Comparative Effectiveness Research Studies Research Articles

Researcher and partner perspectives on the relationship between engagement in research and three uses of patient-centered comparative clinical effectiveness research study findings

BackgroundThe uptake of research findings into clinical practice is critical to providing health care that improves health outcomes for patients. This study explored how Patient-Centered Outcomes Research Institute (PCORI) awardees perceive the relationship between engagement of patients and other partners in research and three uses, or applications, of patient-centered comparative clinical effectiveness research (CER) study findings, which may lead to uptake in clinical practice: (1) Integration into clinical practice guidelines, recognized point-of-care decision tools, or documents that may inform policy; (2) Implementation beyond the study, including at sites outside of the study setting or patient populations; and (3) Active dissemination of findings to specific audiences by parties external to the study team.MethodsThis exploratory qualitative study examined awardee and partner perceptions of what led to each use of study findings and how engaged partners contributed. We purposively selected PCORI-funded research projects with documentation of each use and conducted virtual interviews with 42 individuals (15 PIs or project leads, 2 research team members, and 25 partners) from 17 projects. We conducted thematic analysis of individual projects or project sets, across projects within each use case, and across the three uses.ResultsParticipants described three primary activities in which engaged partners made contributions before, during and after CER studies that facilitated the use of study findings: (1) generating relevant study findings, (2) distributing study findings strategically, and (3) making connections to people or organizations outside the study team. In addition, engagement continued to facilitate the use of study findings during subsequent PCORI-funded implementation and dissemination-specific projects, with partners adapting interventions and creating and tailoring dissemination messages and products. Finally, participants described attributes of teams’ engagement approaches that may have supported partner contributions, including early and ongoing engagement, leveraging partners’ connections and understanding of community needs, and using multiple engagement approaches.ConclusionThis study identified examples of how engagement can help facilitate the use of CER study findings, especially when engagement contributions occur in meaningful ways. Findings from this study suggest a framework for future research on the relationship between engagement in research and uptake of study findings into clinical practice.

Comparative Effectiveness of Antipsychotics in Patients With Schizophrenia Spectrum Disorder

Antipsychotics are the cornerstone of maintenance treatment in schizophrenia spectrum disorders, but it is unclear which agents should be prioritized by prescribers. To investigate the clinical effectiveness of antipsychotics, including recent market entries, in comparison with oral olanzapine in relapse and treatment failure prevention among individuals with schizophrenia spectrum disorder. This comparative effectiveness research study with a within-individual analysis included data from Swedish health care registers of inpatient and specialized outpatient care, sickness absence, and disability pensions among all individuals aged 16 to 65 years who were diagnosed with schizophrenia spectrum disorder from January 1, 2006, to December 31, 2021, including an incident cohort and a prevalent cohort. Specific antipsychotics. The risks for psychosis relapse hospitalization and treatment failure (psychiatric hospitalization, death, or change in an antipsychotic medication) were adjusted for the temporal order of treatments, time since cohort entry, and concomitant drugs. Comparisons of all antipsychotics with oral olanzapine, the most commonly used antipsychotic, were investigated. Among the full cohort of 131 476 individuals, the mean (SD) age of the study cohort was 45.7 (16.2) years (70 054 men [53.3%]). During a median follow-up of 12.0 years [IQR, 5.2-16.0 years], 48.5% of patients (N = 63 730) experienced relapse and 71.1% (N = 93 464) underwent treatment failure at least once. Compared with oral olanzapine, paliperidone 3-month long-acting injectable (LAI) was associated with the lowest adjusted hazard ratio (AHR) in the prevention of relapses (AHR, 0.66; 95% CI, 0.51-0.86), followed by aripiprazole LAI (AHR, 0.77 [95% CI, 0.70-0.84]), olanzapine LAI (AHR, 0.79 [95% CI, 0.73-0.86]), and clozapine (AHR, 0.82 [95% CI, 0.79-0.86]). Quetiapine was associated with the highest risk of relapse (AHR, 1.44 [95% CI, 1.38-1.51]). For prevention of treatment failure, paliperidone 3-month LAI was associated with the lowest AHR (AHR, 0.36 [95% CI, 0.31-0.42]), followed by aripiprazole LAI (AHR, 0.60 [95% CI, 0.57-0.63]), olanzapine LAI (AHR, 0.67 [95% CI, 0.63-0.72]), and paliperidone 1-month LAI (AHR, 0.71 [95% CI, 0.68-0.74]). This comparative effectiveness research study demonstrated large differences in the risk of relapse and treatment failure among specific antipsychotic treatments. The findings contradict the widely held conception that all antipsychotics are equally effective in relapse prevention.

Racial Differences in Pain Assessment and False Beliefs About Race in AI Models

This comparative effectiveness research study examines the association between racial differences in pain assessment and false beliefs about biologization of race by large language models compared with a human baseline.

Conduct of Large, Multisite, Comparative Clinical Effectiveness Research Studies: Learnings From the Patient-Centered Outcomes Research Institute's Palliative Care Learning Network.

Conduct of Large, Multisite, Comparative Clinical Effectiveness Research Studies: Learnings From the Patient-Centered Outcomes Research Institute's Palliative Care Learning Network.

Long-Term Outcomes of Self-Fit vs Audiologist-Fit Hearing Aids

With rising interest in over-the-counter (OTC) hearing aids as an alternative to traditional audiologist-fit devices, understanding their long-term efficacy is crucial. However, given the novelty of the US Food and Drug Administration category of OTC hearing aids, minimal evidence currently supports their long-term efficacy. To compare the long-term self-reported outcomes at 8 months of self-fit OTC hearing aids to the same hearing aids fit by audiologists. Building on a previous randomized clinical trial, this follow-up comparative effectiveness research study reassessed a number of the original participants that were not lost to follow-up. Participants were initially divided into those with self-fit OTC hearing aids and those with audiologist-fit devices. Approximately 8 months after fitting, participants completed self-reported questionnaires. Missing data were addressed through multiple imputation. The original noninferiority trial was conducted at the University of Pretoria in South Africa from April 2022 to August 2022. The current analysis took place between July 7, 2023, to November 20, 2023. In the original trial, participants in the self-fit device group received a pair of OTC hearing aids and independently fit them with remote support as needed. The audiologist-fit device group received the same hearing aids fit by a certified audiologist using best practices. The main outcomes were self-reported hearing aid benefit, measured using the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the International Outcome Inventory for Hearing Aids (IOI-HA). Of 64 participants in the trial, 44 participants were included in the extension study (21 [47.7%] in the audiologist-fit group; 23 [52.3%] in the self-fit group). The mean (SD) age of these participants was 63.0 (13.2) years, and 21 (47.7%) were male. At the long-term follow-up, self-fit and audiologist-fit groups showed no significant differences in the APHAB global score (mean difference, 0.02 [95% CI, -7.1 to 7.1]; Cohen d, 0.01 [95% CI, -0.5 to 0.5]) or the IOI-HA total score (mean difference, 1.5 [95% CI, -1.4 to 4.4]; Cohen d, 0.3 [95% CI, -0.2 to 0.8]). From 6 weeks to 8 months, no clinically meaningful group-time interaction was found between groups for the APHAB global score (Cohen d, 0.1 [95% CI, -0.2 to 0.3]), but a significant interaction for the IOI-HA total score was found (Cohen d, -0.6 [95% CI, -0.8 to -0.3]), with the self-fit group generally performing better. This comparative effectiveness research study demonstrated that self-fit OTC hearing aids can offer comparable long-term benefits to audiologist-fit hearing aids for individuals with mild to moderate hearing loss.

Matched vs Nonmatched Placebos in a Randomized Trial of COVID-19 Treatments

Matched placebo interventions are complex and resource intensive. Recent evidence suggests matched placebos may not always be necessary. Previous studies have predominantly evaluated potential bias of nonmatched placebos (ie, differing on dose, frequency of administration, or formulation) in pain and mental health, but to date no systematic examination has been conducted in infectious disease. To test for differences between nonmatched and matched placebo arms with respect to clinical outcome measures across multiple therapeutics for COVID-19. In a comparative effectiveness research study, a post hoc analysis was conducted of data on individual patients enrolled in a large, multiarm, platform randomized clinical trial in symptomatic adult outpatients with COVID-19 between January 15, 2021, to September 28, 2023, in which the outcomes of both matched and nonmatched placebo groups were reported. Bayesian and frequentist covariate-adjusted techniques were compared with 7 intervention-placebo pairs. Seven matched and nonmatched placebo pairs (for a total of 7 comparisons) were evaluated throughout the primary platform trial. Comparisons were made between treatment and its associated matched (concurrent) placebo, as well as with nonmatched placebo (alone and in combination) assessed at a similar time point. Outcomes assessed included hospitalizations, EuroQol 5-Dimension 5-level scores, and PROMIS Global-10 scores. A total of 7 intervention-control pairs (N = 2684) were assessed, including 1620 (60.4%) women, with mean (SD) age, 47 (15.2) years; the most common comorbidities were obesity (41.9%) and hypertension (37.9%). In a meta-analysis with decoupled SEs, accounting for overlapping placebo patients, the overall odds ratio (OR) of nonmatched compared with matched placebo was 1.01 (95% credible interval, 0.77-1.32), with posterior probability of equivalence, defined as 0.8 ≤ OR ≤ 1.2 (a deviation from perfect equivalence ie, OR = 1, by no more than 0.2) of 85.4%, implying no significant difference. Unadjusted analysis of the event rate difference between all nonmatched and matched placebo groups did not identify any notable differences across all 7 treatment-placebo combinations assessed. Similar analysis that was conducted for patient-reported quality of life outcomes did not yield statistically significant differences. In this post hoc study of a randomized clinical platform trial, pooling matched and nonmatched placebo patient data did not lead to inconsistencies in treatment effect estimation for any of the investigational drugs. These findings may have significant implications for future platform trials, as the use of nonmatched placebo may improve statistical power, or reduce barriers to placebo implementation.

Tissue Loss During Eye Bank Processing

This comparative effectiveness research study assesses the rate of tissue loss in ultrathin Descemet stripping automated endothelial keratoplasty grafts vs descemet membrane endothelial keratoplasty grafts during eye bank processing.

Population-Based Validation of the MIA and MSKCC Tools for Predicting Sentinel Lymph Node Status

Patients with melanoma are selected for sentinel lymph node biopsy (SLNB) based on their risk of a positive SLN. To improve selection, the Memorial Sloan Kettering Cancer Center (MSKCC) and Melanoma Institute Australia (MIA) developed predictive models, but the utility of these models remains to be tested. To determine the clinical utility of the MIA and MSKCC models. This was a population-based comparative effectiveness research study including 10 089 consecutive patients with cutaneous melanoma undergoing SLNB from the Swedish Melanoma Registry from January 2007 to December 2021. Data were analyzed from May to August 2023. The predicted probability of SLN positivity was calculated using the MSKCC model and a limited MIA model (using mitotic rate as absent/present instead of count/mm2 and excluding the optional variable lymphovascular invasion) for each patient. The operating characteristics of the models were assessed and compared. The clinical utility of each model was assessed using decision curve analysis and compared with a strategy of performing SLNB on all patients. Among 10 089 included patients, the median (IQR) age was 64.0 (52.0-73.0) years, and 5340 (52.9%) were male. The median Breslow thickness was 1.8 mm, and 1802 patients (17.9%) had a positive SLN. Both models were well calibrated across the full range of predicted probabilities and had similar external area under the receiver operating characteristic curves (AUC; MSKCC: 70.8%; 95% CI, 69.5-72.1 and limited MIA: 69.7%; 95% CI, 68.4-71.1). At a risk threshold of 5%, decision curve analysis indicated no added net benefit for either model compared to performing SLNB for all patients. At risk thresholds of 10% or higher, both models added net benefit compared to SLNB for all patients. The greatest benefit was observed in patients with T2 melanomas using a threshold of 10%; in that setting, the use of the nomograms led to a net reduction of 8 avoidable SLNBs per 100 patients for the MSKCC nomogram and 7 per 100 patients for the limited MIA nomogram compared to a strategy of SLNB for all. This study confirmed the statistical performance of both the MSKCC and limited MIA models in a large, nationally representative data set. However, decision curve analysis demonstrated that using the models only improved selection for SLNB compared to biopsy in all patients when a risk threshold of at least 7% was used, with the greatest benefit seen for T2 melanomas at a threshold of 10%. Care should be taken when using these nomograms to guide selection for SLNB at the lowest thresholds.

Lung Cancer Screening in Brazil Comparing the 2013 and 2021 USPSTF Guidelines

It is estimated that, from 2023 to 2025, lung cancer (LC) will be the second most frequent cancer in Brazil, but the country does not have an LC screening (LCS) policy. To compare the number of individuals eligible for screening, 5-year preventable LC deaths, and years of life gained (YLG) if LC death is averted by LCS, considering 3 eligibility strategies by sociodemographic characteristics. This comparative effectiveness research study assessed 3 LCS criteria by applying a modified version of the LC-Death Risk Assessment Tool (LCDRAT) and the LC-Risk Assessment Tool (LCRAT). Data are from the 2019 Brazilian National Household Survey. Participants included ever-smokers aged 50 to 80 years. Data analysis was performed from February to May 2023. Exposures included ever-smokers aged 50 to 80 years, US Preventive Services Task Force (USPSTF) 2013 guidelines (ever-smokers aged 55 to 80 years with ≥30 pack-years and <15 years since cessation), and USPSTF 2021 guidelines (ever-smokers aged 50 to 80 years with 20 pack-years and <15 years since cessation). The primary outcomes were the numbers of individuals eligible for LCS, the 5-year preventable deaths attributable to LC, and the number of YLGs if death due to LC was averted by LCS. In Brazil, the eligible population for LCS was 27 280 920 ever-smokers aged 50 to 80 years (13 387 552 female [49.1%]; 13 249 531 [48.6%] aged 50-60 years; 394 994 Asian or Indigenous [1.4%]; 3 111 676 Black [11.4%]; 10 942 640 Pardo [40.1%]; 12 830 904 White [47.0%]; 12 428 536 [45.6%] with an incomplete middle school education; and 12 860 132 [47.1%] living in the Southeast region); 5 144 322 individuals met the USPSTF 2013 criteria for LCS (2 090 636 female [40.6%]; 2 290 219 [44.5%] aged 61-70 years; 66 430 Asian or Indigenous [1.3%]; 491 527 Black [9.6%]; 2 073 836 Pardo [40.3%]; 2 512 529 [48.8%] White; 2 436 221 [47.4%] with an incomplete middle school education; and 2 577 300 [50.1%] living in the Southeast region), and 8 380 279 individuals met the USPSTF 2021 LCS criteria (3 507 760 female [41.9%]; 4 352 740 [51.9%] aged 50-60 years; 119 925 Asian or Indigenous [1.4%]; 839 171 Black [10.0%]; 3 330 497 Pardo [39.7%]; 4 090 687 [48.8%] White; 4 022 784 [48.0%] with an incomplete middle school education; and 4 162 070 [49.7%] living in the Southeast region). The number needed to screen to prevent 1 death was 177 individuals according to the USPSTF 2013 criteria and 242 individuals according to the USPSTF 2021 criteria. The YLG was 23 for all ever-smokers, 19 for the USPSTF 2013 criteria, and 21 for the USPSTF 2021 criteria. Being Black, having less than a high school education, and living in the North and Northeast regions were associated with increased 5-year risk of LC death. In this comparative effectiveness study, USPSTF 2021 criteria were better than USPSTF 2013 in reducing disparities in LC death rates. Nonetheless, the risk of LC death remained unequal, and these results underscore the importance of identifying an appropriate approach for high-risk populations for LCS, considering the local epidemiological context.

Antiplatelet Therapy in Patients With Abdominal Aortic Aneurysm Without Symptomatic Atherosclerotic Disease

Patients with abdominal aortic aneurysm have a high risk of ischemic events associated with concomitant atherosclerotic cardiovascular disease, and current clinical practice guidelines recommend antiplatelet therapy to mitigate this risk. However, in patients with aneurysms without symptomatic atherosclerosis, the benefit of antiplatelet therapy has been sparsely investigated. To estimate the effect of antiplatelets on the risk of ischemic events and bleeding in individuals with abdominal aneurysms with no symptomatic atherosclerotic vascular disease. A comparative effectiveness research study using a target trial emulation framework was performed. Population-based, cross-linked observational data from Danish national health registries containing comprehensive, individual-level information on all Danish citizens were used to evaluate patients who were antiplatelet-naive and diagnosed with abdominal aortic aneurysms, with no record of symptomatic atherosclerotic vascular disease, from January 1, 2010, through August 21, 2021. Prescription filled for aspirin or clopidogrel. Risk of ischemic events (myocardial infarction and/or ischemic stroke) and risk of major bleeding. For target trial emulation, trials were emulated as sequential, contingent on patient eligibility at the time of inclusion, and were evaluated by means of pooled logistic regression models to estimate the intention-to-treat and as-treated effects, expressed as hazard ratio (HR) and event-free survival. A total of 6344 patients (65.2% men; age, 72 [IQR, 64-78] years) provided 131 047 trial cases; 3363 of these cases involved initiation of antiplatelet therapy and 127 684 did not. A total of 182 ischemic events occurred among initiators and 5602 ischemic events occurred among noninitiators, corresponding to an intention-to-treat HR of 0.91 (95% CI, 0.73-1.17) and an estimated absolute event-free survival difference of -0.6% (95% CI, -1.7% to 0.5%). After censoring nonadherent person-time, the treatment HR was 0.90 (95% CI, 0.68-1.20), with similar risk difference. For bleeding, the intention-to-treat HR was 1.26 (95% CI, 0.97-1.58) and the event-free survival difference was 1.0%. The treatment HR was 1.21 (95% CI, 0.82-1.72); the risk difference was similar. In this study, no evidence of effectiveness of antiplatelet therapy to lower the risk of ischemic events and a trend toward higher bleeding risk was noted. The observed differences between the treatment groups were minimal, suggesting limited clinical relevance of antiplatelet treatment.

Levetiracetam vs Lamotrigine as First-Line Antiseizure Medication in Female Patients With Idiopathic Generalized Epilepsy

After the recent limitations to prescribing valproate, many studies have highlighted the challenging management of female patients of reproductive age with idiopathic generalized epilepsy (IGE). However, no study, to the authors' knowledge, has addressed the comparative effectiveness of alternative antiseizure medications (ASMs) in these patients. To compare the effectiveness and safety of levetiracetam and lamotrigine as initial monotherapy in female patients of childbearing age with IGE. This was a multicenter, retrospective, comparative effectiveness cohort study analyzing data from patients followed up from 1994 to 2022. Patients were recruited from 22 primary, secondary, and tertiary adult and child epilepsy centers from 4 countries. Eligible patients were female individuals of childbearing age, diagnosed with IGE according to International League Against Epilepsy (2022) criteria and who initiated levetiracetam or lamotrigine as initial monotherapy. Patients were excluded due to insufficient follow-up after ASM prescription. Levetiracetam or lamotrigine as initial monotherapy. Inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazards regression was performed to compare treatment failure (TF) among patients who received levetiracetam or lamotrigine as initial monotherapy. A total of 543 patients were included in the study, with a median (IQR) age at ASM prescription of 17 (15-21) years and a median (IQR) follow-up of 60 (24-108) months. Of the study population, 312 patients (57.5%) were prescribed levetiracetam, and 231 (42.5%) were prescribed lamotrigine. An IPTW-adjusted Cox model showed that levetiracetam was associated with a reduced risk of treatment failure after adjustment for all baseline variables (IPTW-adjusted hazard ratio [HR], 0.77; 95% CI, 0.59-0.99; P = .04). However, after stratification according to different IGE syndromes, the higher effectiveness of levetiracetam was confirmed only in patients with juvenile myoclonic epilepsy (JME; IPTW-adjusted HR, 0.47; 95% CI, 0.32-0.68; P < .001), whereas no significant differences were found in other syndromes. Patients treated with levetiracetam experienced adverse effects more frequently compared with those treated with lamotrigine (88 of 312 [28.2%] vs 42 of 231 [18.1%]), whereas the 2 ASMs had similar retention rates during follow-up (IPTW-adjusted HR, 0.91; 95% CI, 0.65-1.23; P = .60). Results of this comparative effectiveness research study suggest the use of levetiracetam as initial alternative monotherapy in female patients with JME. Further studies are needed to identify the most effective ASM alternative in other IGE syndromes.

Time to Benefit of Sodium-Glucose Cotransporter-2 Inhibitors Among Patients With Heart Failure

ImportanceEmerging evidence has consistently demonstrated that sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF) hospitalization and cardiovascular (CV) death among patients with HF. However, it remains unclear how long a patient needs to live to potentially benefit from SGLT2 inhibitors in this population.ObjectivesTo estimate the time to benefit from SGLT2 inhibitors among patients with HF.Design, Setting, and ParticipantsThis comparative effectiveness study systematically searched PubMed for completed randomized clinical trials about SGLT2 inhibitors and patients with HF published until September 5, 2022; 5 trials with the year of publication ranging from 2019 to 2022 were eventually included. Statistical analysis was performed from April to October 2022.InterventionAddition of SGLT2 inhibitors or placebo to guideline-recommended therapy.Main Outcomes and MeasuresThe primary outcome was the time to first event of CV death or worsening HF, which was broadly comparable across the included trials.ResultsFive trials consisting of 21 947 patients with HF (7837 [35.7%] were female; mean or median age older than 65 years within each trial) were included. SGLT2 inhibitors significantly reduced the risk of worsening HF or CV death (hazard ratio [HR], 0.77 [95% CI, 0.73-0.82]). Time to first nominal statistical significance (P < .05) was 26 days (0.86 months), and statistical significance was sustained from day 118 (3.93 months) onwards. A mean of 0.19 (95% CI, 0.12-0.35) months were needed to prevent 1 worsening HF or CV death per 500 patients with SGLT2 inhibitors (absolute risk reduction [ARR], 0.002). Likewise, 0.66 (95% CI, 0.43-1.13) months was estimated to avoid 1 event per 200 patients with SGLT2 inhibitors (ARR, 0.005), 1.74 (95% CI, 1.07-2.61) months to avoid 1 event per 100 patients (ARR, 0.010), and 4.96 (95% CI, 3.18-7.26) months to avoid 1 event per 50 patients (ARR, 0.020). Further analyses indicated a shorter time to benefit for HF hospitalization and among patients with diabetes or HF with reduced ejection fraction.Conclusions and RelevanceIn this comparative effectiveness research study of estimating the time to benefit from SGLT2 inhibitors among patients with HF, a rapid clinical benefit in reducing CV death or worsening HF was found, suggesting that their use may be beneficial for most individuals with HF.

Comparative Effectiveness of Percutaneous Microaxial Left Ventricular Assist Device vs Intra-Aortic Balloon Pump or No Mechanical Circulatory Support in Patients With Cardiogenic Shock

Recent studies have produced inconsistent findings regarding the outcomes of the percutaneous microaxial left ventricular assist device (LVAD) during acute myocardial infarction with cardiogenic shock (AMICS). To compare the percutaneous microaxial LVAD vs alternative treatments among patients presenting with AMICS using observational analyses of administrative data. This comparative effectiveness research study used Medicare fee-for-service claims of patients admitted with AMICS undergoing percutaneous coronary intervention from October 1, 2015, through December 31, 2019. Treatment strategies were compared using (1) inverse probability of treatment weighting to estimate the effect of different baseline treatments in the overall population; (2) instrumental variable analysis to determine the effectiveness of the percutaneous microaxial LVAD among patients whose treatment was influenced by cross-sectional institutional practice patterns; (3) an instrumented difference-in-differences analysis to determine the effectiveness of treatment among patients whose treatment was influenced by longitudinal changes in institutional practice patterns; and (4) a grace period approach to determine the effectiveness of initiating the percutaneous microaxial LVAD within 2 days of percutaneous coronary intervention. Analysis took place between March 2021 and December 2022. Percutaneous microaxial LVAD vs alternative treatments (including medical therapy and intra-aortic balloon pump). Thirty-day all-cause mortality and readmissions. Of 23 478 patients, 14 264 (60.8%) were male and the mean (SD) age was 73.9 (9.8) years. In the inverse probability of treatment weighting analysis and grace period approaches, treatment with percutaneous microaxial LVAD was associated with a higher risk-adjusted 30-day mortality (risk difference, 14.9%; 95% CI, 12.9%-17.0%). However, patients receiving the percutaneous microaxial LVAD had a higher frequency of factors associated with severe illness, suggesting possible confounding by measures of illness severity not available in the data. In the instrumental variable analysis, 30-day mortality was also higher with percutaneous microaxial LVAD, but patient and hospital characteristics differed across levels of the instrumental variable, suggesting possible confounding by unmeasured variables (risk difference, 13.5%; 95% CI, 3.9%-23.2%). In the instrumented difference-in-differences analysis, the association between the percutaneous microaxial LVAD and mortality was imprecise, and differences in trends in characteristics between hospitals with different percutaneous microaxial LVAD use suggested potential assumption violations. In observational analyses comparing the percutaneous microaxial LVAD to alternative treatments among patients with AMICS, the percutaneous microaxial LVAD was associated with worse outcomes in some analyses, while in other analyses, the association was too imprecise to draw meaningful conclusions. However, the distribution of patient and institutional characteristics between treatment groups or groups defined by institutional differences in treatment use, including changes in use over time, combined with clinical knowledge of illness severity factors not captured in the data, suggested violations of key assumptions that are needed for valid causal inference with different observational analyses. Randomized clinical trials of mechanical support devices will allow valid comparisons across candidate treatment strategies and help resolve ongoing controversies.

Comparative Effectiveness of Pharmacotherapies for the Risk of Attempted or Completed Suicide Among Persons With Borderline Personality Disorder

Suicidal behavior is a significant clinical concern in individuals with borderline personality disorder (BPD), but the effectiveness of pharmacotherapy on reducing suicide risk has remained unknown. To study the comparative effectiveness of different pharmacotherapies in preventing attempted or completed suicides in patients with BPD in Sweden. In this comparative effectiveness research study, nationwide Swedish register databases of inpatient care, specialized outpatient care, sickness absences, and disability pensions were used to identify patients aged 16 to 65 years with registered treatment contact due to BPD during 2006 to 2021. Data were analyzed from September to December 2022. A within-individual design was used, in which each patient was used as their own control to eliminate selection bias. To control protopathic bias, sensitivity analyses were conducted, in which the first 1 or 2 months of medication exposure were omitted from the analyses. Hazard ratio (HR) for attempted or completed suicide. A total of 22 601 patients with BPD (3540 [15.7%] men; mean [SD] age, 29.2 [9.9] years) were included. During the 16-year follow-up (mean [SD] follow-up, 6.9 [5.1] years), 8513 hospitalizations due to attempted suicide and 316 completed suicides were observed. Attention-deficit/hyperactive disorder (ADHD) medication treatment, compared with its nonuse, was associated with a decrease in the risk of attempted or completed suicide (HR, 0.83; 95% CI, 0.73-0.95; false discovery rate [FDR]-corrected P = .001). Treatment with mood stabilizers did not have a statistically significant association with the main outcome (HR, 0.97; 95% CI, 0.87-1.08; FDR-corrected P = .99). Antidepressant (HR, 1.38; 95% CI, 1.25-1.53; FDR-corrected P < .001) and antipsychotic (HR, 1.18; 95% CI, 1.07-1.30; FDR-corrected P < .001) treatments were associated with an elevated risk of attempted or completed suicide. Of the investigated pharmacotherapies, treatment with benzodiazepines was associated with the highest risk of attempted or completed suicide (HR, 1.61; 95% CI, 1.45-1.78; FDR-corrected P < .001). These results remained similar when controlling for potential protopathic bias. In this comparative effectiveness research study of a Swedish nationwide cohort, ADHD medication was the only pharmacological treatment associated with reduced risk of suicidal behavior among patients with BPD. Conversely, the findings suggest that benzodiazepines should be used with care among patients with BPD due to their association with increased risk of suicide.

Comparative Effectiveness of Intracranial Pressure Monitoring vs No Monitoring in Severe Penetrating Brain Injury Management

Civilian penetrating brain injury (PBI) is associated with high mortality. However, scant literature is available to guide neurocritical care monitoring and management of PBI. To examine the association of intracranial pressure (ICP) monitoring with mortality, intensive care unit (ICU) length of stay (LOS), and dispositional outcomes in patients with severe PBI. This comparative effectiveness research study analyzed data from the Trauma Quality Improvement Program of the National Trauma Data Bank in the US from January 1, 2017, to December 31, 2019. Patients with PBI were identified, and those aged 16 and 60 years who met these inclusion criteria were included: ICU LOS of more than 2 days, Glasgow Coma Scale (GCS) score lower than 9 on arrival and at 24 hours, and Abbreviated Injury Scale score of 3 to 5 for the head region and lower than 3 for other body regions. Patients with bilaterally fixed pupils or incomplete data were excluded. A 1:1 propensity score (PS) matching was used to create a subgroup of patients. Patients were divided into 2 groups: with vs without ICP monitoring. Data analysis was conducted between September and December 2022. Intracranial pressure monitoring vs no monitoring. Outcomes were mortality, rate of withdrawal, ICU LOS, and dispositional outcome. Measures were age, initial systolic blood pressure, initial oxygen saturation level on a pulse oximeter, first-recorded GCS score, GCS score at 24 hours, Abbreviated Injury Scale score, midline shift, and pupillary reactivity. A total of 596 patients (505 males [84.7%]; mean [SD] age, 32.2 [12.3] years) were included, among whom 220 (36.9%) died and 288 (48.3%) had ICP monitoring. The PS matching yielded 466 patients (233 in each group with vs without ICP monitoring). Overall mortality was 35.8%; 72 patients with ICP monitoring (30.9%) died compared with 95 patients (40.8%) without ICP monitoring . Patients with ICP monitoring were more likely to survive (odds ratio [OR], 1.54; 95% CI, 1.05-2.25; P = .03; number needed to treat, 10). No difference in favorable discharge disposition was observed. The PS-weighted analysis included all 596 patients and found that patients with ICP monitoring were more likely to survive than those without (OR, 1.40; 95% CI, 1.10-1.78; P = .005). The E-value for the OR calculated from the PS-matched data set was 1.79. In addition, ICP monitoring vs no monitoring was associated with an increase in median (IQR) ICU LOS (15.0 [8.0-21.0] days vs 7.0 [4.0-12.0] days; P < .001). In this comparative effectiveness research study, PBI management guided by ICP monitoring was associated with decreased mortality and increased ICU LOS, challenging the notion of universally poor outcomes after civilian PBI. Randomized clinical trials that evaluate the efficacy of ICP monitoring in PBI are warranted.

Characterizing modifications to a comparative effectiveness research study: the OPTIMIZE trial—using the Framework for Reporting Adaptations and Modifications to Evidence-based Interventions (FRAME)

BackgroundThe OPTIMIZE trial is a multi-site, comparative effectiveness research (CER) study that uses a Sequential Multiple Assessment Randomized Trial (SMART) designed to examine the effectiveness of complex health interventions (cognitive behavioral therapy, physical therapy, and mindfulness) for adults with chronic low back pain. Modifications are anticipated when implementing complex interventions in CER. Disruptions due to COVID have created unanticipated challenges also requiring modifications. Recent methodologic standards for CER studies emphasize that fully characterizing modifications made is necessary to interpret and implement trial results. The purpose of this paper is to outline the modifications made to the OPTIMIZE trial using the Framework for Reporting Adaptations and Modifications to Evidence-Based Interventions (FRAME) to characterize modifications to the OPTIMIZE trial in response to the COVID pandemic and other challenges encountered.MethodsThe FRAME outlines a strategy to identify and report modifications to evidence-based interventions or implementation strategies, whether planned or unplanned. We use the FRAME to characterize the process used to modify the aspects of the OPTIMIZE trial. Modifications were made to improve lower-than-anticipated rates of treatment initiation and COVID-related restrictions. Contextual modifications were made to permit telehealth delivery of treatments originally designed for in-person delivery. Training modifications were made with study personnel to provide more detailed information to potential participants, use motivational interviewing communication techniques to clarify potential participants’ motivation and possible barriers to initiating treatment, and provide greater assistance with scheduling of assigned treatments.ResultsModifications were developed with input from the trial’s patient and stakeholder advisory panels. The goals of the modifications were to improve trial feasibility without compromising the interventions’ core functions. Modifications were approved by the study funder and the trial steering committee.ConclusionsFull and transparent reporting of modifications to clinical trials, whether planned or unplanned, is critical for interpreting the trial’s eventual results and considering future implementation efforts.Trial registrationClinicalTrials.gov NCT03859713. Registered on March 1, 2019

Comparing Effectiveness and Safety of SGLT2 Inhibitors vs DPP-4 Inhibitors in Patients With Type 2 Diabetes and Varying Baseline HbA1c Levels

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy has been associated with cardiovascular benefits and a few adverse events; however, whether the comparative effectiveness and safety profiles vary with differences in baseline hemoglobin A1c (HbA1c) levels is unknown. To compare cardiovascular effectiveness and safety of treatment with SGLT2i vs dipeptidyl peptidase 4 inhibitor (DPP-4i) in adults with type 2 diabetes (T2D) (1) overall and (2) at varying baseline HbA1c levels. A new-user comparative effectiveness and safety research study was conducted among 144 614 commercially insured adults, initiating treatment with SGLT2i or DPP-4i and with a recorded T2D diagnosis at baseline and at least 1 HbA1c laboratory result recorded within 3 months before treatment initiation. The intervention consisted of the initiation of treatment with SGLT2i or DPP-4i. Primary outcomes were a composite of myocardial infarction, stroke, or all-cause death (modified major adverse cardiovascular events [MACE]) and hospitalization for heart failure (HHF). Safety outcomes were hypovolemia, fractures, falls, genital infections, diabetic ketoacidosis (DKA), acute kidney injury (AKI), and lower-limb amputation. Incidence rate (IR) per 1000 person-years, hazard ratios (HR) and rate differences (RD) with their 95% CIs were estimated controlling for 128 covariates. A total of 144 614 eligible adults (mean [SD] age, 62 [12.4] years; 54% male participants) with T2D initiating treatment with a SGLT2i (n = 60 523) or a DPP-4i (n = 84 091) were identified; 44 099 had an HbA1c baseline value of less than 7.5%, 52 986 between 7.5% and 9%, and 47 529 greater than 9%. Overall, 87 274 eligible patients were 1:1 propensity score-matched: 24 052 with HbA1c less than 7.5%; 32 290 with HbA1c between 7.5% and 9%; and 30 932 with HbA1c greater than 9% (to convert percentage of total hemoglobin to proportion of total hemoglobin, multiply by 0.01). The initiation of SGLT2i vs DPP-4i was associated with a reduction in the risk of modified MACE (IR per 1000 person-years 17.13 vs 20.18, respectively; HR, 0.85; 95% CI, 0.75-0.95; RD, -3.02; 95% CI, -5.23 to -0.80) and HHF (IR per 1000 person-years 3.68 vs 8.08, respectively; HR, 0.46; 95% CI, 0.35 to 0.57; RD -4.37; 95% CI, -5.62 to -3.12) over a mean follow-up of 8 months, with no evidence of treatment effect heterogeneity across the HbA1c levels. Treatment with SGLT2i showed an increased risk of genital infections and DKA and a reduced AKI risk compared with DPP-4i. Findings were consistent by HbA1c levels, except for a more pronounced risk of genital infections associated with SGLT2i for HbA1c levels of 7.5% to 9% (IR per 1000 person-years 68.5 vs 22.8, respectively; HR, 3.10; 95% CI, 2.68-3.58; RD, 46.22; 95% CI, 40.54-51.90). In this comparative effectiveness and safety research study among adults with T2D, SGLT2i vs DPP-4i treatment initiators had a reduced risk of modified MACE and HHF, an increased risk of genital infections and DKA, and a lower risk of AKI, regardless of baseline HbA1c.

Comparative Effectiveness of Immune Checkpoint Inhibitors vs Chemotherapy in Patients With Metastatic Colorectal Cancer With Measures of Microsatellite Instability, Mismatch Repair, or Tumor Mutational Burden

The KEYNOTE-177 trial demonstrated that patients with metastatic colorectal cancer (MCRC) with high microsatellite instability (MSI-H) and/or mismatch repair deficiency (DMMR) have better outcomes when receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy. Data on performance of ICIs in patients with MCRC in standard practice settings remain limited, and direct MMR vs MSI outcome association comparisons are lacking. To validate MSI (determined by next-generation sequencing [NGS]) as a biomarker of ICI effectiveness among patients with MCRC in standard practice settings and examine the association of MSI assessed by NGS, DMMR by immunohistochemistry, and tumor mutational burden (cutoff, 10 mutations/megabase) with ICI outcomes. This comparative effectiveness research study of outcomes in prospectively defined biomarker subgroups used data from a deidentified clinicogenomic database and included patients who received Foundation Medicine testing (FoundationOne or FoundationOne CDx) during routine clinical care at approximately 280 US academic or community-based cancer clinics between March 2014 and December 2021. The population included 1 cohort of patients with MSI-H MCRC who received first-line ICIs or chemotherapy and a second cohort who received ICIs in any line of therapy (LOT) for biomarker examination. ICI therapy or chemotherapy assigned at physician discretion without randomization. The main outcomes were time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Hazard ratios were adjusted for known prognostic imbalances. Comparisons of explanatory power used the likelihood ratio test. A total of 138 patients (median age, 67.0 years [IQR, 56.2-74.0 years]; 73 [52.9%] female) with MSI-H MCRC received first-line ICIs or chemotherapy. A total of 182 patients (median age, 64.5 years [IQR, 55.2-72.0]; 98 [53.8%] female) received ICIs in any LOT. Patients receiving first-line ICIs vs chemotherapy had longer TTNT (median, not reached [NR] vs 7.23 months [IQR, 6.21-9.72 months]; adjusted hazard ratio [AHR], 0.17; 95% CI, 0.08-0.35; P < .001), PFS (median, 24.87 months [IQR, 19.10 months to NR] vs 5.65 months [IQR, 4.70-8.34 months]; AHR, 0.31; 95% CI, 0.18-0.52; P < .001), and OS (median, NR vs 24.1 months [IQR, 13.90 months to NR]; HR, 0.45; 95% CI, 0.23-0.88; P = .02). MSI added to DMMR better anticipated TTNT and PFS in patients receiving ICIs than DMMR alone. The same was not observed when DMMR evaluation was added to MSI. In this comparative effectiveness research study, MSI assessed by NGS robustly identified patients with favorable outcomes on first-line ICIs vs chemotherapy and appeared to better anticipate ICI outcomes compared with DMMR.

Assessing the Discriminatory Ability of Diagnostic Criteria for Ulcerative Pyoderma Gangrenosum and Its Mimickers

This comparative effectiveness research study assesses the discriminatory ability of diagnostic criteria for pyoderma gangrenosum.

Zone 1 Endovascular Balloon Occlusion of the Aorta vs Resuscitative Thoracotomy for Patient Resuscitation After Severe Hemorrhagic Shock

Aortic occlusion (AO) is a lifesaving therapy for the treatment of severe traumatic hemorrhagic shock; however, there remains controversy whether AO should be accomplished via resuscitative thoracotomy (RT) or via endovascular balloon occlusion of the aorta (REBOA) in zone 1. To compare outcomes of AO via RT vs REBOA zone 1. This was a comparative effectiveness research study using a multicenter registry of postinjury AO from October 2013 to September 2021. AO via REBOA zone 1 (above celiac artery) was compared with RT performed in the emergency department of facilities experienced in both procedures and documented in the prospective multicenter Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery (AORTA) registry. Propensity score matching (PSM) with exact institution matching was used, in addition to subgroup multivariate analysis to control for confounders. The study setting included the ED, where AO via RT or REBOA was performed, and participants were adult trauma patients 16 years or older. AO via REBOA zone 1 vs RT. The primary outcome was survival. Secondary outcomes were ventilation-free days (VFDs), intensive care unit (ICU)-free days, discharge Glasgow Coma Scale score, and Glasgow Outcome Score (GOS). A total of 991 patients (median [IQR] age, 32 [25-48] years; 808 male individuals [81.9%]) with a median (IQR) Injury Severity Score of 29 (18-50) were included. Of the total participants, 306 (30.9%) had AO via REBOA zone 1, and 685 (69.1%) had AO via RT. PSM selected 112 comparable patients (56 pairs). REBOA zone 1 was associated with a statistically significant lower mortality compared with RT (78.6% [44] vs 92.9% [52]; P = .03). There were no significant differences in VFD greater than 0 (REBOA, 18.5% [10] vs RT, 7.1% [4]; P = .07), ICU-free days greater than 0 (REBOA, 18.2% [10] vs RT, 7.1% [4]; P = .08), or discharge GOS of 5 or more (REBOA, 7.5% [4] vs RT, 3.6% [2]; P = .38). Multivariate analysis confirmed the survival benefit of REBOA zone 1 after adjustment for significant confounders (relative risk [RR], 1.25; 95% CI, 1.15-1.36). In all subgroup analyses (cardiopulmonary resuscitation on arrival, traumatic brain injury, chest injury, pelvic injury, blunt/penetrating mechanism, systolic blood pressure ≤60 mm Hg on AO initiation), REBOA zone 1 offered an either similar or superior survival. Results of this comparative effectiveness research suggest that REBOA zone 1 provided better or similar survival than RT for patients requiring AO postinjury. These findings provide the ethically necessary equipoise between these therapeutic approaches to allow the planning of a randomized controlled trial to establish the safety and effectiveness of REBOA zone 1 for AO in trauma resuscitation.