Validation of Cardiovascular End Points Ascertainment Leveraging Multisource Electronic Health Records Harmonized Into a Common Data Model in the ADAPTABLE Randomized Clinical Trial

Background: The ADAPTABLE trial (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) is the first randomized trial conducted within the National Patient-Centered Clinical Research Network to use the electronic health record data formatted into a common data model as the primary source of end point ascertainment, without confirmation by standard adjudication. The objective of this prespecified study is to assess the validity of nonfatal end points captured from the National Patient-Centered Clinical Research Network, using traditional blinded adjudication as the gold standard. Methods: A total of 15 076 participants with established atherosclerotic cardiovascular disease were randomized to two doses of aspirin (81 mg and 325 mg once daily). Nonfatal end points (hospitalization for nonfatal myocardial infarction, nonfatal stroke, and major bleeding requiring transfusion of blood products) were captured with the use of programming algorithms applied to National Patient-Centered Clinical Research Network data. A random subset of end points was independently reviewed by a disease-specific expert adjudicator. The positive predictive value of the programming algorithms were calculated separately for end points listed as primary and as nonprimary diagnoses. Results: A total of 225 end points were identified (91 myocardial infarction events, 89 stroke events, and 45 bleeding events), including 142 (63%) that were listed as primary diagnoses. Complete source documents were missing for 14% of events. The positive predictive value were 90%, 72%, and 93% for hospitalizations for myocardial infarction, stroke, and major bleeding, respectively, as compared to adjudication. When only primary diagnoses were considered, positive predictive value were 93%, 91%, and 97%, respectively. When only nonprimary diagnoses were considered, positive predictive value were 82%, 36%, and 71%. Conclusions: As compared with blinded adjudication, clinical end point ascertainment from queries of the National Patient-Centered Clinical Research Network distributed harmonized data was valid to identify hospitalizations for myocardial infarction in ADAPTABLE. The proportion of contradicted events was high for hospitalizations for bleeding and strokes when nonprimary diagnoses were analyzed, but not when only primary diagnoses were considered.

Utilization of Generic Cardiovascular Drugs in Medicare’s Part D Program

Background: Generic medications cost less than brand-name medications and are similarly effective, but brand-name medications are still prescribed. We evaluated patterns in generic cardiovascular medication fills and estimated the potential cost savings with increased substitution of generic for brand-name medications. Methods: This was a cross-sectional study of cardiovascular therapies using the Medicare Part D database of prescription medications in 2017. We evaluated drug fill patterns for therapies with available brand-name and generic options. We determined the generic substitution ratio and estimated the potential savings with increased generic substitution at the national, state, and clinician level. We compared states with laws related to mandatory pharmacist generic substitution and patient consent for substitution. Results: Of ≈$22.9 billion spent on cardiovascular drugs in Medicare Part D prescription programs in 2017, ≈$11.0 billion was spent on medications with both brand-name and generic options. Although only 2.4% of medication fills were for the brand-name choice, they made up 21.2% of total spending. Accounting for estimated brand-name rebates, generic substitution for these medications would save $641 million, including $135 million in costs shouldered by patients. Furthermore, the minority of clinicians with the lowest generic utilization was responsible for a large proportion of the potential cost savings. Conclusions: There are substantial potential cost savings from substituting brand-name medications with generic medications. These savings would be primarily driven by lower use of brand-name therapies by the minority of clinicians who prescribe them at increased rates.

Off-Label Under- and Overdosing of Direct Oral Anticoagulants in Patients With Atrial Fibrillation: A Meta-Analysis

Background: Prescriptions of off-label under- and overdosing of direct oral anticoagulants (DOACs) are common for patients with atrial fibrillation, but their efficacy and safety remain unknown. Methods: Databases were searched for randomized controlled trial or adjusted observational study that compared an off-label versus on-label dosing of DOACs through June 15, 2021. The primary efficacy outcome was ischemic stroke/system embolism (IS/SE), and primary safety outcome was major bleeding. Net clinical outcome was generally defined as the composite of IS/SE, major bleeding, and all-cause death. Hazard ratios (HRs) with 95% CIs were pooled with random-effects models with Hartung-Knapp-Sidik-Jonkman method for adjustment. Results: Sixteen studies with 130 609 patients were included. Compared with on-labeling dosing, off-label underdosing of DOACs was associated with a higher risk of IS/SE (HR, 1.22 [95% CI, 1.05–1.42], P =0.01). The incidence of major bleeding was similar (HR, 0.95 [95% CI, 0.82–1.11], P =0.48). Off-label underdosing was associated with a higher risk of net clinical outcome (HR, 1.19 [95% CI, 1.04–1.40], P =0.04) and all-cause death (HR, 1.24 [95% CI, 1.04–1.48], P =0.02). Stratified analysis of off-label underdosing of DOACs for IS/SE showed subgroup differences among different DOAC types and study regions. Limited data showed that off-label overdosing was associated with a higher risk of IS/SE (HR, 1.26 [95% CI, 1.11–1.43], P =0.003) and major bleeding (HR, 1.30 [95% CI, 1.04–1.62], P =0.025). Conclusions: Compared with on-label dosing, off-label underdosing of DOACs increased the risk of thromboembolic events but did not decrease the risk of bleeding. Limited data for off-label overdosing showed higher risks of thromboembolic and bleeding. Further studies are warranted to confirm the results of off-label overdosing DOACs and subgroup results of underdosing DOACs.

Early Termination of Acute Stroke Randomized Controlled Trials Published Between 2013 and 2020: A Systematic Review

Background: Termination of a clinical trial before the maximum planned sample size is accrued can occur for multiple valid reasons but has implications for the interpretation of results. We undertook a systematic review of contemporary acute stroke trials to document the prevalence of and reasons for early termination. Methods: We searched MEDLINE for randomized controlled trials of acute stroke therapies published between 2013 and 2020 in 9 major clinical journals. Manuscripts describing the primary results of phase 2 and phase 3 trials of acute stroke care were included. Data on study characteristics and adherence to CONSORT reporting guidelines were abstracted and summarized using descriptive statistics. Where feasible, we compared treatment effect sizes between trials terminated early and those not terminated early. Results: Of 96 randomized controlled trials, 39 (41%) were terminated early, 84 (88%) had a data and safety monitoring board, and 57 (59%) reported a prespecified statistical stopping rule. Among the 39 trials terminated early, 10 were discontinued for benefit, 10 due to logistical issues, 8 for futility, 6 because of newly available evidence, 1 for harm, and 4 for other or a combination of reasons. The median percentage of the maximum planned sample size accrued among trials terminated early was 63% (range, 8%–89%). Only 55% of trials (53 of 96) reported whether interim efficacy analyses were conducted, as recommended by the CONSORT guidelines. When 10 endovascular therapy trials were compared according to early termination status, the effect sizes of trials terminated early for benefit were only modestly larger than those not terminated early. Conclusions: The high prevalence of early termination in combination with the wide variety of reasons underscores the necessity of meticulous trial planning and adherence to methodological and reporting guidelines for early termination. Registration: URL: https://www.crd.york.ac.uk/prospero/ ; Unique identifier: CRD42019128727.

Best Practices for Education and Training of Resuscitation Teams for In-Hospital Cardiac Arrest

Background: Survival outcomes following in-hospital cardiac arrest (IHCA) vary significantly across hospitals. Research suggests clinician education and training may play a role. We sought to identify best practices related to the education and training of resuscitation teams. Methods: We conducted a descriptive qualitative analysis of semi-structured interview data obtained from in-depth site visits conducted from 2016-2017 at 9 diverse hospitals within the American Heart Association "Get With The Guidelines" registry, selected based on IHCA survival performance (5 top-, 1 middle-, 3 low-performing). We assessed coded data related to education and training including systems learning, informal feedback and debrief, and formal learning through ACLS and mock codes. Thematic analysis was used to identify best practices. Results: In total, 129 interviews were conducted with a variety of hospital staff including nurses, chaplains, security guards, respiratory therapists, physicians, pharmacists, and administrators, yielding 78 hours and 29 minutes of interview time. Four themes related to training and education were identified: engagement, clear communication, consistency, and responsive leadership. Top-performing hospitals encouraged employee engagement with creative marketing of new programs and prioritizing hands-on learning over passive didactics. Clear communication was accomplished with debriefing, structured institutional review, and continual, frequent education for departments. Consistency was a cornerstone to culture change and was achieved with uniform policies for simulation practice as well as reinforced, routine practice (weekly, monthly, quarterly). Finally, top-performing hospitals had responsive leadership teams across multiple disciplines (nursing, respiratory therapy, pharmacy and medicine), who listened and adapted programs to fit the needs of their staff. Conclusions: Among top-performing hospitals excelling in IHCA survival, we identified core elements for education and training of resuscitation teams. Developing tools to expand these areas for hospitals may improve IHCA outcomes.

Patterns of Prescribing Sodium-Glucose Cotransporter-2 Inhibitors for Medicare Beneficiaries in the United States

Background: Evidence from large randomized clinical trials supports the benefit of sodium-glucose cotransporter-2 inhibitors (SGLT2i) to improve cardiovascular and kidney outcomes in patients with type 2 diabetes mellitus (T2DM) with or at high risk for atherosclerotic cardiovascular disease or chronic kidney disease. Considering this evidence, which has been expanding since the product label indication for empagliflozin to reduce risk of cardiovascular death in 2016, clinician-level variation in the prescription of SGLT2i among US Medicare beneficiaries was evaluated. Methods: Antihyperglycemic medication prescribers were identified as those physicians and advanced practice providers prescribing metformin in Medicare part D prescriber data. In this cross-sectional study, the proportion prescribing SGLT2i was assessed overall and across specialties in 2018, with changes assessed from 2014 to 2018. SGLT2i use was compared with other second-line antihyperglycemic medication classes, sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP4is). Results: Among 232,523 unique clinicians who prescribed metformin for Medicare beneficiaries in 2018 (diabetes-treating clinicians), 45,255 (19.5%) prescribed SGLT2i. There was substantial variation across specialties - from 72% of endocrinologists to 14% of cardiologists who prescribed metformin also prescribed SGLT2i. Between 2014 and 2018, the number prescribing SGLT2i increased 5 fold from 9,048 in 2014 to 45,255 in 2018. Among clinicians who prescribed both sulfonylureas and SGLT2i in 2018, SGLT2i was prescribed to a median 33 beneficiaries for every 100 prescribed sulfonylureas (IQR 18, 67). SGLT2i use relative to sulfonylureas increased from 19 (IQR 11, 34) per 100 in 2014 to 33 (IQR 18, 67) per 100 in 2018 (P-trend <0.001). Conclusions: Eighty percent of clinicians prescribing metformin to Medicare beneficiaries did not prescribe SGLT2i in 2018. Moreover, sulfonylureas prescriptions were 3 times more frequent than those of SGLT2is, although a pattern of increasing uptake may portend future trends. These findings highlight a baseline opportunity to improve care and outcomes for patients with T2DM.

The Role of Frailty in Identifying Benefit from Transcatheter Versus Surgical Aortic Valve Replacement

Background: Frailty is associated with a higher risk for adverse outcomes after aortic valve replacement (AVR) for severe aortic valve stenosis, but whether or not frail patients derive differential benefit from transcatheter (TAVR) vs. surgical (SAVR) AVR is uncertain. Methods: We linked adults ≥ 65 years old in the US CoreValve High Risk (HiR) or Surgical or Transcatheter Aortic-Valve Replacement in Intermediate Risk Patients (SURTAVI) trial to Medicare claims, 2/2/2011-9/30/2015. Two frailty measures, a deficit-based (DFI) and phenotype-based (PFI) frailty index, were generated. The treatment effect of TAVR vs. SAVR was evaluated within frailty index (FI) tertiles for the primary endpoint of death and non-death secondary outcomes, using multivariable Cox regression. Results: Of 1,442 (linkage rate = 60.0%) individuals included, 741 (51.4%) individuals received TAVR and 701 (48.6%) received SAVR (mean age 81.8 ± 6.1 years, 44.0% female). Though 1-year death rates in the highest FI tertiles (DFI 36.7%, PFI 33.8%) were 2-3-fold higher than the lowest tertiles (DFI 13.4%, HR 3.02, 95% CI 2.26-4.02, p < 0.001; PFI 17.9%; HR 2.05, 95% CI 1.58-2.67, p < 0.001), there were no significant differences in the relative or absolute treatment effect of SAVR vs. TAVR across FI tertiles for all death, non-death, and functional outcomes (all interaction p-values > 0.05). Results remained consistent across individual trials, frailty definitions, and when considering the non-linked trial data. Conclusions: Two different frailty indices based on Fried and Rockwood definitions identified individuals at higher risk of death and functional impairment but no differential benefit from TAVR vs. SAVR.