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Introducing longitudinal cumulative dose to describe chemotherapy patterns over time: Case study of a colon cancer trial.
Webster-Clark, M, Keil, AP, Sanoff, HK, Stürmer, T, Westreich, D, Lund, JL
International journal of cancer. 2021;(2):394-402
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Abstract
Adjuvant chemotherapy regimens take months to complete. Despite this, studies evaluate chemotherapy adherence via measures assessed at the end of treatment (eg, number of patients missing any dose, relative dose intensity [RDI]). This approach ignores information like the timing of treatment delays. We propose longitudinal cumulative dose (LCD) to integrate impacts of dose reductions, missed doses and dose delays over time. We obtained data from the 2246 participants in the MOSAIC trial randomized to FOLFOX (all three agents) or 5-FU/LV (only 5-fluorouracil and leucovorin). We evaluated proportions of patients stopping treatment early and reducing, missing or delaying a dose in each arm for each chemotherapy agent at each cycle. We calculated LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each agent and compared it over time and at 24 weeks between treatment arms. Participants randomized to FOLFOX were more likely to stop treatment, reduce doses, miss doses or delay cycles; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. The LCD for 5-fluorouracil differed between arms (FOLFOX arm median: 81%; 5-FU/LV arm median: 96%). Visualizing LCD highlighted the timing of deviations from standard administration in a way RDI could not, with major differences in 5-fluorouracil LCD across treatment arms beginning after the sixth dose. Further evaluation of LCD and its impacts on clinical outcomes may clarify mechanisms for heterogeneous patient outcomes.
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Adherence at 2 years with distribution of essential medicines at no charge: The CLEAN Meds randomized clinical trial.
Persaud, N, Bedard, M, Boozary, A, Glazier, RH, Gomes, T, Hwang, SW, Juni, P, Law, MR, Mamdani, M, Manns, B, et al
PLoS medicine. 2021;(5):e1003590
Abstract
BACKGROUND Adherence to medicines is low for a variety of reasons, including the cost borne by patients. Some jurisdictions publicly fund medicines for the general population, but many jurisdictions do not, and such policies are contentious. To our knowledge, no trials studying free access to a wide range of medicines have been conducted. METHODS AND FINDINGS We randomly assigned 786 primary care patients who reported not taking medicines due to cost between June 1, 2016 and April 28, 2017 to either free distribution of essential medicines (n = 395) or to usual medicine access (n = 391). The trial was conducted in Ontario, Canada, where hospital care and physician services are publicly funded for the general population but medicines are not. The trial population was mostly female (56%), younger than 65 years (83%), white (66%), and had a low income from wages as the primary source (56%). The primary outcome was medicine adherence after 2 years. Secondary outcomes included control of diabetes, blood pressure, and low-density lipoprotein (LDL) cholesterol in patients taking relevant treatments and healthcare costs over 2 years. Adherence to all appropriate prescribed medicines was 38.7% in the free distribution group and 28.6% in the usual access group after 2 years (absolute difference 10.1%; 95% confidence interval (CI) 3.3 to 16.9, p = 0.004). There were no statistically significant differences in control of diabetes (hemoglobin A1c 0.27; 95% CI -0.25 to 0.79, p = 0.302), systolic blood pressure (-3.9; 95% CI -9.9 to 2.2, p = 0.210), or LDL cholesterol (0.26; 95% CI -0.08 to 0.60, p = 0.130) based on available data. Total healthcare costs over 2 years were lower with free distribution (difference in median CAN$1,117; 95% CI CAN$445 to CAN$1,778, p = 0.006). In the free distribution group, 51 participants experienced a serious adverse event, while 68 participants in the usual access group experienced a serious adverse event (p = 0.091). Participants were not blinded, and some outcomes depended on participant reports. CONCLUSIONS In this study, we observed that free distribution of essential medicines to patients with cost-related nonadherence substantially increased adherence, did not affect surrogate health outcomes, and reduced total healthcare costs over 2 years. TRIAL REGISTRATION ClinicalTrials.gov NCT02744963.
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Achieving optimal adherence to medical therapy by telehealth: Findings from the ORBITA medication adherence sub-study.
Thompson, D, Al-Lamee, R, Foley, M, Dehbi, HM, Thom, S, Davies, JE, Francis, DP, Patel, P, Gupta, P, ,
Pharmacology research & perspectives. 2021;(1):e00710
Abstract
INTRODUCTION The ORBITA trial of percutaneous coronary intervention (PCI) versus a placebo procedure for patients with stable angina was conducted across six sites in the United Kingdom via home monitoring and telephone consultations. Patients underwent detailed assessment of medication adherence which allowed us to measure the efficacy of the implementation of the optimization protocol and interpretation of the main trial endpoints. METHODS Prescribing data were collected throughout the trial. Self-reported adherence was assessed, and urine samples collected at pre-randomization and at follow-up for direct assessment of adherence using high-performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS). RESULTS Self-reported adherence was >96% for all drugs in both treatment groups at both stages. The percentage of samples in which drug was detected at pre-randomization and at follow-up in the PCI versus placebo groups respectively was: clopidogrel, 96% versus 90% and 98% versus 94%; atorvastatin, 95% versus 92% and 92% versus 91%; perindopril, 95% versus 97% and 85% versus 100%; bisoprolol, 98% versus 99% and 96% versus 97%; amlodipine, 99% versus 99% and 94% versus 96%; nicorandil, 98% versus 96% and 94% versus 92%; ivabradine, 100% versus 100% and 100% versus 100%; and ranolazine, 100% versus 100% and 100% versus 100%. CONCLUSIONS Adherence levels were high throughout the study when quantified by self-reporting methods and similarly high proportions of drug were detected by urinary assay. The results indicate successful implementation of the optimization protocol delivered by telephone, an approach that could serve as a model for treatment of chronic conditions, particularly as consultations are increasingly conducted online.
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An electronic decision support-based complex intervention to improve management of cardiovascular risk in primary health care: a cluster randomised trial (INTEGRATE).
Webster, R, Usherwood, T, Joshi, R, Saini, B, Armour, C, Critchley, S, Di Tanna, GL, Galgey, S, Hespe, CM, Jan, S, et al
The Medical journal of Australia. 2021;(9):420-427
Abstract
OBJECTIVES To determine whether a multifaceted primary health care intervention better controlled cardiovascular disease (CVD) risk factors in patients with high risk of CVD than usual care. DESIGN, SETTING Parallel arm, cluster randomised trial in 71 Australian general practices, 5 December 2016 - 13 September 2019. PARTICIPANTS General practices that predominantly used an electronic medical record system compatible with the HealthTracker electronic decision support tool, and willing to implement all components of the INTEGRATE intervention. INTERVENTION Electronic point-of-care decision support for general practices; combination cardiovascular medications (polypills); and a pharmacy-based medication adherence program. MAIN OUTCOME MEASURES Proportion of patients with high CVD risk not on an optimal preventive medication regimen at baseline who had achieved both blood pressure and low-density lipoprotein (LDL) cholesterol goals at study end. RESULTS After a median 15 months' follow-up, primary outcome data were available for 4477 of 7165 patients in the primary outcome cohort (62%). The proportion of patients who achieved both treatment targets was similar in the intervention (423 of 2156; 19.6%) and control groups (466 of 2321; 20.1%; relative risk, 1.06; 95% CI, 0.85-1.32). Further, no statistically significant differences were found for a number of secondary outcomes, including risk factor screening, preventive medication prescribing, and risk factor levels. Use of intervention components was low; it was highest for HealthTracker, used at least once for 347 of 3236 undertreated patients with high CVD risk (10.7%). CONCLUSIONS Despite evidence for the efficacy of its individual components, the INTEGRATE intervention was not broadly implemented and did not improve CVD risk management in participating Australian general practices. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry, ACTRN12616000233426 (prospective).
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A Randomized Trial Comparing the Safety, Adherence, and Pharmacodynamics Profiles of Two Doses of Sodium Bicarbonate in CKD: the BASE Pilot Trial.
Raphael, KL, Isakova, T, Ix, JH, Raj, DS, Wolf, M, Fried, LF, Gassman, JJ, Kendrick, C, Larive, B, Flessner, MF, et al
Journal of the American Society of Nephrology : JASN. 2020;(1):161-174
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Abstract
BACKGROUND Oral sodium bicarbonate (NaHCO3) may preserve kidney function in CKD, even if initiated when serum bicarbonate concentration is normal. Adequately powered trials testing this hypothesis have not been conducted, partly because the best dose for testing is unknown. METHODS This multicenter pilot trial assessed the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO3 over 28 weeks in adults with eGFR 20-44 or 45-59 ml/min per 1.73 m2 with urinary albumin/creatinine (ACR) ≥50 mg/g and serum bicarbonate 20-28 meq/L. We randomly assigned 194 participants from ten clinical sites to receive higher-dose (HD-NaHCO3; 0.8 meq/kg of lean body wt per day; n=90) or lower-dose (LD-NaHCO3; 0.5 meq/kg of lean body wt per day; n=52) NaHCO3 or matching placebo (n=52). The dose was adjusted depending on side effects. The prescribed dose at week 28 was the primary outcome; a dose was considered acceptable for a full-scale trial if ≥67% of participants were on full-dose and ≥80% were on ≥25% of the per-protocol dose. RESULTS Mean±SD baseline eGFR was 36±9 ml/min per 1.73 m2, serum bicarbonate was 24±2 meq/L, and median (IQR) ACR was 181 (25-745) mg/g. Both doses were well tolerated without significant changes in BP, weight, or serum potassium. The proportions of adverse events and hospitalizations were similar across the groups. Consequently, 87% in HD-NaHCO3, 96% in LD-NaHCO3, and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO3, 98% in LD-NaHCO3, and 92% in placebo were on ≥25% of the per-protocol dose. Mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in HD-NaHCO3 compared with LD-NaHCO3 at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group. CONCLUSIONS Both NaHCO3 doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of lean body wt per day dose of NaHCO3 may be a reasonable choice for future trials.
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Impact of a Mobile Health Intervention on Long-term Nonadherence After Lung Transplantation: Follow-up After a Randomized Controlled Trial.
Geramita, EM, DeVito Dabbs, AJ, DiMartini, AF, Pilewski, JM, Switzer, GE, Posluszny, DM, Myaskovsky, L, Dew, MA
Transplantation. 2020;(3):640-651
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Abstract
BACKGROUND In a randomized controlled trial, lung transplant recipients (LTRs) using a mobile health intervention, Pocket Personal Assistant for Tracking Health (Pocket PATH), showed better adherence to the medical regimen than LTRs receiving usual care during the first year posttransplant. We examined whether these effects were maintained beyond the end of the trial and evaluated other potential risk factors for long-term nonadherence. METHODS Adherence in 8 areas was evaluated at follow-up in separate LTR and family caregiver (collateral) assessments. Pocket PATH and usual care groups' nonadherence rates were compared; multivariable regression analyses then examined and controlled for other patient characteristics' associations with nonadherence. RESULTS One hundred five LTRs (75% of survivors) were assessed (M = 3.9 years posttransplant, SD = 0.8). Nonadherence rates in the past month were 23%-81% for self-care and lifestyle requirements (diet, exercise, blood pressure monitoring, spirometry), 13%-23% for immunosuppressants and other medications, and 4% for tobacco use, with 31% clinic appointment nonadherence in the past year. In multivariable analysis, the Pocket PATH group showed lower risk of nonadherence to lifestyle requirements (diet/exercise) than the usual care group (P < 0.05). Younger age and factors during the first year posttransplant (acute graft rejection, chronically elevated anxiety, less time rehospitalized, nonadherence at the final randomized controlled trial assessment) were each associated with nonadherence in at least 1 area at follow-up (P < 0.05). CONCLUSIONS Pocket PATH did not have sustained impact on most areas of the regimen, although we identified other risk factors for long-term nonadherence. Future work should explore strategies to facilitate sustained effects of mobile health interventions.
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A primary healthcare information intervention for communicating cardiovascular risk to patients with poorly controlled hypertension: The Education and Coronary Risk Evaluation (Educore) study-A pragmatic, cluster-randomized trial.
Escortell-Mayor, E, Del Cura-González, I, Ojeda-Ruiz, E, Sanz-Cuesta, T, Rodríguez-Salceda, I, García-Soltero, J, Rojas-Giraldo, MJ, Herrera-Municio, P, Jorge-Formariz, A, Lorenzo-Lobato, Á, et al
PloS one. 2020;(1):e0226398
Abstract
PURPOSE Uncertainty exists regarding the best way to communicate cardiovascular risk (CVR) to patients, and it is unclear whether the comprehension and perception of CVR varies according to the format used. The aim of the present work was to determine whether a strategy designed for communicating CVR information to patients with poorly controlled high blood pressure (HBP), but with no background of cardiovascular disease, was more effective than usual care in the control of blood pressure (BP) over the course of a year. METHODS A pragmatic, two-arm, cluster-randomized controlled trial was performed. Consecutive patients aged 40-65 years, all diagnosed with HBP in the last 12 months, and all of whom showed poor control of their condition (systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg), were recruited at 22 primary healthcare centres. Eleven centres were randomly assigned to the usual care arm, and 11 to the informative intervention arm (Educore arm). At the start of the study, the Educore arm subjects were shown the "low risk SCORE table", along with impacting images and information pamphlets encouraging the maintenance of good cardiovascular health. The main outcome variable measured was the control of HBP; the secondary outcome variables were SCORE table score, total plasma cholesterol concentration, use of tobacco, adherence to prescribed treatment, and quality of life. RESULTS The study participants were 411 patients (185 in the Educore arm and 226 in the usual care arm). Multilevel logistic regression showed that, at 12 months, the Educore intervention achieved better control of HBP (OR = 1.57; 1.02 to 2.41). No statistically significant differences were seen between the two arms at 12 months with respect to the secondary outcomes. CONCLUSIONS Compared to usual care, the Educore intervention was associated with better control of HBP after adjusting for age, baseline SBP and plasma cholesterol, at 12 months.
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Evaluating Measures of Pre-ART Adherence Readiness Through Associations with ART Adherence in the Early Months of Treatment.
Azhar, GS, Schneider, S, Hoffman, R, Gordon, K, Ramirez, D, Wagner, G
AIDS and behavior. 2020;(2):648-654
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Determining a patient's readiness to adhere well prior to the start of ART provides an opportunity to address adherence barriers before poor pill taking habits form, and ultimately improve clinical outcomes and resource utilization. Three methods of measuring adherence readiness and their comparative utility in predicting early ART adherence were examined in a sample of 176 patients preparing to start ART. Data were analyzed data from a randomized controlled trial of a cognitive-behavioral adherence intervention. Three measures of pre-ART adherence readiness (provider estimate, 1 week vitamin practice trials, and self-report [HIV Medication Readiness Scale; Transtheoretical Stages of Change item (TSOC)] were examined in association with measures of (1) ART initiation, (2) ART retention, (3) mean electronic dose-taking adherence, and (4) achievement of optimal (85+ % dose-taking) adherence, over the first 3 months of ART. Of the 176 patients, 166 (94.3%) started ART; 124 (74.7% of those who started ART; 70.5% of whole sample) completed the first 3 months of ART. Among the 124 still on ART at month 3, mean dose-taking adherence was 79.3%, and 62 (35.2% of whole sample) achieved optimal adherence. The provider estimate was the only readiness measure significantly associated with each of the four measures of early ART adherence, and it had the highest concordance statistics (71% PPV and 62.3% NPV) with optimal early ART adherence. Practice trial adherence was only associated with ART initiation and retention. Dose-taking adherence over 3 months was significantly correlated with the provider estimate and the two self-reports. Each method of early treatment adherence has its own utility, but the provider estimate had the best overall performance in predicting early ART adherence.
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Effect of Pharmacogenetic Testing for Statin Myopathy Risk vs Usual Care on Blood Cholesterol: A Randomized Clinical Trial.
Vassy, JL, Gaziano, JM, Green, RC, Ferguson, RE, Advani, S, Miller, SJ, Chun, S, Hage, AK, Seo, SJ, Majahalme, N, et al
JAMA network open. 2020;(12):e2027092
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Abstract
IMPORTANCE Nonadherence to statin guidelines is common. The solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotype is associated with simvastatin myopathy risk and is proposed for clinical implementation. The unintended harms of using pharmacogenetic information to guide pharmacotherapy remain a concern for some stakeholders. OBJECTIVE To determine the impact of delivering SLCO1B1 pharmacogenetic results to physicians on the effectiveness of atherosclerotic cardiovascular disease (ASCVD) prevention (measured by low-density lipoprotein cholesterol [LDL-C] levels) and concordance with prescribing guidelines for statin safety and effectiveness. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was performed from December 2015 to July 2019 at 8 primary care practices in the Veterans Affairs Boston Healthcare System. Participants included statin-naive patients with elevated ASCVD risk. Data analysis was performed from October 2019 to September 2020. INTERVENTIONS SLCO1B1 genotyping and results reporting to primary care physicians at baseline (intervention group) vs after 1 year (control group). MAIN OUTCOMES AND MEASURES The primary outcome was the 1-year change in LDL-C level. The secondary outcomes were 1-year concordance with American College of Cardiology-American Heart Association and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for statin therapy and statin-associated muscle symptoms (SAMS). RESULTS Among 408 patients (mean [SD] age, 64.1 [7.8] years; 25 women [6.1%]), 193 were randomized to the intervention group and 215 were randomized to the control group. Overall, 120 participants (29%) had a SLCO1B1 genotype indicating increased simvastatin myopathy risk. Physicians offered statin therapy to 65 participants (33.7%) in the intervention group and 69 participants (32.1%) in the control group. Compared with patients whose physicians did not know their SLCO1B1 results at baseline, patients whose physicians received the results had noninferior reductions in LDL-C at 12 months (mean [SE] change in LDL-C, -1.1 [1.2] mg/dL in the intervention group and -2.2 [1.3] mg/dL in the control group; difference, -1.1 mg/dL; 90% CI, -4.1 to 1.8 mg/dL; P < .001 for noninferiority margin of 10 mg/dL). The proportion of patients with American College of Cardiology-American Heart Association guideline-concordant statin prescriptions in the intervention group was noninferior to that in the control group (12 patients [6.2%] vs 14 patients [6.5%]; difference, -0.003; 90% CI, -0.038 to 0.032; P < .001 for noninferiority margin of 15%). All patients in both groups were concordant with CPIC guidelines for safe statin prescribing. Physicians documented 2 and 3 cases of SAMS in the intervention and control groups, respectively, none of which was associated with a CPIC guideline-discordant prescription. Among patients with a decreased or poor SLCO1B1 transporter function genotype, simvastatin was prescribed to 1 patient in the control group but none in the intervention group. CONCLUSIONS AND RELEVANCE Clinical testing and reporting of SLCO1B1 results for statin myopathy risk did not result in poorer ASCVD prevention in a routine primary care setting and may have been associated with physicians avoiding simvastatin prescriptions for patients at genetic risk for SAMS. Such an absence of harm should reassure stakeholders contemplating the clinical use of available pharmacogenetic results. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02871934.
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A Pilot Randomized Controlled Trial Testing the Feasibility and Acceptability of a SystemCHANGE Intervention to Improve Medication Adherence in Older Adult Stroke Survivors.
Wessol, JL, Russell, CL, Olds, KE
The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses. 2019;(5):259-265
Abstract
BACKGROUND Adhering to an antithrombotic medication regimen is essential to reducing recurrent stroke in adult stroke survivors. The purpose of this study was to evaluate the feasibility and acceptability of the SystemCHANGE (SC) and attention control (AC) intervention in older adult, nonadherent ischemic stroke patients. METHODS A pilot randomized controlled trial was conducted to determine the feasibility and acceptability of an SC versus AC intervention in older adult, nonadherent stroke survivors in the management of antithrombotic medication. Participants were masked to group assignment. Stroke survivors 50 years or older, taking at least 1 once-a-day antithrombotic medication, were recruited from a Midwest Comprehensive Stroke Center-affiliated neurology office. They were screened electronically using the Medication Event Monitoring System for 2 months to determine baseline medication adherence. Nonadherent stroke survivors (medication adherence < 0.97) were randomized to SC or AC intervention and monitored for 3 months. SC focused on redesigning the interpersonal environmental system and daily routines. The AC group was provided education materials on stroke that consisted of stroke risk factor reduction, stroke facts, rehabilitation, and nutrition with the primary investigator. Participation and intervention experience interviews were evaluated for themes. RESULTS Thirty participants were recruited: median age was 64 years, 46.7% of them were male, and they took an average of 7.77 (SD, 3.191; range, 3-15) prescribed medications. The number of over-the-counter medications taken (excluding aspirin) on a regular basis averaged 1.9 (SD, 0.8; range, 1-4). Two participants were nonadherent and were randomized to the 2 arms. Both participants had positive feedback and were not inconvenienced by their participation in the study. Neither participant voiced concerns about the intervention, survey demands, time requirement, or completing the surveys on the primary investigator's laptop. CONCLUSION The SC and AC intervention protocols were feasible and acceptable to the participants in this study. Additional pilot testing is needed to further evaluate the intervention and its effect on medication adherence in this population.