Alexis A. Krumme

Patterns of Initiation of Oral Anticoagulants in Patients with Atrial Fibrillation - Quality and Cost Implications

BACKGROUND Dabigatran, rivaroxaban, and apixaban have been approved for use in patients with atrial fibrillation based upon randomized trials demonstrating their comparable or superior efficacy and safety relative to warfarin. Little is known about their adoption into clinical practice, whether utilization is consistent with the controlled trials on which their approval was based, and how their use has affected health spending for patients and insurers. METHODS We used medical and prescription claims data from a large insurer to identify patients with nonvalvular atrial fibrillation who were prescribed an oral anticoagulant in 2010-2013. We plotted trends in medication initiation over time, assessed corresponding insurer and patient out-of-pocket spending, and evaluated the cumulative number and cost of anticoagulants. We identified predictors of novel anticoagulant initiation using multivariable logistic models. Finally, we estimated the difference in total drug expenditures over 6 months for patients initiating warfarin versus a novel anticoagulant. RESULTS There were 6893 patients with atrial fibrillation that initiated an oral anticoagulant during the study period. By the end of the study period, novel anticoagulants accounted for 62% of new prescriptions and 98% of anticoagulant-related drug costs. Female sex, lower household income, and higher CHADS2, CHA2DS2-VASC, and HAS-BLED scores were significantly associated with lower odds of receiving a novel anticoagulant (P <.001 for each). Average combined patient and insurer anticoagulant spending in the first 6 months after initiation was more than

Initial Choice of Oral Glucose-Lowering Medication for Diabetes Mellitus: A Patient-Centered Comparative Effectiveness Study

900 greater for patients initiating a novel anticoagulant. CONCLUSIONS This study demonstrates rapid adoption of novel anticoagulants into clinical practice, particularly among patients with lower CHADS2 and HAS-BLED scores, and high health care cost consequences. These findings provide important directions for future comparative and cost-effectiveness research.

Effect of Reminder Devices on Medication Adherence: The REMIND Randomized Clinical Trial

IMPORTANCE Although many classes of oral glucose-lowering medications have been approved for use, little comparative effectiveness evidence exists to guide initial selection of therapy for diabetes mellitus. OBJECTIVE To determine the effect of initial oral glucose-lowering agent class on subsequent need for treatment intensification and 4 short-term adverse clinical events. DESIGN, SETTING, AND PARTICIPANTS This study was a retrospective cohort study of patients who were fully insured members of Aetna (a large national health insurer) who had been prescribed an oral glucose-lowering medication from July 1, 2009, through June 30, 2013. Individuals newly prescribed an oral glucose-lowering agent who filled a second prescription for a medication in the same class and with a dosage at or above the World Health Organizations defined daily dose within 90 days of the end-of-days supply of the first prescription were studied. Individuals with interim prescriptions for other oral glucose-lowering medications were excluded. EXPOSURES Initiation of treatment with metformin, a sulfonylurea, a thiazolidinedione, or a dipeptidyl peptidase 4 inhibitor. MAIN OUTCOMES AND MEASURES Time to addition of a second oral agent or insulin, each component separately, hypoglycemia, other diabetes-related emergency department visits, and cardiovascular events. RESULTS A total of 15 516 patients met the inclusion criteria, of whom 8964 (57.8%) started therapy with metformin. In unadjusted analyses, use of medications other than metformin was significantly associated with an increased risk of adding a second oral agent only, insulin only, and a second agent or insulin (P < .001 for all). In propensity score and multivariable-adjusted Cox proportional hazards models, initiation of therapy with sulfonylureas (hazard ratio [HR], 1.68; 95% CI, 1.57-1.79), thiazolidinediones (HR, 1.61; 95% CI, 1.43-1.80), and dipeptidyl peptidase 4 inhibitors (HR, 1.62; 95% CI, 1.47-1.79) was associated with an increased hazard of intensification. Alternatives to metformin were not associated with a reduced risk of hypoglycemia, emergency department visits, or cardiovascular events. CONCLUSIONS AND RELEVANCE Despite guidelines, only 57.8% of individuals began diabetes treatment with metformin. Beginning treatment with metformin was associated with reduced subsequent treatment intensification, without differences in rates of hypoglycemia or other adverse clinical events. These findings have significant implications for quality of life and medication costs.

Association between trajectories of statin adherence and subsequent cardiovascular events

Importance Forgetfulness is a major contributor to nonadherence to chronic disease medications and could be addressed with medication reminder devices. Objective To compare the effect of 3 low-cost reminder devices on medication adherence. Design, Setting, and Participants This 4-arm, block-randomized clinical trial involved 53 480 enrollees of CVS Caremark, a pharmacy benefit manager, across the United States. Eligible participants were aged 18 to 64 years and taking 1 to 3 oral medications for long-term use. Participants had to be suboptimally adherent to all of their prescribed therapies (with a medication possession ratio of 30% to 80%) in the 12 months before randomization. Participants were stratified on the basis of the medications they were using at randomization: medications for cardiovascular or other nondepression chronic conditions (the chronic disease stratum) and antidepressants (the antidepressant stratum). In each stratum, randomization occurred within blocks defined by whether all of the patient’s targeted medications were dosed once daily. Patients were randomized to receive in the mail a pill bottle strip with toggles, digital timer cap, or standard pillbox. The control group received neither notification nor a device. Data were collected from February 12, 2013, through March 21, 2015, and data analyses were on the intention-to-treat population. Main Outcomes and Measures The primary outcome was optimal adherence (medication possession ratio ≥80%) to all eligible medications among patients in the chronic disease stratum during 12 months of follow-up, ascertained using pharmacy claims data. Secondary outcomes included optimal adherence to cardiovascular medications among patients in the chronic disease stratum as well as optimal adherence to antidepressants. Results Of the 53 480 participants, mean (SD) age was 45 (12) years and 56% were female. In the primary analysis, 15.5% of patients in the chronic disease stratum assigned to the standard pillbox, 15.1% assigned to the digital timer cap, 16.3% assigned to the pill bottle strip with toggles, and 15.1% assigned to the control arm were optimally adherent to their prescribed treatments during follow-up. There was no statistically significant difference in the odds of optimal adherence between the control and any of the devices (standard pillbox: odds ratio [OR], 1.03 [95% CI, 0.95-1.13]; digital timer cap: OR, 1.00 [95% CI, 0.92-1.09]; and pill bottle strip with toggles: OR, 0.94 [95% CI, 0.85-1.04]). In direct comparisons, the odds of optimal adherence were higher with a standard pillbox than with the pill bottle strip (OR, 1.10 [95% CI, 1.00-1.21]). Secondary analyses yielded similar results. Conclusions and Relevance Low-cost reminder devices did not improve adherence among nonadherent patients who were taking up to 3 medications to treat common chronic conditions. The devices may have been more effective if coupled with interventions to ensure consistent use or if targeted to individuals with an even higher risk of nonadherence. Trial Registration clinicaltrials.gov Identifier: NCT02015806

Depression, adherence and attrition from care in HIV-infected adults receiving antiretroviral therapy

Trajectory models have been shown to (1) identify groups of patients with similar patterns of medication filling behavior and (2) summarize the trajectory, the average adherence in each group over time. However, the association between adherence trajectories and clinical outcomes remains unclear. This study investigated the association between 12‐month statin trajectories and subsequent cardiovascular events.

Association of a Smartphone Application With Medication Adherence and Blood Pressure Control: The MedISAFE-BP Randomized Clinical Trial

Background A better understanding of the relationship between depression and HIV-related outcomes, particularly as it relates to adherence to treatment, is critical to guide effective support and treatment of individuals with HIV and depression. We examined whether depression was associated with attrition from care in a cohort of 610 HIV-infected adults in rural Rwanda and whether this relationship was mediated through suboptimal adherence to treatment. Methods The association between depression and attrition from care was evaluated with a Cox proportional hazard model and with mediation methods that calculate the direct and indirect effects of depression on attrition and are able to account for interactions between depression and suboptimal adherence. Depression was assessed with the Hopkins Symptom Checklist-15; attrition was defined as death, treatment default, or loss to follow-up. Results Baseline depression was significantly associated with time to attrition after adjustment for receipt of community-based accompaniment, physical functioning quality of life score, and CD4 cell count (HR=2.40, 95% CI 1.27 to 4.52, p=0.005). In multivariable mediation analysis, we found no evidence that the association between depression and attrition after 3 months was mediated by suboptimal adherence (direct effect of depression on attrition: OR=3.90 (1.26 to 12.04), p=0.02; indirect effect: OR=1.07 (0.92 to 1.25), p=0.38). Conclusions Even in the context of high antiretroviral therapy adherence, depression may adversely influence HIV outcomes through a pathway other than suboptimal adherence. Treatment of depression is critical to achieving good mental health and retention in HIV-infected individuals with depression.

Rationale and design of the Medication adherence Improvement Support App For Engagement—Blood Pressure (MedISAFE-BP) trial

Importance Medication nonadherence accounts for up to half of uncontrolled hypertension. Smartphone applications (apps) that aim to improve adherence are widely available but have not been rigorously evaluated. Objective To determine if the Medisafe smartphone app improves self-reported medication adherence and blood pressure control. Design, Setting, and Participants This was a 2-arm, randomized clinical trial (Medication Adherence Improvement Support App For Engagement—Blood Pressure [MedISAFE-BP]). Participants were recruited through an online platform and were mailed a home blood pressure cuff to confirm eligibility and to provide follow-up measurements. Of 5577 participants who were screened, 412 completed consent, met inclusion criteria (confirmed uncontrolled hypertension, taking 1 to 3 antihypertensive medications), and were randomized in a ratio of 1:1 to intervention or control. Interventions Intervention arm participants were instructed to download and use the Medisafe app, which includes reminder alerts, adherence reports, and optional peer support. Main Outcomes and Measures Co–primary outcomes were change from baseline to 12 weeks in self-reported medication adherence, measured by the Morisky medication adherence scale (MMAS) (range, 0-8, with lower scores indicating lower adherence), and change in systolic blood pressure. Results Participants (n = 411; 209 in the intervention group and 202 controls) had a mean age of 52.0 years and mean body mass index, calculated as weight in kilograms divided by height in meters squared, of 35.5; 247 (60%) were female, and 103 (25%) were black. After 12 weeks, the mean (SD) score on the MMAS improved by 0.4 (1.5) among intervention participants and remained unchanged among controls (between-group difference: 0.4; 95% CI, 0.1-0.7; P = .01). The mean (SD) systolic blood pressure at baseline was 151.4 (9.0) mm Hg and 151.3 (9.4) mm Hg, among intervention and control participants, respectively. After 12 weeks, the mean (SD) systolic blood pressure decreased by 10.6 (16.0) mm Hg among intervention participants and 10.1 (15.4) mm Hg among controls (between-group difference: −0.5; 95% CI, −3.7 to 2.7; P = .78). Conclusions and Relevance Among individuals with poorly controlled hypertension, patients randomized to use a smartphone app had a small improvement in self-reported medication adherence but no change in systolic blood pressure compared with controls. Trial Registration clinicaltrials.gov Identifier: NCT02727543

Rationale and design of the Randomized Evaluation to Measure Improvements in Non-adherence from Low-Cost Devices (REMIND) trial

BACKGROUND Hypertension is a major contributor to the health and economic burden imposed by stroke, heart disease, and renal insufficiency. Antihypertensives can prevent many of the harmful effects of elevated blood pressure, but medication nonadherence is a known barrier to the effectiveness of these treatments. Smartphone-based applications that remind patients to take their medications, provide education, and allow for social interactions between individuals with similar health concerns have been widely advocated as a strategy to improve adherence but have not been subject to rigorous testing. METHODS/DESIGN The MedISAFE-BP study is a prospective, randomized control trial designed to evaluate the impact on blood pressure and medication adherence of an mhealth application (Medisafe). Four hundred thirteen patients with uncontrolled hypertension have been enrolled and randomized in a 1:1 fashion to usual care or to the use of the Medisafe mhealth platform. Patients will be followed up for 12 weeks and the trials co-primary outcomes will be change in systolic blood pressure and self-reported medication adherence. DISCUSSION The MedISAFE-BP trial is the first study to rigorously evaluate an mhealth applications effect on blood pressure and medication adherence. The results will inform the potential effectiveness of this simple system in improving cardiovascular disease risk factors and clinical outcomes.

Brief Report: Intensification to Triple Therapy After Treatment With Nonbiologic Disease‐Modifying Antirheumatic Drugs for Rheumatoid Arthritis in the United States From 2009 to 2014

BACKGROUND Long-term adherence to prescription medications for the treatment of chronic disease remains low. While there are many contributors to suboptimal medication use, simple forgetfulness is widely believed to be central. Relatively simple devices may be a particularly cost-efficient and scalable way to promote adherence, however limited data exists about their ability to improve adherence in real-world settings. METHODS/DESIGN The REMIND trial is a prospective, intent-to-treat randomized control trial to evaluate the impact on medication adherence of three simple, low-cost devices (Take-N-Slide(™), the RxTimerCap(™), and a standard pillbox). In March 2014, we enrolled 53,480 individuals 18 to 64 years old taking one to three medications to treat chronic disease whose prescription drug benefits were administered by CVS Caremark. The studys primary outcome is optimal adherence over the 12-month period after randomization. Using a randomization ratio of 1:2 between control and each intervention arm, the study has more than 80% power with an alpha of 5% to detect a 1% difference in the rate of optimal adherence between intervention and control groups and across intervention arms. DISCUSSION The REMIND trial is the first randomized study to rigorously evaluate the impact of simple, low-cost reminder devices on medication adherence. The results will inform comparative cost effectiveness studies of reminder systems in improving medication adherence and clinical outcomes.

Cigarette Purchases at Pharmacies by Patients at High Risk of Smoking-Related Illness

Several trials suggest that triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) and biologic disease‐modifying antirheumatic drugs (DMARDs) have similar efficacy in patients with rheumatoid arthritis (RA). This study was undertaken to investigate intensification to triple therapy after initial nonbiologic prescription among patients with RA.