RESUMO
BACKGROUND: Olpasiran, a small interfering RNA (siRNA), blocks lipoprotein(a) (Lp(a)) production by preventing translation of apolipoprotein(a) mRNA. In phase 2, higher doses of olpasiran every 12 weeks (Q12W) reduced circulating Lp(a) by >95%. OBJECTIVES: This study sought to assess the timing of return of Lp(a) to baseline after discontinuation of olpasiran, as well as longer-term safety. METHODS: OCEAN(a)-DOSE (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study) was a phase 2, dose-finding trial that enrolled 281 participants with atherosclerotic cardiovascular disease and Lp(a) >150 nmol/L to 1 of 4 active doses of olpasiran vs placebo (10 mg, 75 mg, 225 mg Q12W, or an exploratory dose of 225 mg Q24W given subcutaneously). The last dose of olpasiran was administered at week 36; after week 48, there was an extended off-treatment follow-up period for a minimum of 24 weeks. RESULTS: A total of 276 (98.2%) participants entered the off-treatment follow-up period. The median study exposure (treatment combined with off-treatment phases) was 86 weeks (Q1-Q3: 79-99 weeks). For the 75 mg Q12W dose, the off-treatment placebo-adjusted mean percent change from baseline in Lp(a) was -76.2%, -53.0%, -44.0%, and -27.9% at 60, 72, 84, and 96 weeks, respectively (all P < 0.001). The respective off-treatment changes in Lp(a) for the 225 mg Q12W dose were -84.4%, -61.6%, -52.2%, and -36.4% (all P < 0.001). During the extension follow-up phase, no new safety concerns were identified. CONCLUSIONS: Olpasiran is a potent siRNA with prolonged effects on Lp(a) lowering. Participants receiving doses ≥75 mg Q12W sustained a â¼40% to 50% reduction in Lp(a) levels close to 1 year after the last dose. (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study [OCEAN(a)-DOSE]; NCT04270760).
Assuntos
Relação Dose-Resposta a Droga , Lipoproteína(a) , RNA Interferente Pequeno , Humanos , Lipoproteína(a)/sangue , Masculino , Feminino , Pessoa de Meia-Idade , RNA Interferente Pequeno/administração & dosagem , Idoso , Resultado do Tratamento , Método Duplo-Cego , Aterosclerose/tratamento farmacológico , Aterosclerose/sangue , Ácidos Dicarboxílicos , Ácidos GraxosRESUMO
BACKGROUND: Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS: Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS: Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).
Assuntos
Anticolesterolemiantes , Aterosclerose , Hipercolesterolemia , Lipoproteína(a) , RNA Interferente Pequeno , Humanos , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Método Duplo-Cego , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Lipoproteína(a)/análise , Lipoproteína(a)/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Inibidores de PCSK9/uso terapêutico , Ezetimiba/uso terapêuticoRESUMO
BACKGROUND: Data support lipoprotein(a) (Lp[Lp(a)]) being a risk factor for atherosclerotic cardiovascular disease (ASCVD). Olpasiran is a small interfering RNA molecule that markedly reduces Lp(a) production in hepatocytes. STUDY DESIGN: The Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study is a multicenter, randomized, double-blind, placebo-controlled dose-finding study in 281 subjects with established ASCVD and Lp(a) > 150 nmol/L. Patients were randomly allocated to one of 4 active subcutaneous doses of olpasiran (10 mg q12 weeks, 75 mg q12 weeks, 225 mg q 12 weeks, or 225 mg q24 weeks) or matched placebo. The primary objective is to evaluate the effects of olpasiran dosed every 12 weeks compared with placebo on the percent change in Lp(a) from baseline at 36 weeks. Enrollment is now complete and follow-up is ongoing. CONCLUSIONS: OCEAN(a)-DOSE trial is assessing the Lp(a)-lowering efficacy and safety of olpasiran. These data will be used to determine optimal dosing and design for a cardiovascular outcomes trial.
Assuntos
Aterosclerose , Doenças Cardiovasculares , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Humanos , Lipoproteína(a) , Fatores de Risco , Resultado do TratamentoRESUMO
AIMS: Some trials have reported diminished efficacy for statins in the elderly, and in women compared with men. We examined the efficacy and safety of evolocumab by patient age and sex in the FOURIER trial, the first major cardiovascular outcome trial of a PCSK9 inhibitor. METHODS AND RESULTS: FOURIER was a randomised, double blind trial, comparing evolocumab with placebo in 27,564 patients with atherosclerotic cardiovascular disease receiving statin therapy (median follow-up 2.2 years). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina or coronary revascularisation. Cox proportional hazards models were used to assess the efficacy of evolocumab versus placebo stratified by quartiles of patient age and by sex. There were small variations in the cardiovascular event rate across the age range (for the primary endpoint, Kaplan-Meier at 3 years 15.6%, >69 years, vs. 15.1%, ≤56 years, P = 0.45); however, the relative efficacy of evolocumab was consistent regardless of patient age (for the primary endpoint (Q1 hazard ratio, 95% confidence interval) 0.83, 0.72-0.96, Q2 0.88, 0.76-1.01, Q3 0.82, 0.71-0.95, Q4 0.86, 0.74-1.00; Pinteraction = 0.91), and the key secondary endpoint (cardiovascular death, myocardial infarction, stroke) (Q1 0.74 (0.61-0.89), Q2 0.83 (0.69-1.00), Q3 0.78 (0.65-0.94), Q4 0.82 (0.69-0.98)); Pinteraction = 0.81). Women had a lower primary endpoint rate than men (Kaplan-Meier at 3 years 12.5 vs. 15.3%, respectively, P < 0.001). Relative risk reductions in the primary endpoint and key secondary endpoint were similar in women (0.81 (0.69-0.95) and 0.74 (0.61-0.90), respectively) compared with men (0.86 (0.80-0.94) and 0.81 (0.73-0.90), respectively), Pinteraction = 0.48 and 0.44, respectively. Adverse events were more common in women and with increasing age but, with the exception of injection site reactions, there were no important significant differences reported by those assigned evolocumab versus placebo. CONCLUSIONS: The efficacy and safety of evolocumab are similar throughout a broad range of ages and in both men and women.
Assuntos
Anticolesterolemiantes , Pró-Proteína Convertase 9 , Idoso , Angina Instável , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Pré-Escolar , LDL-Colesterol , Método Duplo-Cego , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Lipoprotein apheresis (LA) can effectively lower lipoproteins but is an invasive procedure. OBJECTIVE: The objective of this study was to evaluate whether evolocumab can reduce LA requirement in patients undergoing chronic LA. METHODS: Patients on regular weekly or every-2-week LA and moderate- to high-intensity statin (if tolerated) with pre-LA low-density lipoprotein cholesterol (LDL-C) levels ≥2.6 mmol/L (100 mg/dL) to ≤4.9 mmol/L (190 mg/dL) were randomized to continue the same LA frequency, or discontinue LA and receive evolocumab 140 mg every-2-weeks subcutaneously for 6 weeks. At week 6, all patients received only open-label evolocumab for 18 weeks. The primary endpoint was LA avoidance at the end of 6 weeks based on achieving pre-LA LDL-C <2.6 mmol/L at week 4. RESULTS: Thirty-nine patients (mean [SD] age 62 [10] years, 59% male, 82% with familial hypercholesterolemia) were randomized (evolocumab, n = 19; LA, n = 20). At the end of 6 weeks, more patients receiving evolocumab avoided LA than those receiving LA (84% vs 10%; treatment difference, 74% [95% CI: 45, 87]; P < .0001). Thirty patients (77%) did not require LA at 24 weeks. Evolocumab reduced pre-LA LDL-C by 50% from the baseline to week 4 compared with a 3% increase in the LA arm. Pre-LA LDL-C <1.8 mmol/L (70 mg/dL) was achieved by 10 patients (53%) receiving evolocumab and none receiving LA (week 4). Safety was comparable between arms. CONCLUSION: Evolocumab treatment significantly reduced LA requirement in patients undergoing chronic LA. In addition, >50% of patients achieved LDL-C <1.8 mmol/L on evolocumab alone, demonstrating that in patients with pre-LA LDL-C ≤4.9 mmol/L, evolocumab may replace LA.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Remoção de Componentes Sanguíneos/métodos , Lipoproteínas/sangue , Anticorpos Monoclonais , Proteínas de Transferência de Ésteres de Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/terapia , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/sangueRESUMO
BACKGROUND: Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and in patients with chronic heart failure. OBJECTIVES: This study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy of OM in patients with acute heart failure (AHF). METHODS: Patients admitted for AHF with left ventricular ejection fraction ≤40%, dyspnea, and elevated plasma concentrations of natriuretic peptides were randomized to receive a double-blind, 48-h intravenous infusion of placebo or OM in 3 sequential, escalating-dose cohorts. RESULTS: In 606 patients, OM did not improve the primary endpoint of dyspnea relief (3 OM dose groups and pooled placebo: placebo, 41%; OM cohort 1, 42%; cohort 2, 47%; cohort 3, 51%; p = 0.33) or any of the secondary outcomes studied. In supplemental, pre-specified analyses, OM resulted in greater dyspnea relief at 48 h (placebo, 37% vs. OM, 51%; p = 0.034) and through 5 days (p = 0.038) in the high-dose cohort. OM exerted plasma concentration-related increases in left ventricular systolic ejection time (p < 0.0001) and decreases in end-systolic dimension (p < 0.05). The adverse event profile and tolerability of OM were similar to those of placebo, without increases in ventricular or supraventricular tachyarrhythmias. Plasma troponin concentrations were higher in OM-treated patients compared with placebo (median difference at 48 h, 0.004 ng/ml), but with no obvious relationship with OM concentration (p = 0.95). CONCLUSIONS: In patients with AHF, intravenous OM did not meet the primary endpoint of dyspnea improvement, but it was generally well tolerated, it increased systolic ejection time, and it may have improved dyspnea in the high-dose group. (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure [ATOMIC-AHF]; NCT01300013).
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Ventrículos do Coração/fisiopatologia , Contração Miocárdica/efeitos dos fármacos , Volume Sistólico/fisiologia , Ureia/análogos & derivados , Função Ventricular Esquerda/fisiologia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Troponina/sangue , Ureia/administração & dosagem , Ureia/farmacocinética , Função Ventricular Esquerda/efeitos dos fármacos , Adulto JovemRESUMO
OBJECTIVES: This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses. BACKGROUND: Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients. METHODS: The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and at week 12. RESULTS: Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups. CONCLUSIONS: Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905).
Assuntos
Anticorpos Monoclonais/efeitos dos fármacos , Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertases/antagonistas & inibidores , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Apoptose , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Tolerância a Medicamentos , Feminino , Seguimentos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/imunologia , Masculino , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases serum LDL-cholesterol (LDL-C) concentrations. We assessed the effects of AMG 145, a human monoclonal antibody against PCSK9, in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment. METHODS: In a phase 2 trial done at 52 centres in Europe, the USA, Canada, and Australia, patients (aged 18-75 years) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were randomly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg, 105 mg, or 140 mg, or placebo every 2 weeks; subcutaneous AMG 145 280 mg, 350 mg, or 420 mg or placebo every 4 weeks; or oral ezetimibe 10 mg/day. The primary endpoint was percentage change from baseline in LDL-C concentration at week 12. Analysis was by modified intention to treat. Study personnel and patients were masked to treatment assignment of AMG 145 or placebo. Ezetimibe assignment was open label. This trial is registered with ClinicalTrials.gov, number NCT01375777. FINDINGS: 406 patients were assigned to AMG 145 70 mg (n=45), 105 mg (n=46), or 140 mg (n=45) every 2 weeks; AMG 145 280 mg (n=45), 350 mg (n=45), or 420 mg (n=45) every 4 weeks; placebo every 2 weeks (n=45) or every 4 weeks (n=45); or ezetimibe (n=45). AMG 145 significantly reduced LDL-C concentrations in all dose groups (mean baseline LDL-C concentration 3·7 mmol/L [SD 0·6]; changes from baseline with every 2 weeks AMG 145 70 mg -41·0% [95% CI -46·2 to -35·8]; 105 mg -43·9% [-49·0 to -38·7]; 140 mg -50·9% [-56·2 to -45·7]; every 4 weeks AMG 145 280 mg -39·0% [-44·1 to -34·0]; 350 mg -43·2% [-48·3 to -38·1]; 420 mg -48·0% [-53·1 to -42·9]; placebo every 2 weeks -3·7% [-9·0 to 1·6]; placebo every 4 weeks 4·5% [-0·7 to 9·8]; and ezetimibe -14·7% [-18·6 to -10·8]; p<0·0001 for all doses vs placebo or ezetimibe). Treatment-emergent adverse events occurred in 136 (50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or serious treatment-related adverse events were reported. INTERPRETATION: The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse populations including patients with documented statin intolerance. FUNDING: Amgen.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertases/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone for the prevention of atherosclerotic heart disease, improving clinical outcomes and reducing vascular mortality in patients with hypercholesterolemia. The clinical benefits of LDL-C reduction appear to extend even to patients starting with LDL-C as low as 60-80 mg/dL prior to initiating therapy. Statins are the first-line agents for treating hypercholesterolemia and are effective in reducing LDL-C, but many patients are unable to achieve their optimal lipid targets despite intensive statin therapy. Therefore, there has been a strong impetus for the development of novel pharmacologic agents designed to lower LDL-C further in patients already on statin therapy. Genetic mutations resulting in altered cholesterol homeostasis provide valuable information regarding novel approaches for treating hypercholesterolemia. To that end, mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) were linked to altered levels of LDL-C, illustrating this protein's role in lipid metabolism. PCSK9 promotes degradation of the LDL receptor, preventing its transport back to the cell surface and thereby increasing circulating LDL-C. Conversely, inhibition of PCSK9 can profoundly decrease circulating LDL-C, and thus is an attractive new target for LDL-C-lowering therapy. AMG 145 is a fully human monoclonal immunoglobulin G2 antibody that binds specifically to human PCSK9 and inhibits its interaction with the low-density lipoprotein receptor. In this manuscript, we describe the rationale and design of LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy-Thrombolysis In Myocardial Infarction 57 (LAPLACE-TIMI 57; NCT01380730), a 12-week, randomized, double-blind, dose-ranging, placebo-controlled study designed to assess the safety and efficacy of AMG 145 when added to statin therapy in patients with hypercholesterolemia.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertases/antagonistas & inibidores , Projetos de Pesquisa , Idoso , Anticorpos Monoclonais/farmacocinética , Anticolesterolemiantes/farmacocinética , Biomarcadores/sangue , LDL-Colesterol/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/enzimologia , Masculino , Pessoa de Meia-Idade , Placebos , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/metabolismo , Receptores de LDL/metabolismo , Serina Endopeptidases/metabolismo , Fatores de Tempo , Resultado do TratamentoRESUMO
AIMS: To assess the safety and tolerability of darbepoetin alfa (DA) in the treatment of anaemia in heart failure (HF). METHODS AND RESULTS: In this pooled analysis of three randomized, double-blind, placebo-controlled studies of anaemic [haemoglobin (Hb) < or =12.0 g/dL or < or =12.5 g/dL] symptomatic HF subjects, DA was administered subcutaneously once every 2 weeks and titrated to achieve and maintain a target Hb of 14.0 +/- 1.0 g/dL. In total, 516 subjects were randomized; 231 (44.8%) to placebo, 285 (55.2%) to DA. Darbepoetin alfa was well tolerated, with an adverse event (AE) profile similar to placebo. Most subjects (placebo, 85%; DA, 87%) experienced at least one AE. There was a lower incidence of serious AEs in the DA group (placebo, 43%; DA, 37%) with the most frequent being worsening HF (placebo, 19%; DA, 11%). Treatment-related AEs were reported for 9% and 12% in placebo and DA subjects, respectively. Fewer deaths were reported in DA group (6%) vs. placebo (8%). CONCLUSION: Darbepoetin alfa was well tolerated with an AE profile similar to placebo in HF subjects treated to a target Hb of 14.0 +/- 1.0 g/dL. Contrary to recent data in other patient populations, there was no evidence of increased risk of mortality or cardiovascular events.
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/análogos & derivados , Insuficiência Cardíaca/complicações , Hematínicos/efeitos adversos , Idoso , Anemia/etiologia , Darbepoetina alfa , Eritropoetina/efeitos adversos , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Hemoglobinas/análise , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de SobrevidaRESUMO
BACKGROUND: Substantial evidence suggests that anemia is an independent risk factor for worse outcomes in patients with heart failure (HF). The Study of Anemia in Heart Failure Trial (STAMINA-HeFT) is the largest multicenter, randomized, double-blind, placebo-controlled trial to date evaluating the effect of treating anemia in HF. METHODS AND RESULTS: Patients (N=319) with symptomatic HF, left ventricular ejection fraction < or = 40%, and hemoglobin > or = 9.0 g/dL and < or = 12.5 g/dL were randomized (double-blind) to placebo (N=157) or darbepoetin alfa (N=162) subcutaneously every 2 weeks for 1 year (target hemoglobin, 14.0+/-1.0 g/dL). The primary end point was change from baseline to week 27 in treadmill exercise time. Secondary end points were change from baseline in New York Heart Association class and quality of life at week 27. An additional prespecified efficacy analysis included the time to death by any cause or first HF-related hospitalization by 1 year. At baseline, the median (interquartile range) hemoglobin was 11.4 (10.9, 12.0) g/dL. At week 27, darbepoetin alfa treatment increased median (interquartile range) hemoglobin by 1.8 (1.1, 2.5) g/dL (placebo, 0.3 [-0.2, 1.0] g/dL; P<0.001). Of the patients treated with darbepoetin alfa, 85% achieved 2 consecutive hemoglobin levels of 14.0+/-1.0 g/dL during the study and experienced a hemoglobin increase of > or = 1.0 g/dL from baseline. By intent-to-treat analysis, darbepoetin alfa treatment did not significantly improve exercise duration, New York Heart Association class, or quality of life score compared with placebo. A nonsignificant trend was observed toward a lower risk of all-cause mortality or first HF hospitalization in darbepoetin alfa-treated patients compared with placebo (hazard ratio, 0.68; 95% CI, 0.43, 1.08; P=0.10). Occurrences of adverse events were similar in both treatment groups. CONCLUSIONS: In this study of patients with symptomatic HF and anemia, treatment with darbepoetin alfa was not associated with significant clinical benefits. Darbepoetin alfa treatment was well tolerated and effectively raised hemoglobin. A trend of lower risk of morbidity and mortality was observed.