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BACKGROUND: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear. METHODS: In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed. RESULTS: A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001). CONCLUSIONS: In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).
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Clortalidona , Hidroclorotiazida , Hipertensión , Anciano , Humanos , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Clortalidona/efectos adversos , Clortalidona/uso terapéutico , Diuréticos/efectos adversos , Diuréticos/uso terapéutico , Hidroclorotiazida/efectos adversos , Hidroclorotiazida/uso terapéutico , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversos , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & controlRESUMEN
BACKGROUND: Pragmatic trials are gaining popularity as a cost-effective way to examine treatment effectiveness and generate timely comparative evidence. Incorporating supplementary real-world data is recommended for robust outcome monitoring. However, detailed operational guidelines are needed to inform effective use and integration of heterogeneous databases. OBJECTIVE: Lessons learned from the Veterans Affairs (VA) Diuretic Comparison Project (DCP) are reviewed, providing adaptable recommendations to capture clinical outcomes from real-world data. METHODS: Non-cancer deaths and major cardiovascular (CV) outcomes were determined using VA, Medicare, and National Death Index (NDI) data. Multiple ascertainment strategies were applied, including claims-based algorithms, natural language processing, and systematic chart review. RESULTS: During a mean follow-up of 2.4 (SD = 1.4) years, 907 CV events were identified within the VA healthcare system. Slight delays (â¼1 year) were expected in obtaining Medicare data. An additional 298 patients were found having a CV event outside of the VA in 2016 - 2021, increasing the CV event rate from 3.5 % to 5.7 % (770 of 13,523 randomized). NDI data required â¼2 years waiting period. Such inclusion did not increase the number of deaths identified (all 894 deaths were captured by VA data) but enhanced the accuracy in determining cause of death. CONCLUSION: Our experience supports the recommendation of integrating multiple data sources to improve clinical outcome ascertainment. While this approach is promising, hierarchical data aggregation is required when facing different acquisition timelines, information availability/completeness, coding practice, and system configurations. It may not be feasible to implement comparable applications and solutions to studies conducted under different constraints and practice. The recommendations provide guidance and possible action plans for researchers who are interested in applying cross-source data to ascertain all study outcomes.
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Ensayos Clínicos Pragmáticos como Asunto , Anciano , Humanos , Medicare , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND/AIMS: The US Department of Veterans Affairs Point of Care Clinical Trial Program conducts studies that utilize informatics infrastructure to integrate clinical trial protocols into routine care delivery. The Diuretic Comparison Project compared hydrochlorothiazide to chlorthalidone in reduction of major cardiovascular events in subjects with hypertension. Here we describe the cultural, technical, regulatory, and logistical challenges and solutions that enabled successful implementation of this large pragmatic comparative effectiveness Point of Care clinical trial. METHODS: Patients were recruited from 72 Veterans Affairs Healthcare Systems using centralized processes for subject identification, obtaining informed consent, data collection, safety monitoring, site communication, and endpoint identification with minimal perturbation of the local clinical care ecosystem. Patients continued to be managed exclusively by their clinical care providers without protocol specified study visits, treatment recommendations, or data collection extraneous to routine care. Centralized study processes were operationalized through the application layer of the electronic health record via a data coordinating center staffed by clinical nurses, data scientists, and statisticians without site-based research coordinators. Study data was collected from the Veterans Affairs electronic health record supplemented by Medicare and National Death Index data. RESULTS: The study exceeded its enrolled goal (13,523 subjects) and followed subjects for the 5-year study duration. The key determinant of program success was collaboration between researchers, regulators, clinicians, and administrative staff at the site level to customize study procedures to align with local clinical practice. This flexibility was enabled by designation of the study as minimal risk and determination that clinical care providers were not engaged in research by the Veterans Affairs Central Institutional Review Board. Cultural, regulatory, technical, and logistical problems were identified and solved through iterative collaboration between clinical and research entities. Paramount among these problems was customization of the Veterans Affairs electronic health record and data systems to accommodate study procedures. CONCLUSIONS: Leveraging clinical care for large-scale clinical trials is feasible but requires a rethinking of traditional clinical trial design (and regulation) to better meet requirements of clinical care ecosystems. Study designs must accommodate site-specific practice variation to reduce the impact on clinical care. A tradeoff thus exists between designing trial processes tailored to expedite local study implementation versus those to produce a more refined response to the research question. The availability of a uniform and flexible electronic health record in the Department of Veterans Affairs played a major role in the success of the trial. Conducting Point of Care research in other healthcare systems without such research-friendly infrastructure presents a more formidable challenge.
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Diuréticos , Ecosistema , Anciano , Humanos , Estados Unidos , Medicare , Proyectos de Investigación , Sistemas de Atención de PuntoRESUMEN
Importance: Patients with prior myocardial infarction (MI) or stroke have a greater risk of recurrent cardiovascular (CV) events. Objective: To evaluate the association of chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) with CV outcomes and noncancer deaths in participants with and without prior MI or stroke. Design, Setting, and Participants: This was a prespecified secondary analysis of the Diuretic Comparison Project (DCP), a pragmatic randomized clinical trial conducted within 72 participating Veterans Affairs health care systems from June 2016 to June 2021, in which patients aged 65 years or older with hypertension taking HCTZ at baseline were randomized to continue HCTZ or switch to CTD at pharmacologically comparable doses. This secondary analysis was performed from January 3, 2023, to February 29, 2024. Exposures: Pharmacologically comparable daily dose of HCTZ or CTD and history of MI or stroke. Main Outcomes and Measures: Outcome ascertainment was performed from randomization to the end of the study. The primary outcome consisted of a composite of stroke, MI, urgent coronary revascularization because of unstable angina, acute heart failure hospitalization, or noncancer death. Additional outcomes included achieved blood pressure and hypokalemia (potassium level <3.1 mEq/L; to convert to mmol/L, multiply by 1.0). Results: The DCP randomized 13â¯523 participants to CTD or HCTZ, with a mean (SD) study duration of 2.4 (1.4) years. At baseline, median age was 72 years (IQR, 69-75 years), and 96.8% were male. Treatment effect was evaluated in subgroups of participants with (n = 1455) and without (n = 12â¯068) prior MI or stroke at baseline. There was a significant adjusted interaction between treatment group and history of MI or stroke. Participants with prior MI or stroke randomized to CTD had a lower risk of the primary outcome than those receiving HCTZ (105 of 733 [14.3%] vs 140 of 722 [19.4%]; hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) compared with participants without prior MI or stroke, among whom incidence of the primary outcome was slightly higher in the CTD arm compared with the HCTZ arm (597 of 6023 [9.9%] vs 535 of 6045 [8.9%]; HR, 1.12; 95% CI, 1.00-1.26; P = .054) (P = .01 for interaction). The incidence of a nadir potassium level less than 3.1 mEq/L and hospitalization for hypokalemia differed among those with and without prior MI or stroke when comparing those randomized to CTD vs HCTZ, with a difference only among those without prior MI or stroke (potassium level <3.1 mEq/L: prior MI or stroke, 43 of 733 [5.9%] vs 37 of 722 [5.1%] [P = .57]; no prior MI or stroke, 292 of 6023 [4.9%] vs 206 of 6045 [3.4%] [P < .001]; hospitalization for hypokalemia: prior MI or stroke, 14 of 733 [1.9%] vs 16 of 722 [2.2%] [P = .72]; no prior MI or stroke: 84 of 6023 [1.4%] vs 57 of 6045 [0.9%] [P = .02]). Conclusions and Relevance: Results of this secondary analysis of the DCP trial suggest that CTD may be associated with reduced major adverse CV events and noncancer deaths in patients with prior MI or stroke compared with HCTZ. Trial Registration: ClinicalTrials.gov Identifier: NCT02185417.
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Antihipertensivos , Clortalidona , Hidroclorotiazida , Hipertensión , Infarto del Miocardio , Accidente Cerebrovascular , Humanos , Clortalidona/uso terapéutico , Clortalidona/administración & dosificación , Masculino , Hidroclorotiazida/uso terapéutico , Hidroclorotiazida/administración & dosificación , Anciano , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/complicaciones , Femenino , Hipertensión/tratamiento farmacológico , Antihipertensivos/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Multisite practical clinical trials evaluate treatments in real-world practice. A multisite randomized Veterans Health Administration (VHA) cooperative study (CSP#555) published in 2011 compared the first long-acting injectable (LAI) second-generation antipsychotic (SGA), Risperidone Consta®, in veterans with a diagnosis of schizophrenia or schizoaffective disorder, to oral antipsychotics, with unexpected null results for effectiveness and cost-effectiveness. Whether null results of this type could change VHA practice has not been studied. METHODS: A longitudinal observational analysis was used to evaluate the impact of the trial findings on VHA clinical practices. National administrative data compared new starts on LAI risperidone during the 4 years before the publication of CSP#555 in 2011 to new starts on LAI risperidone during the 4 years after. RESULTS: Among 119,565 Veterans with the indicated diagnoses treated with antipsychotics from 2007 to 2015, the number and proportion of new starts on LAI risperidone declined significantly following the study publication, as did the total number of annual users and drug expenditures. However, data from 2007 to 2010 showed the decline in new starts actually preceded the publication of CSP#555. This change was likely explained by the increase in new starts, total use, and expenditures on a newer medicine, LAI paliperidone, a 4-week LAI treatment, in the 2 years prior to the publication of CSP#555. CONCLUSIONS: The declining use of LAI risperidone likely primarily reflects the substitution of a longer-acting LAI SGA, paliperidone, that came to market 2 years before the study publication, a substitution that may have been reinforced by null CSP#555 study results for LAI risperidone.
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Antipsicóticos , Risperidona , Humanos , Risperidona/efectos adversos , Palmitato de Paliperidona/efectos adversos , Salud de los Veteranos , Inyecciones , Antipsicóticos/uso terapéutico , Preparaciones de Acción Retardada/uso terapéuticoRESUMEN
The goal of this observational study was to identify stroke hospitalizations using International Classification of Disease (ICD)-10 codes and use these codes to develop an ascertainment algorithm for use in pragmatic clinical trials, reducing or eliminating the need for manual chart adjudication in future. Using VA (Veterans Affairs) electronic medical records, 9959 patient charts with ICD-10 codes indicating stroke were screened and a sample of 304 were adjudicated by three clinical reviewers. Hospitalizations were categorized as stroke or non-stroke and positive predictive value (PPV) was calculated for each ICD-10 code that was sampled. The adjudicated codes were categorized for use in a decision tool for identifying stroke in a clinical trial. Of the 304 hospitalizations adjudicated, 192 met the definition of stroke. Of the ICD-10 codes evaluated, I61 yielded the highest PPV (100%) while I63.x yielded the 2nd highest PPV (90%) with a false discovery rate of 10%. A relatively high PPV of ≥80% was associated with codes I60.1-7, I61, I62.9 and I63, which accounted for nearly half of all cases reviewed. Hospitalizations associated with these codes were categorized at positive stroke cases. The incorporation of large administrative datasets, and elimination of trial specific data collection, increases efficiencies, while reducing costs. Accurate algorithms must be developed to allow for identification of clinical endpoints from administrative databases to offer a reliable alternative to study-specific case report form completion. This study demonstrates an example of how to apply medical record data to a decision tool for clinical trial outcomes. CSP597 or clinicaltrials.gov NCT02185417.
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Accidente Cerebrovascular , Humanos , Valor Predictivo de las Pruebas , Registros Electrónicos de Salud , Algoritmos , Bases de Datos FactualesRESUMEN
INTRODUCTION: The COVID-19 pandemic had significant impact on clinical care and clinical trial operations, but the impact on decentralized pragmatic trials is unclear. The Diuretic Comparison Project (DCP) is a Point-of Care (POC) pragmatic trial testing whether chlorthalidone is superior to hydrochlorothiazide in preventing major cardiovascular (CV) events and non-cancer death. DCP utilized telephone consent, data collection from the electronic health record and Medicare, forwent study visits, and limited provider commitment beyond usual care. We assessed the impact of COVID-19 on recruitment, follow-up, data collection, and outcome ascertainment in DCP. METHODS: We compared data from two 8-month periods: Pre-Pandemic (July 2019-February 2020) and Mid-Pandemic (July 2020-February 2021). Consent and randomization rates, diuretic adherence, blood pressure (BP) and electrolyte follow-up rates, records of CV events, hospitalization, and death rates were compared. RESULTS: Providers participated at a lower rate mid-pandemic (65%) than pre-pandemic (71%), but more patients were contacted (7622 vs. 5363) and consented (3718 vs. 3048) mid-pandemic than pre-pandemic. Patients refilled medications and remained on their randomized diuretic equally (90%) in both periods. Overall, rates of BP, electrolyte measurements, and hospitalizations decreased mid-pandemic while deaths increased. CONCLUSIONS: While recruitment, enrollment, and adherence did not suffer during the pandemic, documented blood pressure checks and laboratory evaluations decreased, likely due to fewer in-person visits. VA hospitalizations decreased, despite a considerable number of COVID-related hospitalizations. This suggests changes in clinical care during the pandemic, but the limited impact on DCP's operations during a global pandemic is an important strength of POC trials. CLINICAL TRIAL REGISTRATION: NCT02185417.
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COVID-19 , Anciano , Humanos , COVID-19/epidemiología , Diuréticos , Medicare , Pandemias/prevención & control , Atención Primaria de Salud , Estados Unidos/epidemiologíaRESUMEN
Multi-site randomized effectiveness trials evaluate treatments under real-world conditions. Whether results change practice is under-studied. A 6-month 26-site Veterans Health Administration (VHA) cooperative study published in 2011 compared an oral second-generation antipsychotic, risperidone, to placebo for refractory PTSD with null results. National VHA administrative data compared new starts on risperidone during the 5 years before and after the year of publication. Among the 450,000-841,000 Veterans diagnosed with PTSD annually from 2006 to 2016 the proportion with new starts on risperidone declined every year before and after publication. No evidence of an effect of null study results on VHA clinical practice was observed.
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Antipsicóticos , Trastornos por Estrés Postraumático , Veteranos , Humanos , Antipsicóticos/uso terapéutico , Risperidona/uso terapéutico , Trastornos por Estrés Postraumático/tratamiento farmacológico , Estados Unidos , United States Department of Veterans Affairs , Salud de los VeteranosRESUMEN
Importance: Participant diversity is important for reducing study bias and increasing generalizability of comparative effectiveness research. Objective: Demonstrate the operational efficiency of a centralized electronic health record (EHR)-based model for recruiting difficult-to-reach participants in a pragmatic trial. Design, Setting, and Participants: This comparative effectiveness study was a secondary analysis of Diuretic Comparison Project, a randomized clinical trial conducted between 2016 and 2022 (mean [SD] follow-up, 2.4 [1.4] years) comparing 2 commonly prescribed antihypertensives, which used an EHR-based recruitment model. Electronic study workflows, in tandem with routine clinical practice, were adapted by 72 Veteran Affairs (VA) primary care networks. Data were analyzed from August to December 2022. Main Outcomes and Measures: Measures reflecting recruitment capacity (monthly rate), operational efficiency (median time for completion of electronic procedures), and geographic reach (percentage of patients recruited from rural areas) were examined. Results: A total of 13â¯523 patients with hypertension (mean [SD] age, 72 [5.4] years; 13â¯092 male [96.8%]) were recruited from 537 outpatient clinics. Approximately 205 patients were randomized per month and a median of 35 days (Q1-Q3, 23-80 days) was needed to complete electronic recruitment. The annual income was below the national median for 69% of the cohort. Patients from all 50 states, Puerto Rico, and the District of Columbia were included and 45% resided in rural areas. Conclusions and Relevance: In this secondary analysis of a multicenter pragmatic trial, a centralized EHR-based recruitment model was associated with improved participation from underrepresented groups. These participants often are difficult to reach, with their exclusion potentially biasing trial results; eliminating in-person study visits and local site involvement can minimize barriers for the recruitment of patients from rural and lower socioeconomic areas. Trial Registration: The Diuretic Comparison Project (DCP) was registered on ClinicalTrials.gov Identifier: NCT02185417.
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Diuréticos , Registros Electrónicos de Salud , Humanos , Masculino , Anciano , Antihipertensivos/uso terapéutico , Instituciones de Atención Ambulatoria , RentaRESUMEN
Background: Recent studies have demonstrated a causal role for elevated triglycerides (TG) in incident cardiovascular (CV) events in patients with established coronary heart disease (CHD) and those with CV risk factors alone, particularly diabetes. Objective: Using a large cohort of U.S. veterans with statin-controlled LDL-C levels (40-100 mg/dL), we explored residual CV risk among patients with elevated baseline TG levels (150-499 mg/dL) vs. those with normal TG levels (<150 mg/dL). Methods: We identified veterans receiving a statin but not a TG-lowering agent from the VA electronic health records database, from 2010 to 2015. We compared composite CV event rates (MI, stroke, unstable angina, coronary revascularization, and CV death) between the elevated TG and normal TG groups. We stratified the study cohort according to 3 CV risk groups: (1) no diabetes and no prior CV event, (2) diabetes and no prior CV event, and (3) prior CV event. We calculated crude event rates, rate ratios, and event rate ratios adjusted for age, sex, systolic blood pressure, estimated glomerular filtration rate, and weight. Results: The cohort included 396,189 veterans (predominantly male and white) of whom 109,195 (28%) had elevated TG levels. Those with elevated TG were younger (age 73 vs. 77 years) and had a higher body mass index (31.3 vs. 28.3 Kg/M2). The overall composite crude and adjusted rate ratios comparing the elevated and normal TG groups were 1.10 (1.09, 1.12) and 1.05 (1.03, 1.06), respectively. For CV risk groups 1, 2 and 3, the adjusted rate ratios comparing the elevated and normal TG groups were 0.99 (0.96, 1.02), 1.05 (1.02, 1.08), and 1.07 (1.04, 1.10), respectively. An association of increased rate ratios did not hold for fatal events. Conclusion: Those with elevated TG levels and well-controlled LDL-C on statins showed a modest increase in CV events compared to those with normal TG. Elevated TG levels were associated with increased CV events in patients with established CV disease and with diabetes only, suggesting that elevated TG levels are associated with a similar degree of residual risk in high-risk primary prevention and secondary prevention settings.
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BACKGROUND: Recent US guidelines recommend chlorthalidone over other thiazide-type diuretics for the treatment of hypertension based on its long half-life and proven ability to reduce CVD events. Despite recommendations most clinicians prescribe hydrochlorothiazide (HCTZ) over chlorthalidone (CTD). No randomized controlled data exist comparing these two diuretics on cardiovascular outcomes. METHODS: The Diuretic Comparison Project (DCP) is a multicenter, two-arm, parallel, Prospective Randomized Open, Blinded End-point (PROBE) trial testing the primary hypothesis that CTD is superior to HCTZ in the prevention of non-fatal CVD events and non-cancer death. Patients with hypertension taking HCTZ 25 or 50 mg were randomly assigned to either continue their current HCTZ or switch to an equipotent dose of CTD. The primary outcome is time to the first occurrence of a composite outcome consisting of a non-fatal CVD event (stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, or hospitalization for acute heart failure) or non-cancer death. The trial randomized 13,523 patients at 72 VA medical centers. The study is conducted by a centralized research team with site procedures embedded in the electronic health record and all data collected through administrative claims data, with no study related visits for participants. The trial will have 90% power to detect an absolute reduction in the composite event rate of 2.4%. RESULTS: Enrollment ended in November 2021. There are 4128 participting primary care providers and 16,595 patients individually consented to participate, 13,523 of whom were randomized. CONCLUSIONS: DCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients. CLINICAL TRIAL REGISTRATION: NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].
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Clortalidona , Hipertensión , Antihipertensivos/uso terapéutico , Presión Sanguínea , Clortalidona/farmacología , Clortalidona/uso terapéutico , Diuréticos/uso terapéutico , Registros Electrónicos de Salud , Humanos , Hidroclorotiazida/farmacología , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Estudios ProspectivosRESUMEN
IMPORTANCE AND OBJECTIVE: The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease. DESIGN: Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system. SETTING: 5 VA Medical Centers. PARTICIPANTS: Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2. INTERVENTIONS: Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs. MAIN OUTCOMES AND MEASURES: The primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR. RESULTS: Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. CONCLUSIONS AND RELEVANCE: This randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently. TRIAL REGISTRATION: Clinicaltrials.gov-NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.
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Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Respiración Artificial , Resultado del TratamientoRESUMEN
Pragmatic clinical trials (PCTs) have an established presence in clinical research and yet have only recently garnered attention within the landscape of genomic medicine. Using the PRagmatic-Explanatory Continuum Indicator Summary 2 (PRECIS-2) as a framework, this paper illustrates the application of PCT principles to The Integrating Pharmacogenetics In Clinical Care (I-PICC) Study, a trial of pharmacogenetic testing prior to statin initiation for cardiovascular disease prevention in primary care. The trial achieved high engagement with providers (85% enrolled of those approached) and enrolled a representative sample of participants for which statin therapy would be recommended. The I-PICC Study has a high level of pragmatism, which should enhance the generalizability of its findings. The PRECIS-2 may be useful in the design and evaluation of PCTs of genomic medicine interventions, contributing to the generation of evidence that can bridge the gap between genomics innovation and clinical adoption.
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Pruebas de Farmacogenómica , Ensayos Clínicos Pragmáticos como Asunto , Atención Primaria de Salud/métodos , Proyectos de Investigación , Adulto , Anciano , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/prevención & control , Estudios de Factibilidad , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Persona de Mediana Edad , Variantes FarmacogenómicasRESUMEN
BACKGROUND: The association between the SLCO1B1 rs4149056 variant and statin-associated muscle symptoms (SAMS) is well validated, but the clinical utility of its implementation in patient care is unknown. DESIGN: The Integrating Pharmacogenetics in Clinical Care (I-PICC) Study is a pseudo-cluster randomized controlled trial of SLCO1B1 genotyping among statin-naïve primary care and women's health patients across the Veteran Affairs Boston Healthcare System. Eligible patients of enrolled primary care providers are aged 40-75 and have elevated risk of cardiovascular disease by American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Patients give consent by telephone in advance of an upcoming appointment, but they are enrolled only if and when their provider co-signs an order for SLCO1B1 testing, performed on a blood sample already collected in clinical care. Enrolled patients are randomly allocated to have their providers receive results through the electronic health record at baseline (PGxâ¯+â¯arm) versus after 12â¯months (PGx- arm). The primary outcome is the change in low-density lipoprotein cholesterol (LDL-C) after one year. Secondary outcomes are concordance with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for simvastatin prescribing, concordance with ACC/AHA guidelines for statin use, and incidence of SAMS. With 408 patients, the study has >80% power to exclude a between-group LDL-C difference of 10â¯mg/dL (non-inferiority design) and to detect between-group differences of 15% in CPIC guideline concordance (superiority design). CONCLUSION: The outcomes of the I-PICC Study will inform the clinical utility of preemptive SLCO1B1 testing in the routine practice of medicine, including its proposed benefits and unforeseen risks.
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Aterosclerosis/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Enfermedades Musculares/inducido químicamente , Atención Primaria de Salud , Simvastatina/efectos adversos , Adulto , Anciano , Aterosclerosis/sangre , Aterosclerosis/tratamiento farmacológico , LDL-Colesterol/sangre , Femenino , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Masculino , Persona de Mediana Edad , Enfermedades Musculares/genética , Pruebas de Farmacogenómica , Sistemas de Atención de Punto , Medicina de Precisión , Prevención Primaria , Prevención SecundariaRESUMEN
BACKGROUND: Muscle power is a key predictor of physical function in older adults; however, clinically meaningful improvements in leg-extensor muscle power have yet to be identified. The purpose of this study is to establish the minimal clinically important improvement (MCII) and substantial improvement (SI) for leg-extensor power and muscle contraction velocity in mobility-limited older adults. METHODS: Data were extracted from three randomized trials of leg-extensor muscle power training interventions (3- to 6-month duration). Measurements of leg-extensor power and velocity were obtained using dynamic bilateral leg press at 40% and 70% of the one-repetition maximum. Anchor-based MCIIs were calculated using selected items extracted from the Late Life Function and Disability Instrument. Standard error of measurement and effect size methods were used to calculate the distribution-based MCII. RESULTS: Data from 164 participants (mean age: 76.6 ± 5.6 years; Short Physical Performance Battery score: 7.8 ± 1.3) were used in this analysis. The respective MCII and SI estimates for 40% leg-extensor power were 18.3 (9%) and 30.5 (15%) W, and 23.1 (10%) and 41.6 (18%) W for 70% leg-extensor power. The respective MCII and SI estimates for 40% average velocity were 0.03(7%) and 0.08(18%) m/s, and 0.02(6%) and 0.05(15%) m/s for 70% average velocity. CONCLUSIONS: This is the first study to establish a clinically meaningful improvement of leg-extensor power (9%-10%) and velocity (6%-7%) in mobility-limited older adults. These findings should be used to aid in the design and interpretation of clinical trials and interventions that target improvements in muscle power in this high-risk population.
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Pierna , Limitación de la Movilidad , Fuerza Muscular/fisiología , Recuperación de la Función/fisiología , Entrenamiento de Fuerza , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Contracción Muscular/fisiología , Músculo Esquelético/fisiopatología , Evaluación de Resultado en la Atención de SaludRESUMEN
BACKGROUND: We compared the effects of two uniquely different lower extremity power training interventions on changes in muscle power, physical performance, neuromuscular activation, and muscle cross sectional area in mobility-limited older adults. METHODS: Fifty-two subjects (78±5 years, short physical performance battery score: 8.1±1) were randomized to either 16 weeks of progressive high velocity resistance training performed at low external resistance (40% of the 1-repetition maximum [1-RM] [LO]) or high external resistance (70% of 1RM [HI]). Both groups completed three sets of leg and knee extension exercises at maximum voluntary velocity, two times per week. Neuromuscular activation was assessed using surface electromyography and muscle cross sectional area (CSA) was measured using computed tomography. RESULTS: At 16 weeks, LO and HI exhibited significant and similar within-group increases of leg extensor peak power (~34% vs ~42%), strength (~13% vs ~19%), and SPPB score (1.4±0.3 vs 1.8±0.3 units), respectively (all P < .03). Improvements in neuromuscular activation occurred in LO (P = .03) while small gains in mid-thigh muscle CSA were detected in LO (1.6%, P = .35) and HI (2.1%, P = .17). No significant between-group differences were evident for any measured parameters (all P > .25). CONCLUSIONS: High velocity resistance training with low external resistance yields similar improvements in muscle power and physical performance compared to training with high external resistance in mobility-limited elders. These findings may have important implications for optimizing exercise interventions for older adults with mobility limitations.
Asunto(s)
Extremidad Inferior , Limitación de la Movilidad , Fuerza Muscular/fisiología , Entrenamiento de Fuerza , Anciano , Anciano de 80 o más Años , Electromiografía , Femenino , Humanos , Contracción Isométrica/fisiología , Masculino , Músculo Cuádriceps/diagnóstico por imagen , Músculo Cuádriceps/patología , Músculo Cuádriceps/fisiopatología , Método Simple Ciego , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: This study examined the relationships between leg muscle strength, power, and perceived disease severity in subjects with knee osteoarthritis (OA) in order to determine whether dynamic leg extensor muscle power would be associated with pain and quality of life in knee OA. METHODS: Baseline data on 190 subjects with knee OA (mean ± SD age 60.2 ± 10.4 years, body mass index 32.7 ± 7.2 kg/m(2) ) were obtained from a randomized controlled trial. Knee pain was measured using the Western Ontario and McMaster Universities Osteoarthritis Index, and health-related quality of life was assessed using the Short Form 36 (SF-36). One-repetition maximum (1RM) strength was assessed using the bilateral leg press, and peak muscle power was measured during 5 maximum voluntary velocity repetitions at 40% and 70% of 1RM. RESULTS: In univariate analysis, greater muscle power was significantly associated with pain (r = -0.17, P < 0.02) and also significantly and positively associated with SF-36 physical component summary (PCS) scores (r = 0.16, P < 0.05). After adjustment for multiple covariates, muscle power was a significant independent predictor of pain (P ≤ 0.05) and PCS scores (P ≤ 0.04). However, muscle strength was not an independent determinant of pain or quality of life (P ≥ 0.06). CONCLUSION: Muscle power is an independent determinant of pain and quality of life in knee OA. Compared to strength, muscle power may be a more clinically important measure of muscle function within this population. New trials to systematically examine the impact of muscle power training interventions on disease severity in knee OA are particularly warranted.
Asunto(s)
Articulación de la Rodilla/fisiopatología , Fuerza Muscular/fisiología , Osteoartritis de la Rodilla/fisiopatología , Dolor/fisiopatología , Músculo Cuádriceps/fisiopatología , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiología , Músculo Esquelético/fisiopatología , Músculo Cuádriceps/fisiologíaRESUMEN
BACKGROUND: Whey protein supplementation may augment resistance exercise-induced increases in muscle strength and mass. Further studies are required to determine whether this effect extends to mobility-limited older adults. The objectives of the study were to compare the effects of whey protein concentrate (WPC) supplementation to an isocaloric control on changes in whole-body lean mass, mid-thigh muscle cross-sectional area, muscle strength, and stair-climbing performance in older mobility-limited adults in response to 6 months of resistance training (RT). METHODS: Eighty mobility-limited adults aged 70-85 years were randomized to receive WPC (40g/day) or an isocaloric control for 6 months. All participants also completed a progressive high-intensity RT intervention. Sample sizes were calculated based on the primary outcome of change in whole-body lean mass to give 80% power for a 0.05-level, two-sided test. RESULTS: Lean mass increased 1.3% and 0.6% in the WPC and control groups, respectively. Muscle cross-sectional area was increased 4.6% and 2.9% in the WPC and control groups, respectively, and muscle strength increased 16%-50% in WPC and control groups. Stair-climbing performance also improved in both groups. However, there were no statistically significant differences in the change in any of these variables between groups. CONCLUSIONS: These data suggest that WPC supplementation at this dose does not offer additional benefit to the effects of RT in mobility-limited older adults.
Asunto(s)
Envejecimiento , Composición Corporal/efectos de los fármacos , Suplementos Dietéticos , Ingestión de Energía , Proteínas de la Leche/administración & dosificación , Fuerza Muscular/efectos de los fármacos , Ejercicios de Estiramiento Muscular , Músculo Esquelético/metabolismo , Resistencia Física/efectos de los fármacos , Absorciometría de Fotón/métodos , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Método Doble Ciego , Femenino , Humanos , Masculino , Rango del Movimiento Articular/efectos de los fármacos , Resultado del Tratamiento , Proteína de Suero de LecheRESUMEN
Age-associated loss of muscular strength and muscular power is a critical determinant of loss of physical function and progression to disability in older adults. In this study, we examined the association of systemic vascular function and measures of muscle strength and power in older adults. Measures of vascular endothelial function included brachial artery flow-mediated dilation (FMD) and the pulse wave amplitude reactive hyperemia index (PWA-RHI). Augmentation index (AIx) was taken as a measure of systemic vascular function related to arterial stiffness and wave reflection. Measures of muscular strength included one repetition maximum (1RM) for a bilateral leg press. Peak muscular power was measured during 5 repetitions performed as fast as possible for bilateral leg press at 40% 1RM. Muscular power was associated with brachial FMD (r = 0.43, P < 0.05), PWA-RHI (r = 0.42, P < 0.05), and AIx (r = -0.54, P < 0.05). Muscular strength was not associated with any measure of vascular function. In conclusion, systemic vascular function is associated with lower-limb muscular power but not muscular strength in older adults. Whether loss of muscular power with aging contributes to systemic vascular deconditioning or vascular dysfunction contributes to decrements in muscular power remains to be determined.