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Cardiovascular Benefit of Empagliflozin Across the Spectrum of Cardiovascular Risk Factor Control in the EMPA-REG OUTCOME Trial.
Inzucchi, SE, Khunti, K, Fitchett, DH, Wanner, C, Mattheus, M, George, JT, Ofstad, AP, Zinman, B
The Journal of clinical endocrinology and metabolism. 2020;(9):3025-35
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CONTEXT Control of multiple cardiovascular (CV) risk factors reduces CV events in individuals with type 2 diabetes. OBJECTIVE To investigate this association in a contemporary clinical trial population, including how CV risk factor control affects the CV benefits of empagliflozin, a sodium-glucose cotransporter-2 inhibitor. DESIGN Post hoc analysis. SETTING Randomized CV outcome trial (EMPA-REG OUTCOME). PARTICIPANTS Type 2 diabetes patients with established CV disease. INTERVENTION Empagliflozin or placebo. MAIN OUTCOME MEASURES Risk of CV outcomes-including the treatment effect of empagliflozin-by achieving 7 goals for CV risk factor control at baseline: (1) glycated hemoglobin <7.5%, (2) low-density lipoprotein cholesterol <100 mg/dL or statin use, (3) systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg, (4) pharmacological renin-angiotensin-aldosterone system blockade, (5) normoalbuminuria, (6) aspirin use, (7) nonsmoking. RESULTS In the placebo group, the hazard ratio (HR) for CV death was 4.00 (95% CI, 2.26-7.11) and 2.48 (95% CI, 1.52-4.06) for patients achieving only 0-3 or 4-5 risk factor goals at baseline, respectively, compared with those achieving 6-7 goals. Participants achieving 0-3 or 4-5 goals also had increased risk for the composite outcome of hospitalization for heart failure or CV death (excluding fatal stroke) (HR 2.89 [1.82-4.57] and 1.90 [1.31-2.78], respectively) and 3-point major adverse CV events (HR 2.21 [1.53-3.19] and 1.42 [1.06-1.89]). Empagliflozin significantly reduced these outcomes across all risk factor control categories (P > 0.05 for treatment-by-subgroup interactions). CONCLUSIONS Cardiovascular risk in EMPA-REG OUTCOME was inversely associated with baseline CV risk factor control. Empagliflozin's cardioprotective effect was consistent regardless of multiple baseline risk factor control.
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A randomized controlled trial of levosimendan to reduce mortality in high-risk cardiac surgery patients (CHEETAH): Rationale and design.
Zangrillo, A, Alvaro, G, Pisano, A, Guarracino, F, Lobreglio, R, Bradic, N, Lembo, R, Gianni, S, Calabrò, MG, Likhvantsev, V, et al
American heart journal. 2016;:66-73
Abstract
OBJECTIVE Patients undergoing cardiac surgery are at risk of perioperative low cardiac output syndrome due to postoperative myocardial dysfunction. Myocardial dysfunction in patients undergoing cardiac surgery is a potential indication for the use of levosimendan, a calcium sensitizer with 3 beneficial cardiovascular effects (inotropic, vasodilatory, and anti-inflammatory), which appears effective in improving clinically relevant outcomes. DESIGN Double-blind, placebo-controlled, multicenter randomized trial. SETTING Tertiary care hospitals. INTERVENTIONS Cardiac surgery patients (n = 1,000) with postoperative myocardial dysfunction (defined as patients with intraaortic balloon pump and/or high-dose standard inotropic support) will be randomized to receive a continuous infusion of either levosimendan (0.05-0.2 μg/[kg min]) or placebo for 24-48 hours. MEASUREMENTS AND MAIN RESULTS The primary end point will be 30-day mortality. Secondary end points will be mortality at 1 year, time on mechanical ventilation, acute kidney injury, decision to stop the study drug due to adverse events or to start open-label levosimendan, and length of intensive care unit and hospital stay. We will test the hypothesis that levosimendan reduces 30-day mortality in cardiac surgery patients with postoperative myocardial dysfunction. CONCLUSIONS This trial is planned to determine whether levosimendan could improve survival in patients with postoperative low cardiac output syndrome. The results of this double-blind, placebo-controlled randomized trial may provide important insights into the management of low cardiac output in cardiac surgery.
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Rosuvastatin for Reduction of Myocardial Damage during Coronary Angioplasty - the Remedy Trial.
Briguori, C, Madonna, R, Zimarino, M, Calabrò, P, Quintavalle, C, Salomone, M, Condorelli, G, De Caterina, R
Cardiovascular drugs and therapy. 2016;(5):465-472
Abstract
BACKGROUND Periprocedural myocardial infarction (MI) is a frequent complication of percutaneous coronary intervention (PCI). Statins might reduce its incidence. The aims of the present study are to assess whether such benefit is a class-effect or whether differences exist between various lipid-lowering strategies and whether cardioprotection is exerted by increasing circulating endothelial progenitor cells (EPCs). METHODS The REMEDY study will enroll a total of 1080 patients submitted to elective PCI. Eligible patients will be randomized into 4 groups: 1) placebo; 2) atorvastatin (80 mg + 40 mg before PCI); 3) rosuvastatin (40 mg twice before PCI); and 4) rosuvastatin (5 mg) and ezetimibe (10 mg) twice before PCI. Peri-procedural MI is defined as an elevation of markers of cardiac injury (either CK-MB or troponin I or T) values >5x the upper reference limit estimated at the 99th percentile of the normal distribution, or a rise >20 % in case of baseline values already elevated. EPCs will be assessed before, at 24 h and - in a subset of diabetic patients - at 3 months after PCI (EPC-substudies). The primary endpoint of the main REMEDY study is the rate of peri-procedural MI in each of the 4 treatment arms. Secondary endpoints are the combined occurrence of 1-month major adverse events (MACE, including death, MI, or the need for unplanned revascularization); and any post-procedural increase in serum creatinine. Endpoints of the EPC-substudies are the impact of tested regimens on 1) early (24-h) and 3-month EPC levels and functional activity; 2) stent strut re-endothelialization and neointimal hyperplasia; 3) 1-year MACE. REMEDY will add important information on the cardioprotective effects of statins after PCI.
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Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency†.
Ponikowski, P, van Veldhuisen, DJ, Comin-Colet, J, Ertl, G, Komajda, M, Mareev, V, McDonagh, T, Parkhomenko, A, Tavazzi, L, Levesque, V, et al
European heart journal. 2015;(11):657-68
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AIM: The aim of this study was to evaluate the benefits and safety of long-term i.v. iron therapy in iron-deficient patients with heart failure (HF). METHODS AND RESULTS CONFIRM-HF was a multi-centre, double-blind, placebo-controlled trial that enrolled 304 ambulatory symptomatic HF patients with left ventricular ejection fraction ≤45%, elevated natriuretic peptides, and iron deficiency (ferritin <100 ng/mL or 100-300 ng/mL if transferrin saturation <20%). Patients were randomized 1 : 1 to treatment with i.v. iron, as ferric carboxymaltose (FCM, n = 152) or placebo (saline, n = 152) for 52 weeks. The primary end-point was the change in 6-min-walk-test (6MWT) distance from baseline to Week 24. Secondary end-points included changes in New York Heart Association (NYHA) class, Patient Global Assessment (PGA), 6MWT distance, health-related quality of life (QoL), Fatigue Score at Weeks 6, 12, 24, 36, and 52 and the effect of FCM on the rate of hospitalization for worsening HF. Treatment with FCM significantly prolonged 6MWT distance at Week 24 (difference FCM vs. placebo: 33 ± 11 m, P = 0.002). The treatment effect of FCM was consistent in all subgroups and was sustained to Week 52 (difference FCM vs. placebo: 36 ± 11 m, P < 0.001). Throughout the study, an improvement in NYHA class, PGA, QoL, and Fatigue Score in patients treated with FCM was detected with statistical significance observed from Week 24 onwards. Treatment with FCM was associated with a significant reduction in the risk of hospitalizations for worsening HF [hazard ratio (95% confidence interval): 0.39 (0.19-0.82), P = 0.009]. The number of deaths (FCM: 12, placebo: 14 deaths) and the incidence of adverse events were comparable between both groups. CONCLUSION Treatment of symptomatic, iron-deficient HF patients with FCM over a 1-year period resulted in sustainable improvement in functional capacity, symptoms, and QoL and may be associated with risk reduction of hospitalization for worsening HF (ClinicalTrials.gov number NCT01453608).
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Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI).
Siddiqi, N, Neil, C, Bruce, M, MacLennan, G, Cotton, S, Papadopoulou, S, Feelisch, M, Bunce, N, Lim, PO, Hildick-Smith, D, et al
European heart journal. 2014;(19):1255-62
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AIM: Despite prompt revascularization of acute myocardial infarction (AMI), substantial myocardial injury may occur, in part a consequence of ischaemia reperfusion injury (IRI). There has been considerable interest in therapies that may reduce IRI. In experimental models of AMI, sodium nitrite substantially reduces IRI. In this double-blind randomized placebo controlled parallel-group trial, we investigated the effects of sodium nitrite administered immediately prior to reperfusion in patients with acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS A total of 229 patients presenting with acute STEMI were randomized to receive either an i.v. infusion of 70 μmol sodium nitrite (n = 118) or matching placebo (n = 111) over 5 min immediately before primary percutaneous intervention (PPCI). Patients underwent cardiac magnetic resonance imaging (CMR) at 6-8 days and at 6 months and serial blood sampling was performed over 72 h for the measurement of plasma creatine kinase (CK) and Troponin I. Myocardial infarct size (extent of late gadolinium enhancement at 6-8 days by CMR-the primary endpoint) did not differ between nitrite and placebo groups after adjustment for area at risk, diabetes status, and centre (effect size -0.7% 95% CI: -2.2%, +0.7%; P = 0.34). There were no significant differences in any of the secondary endpoints, including plasma troponin I and CK area under the curve, left ventricular volumes (LV), and ejection fraction (EF) measured at 6-8 days and at 6 months and final infarct size (FIS) measured at 6 months. CONCLUSIONS Sodium nitrite administered intravenously immediately prior to reperfusion in patients with acute STEMI does not reduce infarct size.
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Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge: a randomized clinical trial.
Ho, PM, Lambert-Kerzner, A, Carey, EP, Fahdi, IE, Bryson, CL, Melnyk, SD, Bosworth, HB, Radcliff, T, Davis, R, Mun, H, et al
JAMA internal medicine. 2014;(2):186-93
Abstract
IMPORTANCE Adherence to cardioprotective medication regimens in the year after hospitalization for acute coronary syndrome (ACS) is poor. OBJECTIVE To test a multifaceted intervention to improve adherence to cardiac medications. DESIGN, SETTING, AND PARTICIPANTS In this randomized clinical trial, 253 patients from 4 Department of Veterans Affairs medical centers located in Denver (Colorado), Seattle (Washington); Durham (North Carolina), and Little Rock (Arkansas) admitted with ACS were randomized to the multifaceted intervention (INT) or usual care (UC) prior to discharge. INTERVENTIONS The INT lasted for 1 year following discharge and comprised (1) pharmacist-led medication reconciliation and tailoring; (2) patient education; (3) collaborative care between pharmacist and a patient's primary care clinician and/or cardiologist; and (4) 2 types of voice messaging (educational and medication refill reminder calls). MAIN OUTCOMES AND MEASURES The primary outcome of interest was proportion of patients adherent to medication regimens based on a mean proportion of days covered (PDC) greater than 0.80 in the year after hospital discharge using pharmacy refill data for 4 cardioprotective medications (clopidogrel, β-blockers, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors [statins], and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers [ACEI/ARB]). Secondary outcomes included achievement of blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) level targets. RESULTS Of 253 patients, 241 (95.3%) completed the study (122 in INT and 119 in UC). In the INT group, 89.3% of patients were adherent compared with 73.9% in the UC group (P = .003). Mean PDC was higher in the INT group (0.94 vs 0.87; P< .001). A greater proportion of intervention patients were adherent to clopidogrel (86.8% vs 70.7%; P = .03), statins (93.2% vs 71.3%; P < .001), and ACEI/ARB (93.1% vs 81.7%; P = .03) but not β-blockers (88.1% vs 84.8%; P = .59). There were no statistically significant differences in the proportion of patients who achieved BP and LDL-C level goals. CONCLUSIONS AND RELEVANCE A multifaceted intervention comprising pharmacist-led medication reconciliation and tailoring, patient education, collaborative care between pharmacist and patients' primary care clinician and/or cardiologist, and voice messaging increased adherence to medication regimens in the year after ACS hospital discharge without improving BP and LDL-C levels. Understanding the impact of such improvement in adherence on clinical outcomes is needed prior to broader dissemination of the program. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00903032.
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Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial.
Maggioni, AP, Greene, SJ, Fonarow, GC, Böhm, M, Zannad, F, Solomon, SD, Lewis, EF, Baschiera, F, Hua, TA, Gimpelewicz, CR, et al
European heart journal. 2013;(40):3117-27
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AIMS: The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). METHODS AND RESULTS ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). CONCLUSION This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM.
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Rationale and design of the 'MITOCARE' Study: a phase II, multicenter, randomized, double-blind, placebo-controlled study to assess the safety and efficacy of TRO40303 for the reduction of reperfusion injury in patients undergoing percutaneous coronary intervention for acute myocardial infarction.
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Cardiology. 2012;(4):201-7
Abstract
Treatment of acute ST-elevation myocardial infarction (STEMI) by reperfusion using percutaneous coronary intervention (PCI) or thrombolysis has provided clinical benefits; however, it also induces considerable cell death. This process is called reperfusion injury. The continuing high rates of mortality and heart failure after acute myocardial infarction (AMI) emphasize the need for improved strategies to limit reperfusion injury and improve clinical outcomes. The objective of this study is to assess safety and efficacy of TRO40303 in limiting reperfusion injury in patients treated for STEMI. TRO40303 targets the mitochondrial permeability transition pore, a promising target for the prevention of reperfusion injury. This multicenter, double-blind study will randomize patients with STEMI to TRO40303 or placebo administered just before balloon inflation or thromboaspiration during PCI. The primary outcome measure will be reduction in infarct size (assessed as plasma creatine kinase and troponin I area under the curve over 3 days). The main secondary endpoint will be infarct size normalized to the myocardium at risk (expressed by the myocardial salvage index assessed by cardiac magnetic resonance). The study is being financed under an EU-FP7 grant and conducted under the auspices of the MITOCARE research consortium, which includes experts from clinical and basic research centers, as well as commercial enterprises, throughout Europe. Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present paper describes the rationale, design and the methods of the trial.
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Incidence, clinical predictors, and prognostic impact of worsening renal function in elderly patients with chronic heart failure on intensive medical therapy.
Maeder, MT, Rickli, H, Pfisterer, ME, Muzzarelli, S, Ammann, P, Fehr, T, Hack, D, Weilenmann, D, Dieterle, T, Kiencke, S, et al
American heart journal. 2012;(3):407-14, 414.e1
Abstract
BACKGROUND Incidence, predictors, and prognostic impact of worsening renal function (WRF) in elderly patients with chronic heart failure (HF) undergoing intensive contemporary medical therapy are unknown. METHODS AND RESULTS In 566 patients (age 77 ± 8 years) included in the TIME-CHF, serum creatinine (sCr) was repeatedly measured up to 6 months. Worsening renal function was classified as increase in sCr by 0.2 to 0.3 (WRFI), 0.3 to 0.5 (WRFII), or ≥0.5 mg/dL (WRFIII) within the first 6 months. Outcome events were assessed for 18 months. RESULTS The incidence of WRF I, II, and III was 12%, 19%, and 22%, respectively. Worsening renal function III was associated with increased mortality (hazard ratio 1.98 [95% CI 1.27-3.07, P = .002] vs no WRF), whereas WRF I/II was not. History of renal failure, spironolactone treatment, higher baseline dose, and higher maximal increase in loop diuretic dose were independently associated with the occurrence of WRF III, whereas angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and β-blocker use and allocation to N-terminal pro-B-type natriuretic peptide-guided management were not. Worsening renal function III was an independent predictor of death, death or hospitalization, and death or HF hospitalization also after adjusting for baseline characteristics. CONCLUSIONS One fifth of elderly patients with chronic HF experienced WRF III on 6-month intensive HF treatment. These patients had higher mortality, whereas patients with smaller sCr rises did not. Occurrence of WRF III was associated with high doses of loop diuretics and spironolactone use but not with other treatments.
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Effects of nicorandil on cardiovascular events in patients with coronary artery disease in the Japanese Coronary Artery Disease (JCAD) study.
Horinaka, S, Yabe, A, Yagi, H, Ishimitsu, T, Yamazaki, T, Suzuki, S, Kohro, T, Nagai, R, ,
Circulation journal : official journal of the Japanese Circulation Society. 2010;(3):503-9
Abstract
BACKGROUND Nicorandil has cardioprotective effects in the ischemic myocardium, mimicking ischemic preconditioning, and is thus expected to improve the prognosis of ischemic heart disease (IHD). As part of the Japanese Coronary Artery Disease (JCAD) Study, a multicenter collaborative prospective observational study of a large cohort of coronary artery disease patients, the effect of nicorandil on outcome was examined. METHODS AND RESULTS In total, 2,558 patients with nicorandil treatment and controls subjected to propensity score matching were eligible among 13,812 patients registered in the JCAD study. The mean follow-up interval was 2.7 years. The primary endpoint, death from all causes, was significantly lower, by 35% (hazard ratio 0.65, P=0.0008), in the nicorandil group than in the control group. There were also significant reductions in secondary endpoints, including cardiac death (56%), fatal myocardial infarction (56%), cerebral or vascular death (71%), and congestive heart failure (33%) in the nicorandil group, with no excess of deaths from other non-cardiovascular causes. Treatment with nicorandil reduced the number of deaths from all causes to a similar extent with or without treatment with sulfonylureas. CONCLUSIONS The reduction in cardiovascular death with nicorandil was large in patients with IHD, which has important implications for treatment.