RESUMEN
BACKGROUND: Medications aimed at inhibiting the renin-angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes. METHODS AND FINDINGS: Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke-singly and as a composite endpoint, major cardiovascular outcome-and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality-singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90-1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79-1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96-1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73-1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90-1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72-1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65-1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78-1.84). No significant differences were showed between ACE inhibitors and ARBs with respect to all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, angina pectoris, hospitalization for heart failure, ESRD, or doubling serum creatinine. Findings were limited by the clinical and methodological heterogeneity of the included studies. Potential inconsistency was identified in network meta-analyses of stroke and angina pectoris, limiting the conclusiveness of findings for these single endpoints. CONCLUSIONS: In adults with diabetes, comparisons of different RAS blockers showed similar effects of ACE inhibitors and ARBs on major cardiovascular and renal outcomes. Compared with monotherapies, the combination of an ACE inhibitor and an ARB failed to provide significant benefits on major outcomes. Clinicians should discuss the balance between benefits, costs, and potential harms with individual diabetes patients before starting treatment. REVIEW REGISTRATION: PROSPERO CRD42014014404.
Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Complicaciones de la Diabetes/prevención & control , Diabetes Mellitus/tratamiento farmacológico , Fallo Renal Crónico/prevención & control , Renina/antagonistas & inhibidores , Adulto , Angina de Pecho/prevención & control , Enfermedades Cardiovasculares/mortalidad , Insuficiencia Cardíaca/prevención & control , Hospitalización , Humanos , Infarto del Miocardio/prevención & control , Insuficiencia Renal Crónica/prevención & control , Sistema Renina-Angiotensina , Prevención Secundaria , Accidente Cerebrovascular/prevención & controlRESUMEN
INTRODUCTION: Trazodone was authorized for the treatment of depression in the 1970s. Several additional therapeutic uses have been proposed due to its heterogeneous mechanism. This study aims to determine the use of trazodone in the elderly in Spain. METHODS: A nationwide, longitudinal and descriptive analysis was conducted using data from patients aged >65 years with a first prescription of trazodone during the period 2002-2011. Information on dose, comorbidities and relevant co-medication was gathered from the Spanish Primary Care database BIFAP. Incidence rates of trazodone use per 10,000 person-years were calculated by sex and age. RESULTS: A total of 11,766 patients receiving a first prescription of trazodone were included. The incidence rate of trazodone use was 47.2 (95% CI: 46.33-48.04) per 10,000 person-years. An increasing trend in the use of trazodone was observed (5-fold increase in 2011 as compared to 2002). The most common therapeutic indications were: depression (21.41%), Alzheimer/dementia (20.36%), sleep disorders (16.22%), and anxiety disorder (8.91%). The median dose was 100mg/day. The use of trazodone concomitantly with interacting medicines was frequent: anti-hypertensives (53.60%), and CNS depressors (59.32%). CONCLUSIONS: Trazodone use is increasing in elderly patients, and a high proportion of use in non-approved indications was observed. Trazodone is not being used at high doses, but interacting medicines were frequent, and it may pose additional risks for elderly patients.
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Antidepresivos de Segunda Generación/uso terapéutico , Utilización de Medicamentos/tendencias , Pautas de la Práctica en Medicina/tendencias , Trazodona/uso terapéutico , Anciano , Anciano de 80 o más Años , Trastornos de Ansiedad/tratamiento farmacológico , Bases de Datos Factuales , Demencia/tratamiento farmacológico , Depresión/tratamiento farmacológico , Esquema de Medicación , Utilización de Medicamentos/estadística & datos numéricos , Femenino , Humanos , Estudios Longitudinales , Masculino , Pautas de la Práctica en Medicina/estadística & datos numéricos , Atención Primaria de Salud , Trastornos del Sueño-Vigilia/tratamiento farmacológico , EspañaRESUMEN
The arrival of new drug into the market requires many years of previous research along with the need of continuous evaluation throughout the lifetime of the drug. This warrants pharmacoepidemiological research which may be defined as the study of the use and the effects of drugs in large populations. Nowadays this type of research seems more feasible thanks to the massive expansion of the information sources and data (e.g: clinical patient registries, electronic medical records). However there is a risk of information overload, fragmented evidence and given the enthusiasm aroused by the "Big Data", it must be emphasized that its nature is mainly observational, and therefore subject to bias and confusion. The application of epidemiological methods in this scenario seems essential for any analysis. In short, the management and use of these data sources to generate useful information expansion is the next challenge for the application of research methods in modern pharmacoepidemiology.
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Conjuntos de Datos como Asunto , Farmacoepidemiología/métodos , Sesgo , Registros Electrónicos de Salud , Humanos , Sistema de Registros , Proyectos de InvestigaciónAsunto(s)
Legislación de Medicamentos , Vigilancia de Productos Comercializados , Ensayos Clínicos como Asunto/economía , Ensayos Clínicos como Asunto/legislación & jurisprudencia , Ensayos Clínicos como Asunto/normas , Comités de Ética , Humanos , Vigilancia de Productos Comercializados/economía , Vigilancia de Productos Comercializados/normas , Estudios Prospectivos , Proyectos de Investigación/normas , EspañaRESUMEN
BACKGROUND AND OBJECTIVE: Romiplostim and eltrombopag are thrombopoietin receptor (TPOr) agonists that promote megakaryocyte differentiation, proliferation and platelet production. In 2012, a systematic review and meta-analysis reported a non-statistically significant increased risk of thromboembolic events for these drugs, but analyses were limited by lack of statistical power. Our objective was to update the 2012 meta-analysis examining whether TPOr agonists affect thromboembolism occurrence in adult thrombocytopenic patients. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Updated searches were conduced on PubMed, Cochrane Central, and publicly available registries (up to December 2014). RCTs using romiplostim or eltrombopag in at least one group were included. Relative risks (RR), absolute risk ratios (ARR) and number needed to harm (NNH) were estimated. Heterogeneity was analyzed using Cochran's Q test and I(2) statistic. RESULTS: Fifteen studies with 3026 adult thrombocytopenic patients were included. Estimated frequency of thromboembolism was 3.69% (95% CI: 2.95-4.61%) for TPOr agonists and 1.46% (95% CI: 0.89-2.40%) for controls. TPOr agonists were associated with a RR of thromboembolism of 1.81 (95% CI: 1.04-3.14) and an ARR of 2.10% (95% CI: 0.03-3.90%) meaning a NNH of 48. Overall, we did not find evidence of statistical heterogeneity (p=0.43; I(2)=1.60%). CONCLUSIONS: Our updated meta-analysis suggested that TPOr agonists are associated with a higher risk of thromboemboembolic events compared with controls, and supports the current recommendations included in the European product information on this respect.
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Benzoatos/efectos adversos , Fármacos Hematológicos/efectos adversos , Hidrazinas/efectos adversos , Pirazoles/efectos adversos , Receptores de Trombopoyetina/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/efectos adversos , Trombocitopenia/tratamiento farmacológico , Tromboembolia/inducido químicamente , Trombopoyetina/efectos adversos , Adulto , Benzoatos/uso terapéutico , Fármacos Hematológicos/uso terapéutico , Humanos , Hidrazinas/uso terapéutico , Modelos Estadísticos , Pirazoles/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Trombopoyetina/uso terapéuticoRESUMEN
BACKGROUND: The new recommendations regarding the utilization of high potency statins (intensive therapy) for the treatment of cardiovascular disease have been based on the extrapolation of data coming from clinical trials. The objective is to describe the clinical-epidemiological profile of statin therapy users for the secondary prevention of cardiovascular disease in Spain and to examine the predictors for intensive therapy initiation. METHODS: Cross-sectional study from a sample of 88,751 patients aged ≥45 years-old with previous cardiovascular disease which initiated statin therapy between 1st January 2007 to 31st December 2011. Dose treatments >40 mg simvastatin daily (or equivalent dose if different statin) were considered intensive therapy treatment. Multivariable logistic regression models were built for dependent summary variables to examine the association between and the intensive therapy utilization (vs low-moderate intensity therapy). RESULTS: 16,857 adult patients receiving a first prescription of statin for the secondary prevention of cardiovascular diseases were identified. Predictors for intensive therapy initiation were year of statin prescription, male gender (adjusted OR: 1.70; 95% CI: 1.44-2.00), age >75 years-old (1.39; 1.15-1.69), previous history of coronary artery disease (1.71; 1.44-2.04), previous history of transient ischemic attack (1.24; 0,97-1.59), smoking (1.62; 1.34-1.95), hypertension (1.41; 1.20-1.65) and recent use of fibrates (2.32; 1.27-4.26). CONCLUSIONS: The onset of intensive therapy with statins in secondary was determined by the type of vascular event and age (>75 years-old in which the risk benefit balance could be controversial). No statistically significant differences were found according to the LDL-c levels.
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Enfermedades Cardiovasculares/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Prevención Secundaria , Simvastatina/uso terapéutico , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/epidemiología , Estudios Transversales , Esquema de Medicación , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Farmacoepidemiología , Factores Sexuales , España/epidemiologíaRESUMEN
BACKGROUND AND OBJECTIVE: We evaluated the risk of hepatotoxicity associated to endothelin receptor antagonists. PATIENTS AND METHOD: Systematic searches in PubMed/MEDLINE, the Cochrane Library as well as regulatory agencies websites were performed. Randomized controlled trials in patients receiving endothelin receptor antagonists (bosentan, sitaxentan or ambrisentan) in at least one treatment group were included. Prior to data extraction, definitions of hepatotoxicity were established. Effect sizes with 95% confidence intervals were calculated using random effects models. Heterogeneity was analysed using Cochran's Q and I(2) tests. Publication bias was assessed using Egger's method and funnel plots were generated. RESULTS: Twenty-one trials met the inclusion criteria (3,644 patients). Bosentan was the evaluated drug in 1,689 (74%) patients who received endothelin receptor antagonists. Compared with controls, relative risk for any hepatic adverse reaction was 2.92 (1.85-4.62; I(2)=30.6%). When hepatotoxicity was defined as elevations of liver alanine or aspartate aminotransferases equal or greater than 3 times the upper limit of normal, relative risk was 2.98 (1.69-5.25; I(2) = 40.9%). No evidence of publication bias was found (Egger's method: p = 0.68). CONCLUSIONS: Our results suggest an increased risk of hepatotoxicity in patients receiving endothelin receptor antagonists. Given the limited data available for endothelin receptor antagonists other than bosentan, it is not possible to draw firm conclusions about the individual risk associated for the remaining endothelin receptor antagonists.
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Antihipertensivos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Antagonistas de los Receptores de Endotelina/efectos adversos , Antihipertensivos/uso terapéutico , Biomarcadores/sangre , Bosentán , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Antagonistas de los Receptores de Endotelina/uso terapéutico , Humanos , Hipertensión/tratamiento farmacológico , Isoxazoles/efectos adversos , Isoxazoles/uso terapéutico , Fenilpropionatos/efectos adversos , Fenilpropionatos/uso terapéutico , Piridazinas/efectos adversos , Piridazinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Retirada de Medicamento por Seguridad , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Tiofenos/efectos adversos , Tiofenos/uso terapéutico , Transaminasas/sangreRESUMEN
BACKGROUND: Previous work has suggested that dual blockade using inhibitors of the renin-angiotensin system (RAS) would be associated with an increase in side effects compared to monotherapy. We reexamined the safety of dual RAS blockade, especially in patients at risk, and explored the stability of the evidence accumulated over the years. METHOD: Systematic review with random-effects meta-analyses. We reviewed 15 previously published meta-analyses as the starting point. PubMed/Medline was searched for recent evidence from both observational and randomized controlled trials. Outcomes measures were: mortality (overall and cardiovascular), hyperkalemia, hypotension, renal failure, stroke, and treatment withdrawal due to adverse effects. We calculated relative risks (RR) and confidence intervals (95% CI) RESULTS: Dual RAS blockade was not associated with reduced relative risk (RR) overall mortality (RR:1.00, 0.96-1.05; 21 studies), cardiovascular mortality (RR:1.01, 0.94-1.09; 13 studies) or stroke (RR:1.02; 0.94-1.11; 11 studies) compared to monotherapy. Dual blockade was associated with an increased risk of hyperkalemia (RR:1.58, 1.37-1.81; 34 studies), hypotension (RR:1.66; 1.41-1.95; 25 studies), renal failure (RR:1.52;1.28-1.81; 29 studies) and treatment discontinuation due to adverse events (RR:1.26;1.22-1.30; 37 studies). These results were consistent in cohorts of patients with diabetes mellitus, kidney disease or heart failure. CONCLUSIONS: Dual RAS blockade increased (vs monotherapy) the risks of hyperkalemia, hypotension, renal failure and treatment discontinuation. Dual RAS blockade did not offer additional benefit in reducing overall mortality, cardiovascular mortality or stroke. These findings are consistent over time.
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Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Renina/antagonistas & inhibidores , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Enfermedades Cardiovasculares/mortalidad , Causas de Muerte , Humanos , Hiperpotasemia/inducido químicamente , Hipotensión/inducido químicamente , Enfermedades Renales/inducido químicamente , Masculino , Metaanálisis como Asunto , Estudios Observacionales como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Sistema Renina-Angiotensina/efectos de los fármacos , Accidente Cerebrovascular/prevención & control , Privación de TratamientoRESUMEN
BACKGROUND: For years, anxiolytics and hypnotics have been one of the most prescribed drug classes in most developed countries. The main aim of this study is to explore the pattern of use of anxiolytic and hypnotic drugs during the period 2000-2011, comparing their growth with that of five european countries. METHOD: We performed an ecological and descriptive study of anxiolytics and hypnotics consumption in Spain. Consumption data were obtained from the databases of medications dispensed in community pharmacies and charged through official prescriptions to the totality of the Spanish National Health System. Annual and total-period consumptions were expressed in defined daily doses (DDD) per 1000 inhabitants per day (DDD/1000 person/day) by each treatment subgroup, active substance and attending the plasma half-life of the medication. Approximate comparisons were also made with some European countries. RESULTS: The use of anxiolytics and hypnotics drugs was 56.7 DDD/1000 person/day in 2000 and 82.9 DDD/1000 person/day in 2011 (a +46.1% increase across the period). Lorazepam and alprazolam were the most used anxiolytics (20.5 and 15.6 DDD/1000 person/day in 2011, respectively), whereas lormetazepam was among the hypnotics (18.3 DDD/1000 person/day in 2011). In relative terms, hypnotics´ lormetazepam and zolpidem increased their use by 103.3% and 85.1%, respectively; while anxiolytics´ lorazepam and hydroxyzine increased 75.1% and 72.8%, respectively. In Spain (period 2003-2010), the total increase in the consumption of anxiolytics and hypnotics was +34.3%, with 24.0% for Portugal, 4.0% for Italy, but a reduction of -6.1% for France. CONCLUSIONS: A considerable increase in anxiolytics and hypnotics´ consumption has occurred in Spain during the last decade, being the growth higher than that reported in other European countries.