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AIMS: Although the prevalence of heart failure (HF) increases markedly with advancing age, surprisingly little is known about HF in the very elderly. The aim of this study was to describe the clinical characteristics and outcomes of octogenarians with HF. METHODS AND RESULTS: Individual participant meta-analysis of patients with HF and reduced, mildly reduced, and preserved ejection fraction (HFrEF, HFmrEF, and HFpEF, respectively) enrolled in eight large randomized trials. Overall, the proportion of octogenarians was 1518 of 20 168 patients (7.5%) with HFrEF, 610 of 4609 (13.2%) with HFmrEF, and 3130 of 15 354 (20.4%) with HFpEF. Regardless of HF phenotype, octogenarian patients were more often female and had more comorbidities, more symptoms and signs of congestion, and worse health status (but not quality of life), in comparison to patients aged <80 years. The incidence (per 100 person-years) of the composite of cardiovascular death or HF hospitalization was 13.3 (95% confidence interval [CI] 12.7-14.0) in octogenarians versus 9.5 (95% CI 9.3-9.7) in non-octogenarians (adjusted hazard ratio [aHR] 1.40, 95% CI 1.32-1.48). Each component of the composite was more frequent in octogenarians with rates of cardiovascular mortality of 7.0 (95% CI 6.5-7.4) per 100 person-years versus 4.9 (95% CI 4.8-5.1) in non-octogenarians (aHR 1.60, 95% CI 1.48-1.72, p < 0.001). Octogenarians received less evidence-based therapy, especially mineralocorticoid receptor antagonists, than younger patients. CONCLUSION: Despite worse health status and higher hospitalization and mortality rates, octogenarians were undertreated compared to younger patients.
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BACKGROUND: ST-segment-elevation myocardial infarction (STEMI) guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. Full-dose tenecteplase is associated with an increased risk of intracranial hemorrhage in older patients. Whether pharmaco-invasive treatment with half-dose tenecteplase is effective and safe in older patients with STEMI is unknown. METHODS: STREAM-2 (Strategic Reperfusion in Elderly Patients Early After Myocardial Infarction) was an investigator-initiated, open-label, randomized, multicenter study. Patients ≥60 years of age with ≥2 mm ST-segment elevation in 2 contiguous leads, unable to undergo primary PCI within 1 hour, were randomly assigned (2:1) to half-dose tenecteplase followed by coronary angiography and PCI (if indicated) 6 to 24 hours after randomization, or to primary PCI. Efficacy end points of primary interest were ST resolution and the 30-day composite of death, shock, heart failure, or reinfarction. Safety assessments included stroke and nonintracranial bleeding. RESULTS: Patients were assigned to pharmaco-invasive treatment (n=401) or primary PCI (n=203). Median times from randomization to tenecteplase or sheath insertion were 10 and 81 minutes, respectively. After last angiography, 85.2% of patients undergoing pharmaco-invasive treatment and 78.4% of patients undergoing primary PCI had ≥50% resolution of ST-segment elevation; their residual median sums of ST deviations were 4.5 versus 5.5 mm, respectively. Thrombolysis In Myocardial Infarction flow grade 3 at last angiography was ≈87% in both groups. The composite clinical end point occurred in 12.8% (51/400) of patients undergoing pharmaco-invasive treatment and 13.3% (27/203) of patients undergoing primary PCI (relative risk, 0.96 [95% CI, 0.62-1.48]). Six intracranial hemorrhages occurred in the pharmaco-invasive arm (1.5%): 3 were protocol violations (excess anticoagulation in 2 and uncontrolled hypertension in 1). No intracranial bleeding occurred in the primary PCI arm. The incidence of major nonintracranial bleeding was low in both groups (<1.5%). CONCLUSIONS: Halving the dose of tenecteplase in a pharmaco-invasive strategy in this early-presenting, older STEMI population was associated with electrocardiographic changes that were at least comparable to those after primary PCI. Similar clinical efficacy and angiographic end points occurred in both treatment groups. The risk of intracranial hemorrhage was higher with half-dose tenecteplase than with primary PCI. If timely PCI is unavailable, this pharmaco-invasive strategy is a reasonable alternative, provided that contraindications to fibrinolysis are observed and excess anticoagulation is avoided. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02777580.
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Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Idoso , Tenecteplase/uso terapêutico , Fibrinolíticos/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio/tratamento farmacológico , Hemorragias Intracranianas/induzido quimicamente , Hemorragia/induzido quimicamente , Resultado do Tratamento , Anticoagulantes/uso terapêutico , Terapia Trombolítica/efeitos adversosRESUMO
BACKGROUND: Type 2 diabetes and prediabetes are risk factors for heart failure and adverse heart failure outcomes. The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial showed that dapagliflozin was associated with a reduction in the primary outcome of worsening heart failure or cardiovascular mortality in patients with heart failure with mildly reduced or preserved ejection fraction. We aimed to assess the efficacy and safety of oral dapagliflozin in these patients by their baseline glycaemia categories. METHODS: DELIVER was an international, multicentre, double-blind, randomised, placebo-controlled trial done in 350 health-care centres and hospitals across 20 countries. Patients aged 40 years or older with New York Heart Association class II-IV, left ventricular ejection fraction of more than 40%, elevated natriuretic peptides (N-terminal pro B-type natriuretic peptide ≥300 pg/mL or ≥600 pg/mL for patients in atrial fibrillation or flutter), and evidence of structural heart disease were randomly assigned (1:1) to 10 mg dapagliflozin or placebo, administered orally, and followed up for a median of 2·3 years (IQR 1·7-2·8). The primary outcome, a composite of time from randomisation to first worsening heart failure events (defined as an unplanned hospitalisation or urgent heart failure visit requiring intravenous therapy) or cardiovascular death, in participants with type 2 diabetes (history of or identified by HbA1c ≥6·5% [48 mmol/mol] at baseline) or prediabetes (HbA1c 5·7 to <6·5% [39 mmol/mol to <48 mmol/mol] at baseline) was compared with those with normoglycaemia (HbA1c <5·7% [39 mmol/mol]). Efficacy of dapagliflozin versus placebo was assessed according to glycaemic status and based on HbA1c as a continuous measure. The full-analysis set comprised all patients who were randomly assigned to study treatment, with patients analysed according to their randomised treatment assignment, irrespective of the treatment received (ie, intention to treat). The safety analysis set comprised patients who were randomly assigned to study treatment and who took at least one dose of investigational product, with patients analysed according to the treatment actually received. This trial is registered with ClinicalTrials.gov, NCT03619213. FINDINGS: Between Sept 1, 2018, and Jan 18, 2021, 6263 patients were randomly assigned to oral dapagliflozin (n=3131) or placebo (n=3132). Of these patients, 1175 had normoglycaemia, 1934 had prediabetes, and 3150 had type 2 diabetes and were included in the glycaemia subgroup analysis (3515 [56·2%] of 6263 patients were men and 4435 [70·9%] were White). The incidence rate of the primary outcome was 6·9 per 100 patient-years in the normoglycaemia subgroup (reference), increasing to 7·6 per 100 patient-years in the prediabetes subgroup (hazard ratio 1·09 [95% CI 0·90-1·31]) and 10·1 per 100 patient-years in the type 2 diabetes subgroup (1·46 [1·24-1·73]; p<0·0001 for trend). Dapagliflozin reduced the risk of the primary outcome versus placebo in each subgroup (hazard ratio 0·77 [95% CI 0·57-1·04], log-rank p=0·088, for patients with normoglycaemia, 0·87 [0·69-1·08], log-rank p=0·21, for patients with prediabetes, and 0·81 [0·69-0·95], log-rank p=0·0077, for patients with type 2 diabetes; pinteraction=0·82) and across the continuous HbA1c range (pinteraction=0·85). Volume-related or renal serious adverse events or adverse events leading to discontinuation of the study drug, hypoglycaemia, and amputations were not differentially affected by treatment in any of the glycaemia categories. INTERPRETATION: In patients with heart failure with mildly reduced or preserved ejection fraction, oral dapagliflozin improved heart failure outcomes to a similar extent in three glycaemia subgroups: normoglycaemia, prediabetes, and type 2 diabetes. Moreover, the heart failure benefits of dapagliflozin seem to be consistent across a continuous glycaemic range. FUNDING: AstraZeneca.
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Estado Pré-Diabético , Masculino , Humanos , Feminino , Volume Sistólico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estado Pré-Diabético/complicações , Função Ventricular Esquerda , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , GlicemiaRESUMO
OBJECTIVES: This study investigated the prognostic importance of heart failure (HF) signs and symptoms in patients with heart failure and preserved ejection fraction (HFpEF), and the effect of sacubitril/valsartan on HF signs and symptoms. BACKGROUND: In patients with HFpEF, worsening of HF symptoms, as a marker of cardiac decompensation, is frequently the reason for hospitalization. In this heterogenous disease entity, the prognostic value of HF signs and symptoms with regard to cardiovascular (CV) outcomes is poorly defined. METHODS: The authors examined the association between baseline HF signs and symptoms (rest dyspnea, exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue, edema, jugular venous distension, rales, and third heart sound) as well as burden of these HF signs and symptoms (classified as ≤2 and ≥3 HF signs and symptoms) and the primary composite of total HF hospitalizations and CV death, its components, and all-cause death in 4,725 patients enrolled in PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HFpEF) with available signs and symptoms at randomization. Response to sacubitril/valsartan on the basis of the presence of signs and symptoms was evaluated. Effects of sacubitril/valsartan on signs and symptoms over time were assessed using binary repeated-measures logistic regression. RESULTS: Patients with high (≥3) burden of HF signs and symptoms (n = 1,772 [38%]) were more commonly women, had slightly lower left ventricular ejection fractions, higher body mass index, and more advanced New York Heart Association functional class compared with patients with low (≤2) burden (n = 2,953 [62%]) (p < 0.001 for all). Levels of N-terminal pro-B-type natriuretic peptide did not differ significantly between groups (p = 0.14). Greater burden of signs and symptoms was associated with higher risk for total HF hospitalizations and CV death (rate ratio [RR]: 1.50; 95% confidence interval [CI]: 1.30 to 1.74) and all-cause death (RR: 1.41; 95% CI: 1.21 to 1.65). Among individual signs and symptoms, orthopnea (RR: 1.29; 95% CI: 1.04 to 1.61) and rales (RR: 1.52; 95% CI: 1.10 to 2.10) were most predictive of the primary endpoint. Treatment response to sacubitril/valsartan was not significantly modified by burden of HF signs and symptoms (p for interaction = 0.08), though patients with orthopnea appeared to derive greater benefit from sacubitril/valsartan (RR: 0.67; 95% CI: 0.49 to 0.90) than those without orthopnea (RR: 0.97; 95% CI: 0.82 to 1.14; p for interaction = 0.04). Compared with valsartan, sacubitril/valsartan did not significantly decrease overall burden of HF signs and symptoms over time (odds ratio: 0.84; 95% CI: 0.67 to 1.07) but did reduce exertional dyspnea (odds ratio: 0.76; 95% CI: 0.63 to 0.93). CONCLUSIONS: High burden of HF signs and symptoms, particularly the presence of orthopnea and rales, portends a higher risk for adverse CV events in patients with HF with preserved ejection fraction. Sacubitril/valsartan did not significantly decrease the burden of HF signs and symptoms over time but did reduce exertional dyspnea relative to valsartan. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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Insuficiência Cardíaca , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Humanos , Prognóstico , Estudos Prospectivos , Volume SistólicoRESUMO
BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).
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Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Doenças Cardiovasculares/mortalidade , Insuficiência Cardíaca/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Neprilisina/antagonistas & inibidores , Tetrazóis/administração & dosagem , Valsartana/administração & dosagem , Idoso , Aminobutiratos/efeitos adversos , Angioedema/induzido quimicamente , Antagonistas de Receptores de Angiotensina/efeitos adversos , Compostos de Bifenilo , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipotensão/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Fatores Sexuais , Método Simples-Cego , Volume Sistólico , Tetrazóis/efeitos adversos , Valsartana/efeitos adversosRESUMO
BACKGROUND: The safety and efficacy of ticagrelor in patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remain uncertain. OBJECTIVES: The primary objective of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial is to evaluate the short-term safety of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. Key secondary objectives are to assess the safety and efficacy of ticagrelor compared with clopidogrel at 12-months. DESIGN: The TREAT trial is a multicenter, randomized, phase III, Prospective randomized open blinded end-point (PROBE) study that enrolled 3,799 patients in 152 sites from 10 countries. Following administration of fibrinolytic therapy patients were randomized to a loading dose of ticagrelor 180 mg or clopidogrel 300 mg followed by a maintenance dose of ticagrelor 90 mg twice daily or clopidogrel 75 mg/day for 12-months. The primary outcome is the rate of TIMI major bleeding at 30-days and will be assessed for non-inferiority using an intention-to-treat analysis. Co-treatments include aspirin and anticoagulants. Other evidence based therapies are also recommended. Secondary efficacy outcome include a composite of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack or other arterial thrombotic event. All-cause mortality as well as individual components of the combined efficacy endpoint will also be ascertained. SUMMARY: TREAT is an international randomized controlled trial comparing ticagrelor with clopidogrel in STEMI patients treated with fibrinolytic therapy. The results of this trial will inform clinical practice and international guidelines.