Impact of the PATH Statement on Analysis and Reporting of Heterogeneity of Treatment Effect in Clinical Trials: A Scoping Review.

Background: The Predictive Approaches to Treatment Effect Heterogeneity (PATH) Statement provides guidance for using predictive modeling to identify differences (i.e., heterogeneity) in treatment effects (benefits and harms) among participants in randomized clinical trials (RCTs). It distinguished risk modeling, which uses a multivariable model to predict risk of trial outcome(s) and then examines treatment effects within strata of predicted risk, from effect modeling, which predicts trial outcomes using models that include treatment, individual participant characteristics and interactions of treatment with selected characteristics. Purpose: To describe studies of heterogeneous treatment effects (HTE) that use predictive modeling in RCT data and cite the PATH Statement. Data Sources: The Cited By functions in PubMed, Google Scholar, Web of Science and SCOPUS databases (Jan 7, 2020 - June 5, 2023). Study Selection: 42 reports presenting 45 predictive models. Data Extraction: Double review with adjudication to identify risk and effect modeling and examine consistency with Statement consensus statements. Credibility of HTE findings was assessed using criteria adapted from the Instrument to assess Credibility of Effect Modification Analyses (ICEMAN). Clinical importance of credible HTE findings was also assessed. Data Synthesis: The numbers of reports, especially risk modeling reports, increased year-on-year. Consistency with consensus statements was high, except for two: only 15 of 32 studies with positive overall findings included a risk model; and most effect models explored many candidate covariates with little prior evidence for effect modification. Risk modeling was more likely than effect modeling to identify both credible HTE (14/19 vs 5/26) and clinically important HTE (10/19 vs 4/26). Limitations: Risk of reviewer bias: reviewers assessing credibility and clinical importance were not blinded to adherence to PATH recommendations. Conclusions: The PATH Statement appears to be influencing research practice. Risk modeling often uncovered clinically important HTE; effect modeling was more often exploratory.

Improving blood pressure control through a clinical pharmacist outreach program in patients with diabetes mellitus in 2 high-performing health systems: the adherence and intensification of medications cluster randomized, controlled pragmatic trial.

BACKGROUND: Even in high-performing health systems, some patients with diabetes mellitus have poor blood pressure (BP) control because of poor medication adherence and lack of medication intensification. We examined whether the Adherence and Intensification of Medications intervention, a pharmacist-led intervention combining elements found in efficacy studies to lower BP, improved BP among patients with diabetes mellitus with persistent hypertension and poor refill adherence or insufficient medication intensification in 2 high-performing health systems. METHODS AND RESULTS: We conducted a prospective, multisite cluster randomized pragmatic trial with randomization of 16 primary care teams at 5 medical centers (3 Veterans Affairs and 2 Kaiser Permanente) to the Adherence and Intensification of Medications intervention or usual care. The primary outcome was relative change in systolic BP (SBP), comparing 1797 intervention with 2303 control team patients, from 6 months preceding to 6 months after the 14-month intervention period. We examined shorter-term changes in SBP as a secondary outcome. The mean SBP decrease from 6 months before to 6 months after the intervention period was ≈9 mm Hg in both arms. Mean SBPs of eligible intervention patients were 2.4 mm Hg lower (95% CI: -3.4 to -1.5; P<0.001) immediately after the intervention than those achieved by control patients. CONCLUSIONS: The Adherence and Intensification of Medications program more rapidly lowered SBPs among intervention patients, but usual-care patients achieved equally low SBP levels by 6 months after the intervention period. These findings show the importance of evaluating in different real-life clinical settings programs found in efficacy trials to be effective before urging their widespread adoption in all settings. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00495794.

Incidence and prognosis of resistant hypertension in hypertensive patients.

BACKGROUND: Despite a recent American Heart Association (AHA) consensus statement emphasizing the importance of resistant hypertension, the incidence and prognosis of this condition are largely unknown. METHODS AND RESULTS: This retrospective cohort study in 2 integrated health plans included patients with incident hypertension in whom treatment was begun between 2002 and 2006. Patients were followed up for the development of resistant hypertension based on AHA criteria of uncontrolled blood pressure despite use of ≥3 antihypertensive medications, with data collected on prescription filling information and blood pressure measurement. We determined incident cardiovascular events (death or incident myocardial infarction, heart failure, stroke, or chronic kidney disease) in patients with and without resistant hypertension with adjustment for patient and clinical characteristics. Among 205 750 patients with incident hypertension, 1.9% developed resistant hypertension within a median of 1.5 years from initial treatment (0.7 cases per 100 person-years of follow-up). These patients were more often men, were older, and had higher rates of diabetes mellitus than nonresistant patients. Over 3.8 years of median follow-up, cardiovascular event rates were significantly higher in those with resistant hypertension (unadjusted 18.0% versus 13.5%, P<0.001). After adjustment for patient and clinical characteristics, resistant hypertension was associated with a higher risk of cardiovascular events (hazard ratio, 1.47; 95% confidence interval, 1.33-1.62). CONCLUSIONS: Among patients with incident hypertension in whom treatment was begun, 1 in 50 patients developed resistant hypertension. Patients with resistant hypertension had an increased risk of cardiovascular events, which supports the need for greater efforts toward improving hypertension outcomes in this population.

Dynamic marginal structural modeling to evaluate the comparative effectiveness of more or less aggressive treatment intensification strategies in adults with type 2 diabetes.

PURPOSE: Chronic disease care typically involves treatment decisions that are frequently adjusted to the patient's evolving clinical course (e.g., hemoglobin A1c monitoring and treatment intensification in diabetes patients). Thus, in comparative effectiveness and safety research (CER), it often is less clinically relevant to contrast the health effects of static treatment decisions than to compare the effectiveness of competing medical guidelines, that is, adaptive treatment strategies that map the patient's unfolding clinical course to subsequent treatment decisions. With longitudinal observational studies, treatment decisions at any point in time may be influenced by clinical factors that also are risk factors for the outcome of interest. Such time-dependent confounders cannot be properly handled with standard statistical approaches, because such confounders may be influenced by previous treatment decisions and may thus lie on causal pathways between the very outcomes and early treatment decisions whose effects are under study. Under explicit assumptions, we motivate the application of inverse probability weighting estimation to fit dynamic marginal structural models (MSMs) in observational studies to address pragmatic CER questions and properly adjust for time-dependent confounding and informative loss to follow-up. METHODS: We review the principles behind this modeling approach and describe its application in an observational study of type 2 diabetes patients to investigate the comparative effectiveness of four adaptive treatment intensification strategies for glucose control on subsequent development or progression of urinary albumin excretion. RESULTS: Results indicate a protective effect of more aggressive treatment intensification strategies in patients already on two or more oral agents or basal insulin. These conclusions are concordant with recent randomized trials. CONCLUSIONS: Inverse probability weighting estimation to fit dynamic MSM is a viable and appealing alternative to inadequate standard modeling approaches in many CER problems where time-dependent confounding and informative loss to follow-up are expected.

A protocol for active surveillance of acute myocardial infarction in association with the use of a new antidiabetic pharmaceutical agent.

PURPOSE: To describe a protocol for active surveillance of acute myocardial infarction (AMI) in users of a recently approved oral antidiabetic medication, saxagliptin, and to provide the rationale for decisions made in drafting the protocol. METHODS: A new-user cohort design is planned for evaluating data from at least four Mini-Sentinel data partners from 1 August 2009 (following US Food and Drug Administration's approval of saxagliptin) through mid-2013. New users of saxagliptin will be compared in separate analyses with new users of sitagliptin, pioglitazone, long-acting insulins, and second-generation sulfonylureas. Two approaches to controlling for confounding will be evaluated: matching by exposure propensity score and stratification by AMI risk score. The primary analyses will use Cox regression models specified in a way that does not require pooling of patient-level data from the data partners. The Cox models are fit to summarized data on risk sets composed of saxagliptin users and similar comparator users at the time of an AMI. Secondary analyses will use alternative methods including Poisson regression and will explore whether further adjustment for covariates available only at some data partners (e.g., blood pressure) modifies results. RESULTS: The results of this study are pending. CONCLUSIONS: The proposed protocol describes a design for surveillance to evaluate the safety of a newly marketed agent as postmarket experience accrues. It uses data from multiple partner organizations without requiring sharing of patient-level data and compares alternative approaches to controlling for confounding. It is hoped that this initial active surveillance project of the Mini-Sentinel will provide insights that inform future population-based surveillance of medical product safety.

Improving treatment intensification to reduce cardiovascular disease risk: a cluster randomized trial.

BACKGROUND: Blood pressure, lipid, and glycemic control are essential for reducing cardiovascular disease (CVD) risk. Many health care systems have successfully shifted aspects of chronic disease management, including population-based outreach programs designed to address CVD risk factor control, to non-physicians. The purpose of this study is to evaluate provision of new information to non-physician outreach teams on need for treatment intensification in patients with increased CVD risk. METHODS: Cluster randomized trial (July 1-December 31, 2008) in Kaiser Permanente Northern California registry of members with diabetes mellitus, prior CVD diagnoses and/or chronic kidney disease who were high-priority for treatment intensification: blood pressure ≥ 140 mmHg systolic, LDL-cholesterol ≥ 130 mg/dl, or hemoglobin A1c ≥ 9%; adherent to current medications; no recent treatment intensification). Randomization units were medical center-based outreach teams (4 intervention; 4 control). For intervention teams, priority flags for intensification were added monthly to the registry database with recommended next pharmacotherapeutic steps for each eligible patient. Control teams used the same database without this information. Outcomes included 3-month rates of treatment intensification and risk factor levels during follow-up. RESULTS: Baseline risk factor control rates were high (82-90%). In eligible patients, the intervention was associated with significantly greater 3-month intensification rates for blood pressure (34.1 vs. 30.6%) and LDL-cholesterol (28.0 vs 22.7%), but not A1c. No effects on risk factors were observed at 3 months or 12 months follow-up. Intervention teams initiated outreach for only 45-47% of high-priority patients, but also for 27-30% of lower-priority patients. Teams reported difficulties adapting prior outreach strategies to incorporate the new information. CONCLUSIONS: Information enhancement did not improve risk factor control compared to existing outreach strategies at control centers. Familiarity with prior, relatively successful strategies likely reduced uptake of the innovation and its potential for success at intervention centers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00517686.

Combination therapy as initial treatment for newly diagnosed hypertension.

BACKGROUND: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends that clinicians consider the use of multidrug therapy to increase likelihood of achieving blood pressure goal. Little is known about recent patterns of combination antihypertensive therapy use in patients being initiated on hypertension treatment. METHODS: We investigated combination antihypertensive therapy use in newly diagnosed hypertensive patients from the Cardiovascular Research Network Hypertension Registry. Multivariable logistic regression was used to assess the relationship between combination antihypertensive therapy and 12-month blood pressure control. RESULTS: Between 2002 and 2007, a total of 161,585 patients met criteria for incident hypertension and were initiated on treatment. During the study period, an increasing proportion of patients were treated initially with combination rather than with single-agent therapy (20.7% in 2002 compared with 35.8% in 2007, P < .001). This increase in combination therapy use was more pronounced in patients with stage 2 hypertension, whose combination therapy use increased from 21.6% in 2002 to 44.5% in 2007. Nearly 90% of initial combination therapy was accounted for by 2 combinations, a thiazide and a potassium-sparing diuretic (47.6%) and a thiazide and an angiotensin-converting enzyme inhibitor (41.4%). After controlling for relevant clinical factors, including subsequent intensification of treatment and medication adherence, combination therapy was associated with increased odds of blood pressure control at 12 months (odds ratio compared with single-drug initial therapy 1.20; 95% CI 1.15-1.24, P < .001). CONCLUSIONS: Initial treatment of hypertension with combination therapy is increasingly common and is associated with better long-term blood pressure control.

ADHD medications and risk of serious cardiovascular events in young and middle-aged adults.

CONTEXT: More than 1.5 million US adults use stimulants and other medications labeled for treatment of attention-deficit/hyperactivity disorder (ADHD). These agents can increase heart rate and blood pressure, raising concerns about their cardiovascular safety. OBJECTIVE: To examine whether current use of medications prescribed primarily to treat ADHD is associated with increased risk of serious cardiovascular events in young and middle-aged adults. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, population-based cohort study using electronic health care records from 4 study sites (OptumInsight Epidemiology, Tennessee Medicaid, Kaiser Permanente California, and the HMO Research Network), starting in 1986 at 1 site and ending in 2005 at all sites, with additional covariate assessment using 2007 survey data. Participants were adults aged 25 through 64 years with dispensed prescriptions for methylphenidate, amphetamine, or atomoxetine at baseline. Each medication user (n = 150,359) was matched to 2 nonusers on study site, birth year, sex, and calendar year (443,198 total users and nonusers). MAIN OUTCOME MEASURES: Serious cardiovascular events, including myocardial infarction (MI), sudden cardiac death (SCD), or stroke, with comparison between current or new users and remote users to account for potential healthy-user bias. RESULTS: During 806,182 person-years of follow-up (median, 1.3 years per person), 1357 cases of MI, 296 cases of SCD, and 575 cases of stroke occurred. There were 107,322 person-years of current use (median, 0.33 years), with a crude incidence per 1000 person-years of 1.34 (95% CI, 1.14-1.57) for MI, 0.30 (95% CI, 0.20-0.42) for SCD, and 0.56 (95% CI, 0.43-0.72) for stroke. The multivariable-adjusted rate ratio (RR) of serious cardiovascular events for current use vs nonuse of ADHD medications was 0.83 (95% CI, 0.72-0.96). Among new users of ADHD medications, the adjusted RR was 0.77 (95% CI, 0.63-0.94). The adjusted RR for current use vs remote use was 1.03 (95% CI, 0.86-1.24); for new use vs remote use, the adjusted RR was 1.02 (95% CI, 0.82-1.28); the upper limit of 1.28 corresponds to an additional 0.19 events per 1000 person-years at ages 25-44 years and 0.77 events per 1000 person-years at ages 45-64 years. CONCLUSIONS: Among young and middle-aged adults, current or new use of ADHD medications, compared with nonuse or remote use, was not associated with an increased risk of serious cardiovascular events. Apparent protective associations likely represent healthy-user bias.

System-based participatory research in health care: an approach for sustainable translational research and quality improvement.

Translational research seeks to improve health care by promoting action and change in real-world health care settings. Although translational research advocates a break from the traditional researcher-initiated approach to science, strategies to successfully engage clinicians and leaders of health care delivery organizations in research are still under development. We propose that applying the principles of community-based participatory research in a way that considers delivery systems-including their leaders, clinicians, and staff-as a focal community can enhance the ability of translational research to improve health care. Applying participatory research methods, such as engaging in collaborative partnerships, building on existing community strengths, investing in long-term relationships, and engaging in research as a cyclical, iterative process, can be a successful approach to sustainable quality improvement at the systems level.

Thiazolidinediones, cardiovascular disease and cardiovascular mortality: translating research into action for diabetes (TRIAD).

BACKGROUND: Studies have associated thiazolidinedione (TZD) treatment with cardiovascular disease (CVD) and questioned whether the two available TZDs, rosiglitazone and pioglitazone, have different CVD risks. We compared CVD incidence, cardiovascular (CV), and all-cause mortality in type 2 diabetic patients treated with rosiglitazone or pioglitazone as their only TZD. METHODS: We analyzed survey, medical record, administrative, and National Death Index (NDI) data from 1999 through 2003 from Translating Research Into Action for Diabetes (TRIAD), a prospective observational study of diabetes care in managed care. Medications, CV procedures, and CVD were determined from health plan (HP) administrative data, and mortality was from NDI. Adjusted hazard rates (AHR) were derived from Cox proportional hazard models adjusted for age, sex, race/ethnicity, income, history of diabetic nephropathy, history of CVD, insulin use, and HP. RESULTS: Across TRIAD's 10 HPs, 1,815 patients (24%) filled prescriptions for a TZD, 773 (10%) for only rosiglitazone, 711 (10%) for only pioglitazone, and 331 (4%) for multiple TZDs. In the seven HPs using both TZDs, 1,159 patients (33%) filled a prescription for a TZD, 564 (16%) for only rosiglitazone, 334 (10%) for only pioglitazone, and 261 (7%) for multiple TZDs. For all CV events, CV, and all-cause mortality, we found no significant difference between rosiglitazone and pioglitazone. CONCLUSIONS: In this relatively small, prospective, observational study, we found no statistically significant differences in CV outcomes for rosiglitazone- compared to pioglitazone-treated patients. There does not appear to be a pattern of clinically meaningful differences in CV outcomes for rosiglitazone- versus pioglitazone-treated patients.

Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure.

PURPOSE: Osteonecrosis of the jaw (ONJ) is a serious complication associated with bisphosphonate therapy, but its epidemiology in the setting of oral bisphosphonate therapy is poorly understood. The present study examined the prevalence of ONJ in patients receiving chronic oral bisphosphonate therapy. MATERIALS AND METHODS: We mailed a survey to 13,946 members who had received chronic oral bisphosphonate therapy as of 2006 within a large integrated health care delivery system in Northern California. Respondents who reported ONJ, exposed bone or gingival sores, moderate periodontal disease, persistent symptoms, or complications after dental procedures were invited for examination or to have their dental records reviewed. ONJ was defined as exposed bone (of >8 weeks' duration) in the maxillofacial region in the absence of previous radiotherapy. RESULTS: Of the 8,572 survey respondents (71 +/- 9 years, 93% women), 2,159 (25%) reported pertinent dental symptoms. Of these 2,159 patients, 1,005 were examined and an additional 536 provided dental records. Nine ONJ cases were identified, representing a prevalence of 0.10% (95% confidence interval 0.05% to 0.20%) among the survey respondents. Of the 9 cases, 5 had occurred spontaneously (3 in palatal tori) and 4 occurred in previous extraction sites. An additional 3 patients had mandibular osteomyelitis (2 after extraction and 1 with implant failure) but without exposed bone. Finally, 7 other patients had bone exposure that did not fulfill the criteria for ONJ. CONCLUSIONS: ONJ occurred in 1 of 952 survey respondents with oral bisphosphonate exposure (minimum prevalence of 1 in 1,537 of the entire mailed cohort). A similar number had select features concerning for ONJ that did not meet the criteria. The results of the present study provide important data on the spectrum of jaw complications among patients with oral bisphosphonate exposure.

Social disparities in dental insurance and annual dental visits among medically insured patients with diabetes: the Diabetes Study of Northern California (DISTANCE) Survey.

INTRODUCTION: People with diabetes are at increased risk of periodontal disease and tooth loss. Healthy People 2010 set a goal that 71% or more of people with diabetes should have an annual dental exam. METHODS: We assessed dental insurance and annual dental visits among dentate respondents from the Diabetes Study of Northern California (DISTANCE) Survey cohort (N = 20,188), an ethnically stratified, random sample of patients with diabetes aged 30 to 75 years receiving medical care from Kaiser Permanente Northern California. We calculated predicted probabilities for an annual dental visit (PPADV) by using regression models that incorporated age, sex, education level, annual household income, and self-reported race/ethnicity, stratified by whether the respondent had dental insurance. RESULTS: Among 12,405 dentate patients, 9,257 (75%) had dental insurance. Annual dental visits were reported by 7,557 (82%) patients with dental insurance and 1,935 (61%) patients without dental insurance. The age-sex adjusted odds ratio for an annual dental visit was 2.66 (95% confidence interval, 2.33-3.03) for patients with dental insurance compared to those without dental insurance. For patients with dental insurance, the PPADV was 71% or more for all except those with the lowest household income. In contrast, for those without dental insurance, the PPADV was less than 71% for all except those with the most education or the highest income. We found some racial/ethnic subgroups were more likely than others to take advantage of dental insurance to have an annual dental visit. CONCLUSION: Patients with diabetes in this managed care population who lacked dental insurance failed to meet the Healthy People 2010 goal for an annual dental visit. An increased effort should be made to promote oral health among people with diabetes.

Examining the role of funders in ensuring value and reducing waste in research: An organizational case-study of the Patient-Centered Outcomes Research Institute.

International experts have recommended actions that funders can take to improve the value of research investments. They state that self-assessment and public sharing are the basis for accountability and improvement. We examined our policies and practice to determine the extent to which the Patient-Centered Outcomes Research Institute's (PCORI) policies and practices as a research funder align with international best practice recommendations. A self-audit of current policies and practice against 17 recommendations and 35 sub-recommendations representing five major stages of research production, based on adapted methods used for self-assessment by another funder, was performed.  Fit of existing PCORI policies and practices with 35 sub-recommendations, qualitative assessment of adequacy (area of strength; area of partial strength; area of growth; not applicable) for 17 recommendations for five stages of research production was assessed. Of the 17 recommendations, 15 were applicable to PCORI's research mission and focus.  PCORI has policies and practices in place for all elements of six recommendations ("area of strength") and policies that address each element but with some still in active development for three ("area of partial strength"). PCORI is partially addressing six of the 15 relevant recommendations ("area of growth"). Areas for growth include making study protocols publicly available, improving policies on data sharing, and enhancing collaboration with other funders to reduce redundant funding. A voluntary consortium of international funders is underway to encourage further progress, including additional self-assessment and public sharing for accountability. These findings indicate PCORI has undertaken efforts to align its funding practices with international recommendations to ensure the value of public dollars invested in research.  Further efforts will likely require additional coordination and collaboration between funders and stakeholders.