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1.
Lancet ; 394(10211): 1816-1826, 2019 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-31668726

RESUMO

BACKGROUND: Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice. METHODS: We developed a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. The framework addressed residual confounding, publication bias, and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested. FINDINGS: Using 4·9 million patients, we generated 22 000 calibrated, propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR 0·84, 95% CI 0·75-0·95), hospitalisation for heart failure (0·83, 0·74-0·95), and stroke (0·83, 0·74-0·95) risk while on initial treatment. Safety profiles also favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes. INTERPRETATION: This comprehensive framework introduces a new way of doing observational health-care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension-in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers. FUNDING: US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Adolescente , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Criança , Estudos de Coortes , Pesquisa Comparativa da Efetividade/métodos , Bases de Dados Factuais , Diuréticos/efeitos adversos , Diuréticos/uso terapêutico , Medicina Baseada em Evidências/métodos , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/prevenção & controle , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Adulto Jovem
2.
Rev Cardiovasc Med ; 20(3): 111-120, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601085

RESUMO

Randomized controlled trials have demonstrated the benefits of guideline-directed medical therapy in the outpatient setting for treatment of chronic heart failure. However, the benefits of continuation (or discontinuation) of major chronic heart failure therapies when treating acute heart failure during hospitalization are less clear. Real and anticipated worsening renal function, hyperkalemia and hypotension are the three major reasons for discontinuation of renin-angiotensin-aldosterone system inhibitors during hospitalization, and a failure to resume renin-angiotensin-aldosterone system inhibitors before discharge could worsen cardiovascular outcomes. Available data, mostly observational, shows that continuation or initiation of renin-angiotensin-aldosterone system inhibitors appears efficacious, safe, and well tolerated in majority of acute heart failure patients during hospitalization. Worsening renal function portends poor prognosis only if associated with congestion in acute heart failure, and clinicians should not de-escalate diuretic therapy routinely for worsening renal function.


Assuntos
Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Síndrome Cardiorrenal/tratamento farmacológico , Diuréticos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Admissão do Paciente , Sistema Renina-Angiotensina/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Síndrome Cardiorrenal/diagnóstico , Síndrome Cardiorrenal/mortalidade , Síndrome Cardiorrenal/fisiopatologia , Tomada de Decisão Clínica , Diuréticos/efeitos adversos , Esquema de Medicação , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Fatores de Risco , Resultado do Tratamento
3.
Mayo Clin Proc ; 94(11): 2220-2229, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31619367

RESUMO

OBJECTIVE: To assess the patterns of angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACE-I/ARB) discontinuation in the setting of chronic kidney disease (CKD) progression in real-world clinical practice. PATIENTS AND METHODS: We identified incident ACE-I/ARB users with a baseline estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2 and without end-stage renal disease in the Geisinger Health System between January 1, 2004, and December 31, 2015. We investigated the associations of CKD stage, hospitalizations with and without acute kidney injury (AKI), serum potassium, bicarbonate level, thiazide, and loop diuretic use with ACE-I/ARB discontinuation. RESULTS: Among the 53,912 ACE-I/ARB users, the mean age was 59.9 years, and 50.6% were female. More than half of users discontinued ACE-I/ARB within 5 years of therapy initiation. The risk of ACE-I/ARB discontinuation increased with more advanced CKD stage. For example, patients who initiated ACE-I/ARB with CKD stage G4 (eGFR: 15-29 mL/min/1.73 m2) were 2.09-fold (95% CI, 1.87-2.34) more likely to discontinue therapy than those with eGFR ≥ 90 mL/min/1.73 m2. Potassium level greater than 5.3 mEq/L, systolic blood pressure ≤ 90 mm Hg, bicarbonate level < 22 mmol/L, and intervening hospitalization-particularly AKI-related-were also strong risk factors for ACE-I/ARB discontinuation. Thiazide diuretic use was associated with lower risk, whereas loop diuretic use was associated with higher risk of discontinuation. CONCLUSION: In a real-world cohort, discontinuation of ACE-I/ARB was common, particularly in patients with lower eGFR. Hyperkalemia, hypotension, low bicarbonate level, and hospitalization (AKI-related, in particular) were associated with a higher risk of ACE-I/ARB discontinuation. Additional studies are needed to evaluate the risk-benefit balance of discontinuing ACE-I/ARB in the setting of CKD progression.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Adesão à Medicação , Insuficiência Renal Crônica/tratamento farmacológico , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco
4.
Medicine (Baltimore) ; 98(39): e17296, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574852

RESUMO

The angiotensin-receptor-neprilysin inhibitor (ARNI) reduced cardiovascular deaths and heart failure hospitalization in patients with heart failure of reduced ejection fraction (HFrEF). Its role in non-HFrEF patients was not clear. This study aims to answer this question.In this retrospective study, we enrolled 928 patients diagnosed with non-HFrEF, 492 of them received angiotensin converting enzyme inhibitor (ACEI) and the rest 436 received angiotensin-receptor-neprilysin inhibitor. Outcomes were compared by Kaplan-Meier survival analysis and various clinical parameters were investigated using Cox multivariable analysis, followed by interaction analysis. Minnesota living with heart failure Questionnaire (MLHFQ) was employed as one of the criteria to assess heart failure outcome.The cardiovascular (CV) death or HF hospitalization at 24 months occurred in 49 patients in ACEI group compared with 31 in ARNI group (Hazard Ratio (HR): 1.231, 95% confidence Interval (CI): 1.080-2.460, P = .031). And ARNI showed better prognosis of HF hospitalization (HR: 1.283, 95%CI: 1.065-1.360, P = .038). Cumulative Kaplan-Meier estimates of endpoints, ARNI could reduce the incidence of CV death or HF hospitalization (P = .042) and HF hospitalization (P = .035). The stratified analysis revealed that participants with age less than 70 years old had a lower incidence of CV death or HF hospitalization (HR: 1.194, 95%CI: 1.011-1992, P = .031) after treated with ARNI. Patients received diuretics could benefit from ARNI (HR: 1.383, 95%CI: 1.082-1.471, P = .019). Similar results were also observed in patients with heart rate lower than 90 bpm (HR: 1.556, 95%CI: 1.045-2.386, P = .003) and patients with atrial fibrillation history (HR: 1.873, 95%CI: 1.420-2.809, P = .011). ARNI could improve the quality of life both from the total, emotional and physical aspects.ARNI is an efficacy treatment strategy to improve the outcome and quality of life in patients with non-HFrEF.


Assuntos
Antagonistas de Receptores de Angiotensina , Insuficiência Cardíaca , Hospitalização/estatística & dados numéricos , Neprilisina/antagonistas & inibidores , Qualidade de Vida , Volume Sistólico , Idoso , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , China/epidemiologia , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/psicologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Função Ventricular Esquerda
5.
Nat Commun ; 10(1): 4202, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519895

RESUMO

It remains disputable about perioperative use of renin-angiotensin system inhibitors (RASi) and their outcome effects. This multicenter retrospective cohort study examines association between use of perioperative RASi and outcomes in patients undergoing coronary artery bypass graft and/or valve surgery. After the exclusion, the patients are divided into 2 groups with or without preoperative RASi (PreRASi, n = 8581), or 2 groups with or without postoperative RASi (PostRASi, n = 8130). With using of propensity scores matching to reduce treatment selection bias, the study shows that PreRASi is associated with a significant reduction in postoperative 30-day mortality compared with without one (3.41% vs. 5.02%); PostRASi is associated with reduced long-term mortality rate compared with without one (6.62% vs. 7.70% at 2-year; 17.09% vs. 19.95% at 6-year). The results suggest that perioperative use of RASi has a significant benefit for the postoperative and long-term survival among patients undergoing cardiac surgery.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Assistência Perioperatória , Sistema Renina-Angiotensina/efeitos dos fármacos , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Ponte de Artéria Coronária , Feminino , Valvas Cardíacas/cirurgia , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
6.
N Engl J Med ; 381(17): 1609-1620, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31475794

RESUMO

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.).


Assuntos
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 , Método Duplo-Cego , 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 adversos
7.
Medicine (Baltimore) ; 98(33): e16872, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415426

RESUMO

Patients undergoing surgery and taking angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) are susceptible to complications related to intraoperative hypotension. Perioperative continuation of such medications in patients undergoing colorectal surgery may be associated with more harm than benefit, as these patients are often exposed to other risk factors which may contribute to intraoperative hypotension. Our objectives were to assess the incidence and severity of postinduction hypotension as well as the rates of acute kidney injury (AKI), 30-day all-cause mortality, 30-day readmission, and hospital length of stay in adult patients undergoing colorectal surgery who take ACEi/ARB.We performed a retrospective chart review of patients undergoing colorectal surgery of ≥4 hour duration at a tertiary care academic medical center between January 2011 and November 2016. The preoperative and intraoperative characteristics as well as postoperative outcomes were compared between patients taking ACEi/ARB and patients not taking these medications.Of the 1020 patients meeting inclusion criteria, 174 (17%) were taking either ACEi or ARB before surgery. Patients taking these medications were more likely to receive both postinduction and intraoperative phenylephrine and ephedrine. The incidences of postoperative AKI (P = .35), 30-day all-cause mortality (P = .36), 30-day hospital readmission (P = .45), and hospital length of stay (P = .25), were not significantly different between the 2 groups.Our results support the current recommendation that ACEi/ARB use is probably safe within the colorectal surgery population during the perioperative period. Intraoperative hypotension should be expected and treated with vasopressors.


Assuntos
Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Cirurgia Colorretal/efeitos adversos , Hipotensão/induzido quimicamente , Assistência Perioperatória/métodos , Lesão Renal Aguda/induzido quimicamente , Adulto , Estudos de Casos e Controles , Cirurgia Colorretal/mortalidade , Feminino , Humanos , Hipotensão/tratamento farmacológico , Masculino , Estudos Retrospectivos , Vasoconstritores/uso terapêutico
8.
Int J Clin Pharmacol Ther ; 57(10): 483-488, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31426904

RESUMO

AIM: The aim of this study was to investigate the potential association between antihypertensive therapy and the incidence of Parkinson's disease (PD) in patients followed in general practices in Germany. MATERIALS AND METHODS: This study included patients aged ≥ 40 who had received initial diagnoses of PD in 1,203 general practices in Germany between January 2013 and December 2017 (index date). After applying similar inclusion criteria, PD cases were matched to non-PD controls using propensity scores based on age, sex, and treating physician. The primary outcome of the study was the incidence of PD as a function of the use of antihypertensive drugs (diuretics, ß-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers). Logistic regression models were conducted to study the association between the use of antihypertensive drugs and the incidence of PD after adjusting for codiagnoses and antihypertensive cotherapy. RESULTS: The present study included 9,127 patients with PD and 9,127 patients without PD (mean age: 75.8 years; 48.4% women). The at-least-once use of diuretics (44.8% versus 38.4%; odds ratio (OR) = 1.23 (1.15-1.32)) was associated with an increased incidence of PD. However, this effect was not maintained for a therapy duration of at least 3 years, and no association was observed between the diuretic therapy duration and PD incidence. For all other antihypertensive drug classes, we found no significant associations with PD incidence. CONCLUSION: No association was found between antihypertensive therapy duration and PD incidence. Further epidemiological studies are needed to compare the effects of subclasses of antihypertensives on PD.


Assuntos
Anti-Hipertensivos/efeitos adversos , Hipertensão/tratamento farmacológico , Doença de Parkinson/complicações , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diuréticos/efeitos adversos , Diuréticos/uso terapêutico , Feminino , Medicina Geral , Alemanha , Humanos , Hipertensão/complicações , Incidência , Masculino
9.
Drugs Aging ; 36(7): 667-674, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30949984

RESUMO

BACKGROUND: The use of renin-angiotensin-aldosterone system inhibitors has increased over the past few years. There are conflicting data as to their relationship with acute kidney injury following surgery. OBJECTIVES: The objective of the article was to evaluate the risk of acute kidney injury in diabetic older patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and their medical outcomes following fragility hip fracture surgery. METHODS: Consecutive diabetic patients presenting with fragility hip fractures to our primary trauma center between January 2012 and June 2016 were included. Demographic and clinical data, including co-morbidities, medication use, and laboratory results, were collected from the electronic medical records. The primary outcome was the incidence of acute kidney injury; the secondary outcome was 1-year mortality. RESULTS: Two hundred and seventeen patients were included; 125 were receiving treatment with medications targeting the renin-angiotensin-aldosterone system. Demographic and clinical characteristics were similar between groups. No association was found between the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and the risk of acute kidney injury, which occurred in 25% of the cohort. Univariate analysis revealed that diuretic use, particularly furosemide, increased the risk of acute kidney injury during hospitalization (p = 0.003). However, in a multivariate analysis, only age and estimated glomerular filtration rates were associated with an increased risk of acute kidney injury. Patients with acute kidney injury were found to have increased mortality during the first post-operative year (p < 0.001). CONCLUSIONS: Acute kidney injury is a frequent complication after hip fracture surgery in elderly diabetic patients and is associated with increased 1-year mortality; however, it was not found to be associated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker pre-fracture treatment.


Assuntos
Lesão Renal Aguda/etiologia , Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Diabetes Mellitus/tratamento farmacológico , Fraturas do Quadril/cirurgia , Lesão Renal Aguda/induzido quimicamente , Fatores Etários , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Angiotensinogênio , Estudos de Coortes , Diabetes Mellitus/fisiopatologia , Feminino , Taxa de Filtração Glomerular , Humanos , Incidência , Masculino , Sistema Renina-Angiotensina/efeitos dos fármacos , Estudos Retrospectivos
10.
Trials ; 20(1): 160, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30836981

RESUMO

BACKGROUND: Chronic treatment of hypertension or heart failure very often includes an angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) as renin-angiotensin system inhibitors (RASi) treatments. To stop or not to stop these medications before major surgery remains an unresolved issue. The lack of evidence leads to conflicting guidelines with respect to RASi management before major surgery. The purpose of this study is to evaluate the impact of a strategy of RASi continuation or discontinuation on perioperative complications in patients undergoing major non-cardiac surgery. METHODS: This is a multicenter, open-labeled randomized controlled trial in > 30 French centers. In the experimental group, RASi will be continued while the treatment will be stopped 48 h before the surgery in the control arm. The primary endpoint is a composite endpoint of major complications after surgery. An endpoint adjudication committee will review clinical data and adjudicate efficacy endpoints while blinded to the assigned study drug group. Main analysis will be by intention-to-treat comparing the composite outcome measure at 28 days in the two groups. A total of 2222 patients are planned to detect an absolute complications difference of 5%. DISCUSSION: The results of the trial should provide robust evidence to anesthesiologists and surgeons regarding management of RASi before major non-cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03374449 . Registered on 11 December 2017.


Assuntos
Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/tratamento farmacológico , Assistência Perioperatória/métodos , Sistema Renina-Angiotensina/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Esquema de Medicação , França , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Estudos Multicêntricos como Assunto , Assistência Perioperatória/efeitos adversos , Complicações Pós-Operatórias/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
11.
PLoS One ; 14(2): e0212907, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30817783

RESUMO

BACKGROUND: Current heart failure (HF) guidelines recommend titrating angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and beta-blockers (BBs) to target doses used in pivotal placebo-controlled randomized controlled trials (RCTs). Despite a number of RCTs comparing different doses (i.e. higher versus lower doses) of ACEIs, ARBs and BBs, the effects of higher versus lower doses on efficacy and safety remains unclear. For this reason, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of higher versus lower doses of ACEIs, ARBs and BBs in patients with HFrEF. METHODS: We searched MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) via Ovid from inception to April 25th, 2018 and opentrials.net and clinicaltrials.gov for relevant trials that compared different doses of medications in heart failure. We analyzed trials by drug class (ACEIs, ARBs, and BBs) for efficacy outcomes (all-cause mortality, cardiovascular mortality, all-cause hospitalizations, HF hospitalizations, HF worsening). For safety outcomes, we pooled trials within and across drug classes. RESULTS: Our meta-analysis consisted of 14 RCTs. Using GRADE criteria, the quality of evidence for ACEIs and ARBs was assessed as generally moderate for efficacy and high for adverse effects, whereas overall quality for BBs was very low to low. Over ~2-4 years higher versus lower doses of ACEIs, ARBs or BBs did not significantly reduce all-cause mortality [ACEIs relative risk (RR) 0.94 (95% confidence interval 0.87-1.02)], ARBs RR 0.96 (0.87-1.04), BBs RR 0.25 (0.06-1.01)] or all cause hospitalizations [ACEIs relative risk (RR) 0.94 (95% confidence interval 0.86-1.02)], ARBs RR 0.98 (0.93-1.04), BBs RR 0.93 (0.39-2.24)]. However, all point estimates favoured higher doses. Higher doses of ARBs significantly reduced hospitalization for HF [RR 0.89 (0.80-0.99)- 2.8% ARR], and higher doses of ACEIs and ARBs significantly reduced HF worsening [RR 0.85 (0.79-0.92)- 5.1% ARR and 0.91 (0.84-0.99)- 3.2% ARR, respectively] compared to lower doses. None of the differences between higher versus lower doses of BBs were significant; however, precision was low. Higher doses of these medications compared to lower doses increased the risk of discontinuation due to adverse events, hypotension, dizziness, and for ACEIs and ARBs, increased hyperkalemia and elevations in serum creatinine. Absolute increase in harms for adverse effects ranged from ~ 3 to 14%. CONCLUSIONS: Higher doses of ACEIs and ARBs reduce the risk of HF worsening compared to lower doses, and higher doses of ARBs also reduce the risk of HF hospitalization but the evidence is sparse and imprecise. Higher doses increase the chance of adverse effects compared to lower doses. Evidence for BBs is inconclusive. These results support initially always starting at low doses of ACEIs/ARBs and only titrating the dose up if the patient tolerates dose increases.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas Adrenérgicos beta/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Segurança , Volume Sistólico , Resultado do Tratamento
12.
Cardiology ; 142(1): 4-6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30852576

RESUMO

The uptake of sacubitril/valsartan since the PARADIGM study confirmed its beneficial effects on outcomes over enalapril in chronic systolic heart failure has inevitably led to potential interactions with co-prescribed medications in real-world patients. We report two cases that raise the possibility of an interaction between sacubitril/valsartan and the class Ib anti-arrhythmic mexiletine resulting in proarrhythmic effects. We discuss the pharmacokinetics of both agents and posit potential mechanistic interactions that suggest caution should be used and careful monitoring for (ventricular) arrhythmias applied in patients receiving sacubitril/valsartan and mexiletine.


Assuntos
Aminobutiratos/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Mexiletina/efeitos adversos , Tetrazóis/efeitos adversos , Idoso , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacocinética , Interações de Medicamentos , Feminino , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Humanos , Masculino , Mexiletina/farmacocinética , Tetrazóis/farmacocinética
13.
Dig Dis Sci ; 64(7): 1938-1944, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30725290

RESUMO

BACKGROUND: Preclinical data demonstrate that activation of the renin-angiotensin system (RAS) contributes to mucosal inflammation, and RAS inhibition by angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) improves colitis in animal models. Less is known regarding the effects of RAS inhibition on clinical outcomes in inflammatory bowel disease (IBD) patients. AIM: Evaluate the impact of ACEI and ARB on clinical outcomes in IBD. METHODS: Rates of IBD-related hospitalizations, operations, and corticosteroid use were evaluated retrospectively in two groups. First, 111 IBD patients taking an ACEI or ARB were compared to nonusers matched 1:1 based on sex, age, diagnosis, disease location, and hypertension diagnosis. Second, outcomes in a cohort of 130 IBD patients were compared prior to and during ACEI/ARB exposure. RESULTS: Compared to matched controls, all IBD patients together with ACEI/ARB exposure had fewer hospitalizations (OR 0.26, p < 0.01), operations (OR 0.08, p = 0.02), and corticosteroid prescriptions (OR 0.5, p = 0.01). Comparing outcomes before and during ACEI/ARB use, there were no differences in hospitalizations, operations, or corticosteroid use for all IBD patients together, but patients with UC had increased hospitalizations (0.08 pre- vs. 0.16 during ACEI/ARB exposure, p = 0.03) and decreased corticosteroid use (0.24 pre-ACEI/ARB vs. 0.12 during ACEI/ARB exposure, p < 0.01) during ACEI/ARB use. CONCLUSIONS: IBD patients with ACEI/ARB exposure had fewer hospitalizations, operations, and corticosteroid use compared to matched controls. No differences in outcomes were observed in individuals on ACEI/ARB therapy when compared to a period of time prior to medication exposure.


Assuntos
Corticosteroides/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Colectomia , Colite Ulcerativa/terapia , Doença de Crohn/terapia , Admissão do Paciente , Sistema Renina-Angiotensina/efeitos dos fármacos , Corticosteroides/efeitos adversos , Idoso , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Colectomia/efeitos adversos , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/metabolismo , Colite Ulcerativa/fisiopatologia , Doença de Crohn/diagnóstico , Doença de Crohn/metabolismo , Doença de Crohn/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transdução de Sinais , Fatores de Tempo , Resultado do Tratamento
14.
Eur J Intern Med ; 62: 58-66, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30737061

RESUMO

PURPOSE: Although guidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF) should be treated with renin-angiotensin system (RAS) inhibitors, the long-term efficacy of RAS inhibitors in HFrEF patients with moderate-to-severe chronic kidney disease (CKD) remains unclear. METHODS: The present study included consecutive patients hospitalized for acute heart failure across five Japanese teaching hospitals. The impact of RAS inhibitors on 2-year all-cause mortality was evaluated in patients with an ejection fraction ≤40% and CKD, defined as an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2, at discharge. Its severity was subclassified from 3B to 5 according to eGFR. RESULTS: Overall, 553 patients (age, 76 ±â€¯11 years; 68% male) were included. RAS inhibitors were prescribed more frequently in 227 patients with stage 3B (71.2%) than in 107 patients with stage 4 or 5 CKD (45.7%). All-cause mortality was recorded in 119 patients (23.4%) (55 [18.5%] patients with stage 3B; 64 [30.3%] patients with stage 4 or 5 CKD), within the median follow-up period of 609 (220-983) days. After many-to-one propensity score matching (87 pairs in stage 3; 60 pairs in stage 4 or 5 CKD), those with RAS inhibitors had reduced mortality rate in stage 3B (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.19-0.83) but not in stage 4 or 5 CKD (HR, 1.08; 95% CI, 0.57-2.03). CONCLUSIONS: In HFrEF patients with CKD, RAS inhibitors are associated with reduction in mortality in stage 3B CKD, but the association is less clear in stage 4 or 5 CKD.


Assuntos
Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Causas de Morte , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca Sistólica/mortalidade , Humanos , Japão/epidemiologia , Masculino , Análise Multivariada , Pontuação de Propensão , Estudos Prospectivos , Insuficiência Renal Crônica/mortalidade , Análise de Sobrevida
15.
Am J Cardiovasc Drugs ; 19(3): 259-286, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30737754

RESUMO

INTRODUCTION: Current guidelines recommend renin-angiotensin-aldosterone system (RAAS) inhibitors in the treatment of diabetic kidney disease (DKD). However, evidence suggests that the combined use of RAAS blockers may be associated with increased rates of adverse events. OBJECTIVES: Our objective was to examine the efficacy and safety of dual blockade of the RAAS in patients with DKD. METHODS: This was a systematic review and meta-analysis of randomized controlled trials (RCTs) published between January 1990 and January 2018 sourced via the PubMed, EMBASE, and Cochrane Library databases. RCTs were included if they investigated the efficacy and safety of dual blockade therapy compared with monotherapy in patients with DKD. Random effects models were used in meta-analysis to account for heterogeneities in effect sizes across the reviewed studies. Analyses were stratified by blood pressure and albuminuria. We further conducted subgroup analyses by considering various combinations of RAAS inhibitors. RESULTS: Based on 42 RCTs with 14,576 patients, dual RAAS blockade therapy was associated with significant decreases in blood pressure, albuminuria, and proteinuria. However, dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality, cardiovascular mortality, or progression to end-stage renal disease (ESRD). Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy. However, glomerular filtration rates (GFR) did not decrease significantly with dual therapy. In subgroup analysis, an angiotensin-converting enzyme inhibitor (ACEI) plus an angiotensin-receptor blocker (ARB) or a direct renin inhibitor (DRI) plus an ACEI/ARB did not significantly increase the risk of hyperkalemia, hypotension, and adverse events, and the risk of hypotension increased significantly within the normotensive subgroup but not within the hypertensive subgroup. The risk of hyperkalemia increased significantly in patients with DKD with macroalbuminuria but not in those with microalbuminuria. CONCLUSION: Dual inhibition therapy is superior to monotherapy for blood pressure control and urine protein reduction, though such superiority does not translate into improvements in longer-term outcomes, such as reduced progression to ESRD, all-cause mortality, and cardiovascular mortality. An ACEI plus an ARB or a DRI plus an ACEI/ARB may be a safe and effective therapy for patients with DKD, and combination therapy may be suitable for patients with DKD and hypertension and microalbuminuria.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Renina/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Quimioterapia Combinada , Humanos , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
18.
Artigo em Inglês | MEDLINE | ID: mdl-30497942

RESUMO

In 2018, it is unusual for women with chronic kidney disease (CKD) to be told that pregnancy is not an option. Maternal and foetal outcomes have steadily improved over the last 50 years and a successful pregnancy, resulting in a healthy infant without detrimental to maternal health, is commonplace. Nevertheless, the incidence of adverse outcomes including pre-eclampsia, preterm birth and small-for-gestational age infants is higher for women with CKD than the general population, requiring enhanced monitoring. Furthermore, as women with more advanced renal disease including dialysis recipients are supported in contemplating pregnancy, the importance of an experienced multidisciplinary team (MDT) has become crucial. Pre-pregnancy planning underpins optimisation of pregnancy outcomes.


Assuntos
Anti-Hipertensivos/efeitos adversos , Hipertensão/tratamento farmacológico , Complicações na Gravidez/etiologia , Complicações na Gravidez/terapia , Cuidado Pré-Natal/métodos , Insuficiência Renal Crônica/terapia , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Contraindicações de Medicamentos , Aconselhamento Diretivo , Diuréticos/efeitos adversos , Feminino , Humanos , Imunossupressão , Transplante de Rim , Gravidez , Diálise Renal , Insuficiência Renal Crônica/complicações
19.
Dermatol Ther ; 32(1): e12748, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30238580

RESUMO

Pemphigus is a group of autoimmune diseases characterized by the formation of erosions and/or flaccid bullae of the skin and/or mucosae. The definition "drug-induced pemphigus" has been coined to indicate cases of pemphigus with clinical, histological and immunopathologic features similar to those of the idiopathic disease but induced by systemic ingestion or local use of some drugs. The present authors analyzed a case series of three case reports with clinical and pharmacological features compatible with the diagnosis of angiotensin converting enzyme inhibitors or angiotensin II receptor blocker drug-induced pemphigus. The patients were visited by the dermatological Unit of Magna Graecia University in Catanzaro. All suspected drug induced pemphigus were treated by suspending the suspected drug and by starting a treatment with systemic corticosteroid drugs, leading to a remission of the clinical manifestations in some months. When a drug induced bullous disease is probable, it is necessary to interrupt the suspected substance and to start a high dose treatment with corticosteroid drugs to resolve the clinical case in a short period of time.


Assuntos
Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Erupção por Droga/etiologia , Pênfigo/induzido quimicamente , Pele/efeitos dos fármacos , Corticosteroides/administração & dosagem , Idoso , Erupção por Droga/diagnóstico , Erupção por Droga/tratamento farmacológico , Erupção por Droga/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pênfigo/diagnóstico , Pênfigo/tratamento farmacológico , Pênfigo/imunologia , Indução de Remissão , Pele/imunologia , Pele/patologia , Resultado do Tratamento
20.
Basic Clin Pharmacol Toxicol ; 124(1): 115-122, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30003686

RESUMO

Although angiotensin-converting enzyme inhibitor-related angioedema is well known, angiotensin II receptor blocker (ARB)-related angioedema has not been extensively studied because of its lower incidence. Therefore, ARB-related angioedema is likely to be overlooked in the clinical setting. We analysed the medical records of adults who had been prescribed ARB and diagnosed with angioedema between 2009 and 2015. All adults over the age of 18 years who were initially administered ARB between 1 January 2009 and 31 December 2015 were selected as participants in this study. To confirm whether the angioedema was actually due to the administration of ARB, we conducted a chart review. A total of 35 584 patients were prescribed ARB for the first time when visiting the Seoul St. Mary's Hospital during the study period. Twenty-four patients diagnosed with angioedema for other reasons prior to their first prescription of ARB were excluded from this study. ARB-related angioedema was suspected in six of 35 560 patients (0.02%) who were initially prescribed ARB during the study period. The manifestation of ARB-related angioedema ranged from several days (1/6 case) to several years (3/6 cases). Some patients continued taking ARB with intermittent antihistamine or steroid therapy. In such cases, angioedema symptoms improved but did not completely resolve. Its diagnosis can be delayed and the symptoms may be recurrent as symptoms improve with antihistamine use. In some cases, the same person had different reactions depending on the type of ARB. Definitively diagnosing ARB-related angioedema is difficult, and physicians often overlook angioedema without suspecting that it is an adverse effect of ARB. Close attention of physicians and improved patient education can reduce the incidence of ARB-related angioedema.


Assuntos
Angioedema/epidemiologia , Antagonistas de Receptores de Angiotensina/efeitos adversos , Hipertensão/tratamento farmacológico , Idoso , Angioedema/induzido quimicamente , Angioedema/diagnóstico , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Resultado do Tratamento
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