RESUMO
BACKGROUND: Chronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease (CVD) or diabetes. Commonly used medications to treat CVD are less effective among patients with reduced kidney function. METHODS: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was a multicenter, double-blind, placebo-controlled trial that randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL) who had CVD or diabetes and 1 additional risk factor to treatment with icosapent ethyl (4 g daily) or placebo. Patients from REDUCE-IT were categorized by prespecified estimated glomerular filtration rate (eGFR) categories to analyze the effect of icosapent ethyl on the primary end point (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) and key secondary end point (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Among the 8179 REDUCE-IT patients, median baseline eGFR was 75 mL·min-1·1.73 m-2 (range, 17-123 mL·min-1·1.73 m-2). There were no meaningful changes in median eGFR for icosapent ethyl versus placebo across study visits. Treatment with icosapent ethyl led to consistent reduction in both the primary and key secondary composite end points across baseline eGFR categories. Patients with eGFR <60 mL·min-1·1.73 m-2 treated with icosapent ethyl had the largest absolute and similar relative risk reduction for the primary composite end point (icosapent ethyl versus placebo, 21.8% versus 28.9%; hazard ratio [HR], 0.71 [95% CI, 0.59-0.85]; P=0.0002) and key secondary composite end point (16.8% versus 22.5%; HR 0.71 [95% CI, 0.57-0.88]; P=0.001). The numeric reduction in cardiovascular death was greatest in the eGFR <60 mL·min-1·1.73 m-2 group (icosapent ethyl: 7.6%; placebo: 10.6%; HR, 0.70 [95% CI, 0.51-0.95]; P=0.02). Although patients with eGFR <60 mL·min-1·1.73 m-2 treated with icosapent ethyl had the highest numeric rates of atrial fibrillation/flutter (icosapent ethyl: 4.2%; placebo 3.0%; HR 1.42 [95% CI, 0.86-2.32]; P=0.17) and serious bleeding (icosapent ethyl: 5.4%; placebo 3.6%; HR, 1.40 [95% CI, 0.90-2.18]; P=0.13), HRs for atrial fibrillation/flutter and serious bleeding were similar across eGFR categories (P-interaction for atrial fibrillation/flutter=0.92; P-interaction for serious bleeding=0.76). CONCLUSIONS: In REDUCE-IT, icosapent ethyl reduced fatal and nonfatal ischemic events across the broad range of baseline eGFR categories. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.
Assuntos
Doenças Cardiovasculares , Ácido Eicosapentaenoico/análogos & derivados , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Renal Crônica , Idoso , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/fisiopatologia , Método Duplo-Cego , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/prevenção & controleRESUMO
BACKGROUND: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. METHODS: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. RESULTS: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63-0.92]; P=0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56-0.87]; P=0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50-0.81]; P=0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%-10.2%) in first events, with a number needed to treat of 16 (95% CI, 10-44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P=0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. CONCLUSIONS: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.
Assuntos
Ponte de Artéria Coronária , Ácido Eicosapentaenoico/análogos & derivados , Isquemia/prevenção & controle , Idoso , Método Duplo-Cego , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Humanos , Isquemia/etiologia , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Patients with elevated triglycerides despite statin therapy have increased risk for ischemic events, including coronary revascularizations. METHODS: REDUCE-IT (The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL), controlled low-density lipoprotein (41-100 mg/dL), and either established cardiovascular disease or diabetes plus other risk factors to receive icosapent ethyl 4 g/d or placebo. The primary and key secondary composite end points were significantly reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes. RESULTS: A total of 8179 randomly assigned patients were followed for 4.9 years (median). First revascularizations were reduced to 9.2% (22.5/1000 patient-years) with icosapent ethyl versus 13.3% (33.7/1000 patient-years) with placebo (hazard ratio, 0.66 [95% CI, 0.58-0.76]; P<0.0001; number needed to treat for 4.9 years=24); similar reductions were observed in total (first and subsequent) revascularizations (negative binomial rate ratio, 0.64 [95% CI, 0.56-0.74]; P<0.0001), and across elective, urgent, and emergent revascularizations. Icosapent ethyl significantly reduced percutaneous coronary intervention (hazard ratio, 0.68 [95% CI, 0.59-0.79]; P<0.0001) and coronary artery bypass grafting (hazard ratio, 0.61 [95% CI, 0.45-0.81]; P=0.0005). CONCLUSIONS: Icosapent ethyl reduced the need for first and subsequent coronary revascularizations in statin-treated patients with elevated triglycerides and increased cardiovascular risk. To our knowledge, icosapent ethyl is the first non-low-density lipoprotein-lowering treatment that has been shown to reduce coronary artery bypass grafting in a blinded, randomized trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Ácido Eicosapentaenoico/análogos & derivados , Revascularização Miocárdica/métodos , Inibidores da Agregação Plaquetária/uso terapêutico , Idoso , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus/fisiopatologia , Método Duplo-Cego , Ácido Eicosapentaenoico/uso terapêutico , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular events) and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03). A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004). Serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06). CONCLUSIONS: Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo. (Funded by Amarin Pharma; REDUCE-IT ClinicalTrials.gov number, NCT01492361 .).
Assuntos
Doenças Cardiovasculares/prevenção & controle , Ácido Eicosapentaenoico/análogos & derivados , Hipertrigliceridemia/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Idoso , Doenças Cardiovasculares/mortalidade , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Ácido Eicosapentaenoico/uso terapêutico , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Prevenção Secundária , Triglicerídeos/sangueRESUMO
BACKGROUND: Some trials have found that patients from the United States derive less benefit than patients enrolled outside the United States. This prespecified REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl - Intervention Trial) subgroup analysis was conducted to determine the degree of benefit of icosapent ethyl in the United States. METHODS: REDUCE-IT randomized 8179 statin-treated patients with qualifying triglycerides ≥135 and <500 mg/dL and low-density lipoprotein cholesterol >40 and ≤100 mg/dL and a history of atherosclerosis or diabetes mellitus to icosapent ethyl 4 g/d or placebo. The primary composite end point was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary composite end point was cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. A hierarchy was prespecified for examination of individual and composite end points. RESULTS: A total of 3146 US patients (38.5% of the trial) were randomized and followed for a median of 4.9 years; 32.3% were women and 9.7% were Hispanic. The primary composite end point occurred in 24.7% of placebo-treated patients versus 18.2% of icosapent ethyl-treated patients (hazard ratio [HR], 0.69 [95% CI, 0.59-0.80]; P=0.000001); the key secondary composite end point occurred in 16.6% versus 12.1% (HR, 0.69 [95% CI, 0.57-0.83]; P=0.00008). All prespecified hierarchical end points were meaningfully and significantly reduced, including cardiovascular death (6.7% to 4.7%; HR, 0.66 [95% CI, 0.49-0.90]; P=0.007), myocardial infarction (8.8% to 6.7%; HR, 0.72 [95% CI, 0.56-0.93]; P=0.01), stroke (4.1% to 2.6%; HR, 0.63 [95% CI, 0.43-0.93]; P=0.02), and all-cause mortality (9.8% to 7.2%; HR, 0.70 [95% CI, 0.55-0.90]; P=0.004); for all-cause mortality in the US versus non-US patients, Pinteraction=0.02. Safety and tolerability findings were consistent with the full study cohort. CONCLUSIONS: Whereas the non-US subgroup showed significant reductions in the primary and key secondary end points, the US subgroup demonstrated particularly robust risk reductions across a variety of individual and composite end points, including all-cause mortality. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01492361.
Assuntos
LDL-Colesterol/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Idoso , Método Duplo-Cego , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Fatores de Risco , Acidente Vascular Cerebral/mortalidade , Estados UnidosRESUMO
OBJECTIVE: The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed viral upper respiratory infection (URI)-related morbidity and mortality in adults with established atherosclerotic cardiovascular disease (ASCVD). BACKGROUND: IPE is a highly purified and stable omega-3 fatty acid prescription medication that is approved for cardiovascular risk reduction in high-risk adults on statin therapy with elevated triglycerides. Preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral URIs. METHODS: MITIGATE is a virtual, electronic health record-based, open-label, randomized, pragmatic clinical trial enrolling â¼16,500 participants within Kaiser Permanente Northern California - a fully integrated and learning health care delivery system with 21 hospitals and >255 ambulatory clinics serving â¼4.5 million members. Adults ≥50 years with established ASCVD and no prior history of coronavirus disease 2019 (COVID-19) will be prospectively identified and pre-randomized in a 1:10 allocation ratio (â¼ 1,500 IPE: â¼15,000 usual care) stratified by age and previous respiratory health status to the intervention (IPE 2 grams by mouth twice daily with meals) vs the control group (usual care) for a minimum follow-up duration of 6 months. The co-primary endpoints are moderate-to-severe laboratory-confirmed viral URI and worst clinical status due to a viral URI at any point in time. CONCLUSION: The MITIGATE study will inform clinical practice by providing evidence on the real-world clinical effectiveness of pretreatment with IPE to prevent and/or reduce the sequelae of laboratory-confirmed viral URIs in a high-risk cohort of patients with established ASCVD.
Assuntos
Aterosclerose/complicações , COVID-19/complicações , Doenças Cardiovasculares/prevenção & controle , Ácido Eicosapentaenoico/análogos & derivados , Inibidores da Agregação Plaquetária/uso terapêutico , Idoso , Doenças Cardiovasculares/complicações , Ácido Eicosapentaenoico/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Infecções Respiratórias/complicações , Infecções Respiratórias/virologiaRESUMO
AIM: To determine whether high triglycerides (TG) in the presence of statin-controlled LDL-C influence the risk of cardiovascular disease (CVD) among patients with diabetes in real-world clinical practice. MATERIALS AND METHODS: We identified adults with diabetes from the Southern California and Pacific Northwest regions of Kaiser Permanente. We included patients undergoing statin therapy with LDL-C from 40-100 mg/dL who were not undergoing other lipid-lowering therapies and had a prior diagnosis of atherosclerotic CVD or at least one other CVD risk factor. We grouped patients into high TG (200-499 mg/dL; n = 5542) or normal TG (<150 mg/dL, n = 22 411) from January 2010 through December 2016 to compare incidence rates and rate ratios of first non-fatal myocardial infarction (MI), non-fatal stroke, unstable angina and coronary revascularization. We adjusted multivariable analyses for age, sex, race/ethnicity, smoking status, blood pressure, HbA1c, serum creatinine, presence of ischaemic heart disease and study site. RESULTS: Adjusted rate ratios for the four outcomes were all statistically significantly different. The incidence rate for non-fatal MI was 30% higher in the high TG group (rate ratio, 1.30; 95% CI, 1.08-1.58; P = 0.006). The rate was 23% higher for non-fatal stroke (1.23, 1.01-1.49, P = 0.037), 21% higher for coronary revascularization (rate ratio, 1.21; 95% CI, 1.02-1.43; P = 0.027) and was, non-significantly, 33% higher for unstable angina (rate ratio, 1.33; 95% CI, 0.87-2.03; P = 0.185). CONCLUSIONS: Despite statin-controlled LDL-C levels, CV events were greater among patients with diabetes and high TG levels. Because we controlled for cardiometabolic risk factors, it is likely that the difference in TG levels contributed to the excess risk observed in patients with high TGs.
Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/etiologia , LDL-Colesterol/efeitos dos fármacos , Diabetes Mellitus/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertrigliceridemia/complicações , Hipertrigliceridemia/tratamento farmacológico , Idoso , California/epidemiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Complicações do Diabetes/sangue , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/epidemiologia , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Hipertrigliceridemia/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangueRESUMO
BACKGROUND: A decade ago, statin persistence was < 50% after 1 year, and recent short-term analyses have revealed very little progress in improving statin persistence, even in patients with a prior cardiovascular (CV) event. Data on longer-term statin persistence are lacking. We measured long-term statin persistence in patients with high CV risk. METHODS: This retrospective administrative claims analysis of the Optum Research Database included patients aged ≥ 45 years with diabetes and/or atherosclerotic CV disease (ASCVD) who had a statin prescription filled in 2010. It included an elevated triglycerides (TG) cohort of patients with index date in 2010 and TG ≥ 150 mg/dL (n = 23,181) and a propensity-matched comparator cohort with TG < 150 mg/dL and high-density lipoprotein cholesterol > 40 mg/dL (n = 23,181). Both cohorts were followed for ≥ 6 months up to March 2016. RESULTS: The probability of remaining on a prescription fill for index statin therapy was 47% after 1 year and 19% after 5 years in both cohorts. Statin persistence was worse among women than men, and among younger versus older patients (P < 0.001 for all comparisons). After 5 years, the probability of remaining on a prescription fill for index statin was < 25% across all subgroups assessed including patients with and without baseline revascularization, heart failure, peripheral artery disease and renal disease. Similar results were observed in a subcohort analysis of patients with TG 200-499 mg/dL. CONCLUSIONS: Long-term statin persistence after 5 years is alarmingly low (< 25%) and is a public health concern.
Assuntos
Aterosclerose/tratamento farmacológico , LDL-Colesterol/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Triglicerídeos/sangue , Idoso , Angina Pectoris/sangue , Angina Pectoris/tratamento farmacológico , Angina Pectoris/fisiopatologia , Aterosclerose/sangue , Aterosclerose/fisiopatologia , HDL-Colesterol/sangue , LDL-Colesterol/antagonistas & inibidores , Comorbidade , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/fisiopatologia , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/fisiopatologia , Duração da Terapia , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Revisão da Utilização de Seguros/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/fisiopatologia , Estudos Retrospectivos , Fatores Sexuais , Triglicerídeos/antagonistas & inibidoresRESUMO
OBJECTIVE: To evaluate the efficacy of LX9211 in reducing pain related to diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS: In this double-blind, multicenter, proof-of-concept trial, 319 individuals with diabetic peripheral neuropathic pain (DPNP) were randomized (1:1:1) to LX9211 10 mg (n = 106), LX9211 20 mg (n = 106), or matching placebo (n = 107), administered once daily for 6 weeks. DPNP was rated daily with an 11-point numerical rating scale. The primary end point was change from baseline to week 6 in the average daily pain score. The difference between each LX9211 group and placebo was evaluated with mixed-model repeated-measures analysis. RESULTS: For those on low-dose LX9211 the primary efficacy end point was achieved: -1.39 vs. -0.72 points for placebo, least squares mean (SE) difference -0.67 (0.249), 95% CI -1.16 to -0.18, P = 0.007; results for high-dose LX9211 demonstrated improvement in pain severity versus placebo (-1.27 vs. -0.72 points, respectively), but the between-group LS mean difference did not reach the prespecified statistical significance (-0.55 [0.254], 95% CI -1.06 to -0.05, P = 0.030). Treatment benefit was observed beginning at week 1 and maintained thereafter. Results for LX9211 also demonstrated improvement in several patient-reported secondary outcomes. Most common adverse events (AEs) were dizziness, nausea, and headache. More participants treated with LX9211 (20 mg, n = 28 [26.4%]; 10 mg, 17 [16.0%]) than placebo (3 [2.8%]) discontinued study drug prematurely due to AEs; serious AEs were uncommon (2 [1.9%], 0, and 1 [0.9%], respectively). CONCLUSIONS: These preliminary findings of improvement in DPNP with LX9211 support further investigation in larger trials.
Assuntos
Neuropatias Diabéticas , Humanos , Método Duplo-Cego , Neuropatias Diabéticas/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neuralgia/tratamento farmacológico , Adulto , Resultado do Tratamento , Estudo de Prova de ConceitoRESUMO
Background: Recent studies have demonstrated a causal role for elevated triglycerides (TG) in incident cardiovascular (CV) events in patients with established coronary heart disease (CHD) and those with CV risk factors alone, particularly diabetes. Objective: Using a large cohort of U.S. veterans with statin-controlled LDL-C levels (40-100 mg/dL), we explored residual CV risk among patients with elevated baseline TG levels (150-499 mg/dL) vs. those with normal TG levels (<150 mg/dL). Methods: We identified veterans receiving a statin but not a TG-lowering agent from the VA electronic health records database, from 2010 to 2015. We compared composite CV event rates (MI, stroke, unstable angina, coronary revascularization, and CV death) between the elevated TG and normal TG groups. We stratified the study cohort according to 3 CV risk groups: (1) no diabetes and no prior CV event, (2) diabetes and no prior CV event, and (3) prior CV event. We calculated crude event rates, rate ratios, and event rate ratios adjusted for age, sex, systolic blood pressure, estimated glomerular filtration rate, and weight. Results: The cohort included 396,189 veterans (predominantly male and white) of whom 109,195 (28%) had elevated TG levels. Those with elevated TG were younger (age 73 vs. 77 years) and had a higher body mass index (31.3 vs. 28.3 Kg/M2). The overall composite crude and adjusted rate ratios comparing the elevated and normal TG groups were 1.10 (1.09, 1.12) and 1.05 (1.03, 1.06), respectively. For CV risk groups 1, 2 and 3, the adjusted rate ratios comparing the elevated and normal TG groups were 0.99 (0.96, 1.02), 1.05 (1.02, 1.08), and 1.07 (1.04, 1.10), respectively. An association of increased rate ratios did not hold for fatal events. Conclusion: Those with elevated TG levels and well-controlled LDL-C on statins showed a modest increase in CV events compared to those with normal TG. Elevated TG levels were associated with increased CV events in patients with established CV disease and with diabetes only, suggesting that elevated TG levels are associated with a similar degree of residual risk in high-risk primary prevention and secondary prevention settings.
RESUMO
OBJECTIVE: Patients with risk factors for or established atherosclerotic cardiovascular disease (ASCVD) remain at high risk for subsequent ischemic events despite statin therapy. Triglyceride (TG) levels may contribute to residual ASCVD risk, and the performance of global risk assessment calculators across a broad range of TG levels is unknown. METHODS: We performed a retrospective cohort study of Kaiser Permanente Northern California members aged ≥45 years with ≥1 ASCVD risk factor (primary prevention cohort) or established ASCVD (secondary prevention cohort) between 2010 and 2017 who were receiving statin therapy and had a low-density lipoprotein cholesterol between 41-100 mg/dL. Global ASCVD risk assessment was performed using both the Kaiser Permanente ASCVD Risk Estimator (KPARE) and the ACC/AHA ASCVD Pooled Cohort Equation (PCE). Outcomes included major adverse cardiovascular events (MACE) defined as myocardial infarction, stroke, or peripheral artery disease, and expanded MACE (MACE + coronary revascularization + hospitalization for unstable angina). RESULTS: Among 373,389 patients in the primary prevention cohort, median TG was 122 mg/dL (IQR 88-172 mg/dL) and there were 0.2 MACE events and 0.3 expanded MACE events per 100-person years. Among 97,832 patients in the secondary prevention cohort, median TG level was 116 mg/dL (IQR 84-164 mg/dL) and there were 9.6 MACE events and 22.0 expanded MACE events per 100-person years. KPARE and the ACC/AHA PCE stratified patients for MACE and expanded MACE over the entire range of TGs. CONCLUSION: In a cohort receiving statin therapy for primary or secondary prevention, we found global assessment further improves risk stratification for initial and/or recurrent ASCVD events irrespective of baseline TG level.
RESUMO
BACKGROUND: REDUCE-IT was a double-blind trial that randomized 8,179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in the primary endpoint, including death from cardiovascular (CV) causes. The specific impact of IPE among patients with prior myocardial infarction (MI) was unknown. OBJECTIVES: Our goal was to examine the benefit of IPE on ischemic events among patients with prior MI in REDUCE-IT. METHODS: We performed post hoc analyses of patients with prior MI. The primary endpoint was CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was CV death, MI, or stroke. RESULTS: A total of 3,693 patients had a history of prior MI. The primary endpoint was reduced from 26.1% to 20.2% with IPE vs placebo; HR: 0.74 (95% CI: 0.65-0.85; P = 0.00001). The key secondary endpoint was reduced from 18.0% to 13.3%; HR: 0.71 (95% CI: 0.61-0.84; P = 0.00006). There was also a significant 35% relative risk reduction in total ischemic events (P = 0.0000001), a 34% reduction in MI (P = 0.00009), a 30% reduction in CV death (P = 0.01), and a 20% lower rate of all-cause mortality (P = 0.054), although there was a slight increase in atrial fibrillation. Sudden cardiac death and cardiac arrest were also significantly reduced by 40% and 56%, respectively. CONCLUSIONS: Patients with a history of prior MI in REDUCE-IT treated with IPE demonstrated large and significant relative and absolute risk reductions in ischemic events, including CV death. (A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. [REDUCE-IT]; NCT01492361).
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Hipertrigliceridemia , Infarto do Miocárdio , Acidente Vascular Cerebral , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controleRESUMO
Background Patients who undergo percutaneous coronary intervention (PCI) are at increased risk for recurrent cardiovascular events despite aggressive medical therapy. Methods and Results This post hoc analysis focused on the subset of patients with prior PCI enrolled in REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial), a multicenter, randomized, double-blind, placebo-controlled trial of icosapent ethyl versus placebo. Icosapent ethyl was added to statins in patients with low-density lipoprotein cholesterol <100 mg/dL and fasting triglycerides 135-499 mg/dL. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. There were 8179 patients randomized in REDUCE-IT followed for a median of 4.9 years, and 3408 (41.7%) of them had a prior PCI with a median follow-up of 4.8 years. These patients were randomized a median of 2.9 years (11 days to 30.7 years) after PCI. Among patients treated with icosapent ethyl versus placebo, there was a 34% reduction in the primary composite end point (hazard ratio [HR], 0.66; 95% CI, 0.58-0.76; P<0.001; number needed to treat4.8 years=12) and a 34% reduction in the key secondary composite end point of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR, 0.66; 95% CI, 0.56-0.79; P<0.001; NNT4.8 years=19) versus placebo. Similarly, large reductions occurred in total coronary revascularizations and revascularization subtypes. There was also a 39% reduction in total events (rate ratio, 0.61; 95% CI, 0.52-0.72; P<0.001). Conclusions Among patients treated with statins with elevated triglycerides and a history of prior PCI, icosapent ethyl substantially reduced the risk of recurrent events during an average of ~5 years of follow-up with a number needed to treat of only 12. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Infarto do Miocárdio , Intervenção Coronária Percutânea , Acidente Vascular Cerebral , Método Duplo-Cego , Ácido Eicosapentaenoico/análogos & derivados , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Isquemia/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Intervenção Coronária Percutânea/efeitos adversos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento , TriglicerídeosRESUMO
More than 56 million Americans have hypertriglyceridemia, including over 12 million statin-treated individuals. However, the contribution of elevated and high triglyceride levels to cardiovascular disease and death has not been extensively studied using real-world analyses. We review recent analyses of the Optum Research Database, which included patients aged ≥45 years with diabetes and/or atherosclerotic cardiovascular disease and on statin therapy. Triglyceride levels ≥150 and 200-499 mg/dl were significantly associated with a 25.8 and 34.9% increased relative risk of cardiovascular events, respectively, versus patients with triglyceride levels <150 mg/dl. In addition, hypertriglyceridemia predicted peripheral arterial revascularization, new heart failure diagnosis and new-onset renal disease. Increased triglyceride levels were also significantly associated with increased healthcare resource utilization and costs. Interventions such as icosapent ethyl reduce triglycerides and associated cardiovascular disease risk.
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Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipertrigliceridemia , Aterosclerose/epidemiologia , Doenças Cardiovasculares/epidemiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertrigliceridemia/complicações , Hipertrigliceridemia/epidemiologia , TriglicerídeosRESUMO
Background Patients with risk factors or established atherosclerotic cardiovascular disease remain at high-risk for ischemic events. Triglyceride levels may play a causal role. Methods and Results We performed a retrospective study of adults aged ≥45 years receiving statin therapy, with a low-density lipoprotein cholesterol of 41 to 100 mg/dL, and ≥1 risk factor or established atherosclerotic cardiovascular disease between 2010 and 2017. Outcomes included death, all-cause hospitalization, and major adverse cardiovascular events (myocardial infarction, stroke, or peripheral artery disease). The study sample included 373 389 primary prevention patients and 97 832 secondary prevention patients. The primary prevention cohort had a mean age of 65±10 years, with 51% women and 44% people of color, whereas the secondary prevention cohort had a mean age of 71±11 years, with 37% women and 32% people of color. Median triglyceride levels for the primary and secondary prevention cohorts were 122 mg/dL (interquartile range, 88-172 mg/dL) and 116 mg/dL (interquartile range, 84-164 mg/dL), respectively. In multivariable analyses, primary prevention patients with triglyceride levels ≥150 mg/dL were at lower adjusted risk of death (hazard ratio [HR], 0.91; 95% CI, 0.89-0.94) and higher risk of major adverse cardiovascular events (HR, 1.14; 95% CI, 1.05-1.24). In the secondary prevention cohort, patients with triglyceride levels ≥150 mg/dL were at lower adjusted risk of death (HR, 0.95; 95% CI, 0.92-0.97) and higher risk of all-cause hospitalization (HR, 1.03; 95% CI, 1.01-1.05) and major adverse cardiovascular events (HR, 1.04; 95% CI, 1.05-1.24). Conclusions In a contemporary cohort receiving statin therapy, elevated triglyceride levels were associated with a greater risk of atherosclerotic cardiovascular disease events and lower risk of death.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Adulto , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , TriglicerídeosRESUMO
BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE. OBJECTIVES: The purpose of this study was to determine the effects of IPE on investigator-reported events. METHODS: Potential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance. RESULTS: There was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints. CONCLUSIONS: IPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361).
Assuntos
Ácido Eicosapentaenoico/análogos & derivados , Determinação de Ponto Final , Idoso , Angina Instável/epidemiologia , Ácido Eicosapentaenoico/uso terapêutico , Feminino , Humanos , Hipertrigliceridemia/tratamento farmacológico , Reguladores do Metabolismo de Lipídeos/uso terapêutico , Masculino , Infarto do Miocárdio/epidemiologia , Revascularização Miocárdica/estatística & dados numéricos , Acidente Vascular Cerebral/epidemiologiaRESUMO
INTRODUCTION: Hypertriglyceridemia is associated with increased atherosclerotic cardiovascular disease (ASCVD) event risk, which persists even in statin-treated patients. The objective of this analysis was to estimate the prevalence of triglyceride (TG) levels ≥ 150 mg/dl in statin-treated adults with diabetes or ASCVD in the United States. METHODS: Laboratory data, medical history, and prescription data from 40,617 subjects who participated in the US National Health and Nutrition Examination Survey (NHANES) spanning 8 years (four 2-year surveys; 2007-2014) were analyzed. Patients included were ≥ 20 years old and had morning fasting (at least 8.5 h) TG values available. The proportion and weighted number of individuals in the US population with TG ≥ 150 mg/dl was calculated according to statin use, as well as in key subgroups of statin-treated patients including those with low-density lipoprotein cholesterol (LDL-C) levels < 100 mg/dl, type 2 diabetes, ASCVD, and those with type 2 diabetes and ASCVD. RESULTS: A total of 9593 subjects, projected to represent 219.9 million Americans, met the study entry criteria and were included in the analysis. Of these, 2523 had TG levels ≥ 150 mg/dl, translating to a prevalence of 25.9% and representing 56.9 million Americans. Among statin-treated adults, the proportion with TG levels ≥ 150 mg/dl was 31.6% (12.3 million) and ranged from 27.6 to 39.5% for those who also had LDL-C levels < 100 mg/dl and type 2 diabetes or ASCVD. CONCLUSIONS: Over 12 million Americans are treated with a statin and have TG levels ≥ 150 mg/dl. Interventions such as icosapent ethyl that have been shown to reduce ASCVD event risk in this elevated TG population with type 2 diabetes or established ASCVD can provide substantial clinical benefit for these patients.
RESUMO
BACKGROUND: Elevated triglycerides (TGs) are associated with atherosclerotic cardiovascular disease (ASCVD). Despite statin therapy, many US adults have borderline or elevated TG levels. Not characterized is the ASCVD risk associated with borderline TG levels in statin users, including the estimated number of adults who will sustain ASCVD events. METHODS: We studied 4986 US adults (weighted to 113 million) aged 40-74 from the National Health and Nutrition Examination Surveys 2007-2014. The proportion of persons at low (<5%), borderline (5-<7.5%), intermediate (7.5-<20%), and high (≥20%) 10-year ASCVD risk among those on statins was quantified for low (<70 âmg/dL, 70-<100 âmg/dL), borderline (100-<135 âmg/dL and 135-<150 âmg/dL), borderline high (150-<200 âmg/dL), and elevated (≥200 âmg/dL) TGs. Multiple logistic regression examined these TG categories in relation to high risk status. RESULTS: Overall, 18.6% of participants had TG â< â70 âmg/dL, 24.2% TG 70-<100 âmg/dL, 22.0% TG 100-<135 âmg/dL, 6.2% TG 135-<150 âmg/dL, 15.0% TG 150-<200 âmg/dL, and 14.0% TG â≥ â200 âmg/dL. Mean 10-year ASCVD risk for these groups were 5.6%, 6.9%, 7.8%, 10.3%, 9.6% and 10.8%, respectively (p â< â0.0001). One-fifth or more of statin users with TGs over 135 âmg/dL were at ≥ 20% 10-year ASCVD risk and ≥60% of persons in all TG groups were at borderline or higher ASCVD risk. Compared to those with TGs <70 âmg/dL, multiple logistic regression showed odds ratios of 3.1 to 4.6 (p â< â0.05 to p â< â0.01) for those in TG groups ≥135 âmg/dL in the overall sample, but 3.4 to 8.1 (p â< â0.05 to p < 0.01) for those in TG groups of ≥100 âmg/dL in statin users, despite adjustment including HDL-C. CONCLUSION: Many US adults with borderline levels of TGs are at elevated ASCVD risk despite statin therapy, suggesting the need first for greater lifestyle modification efforts, and when indicated, evidence-based therapies known to reduce this residual ASCVD risk.
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The reduction of cardiovascular events with icosapent ethyl-intervention (REDUCE-IT) trial showed in persons with prior cardiovascular disease (CVD) or diabetes mellitus (DM) that icosapent ethyl (IPE) reduced CVD events by 25%. We projected the preventable initial and total CVD events if REDUCE-IT trial eligibility criteria were applied to US adults. We identified US adults with available REDUCE-IT inclusion criteria from NHANES Surveys 1999-2016 and estimated primary (CVD death, nonfatal myocardial infarction, stroke, revascularization, or unstable angina) and secondary composite (CVD death, nonfatal MI or stroke) events using REDUCE-IT published event rates in the IPE and placebo groups, the difference being the number of preventable events. From 11,445 adults aged ≥45 years (representing 111.1 million [M]), a total of 319 persons (3.0 M) fit key REDUCE-IT eligibility criteria: triglycerides of 135 to 499 mg/dL, HbA1c <10%, blood pressure <200/100 mm Hg, and on a statin with LDL-C of 40 to 99 mg/dL. 63% had prior CVD and 37% had DMâ¯+â¯≥1 risk factor (primary prevention cohort). If these persons are given IPE for the REDUCE-IT median trial period of 4.9 years, we estimated preventing a total 349,817 (71,391/year) primary CVD outcomes of which 146,011 (29,798/year) were initial events. Most (24,151) preventable events were from the secondary prevention cohort. Using FDA eligibility criteria, an estimated 4.6 million persons would be eligible for IPE, with 60,544 preventable primary CVD outcomes annually from REDUCE-IT USA event rates. In conclusion, many CVD events in US adults with known CVD or DM and well-controlled LDL-C on statin therapy can be prevented with IPE.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus/tratamento farmacológico , Ácido Eicosapentaenoico/análogos & derivados , Definição da Elegibilidade , Reguladores do Metabolismo de Lipídeos/uso terapêutico , Revascularização Miocárdica/estatística & dados numéricos , Idoso , Angina Instável/prevenção & controle , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/mortalidade , Ácido Eicosapentaenoico/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Inquéritos Nutricionais , Prevenção Primária , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controleRESUMO
BACKGROUND: Elevated triglycerides (TGs) are associated with increased risk of cardiovascular disease (CVD), but the best way to both measure TGs and assess TG-related risk remains unknown. OBJECTIVE: The objective of the study was to evaluate the association between TGs and CVD and determine whether the average of a series of TG measurements is more predictive of CVD risk than a single TG measurement. METHODS: We examined 15,792 study participants, aged 40-65 years, free of CVD from the Atherosclerosis Risk in Communities and Framingham Offspring studies, using fasting TG measurements across multiple examinations over time. With up to 10 years of follow-up, we assessed time-to-first CVD event, as well as a composite of myocardial infarction, stroke, or cardiovascular death. RESULTS: Compared with a single TG measurement, average TGs over time had greater discrimination for CVD risk (C-statistic, 0.60 vs 0.57). Risk for CVD increased as average TGs rose until an inflection point of ~100 mg/dL in men and ~200 mg/dL in women, above which this risk association plateaued. The relationship between average TGs and CVD remained statistically significant in multivariable modeling adjusting for low-density lipoprotein cholesterol, and interactions were found by sex and high-density lipoprotein cholesterol level. CONCLUSIONS: The average of several TG readings provides incremental improvements for the prediction of CVD relative to a single TG measurement. Regardless of the method of measurement, higher TGs were associated with increased CVD risk, even at levels previously considered "optimal" (<150 mg/dL).