assessment of Insulin Resistance [HOMA-IR] was 26% and remained stable at 6 months); the adjunct of HCT blunted the reduction in HOMA-IR. No significant changes on lipid profile were noted with nebivolol, either alone or in combination therapy. CONCLUSION: Nebivolol is effective in mild-to-moderate hypertension and associated with favorable metabolic effects. The addition of HCT optimizes BP control in a high number of patients resistant to monotherapy without a negative impact on patients' glucose and lipid profile.

Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study.

OBJECTIVES: This study investigated the effect of a 12-week long-acting testosterone administration on maximal exercise capacity, ventilatory efficiency, muscle strength, insulin resistance, and baroreflex sensitivity (BRS) in elderly patients with chronic heart failure (CHF). BACKGROUND: CHF is characterized by a metabolic shift favoring catabolism and impairment in skeletal muscle bulk and function that could be involved in the pathophysiology of heart failure. METHODS: Seventy elderly patients with stable CHF-median age 70 years, ejection fraction 31.8 +/- 7%-were randomly assigned to receive testosterone (n = 35, intramuscular injection every 6 weeks) or placebo (n = 35), both on top of optimal medical therapy. At baseline and at the end of the study, all patients underwent echocardiogram, cardiopulmonary exercise test, 6-min walk test (6MWT), quadriceps maximal voluntary contraction (MVC), and isokinetic strength (peak torque) and BRS assessment (sequences technique). RESULTS: Baseline peak oxygen consumption (VO(2)) and quadriceps isometric strength showed a direct relation with serum testosterone concentration. Peak VO(2) significantly improved in testosterone but was unchanged in placebo. Insulin sensitivity was significantly improved in testosterone. The MVC and peak torque significantly increased in testosterone but not in placebo. The BRS significantly improved in testosterone but not in placebo. Increase in testosterone levels was significantly related to improvement in peak VO(2) and MVC. There were no significant changes in left ventricular function either in testosterone or placebo. CONCLUSIONS: These results suggest that long-acting testosterone therapy improves exercise capacity, muscle strength, glucose metabolism, and BRS in men with moderately severe CHF. Testosterone benefits seem to be mediated by metabolic and peripheral effects.

Metabolic syndrome predicts lower functional recovery in female but not in male patients after an acute cardiac event.

AIMS: To evaluate whether metabolic syndrome MS has a gender dependent effect on the recovery of functional capacity in patients (pts) with coronary heart disease (CHD) undergoing a cardiac rehabilitation program. METHODS AND RESULTS: We studied 286 CHD patients, age 66.2+/-10.6 (median+/-SD); M/F 187/99. Patients were divided into two groups according to the presence (MS, 48%) or not (nMS, 52%) of MS. MS was present in 48% of patients. Functional capacity was assessed by the distance walked at six minute walking test (6MWT), and by a maximal exercise test. Compared to patients without MS, those with MS walked a lower distance at 6MWT (438+/-110 vs 408+/-123 m; p<0.05), had a lower maximal exercise capacity (7.6+/-1.8 vs 9.3+/-1.2 MET; p<0.05) and a lower heart rate recovery (HRR) (16+/-9 vs 22+/-8; p<0.05). Male patients with or without MS had a similar degree of functional recovery (51%) while women with MS had a significantly lower recovery than nMS (20% vs 40%). In a multivariate logistic regression model, including body mass index, age, gender hypertension, ejection fraction and diabetes, MS predicted a reduced performance at 6MWT in the overall population (OR 1.4, 95% CI 1.7 to 2.4) and in women (OR 1.31; 95% CI 1.20-1.62), while it was not predictive in males. CONCLUSIONS: CAD patients with MS have lower functional recovery and HRR than nMS. However MS is an independent predictor of lower exercise capacity only in female gender.