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Clinical Efficacy and Safety of Alirocumab After Acute Coronary Syndrome According to Achieved Level of Low-Density Lipoprotein Cholesterol: A Propensity Score-Matched Analysis of the ODYSSEY OUTCOMES Trial.
Schwartz, GG, Gabriel Steg, P, Bhatt, DL, Bittner, VA, Diaz, R, Goodman, SG, Jukema, JW, Kim, YU, Li, QH, Manvelian, G, et al
Circulation. 2021;(11):1109-1122
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Abstract
BACKGROUND Recent international guidelines have lowered recommended target levels of low-density lipoprotein cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below the conventional targets. Inferences from previous analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score-matching analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) which compared alirocumab with placebo in 18 924 patients with recent acute coronary syndrome receiving intensive or maximum-tolerated statin treatment. METHODS Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: <25 (n=3357), 25 to 50 (n=3692), or >50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence by using 1:1 propensity score matching. RESULTS Across achieved LDL-C strata of the alirocumab group, patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After propensity score matching, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio, 95% CI, and absolute risk reduction (number per 100 patient-years) for MACE were similar in those with achieved LDL-C <25 mg/dL (hazard ratio, 0.74 [95% CI, 0.62-0.89]; absolute risk reduction, 0.92) or 25 to 50 mg/dL (hazard ratio, 0.74 [95% CI, 0.64-0.87]; absolute risk reduction, 1.05). Patients with achieved LDL-C >50 mg/dL had poorer adherence and derived less benefit (hazard ratio, 0.87 [95% CI, 0.73-1.04]; absolute risk reduction, 0.62). No safety concerns were associated with a limited period of LDL-C levels <15 mg/dL. CONCLUSIONS After accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-C levels <25 mg/dL had a reduction in the risk of MACE that was similar to that of patients who achieved LDL-C levels of 25 to 50 mg/dL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.
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Baseline Low-Density Lipoprotein Cholesterol and Clinical Outcomes of Combining Ezetimibe With Statin Therapy in IMPROVE-IT.
Oyama, K, Giugliano, RP, Blazing, MA, Park, JG, Tershakovec, AM, Sabatine, MS, Cannon, CP, Braunwald, E
Journal of the American College of Cardiology. 2021;(15):1499-1507
Abstract
BACKGROUND The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL despite maximally tolerated statin. OBJECTIVES The purpose of this study was to evaluate the relationship between baseline LDL-C above and below 70 mg/dL and the benefit of adding ezetimibe to statin in patients post-acute coronary syndrome (ACS). METHODS IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a double-blind, placebo-controlled, randomized trial of ezetimibe/simvastatin vs placebo/simvastatin in post-ACS patients followed for 6 years (median). A total of 17,999 patients were stratified by LDL-C at qualifying event into 3 groups (50-<70, 70-<100, and 100-125 mg/dL). The primary endpoint was a composite of cardiovascular death, major coronary events, or stroke. RESULTS Absolute differences in median LDL-C achieved at 4 months between treatment arms were similar (17-20 mg/dL). The effect of ezetimibe/simvastatin vs placebo/simvastatin on primary endpoint was consistent regardless of baseline LDL-C of 50-<70 mg/dL (HR: 0.92 [95% CI: 0.80-1.05]), 70-<100 mg/dL (HR: 0.93 [95% CI: 0.87-1.01]), or 100-125 mg/dL (HR: 0.94 [95% CI: 0.86-1.03]; P interaction = 0.95). Normalized relative risk reductions per 1-mmol/L difference in achieved LDL-C at 4 months between treatment arms were 21% in patients with baseline LDL-C of 50-<70 mg/dL, 16% in those with 70-<100 mg/dL, and 13% in those with 100-125 mg/dL (P interaction = 0.91). No significant treatment interactions by baseline LDL-C were present for safety endpoints. CONCLUSIONS Adding ezetimibe to statin consistently reduced the risk for cardiovascular events in post-ACS patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C <70 mg/dL. (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878).
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Efficacy of nicorandil on the prevention of contrast-induced nephropathy in patients with coronary heart disease undergoing percutaneous coronary intervention.
Zhang, X, Yang, S, Zhang, P, Fu, N
Coronary artery disease. 2020;(3):284-288
Abstract
OBJECTIVES The purpose of this study was to explore the effect of nicorandil on the incidence of contrast-induced nephropathy in patients with coronary heart disease undergoing percutaneous coronary intervention. METHODS This study randomized 300 patients undergoing percutaneous coronary intervention to receive conventional treatment in the control group (hydration only; n = 150) vs. nicorandil therapy (nicorandil 10 mg three times daily plus hydration; n = 150). The primary endpoint was the incidence of contrast-induced nephropathy, defined as rise in serum creatinine ≥44.2 μmol/L or >25% above baseline within 72 hours after exposure to contrast administered during percutaneous coronary intervention. Secondary endpoints included differences in post-percutaneous coronary intervention serum creatinine, blood urea nitrogen, creatinine clearance rate, cystatin-C, and occurrence of major adverse events. RESULTS Contrast-induced nephropathy incidence was 3.3% (5/150) in the nicorandil group vs. 10.7% (16/150) in the control group (P < 0.05). At 48 and 72 hours after contrast administration, cystatin-C levels were significantly lower and creatinine clearance rate were significantly higher with nicroandil therapy compared to conventional treatment (all P values <0.05). No statistical difference was observed in the incidence of major post-procedure side effect events in hospital and fourteen days of follow-up period between the nicorandil group and control group (3.3% vs. 4.0%, P > 0.05). CONCLUSION Compared to conventional treatment, oral nicorandil therapy was associated with less contrast-induced nephropathy and improved renal function following contrast administration during percutaneous coronary intervention.
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Dose-Response Effect of a Digital Health Intervention During Cardiac Rehabilitation: Subanalysis of Randomized Controlled Trial.
Widmer, RJ, Senecal, C, Allison, TG, Lopez-Jimenez, F, Lerman, LO, Lerman, A
Journal of medical Internet research. 2020;(2):e13055
Abstract
BACKGROUND Previous data have validated the benefit of digital health interventions (DHIs) on weight loss in patients following acute coronary syndrome entering cardiac rehabilitation (CR). OBJECTIVE The primary purpose of this study was to test the hypothesis that increased DHI use, as measured by individual log-ins, is associated with improved weight loss. Secondary analyses evaluated the association between log-ins and activity within the platform and exercise, dietary, and medication adherence. METHODS We obtained DHI data including active days, total log-ins, tasks completed, educational modules reviewed, medication adherence, and nonmonetary incentive points earned in patients undergoing standard CR following acute coronary syndrome. Linear regression followed by multivariable models were used to evaluate associations between DHI log-ins and weight loss or dietary adherence. RESULTS Participants (n=61) were 79% male (48/61) with mean age of 61.0 (SD 9.7) years. We found a significant positive association of total log-ins during CR with weight loss (r2=.10, P=.03). Educational modules viewed (r2=.11, P=.009) and tasks completed (r2=.10, P=.01) were positively significantly associated with weight loss, yet total log-ins were not significantly associated with differences in dietary adherence (r2=.05, P=.12) or improvements in minutes of exercise per week (r2=.03, P=.36). CONCLUSIONS These data extend our previous findings and demonstrate increased DHI log-ins portend improved weight loss in patients undergoing CR after acute coronary syndrome. DHI adherence can potentially be monitored and used as a tool to selectively encourage patients to adhere to secondary prevention lifestyle modifications. TRIAL REGISTRATION ClinicalTrials.gov (NCT01883050); https://clinicaltrials.gov/ct2/show/NCT01883050.
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Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery.
Goodman, SG, Aylward, PE, Szarek, M, Chumburidze, V, Bhatt, DL, Bittner, VA, Diaz, R, Edelberg, JM, Hanotin, C, Harrington, RA, et al
Journal of the American College of Cardiology. 2019;(9):1177-1186
Abstract
BACKGROUND Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death. OBJECTIVES This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). METHODS Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. The primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n = 16,896); index CABG after qualifying ACS, but before randomization (n = 1,025); or CABG before the qualifying ACS (n = 1,003). RESULTS In each CABG category, hazard ratios (95% confidence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% confidence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [-2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [-0.1% to 1.0%], 0.5% [-1.9% to 2.9%], and 3.6% [0.0% to 7.2%]). CONCLUSIONS Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).
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Effects of Ezetimibe-Statin Combination Therapy on Coronary Atherosclerosis in Acute Coronary Syndrome.
Hibi, K, Sonoda, S, Kawasaki, M, Otsuji, Y, Murohara, T, Ishii, H, Sato, K, Koshida, R, Ozaki, Y, Sata, M, et al
Circulation journal : official journal of the Japanese Circulation Society. 2018;(3):757-766
Abstract
BACKGROUND The results of previous clinical trials on the effects of ezetimibe-statin combination therapy on atherosclerosis are inconsistent, and the anti-atherosclerotic effect of ezetimibe remains controversial.Methods and Results:We conducted a prospective, randomized open-label study at 10 centers. One hundred and twenty-eight statin-naïve patients with acute coronary syndrome (ACS) undergoing intravascular ultrasound (IVUS)-guided percutaneous coronary intervention were randomized to receive either 2 mg/day pitavastatin plus 10 mg/day ezetimibe, or 2 mg/day pitavastatin. One hundred and 3 patients had evaluable IVUS of non-culprit coronary lesions at baseline and at follow-up. The primary endpoint was the percentage change in non-culprit coronary plaque volume (PV) and lipid PV on integrated backscatter IVUS. Mean low-density lipoprotein cholesterol was reduced from 123 mg/dL to 64 mg/dL in the combination therapy group (n=50) and 126 mg/dL to 87 mg/dL in the statin alone group (n=53; between-group difference, 16.9%, P<0.0001). The percent change in PV was -5.1% in the combination therapy group and -6.2% in the statin alone group (P=0.66), although both groups had reduction of PV compared with baseline (both P<0.01). The percent change in lipid PV did not differ between the groups (4.3 vs. -3.0%, P=0.37). CONCLUSIONS In statin-naïve patients with ACS, combined therapy with ezetimibe and statin did not result in a significant change in coronary plaque regression or tissue component compared with statin alone. [Clinical Trial Registration: www.clinicaltrials.gov (NCT00549926)].
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METoclopramide Administration as a Strategy to Overcome MORPHine-ticagrelOr Interaction in PatientS with Unstable Angina PectorIS-The METAMORPHOSIS Trial.
Sikora, J, Niezgoda, P, Barańska, M, Buszko, K, Skibińska, N, Sroka, W, Pstrągowski, K, Siller-Matula, J, Bernd, J, Gorog, D, et al
Thrombosis and haemostasis. 2018;(12):2126-2133
Abstract
Extensive search for methods of overcoming morphine-related delay of the absorption and onset of action of oral P2Y12 inhibitors in patients presenting with acute coronary syndrome is on-going. The aim of the trial was to investigate whether metoclopramide co-administration could reduce this delay and improve the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ticagrelor and its active metabolite AR-C124900XX. Plasma concentration of both compounds and platelet reactivity were evaluated in nine pre-defined time points within 6 hours after administration of ticagrelor loading dose. The results of our study show that mean platelet activity within the first hour was noticeably higher in metoclopramide-naive patients. Moreover, ticagrelor mean plasma concentration was significantly higher within the initial four time points (15, 30, 45, 60 minutes) in patients receiving metoclopramide (p = 0.039; p = 0.009; p = 0.005; p = 0.008, respectively). To conclude, the co-administration of metoclopramide in patients presenting with unstable angina and treated with morphine, has a beneficial effect on the PK/PD profile of ticagrelor and its metabolite; however, its impact on ST-elevation myocardial infarction patients requires further investigation.
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Effect of calcifediol treatment on cardiovascular outcomes in patients with acute coronary syndrome and percutaneous revascularization.
Navarro-Valverde, C, Quesada-Gómez, JM, Pérez-Cano, R, Fernández-Palacín, A, Pastor-Torres, LF
Medicina clinica. 2018;(9):345-352
Abstract
BACKGROUND AND OBJECTIVES Vitamin D deficiency has been consistently linked with cardiovascular diseases. However, results of intervention studies are contradictory. The aim of this study was to evaluate the effect of treatment with calcifediol (25(OH)D3) on the cardiovascular system of patients with non-ST-elevation acute coronary syndrome after percutaneous coronary intervention. PATIENTS AND METHODS A prospective study assessing≥60-year-old patients with non-ST-elevation acute coronary syndrome, coronary artery disease and percutaneous revascularisation. We randomly assigned 41 patients (70.6±6.3 years) into 2 groups: Standard treatment+25(OH)D3 supplementation or standard treatment alone. Major adverse cardiovascular events (MACE) were evaluated at the conclusion of the 3-month follow-up period. 25(OH)D levels were analysed with regard to other relevant analytical variables and coronary disease extent. RESULTS Basal levels of 25(OH)D≤50nmol/L were associated with multivessel coronary artery disease (RR: 2.6 [CI 95%:1.1-7.1], P=.027) and 25(OH)D≤50nmol/L+parathormone ≥65pg/mL levels correlated with increased risk for MACE (RR: 4 [CI 95%: 1.1-21.8], P=.04]. One MACE was detected in the supplemented group versus five in the control group (P=.66). Among patients with 25(OH)D levels≤50nmol/L at the end of the study, 28.6% had MACE versus 0% among patients with 25(OH)D>50nmol/L (RR: 1,4; P=.037). CONCLUSIONS Vitamin D deficiency plus secondary hyperparathyroidism may be an effective predictor of MACE. A trend throughout the follow up period towards a reduction in MACE among patients supplemented with 25(OH)D3 was detected. 25(OH)D levels≤50nmol/L at the end of the intervention period were significantly associated with an increased number of MACE, hence, 25(OH)D level normalisation could improve cardiovascular health in addition to bone health.
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TEXT messages to improve MEDication adherence and Secondary prevention (TEXTMEDS) after acute coronary syndrome: a randomised clinical trial protocol.
Chow, CK, Thiagalingam, A, Santo, K, Kok, C, Thakkar, J, Stepien, S, Billot, L, Jan, S, Joshi, R, Hillis, GS, et al
BMJ open. 2018;(1):e019463
Abstract
BACKGROUND Identifying simple, low-cost and scalable means of supporting lifestyle change and medication adherence for patients following a cardiovascular (CV) event is important. OBJECTIVE The TEXTMEDS (TEXT messages to improve MEDication adherence and Secondary prevention) study aims to investigate whether a cardiac education and support programme sent via mobile phone text message improves medication adherence and risk factor levels in patients following an acute coronary syndrome (ACS). STUDY DESIGN A single-blind, multicentre, randomised clinical trial of 1400 patients after an ACS with 12 months follow-up. The intervention group will receive multiple weekly text messages that provide information, motivation, support to adhere to medications, quit smoking (if relevant) and recommendations for healthy diet and exercise. The primary endpoint is the percentage of patients who are adherent to cardioprotective medications and the key secondary outcomes are mean systolic blood pressure (BP) and low-density lipoprotein cholesterol. Secondary outcomes will also include total cholesterol, mean diastolic BP, the percentage of participants who are adherent to each cardioprotective medication class, the percentage of participants who achieve target levels of CV risk factors, major vascular events, hospital readmissions and all-cause mortality. The study will be augmented by formal economic and process evaluations to assess acceptability, utility and cost-effectiveness. SUMMARY The study will provide multicentre randomised trial evidence of the effects of a text message-based programme on cardioprotective medication adherence and levels of CV risk factors. ETHICS AND DISSEMINATION Primary ethics approval was received from Western Sydney Local Health District Human Research Ethics Committee (HREC2012/12/4.1 (3648) AU RED HREC/13/WMEAD/15). Results will be disseminated via peer-reviewed publications and presentations at international conferences. TRIAL REGISTRATION NUMBER ACTRN12613000793718; Pre-results.
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One-Year Outcome of Intensive Insulin Therapy Combined to Glucose-Insulin-Potassium in Acute Coronary Syndrome: A Randomized Controlled Study.
Bouida, W, Beltaief, K, Msolli, MA, Bzeouich, N, Sekma, A, Echeikh, M, Mzali, M, Boubaker, H, Grissa, MH, Boukef, R, et al
Journal of the American Heart Association. 2017;(11)
Abstract
BACKGROUND A number of factors may offset the cardioprotective effects of glucose-insulin-potassium (GIK) on outcome of patients with acute coronary syndrome, such as hyperglycemia induced by this cocktail infusion. We performed a study to evaluate the effect of intensive insulin therapy in association with GIK on 1-year outcome in patients hospitalized for acute coronary syndrome. METHODS AND RESULTS In a randomized prospective controlled trial we included 772 patients with non-ST-segment elevation acute coronary syndrome. Patients were randomized into 3 groups: GIKI2 group, who received GIK with intensive insulin therapy for 24 hours; GIK group, who received GIK with nonintensive insulin therapy; and control group, who received usual care. The primary outcome criteria were the rates of major cardiovascular events combining death, reinfarction, and stroke rate at 1 year. In addition, we measured platelet function assay-100 and plasminogen activator inhibitor-1 at admission and 24 hours later. Based on an intention-to-treat analysis, major cardiovascular events at 1 year was 12.8% in the GIKI2 group, 15.5% in the GIK group, and 20.5% in the placebo group; the difference was significant between the GIK2 and control groups (P=0.01). Platelet function assay-100 at 24 hours decreased significantly from baseline in the control group but not in the GIKI2 group. Plasminogen activator inhibitor-1 decreased significantly in the GIKI2 group but significantly increased in the control group. Minor hypoglycemic events were more frequent in the GIKI2 group compared with other groups. CONCLUSIONS GIKI2 led to improvement of 1-year outcome rates in patients with non-ST-segment elevation acute coronary syndrome. This beneficial effect was associated with a decrease in platelet reactivity and an increase on fibrinolysis tests. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00965406.