Individualized clinical decisions within standard-of-care pragmatic clinical trials: Implications for consent.

Pragmatic clinical trials of standard-of-care interventions compare the relative merits of medical treatments already in use. Traditional research informed consent processes pose significant obstacles to these trials, raising the question of whether they may be conducted with alteration or waiver of informed consent. However, to even be eligible, such a trial in the United States must have no more than minimal research risk. We argue that standard-of-care pragmatic clinical trials can be designed to ensure that they are minimal research risk if the random assignment of an intervention in a pragmatic clinical trial can accommodate individualized, clinically motivated decision-making for each participant. Such a design will ensure that the patient-participants are not exposed to any risks beyond the clinical risks of the interventions, and thus, the trial will have minimal research risk. We explain the logic of this view by comparing three scenarios of standard-of-care pragmatic clinical trials: one with informed consent, one without informed consent, and one recently proposed design called Decision Architecture Randomization Trial. We then conclude by briefly showing that our proposal suggests a natural way to determine when to use an alteration versus a waiver of informed consent.

Role of primary care in opioid prescribing for older head and neck cancer survivors.

BACKGROUND: Older head and neck cancer (HNC) survivors have concerning rates of potentially unsafe opioid prescribing. Identifying the specialties of opioid prescribers for HNC survivors is critical for targeting the settings for opioid safety interventions. This study hypothesized that oncology and surgery providers are primarily responsible for opioid prescriptions in the year after treatment but that primary care providers (PCPs) are increasingly involved in prescribing over time. METHODS: Using linked Surveillance, Epidemiology, and End Results-Medicare data, a retrospective analysis was conducted of adults aged >65 years diagnosed between 2014 and 2017 with stage I-III HNC and who had ≥6 months of treatment-free follow-up through 2019. Starting at treatment completion, opioid fills were assigned to a prescriber specialty: oncology, surgery, primary care, pain management, or other. Prescriber patterns were summarized for each year of follow-up. Multinomial logistic regression models captured the likelihood of opioids being prescribed by each specialty. RESULTS: Among 5135 HNC survivors, 2547 (50%) had ≥1 opioid fill (median, 2.1-year follow-up). PCPs prescribed 47% of all fills (42%-55% each year). PCPs prescribed opioids to 45% of survivors with ≥1 opioid fill, which was a greater share than other specialties. PCPs prescribed longer supplies of opioids (median, 20 days/fill; median, 30 days/year) than oncologists or surgeons. The likelihood of an opioid being prescribed by an oncology provider was four times lower than that of it being prescribed by a PCP. CONCLUSIONS: PCP involvement in opioid prescribing remains high throughout HNC survivorship. Interventions to improve the safety of opioid prescribing should target primary care, as is typical for opioid reduction efforts in the noncancer population.

Application of a data continuity prediction algorithm to an electronic health record-based pharmacoepidemiology study.

BACKGROUND AND OBJECTIVES: Use of algorithms to identify patients with high data-continuity in electronic health records (EHRs) may increase study validity. Practical experience with this approach remains limited. METHODS: We developed and validated four algorithms to identify patients with high data continuity in an EHR-based data source. Selected algorithms were then applied to a pharmacoepidemiologic study comparing rates of COVID-19 hospitalization in patients exposed to insulin versus noninsulin antidiabetic drugs. RESULTS: A model using a short list of five EHR-derived variables performed as well as more complex models to distinguish high- from low-data continuity patients. Higher data continuity was associated with more accurate ascertainment of key variables. In the pharmacoepidemiologic study, patients with higher data continuity had higher observed rates of the COVID-19 outcome and a large unadjusted association between insulin use and the outcome, but no association after propensity score adjustment. DISCUSSION: We found that a simple, portable algorithm to predict data continuity gave comparable performance to more complex methods. Use of the algorithm significantly impacted the results of an empirical study, with evidence of more valid results at higher levels of data continuity.

Validation of an international classification of disease, tenth revision, clinical modification (ICD-10-CM) algorithm in identifying severe hypoglycaemia events for real-world studies.

AIM: The transition to the ICD-10-CM coding system has reduced the utility of hypoglycaemia algorithms based on ICD-9-CM diagnosis codes in real-world studies of antidiabetic drugs. We mapped a validated ICD-9-CM hypoglycaemia algorithm to ICD-10-CM codes to create an ICD-10-CM hypoglycaemia algorithm and assessed its performance in identifying severe hypoglycaemia. MATERIALS AND METHODS: We assembled a cohort of Medicare patients with DM and linked electronic health record (EHR) data to the University of North Carolina Health System and identified candidate severe hypoglycaemia events from their Medicare claims using the ICD-10-CM hypoglycaemia algorithm. We confirmed severe hypoglycaemia by EHR review and computed a positive predictive value (PPV) of the algorithm to assess its performance. We refined the algorithm by removing poor performing codes (PPV ≤0.5) and computed a Cohen's κ statistic to evaluate the agreement of the EHR reviews. RESULTS: The algorithm identified 642 candidate severe hypoglycaemia events, and we confirmed 455 as true severe hypoglycaemia events, PPV of 0.709 (95% confidence interval: 0.672, 0.744). When we refined the algorithm, the PPV increased to 0.893 (0.862, 0.918) and missed <2.42% (<11) true severe hypoglycaemia events. Agreement between reviewers was high, κ = 0.93 (0.89, 0.97). CONCLUSIONS: We translated an ICD-9-CM hypoglycaemia algorithm to an ICD-10-CM version and found its performance was modest. The performance of the algorithm improved by removing poor performing codes at the trade-off of missing very few severe hypoglycaemia events. The algorithm has the potential to be used to identify severe hypoglycaemia in real-world studies of antidiabetic drugs.

Sodium-glucose cotransporter-2 inhibitors for hypergycemia in phosphoinositide 3-kinase pathway inhibition.

PURPOSE: Phosphoinositide 3-kinase (PI3K) inhibition is used for the treatment of certain cancers, but can cause profound hyperglycemia and insulin resistance, for which sodium-glucose cotransporter-2 (SGLT2) inhibitors have been proposed as a preferred therapy. The objective of this research is to assess the effectiveness and safety of SGLT2 inhibitors for hyperglycemia in PI3K inhibition. METHODS: We conducted a single-center retrospective review of adults initiating the PI3K inhibitor alpelisib. Exposure to different antidiabetic drugs and adverse events including diabetic ketoacidosis (DKA) were assessed through chart review. Plasma and point-of-care blood glucoses were extracted from the electronic medical record. Change in serum glucose and the rate of DKA on SGLT2 inhibitor versus other antidiabetic drugs were examined as co-primary outcomes. RESULTS: We identified 103 patients meeting eligibility criteria with median follow-up of 92 days after starting alpelisib. When SGLT2 inhibitors were used to treat hyperglycemia, they were associated with a decrease in mean random glucose by -46 mg/dL (95% CI - 77 to - 15) in adjusted linear modeling. Five cases of DKA were identified, two occurring in patients on alpelisib plus SGLT2 inhibitor. Estimated incidence of DKA was: alpelisib plus SGLT2 inhibitor, 48 DKA cases per 100 patient-years (95% CI 6, 171); alpelisib with non-SGLT2 inhibitor antidiabetic drugs, 15 (95% CI 2, 53); alpelisib only, 4 (95% CI 0.1, 22). CONCLUSIONS: SGLT2 inhibitors are effective treatments for hyperglycemia in the setting of PI3K inhibition.

Group sequential testing under instrumented difference-in-differences approach.

Unmeasured confounding is a major obstacle to reliable causal inference based on observational studies. Instrumented difference-in-differences (iDiD), a novel idea connecting instrumental variable and standard DiD, ameliorates the above issue by explicitly leveraging exogenous randomness in an exposure trend. In this article, we utilize the above idea of iDiD, and propose a novel group sequential testing method that provides valid inference even in the presence of unmeasured confounders. At each time point, we estimate the average or conditional average treatment effect under iDiD setting using the data accumulated up to that time point, and test the significance of the treatment effect. We derive the joint distribution of the test statistics under the null using the asymptotic properties of M-estimation, and the group sequential boundaries are obtained using the α $$ \alpha $$ -spending functions. The performance of our proposed approach is evaluated on both synthetic data and Clinformatics Data Mart Database (OptumInsight, Eden Prairie, MN) to examine the association between rofecoxib and acute myocardial infarction, and our method detects significant adverse effect of rofecoxib much earlier than the time when it was finally withdrawn from the market.

Exocrine Pancreatic Insufficiency Induced by Immune Checkpoint Inhibitors.

BACKGROUND: Scant data describe exocrine pancreatic insufficiency (EPI) secondary to immune checkpoint inhibitor (ICI) use. The goal of this study is to describe the incidence, risk factors, and clinical characteristics of patients with ICI-related EPI. PATIENTS AND METHODS: A single center, retrospective case-control study was performed of all ICI-treated patients at Memorial Sloan Kettering Cancer Center between January 2011 and July 2020. ICI-related EPI patients had steatorrhea with or without abdominal discomfort or weight loss, started pancrelipase after initiation of ICI, and demonstrated symptomatic improvement with pancrelipase. Controls were matched 2:1 by age, race, sex, cancer type, and year of ICI start. RESULTS: Of 12 905 ICI-treated patients, 23 patients developed ICI-related EPI and were matched to 46 controls. The incidence rate of EPI was 1.18 cases per 1000 person-years and the median onset of EPI was 390 days after the first dose of ICI. All 23 (100%) EPI cases had steatorrhea that improved with pancrelipase, 12 (52.2%) had weight loss, and 9 (39.1%) had abdominal discomfort; none had changes of chronic pancreatitis on imaging. Nine (39%) EPI patients had episodes of clinical acute pancreatitis preceding the onset of EPI, compared to 1 (2%) control (OR 18.0 (2.5-789.0), P < .001). Finally, the EPI group exhibited higher proportions of new or worsening hyperglycemia after ICI exposure compared with the control group (9 (39.1%) vs. 3 (6.5%), P < .01). CONCLUSION: ICI-related EPI is a rare but clinically significant event that should be considered in patients with late onset diarrhea after ICI treatment and often is associated with development of hyperglycemia and diabetes.

Preoperative glucose in surgical oncology patient is not associated with postoperative outcomes after adjustment for frailty.

BACKGROUND: Observational studies have shown associations between even small elevations in preoperative glucose and poorer outcomes, including increased length of stay (LOS) and higher mortality. This has led to calls for aggressive glycemic control in the preoperative period, including delay of treatment until glucose is reduced. However, it is not known whether there is a direct causal effect of blood glucose or whether adverse outcomes result from overall poorer health in patients with higher glucose. METHODS: Analysis was performed using a retrospective database of patients aged 65 and older who underwent cancer surgery. The last measured preoperative glucose was the exposure variable. The primary outcome was extended LOS (>4 days). Secondary outcomes included mortality, acute kidney injury (AKI), major postoperative complications during the admission period, and readmission within 30 days. The primary analysis was a logistic regression with prespecified covariates: age, sex, surgical service, and the Memorial Sloan Kettering-Frailty Index. In an exploratory analysis, lasso regression was used to select covariates from a list of 4160 candidate variables. RESULTS: This study included 3796 patients with a median preoperative glucose of 104 mg/dL (interquartile range: 93-125). Higher preoperative glucose was univariately associated with increased odds of LOS > 4 days (odds ratio [OR]: 1.45, 95% confidence interval [CI]: 1.22-1.73), with similar results for AKI, readmission, and mortality. Adjustment for confounders eliminated these associations for LOS (OR: 0.97 [95% CI: 0.80-1.18]) and attenuated all other glucose-outcome associations. Lasso regression gave comparable results to the primary analysis. Using the upper bound of the respective 95% confidence interval, we estimated that, at best, successful reduction of elevated preoperative glucose would reduce the risk of LOS > 4 days, 30-day major complication, and 30-day mortality by 4%, 0.5%, and 1.3%, respectively. CONCLUSIONS: Poor outcomes following cancer surgery in older adults with elevated glucose are most likely related to poorer overall health in these patients rather than a direct causal effect of glucose. Aggressive glycemic management in the preoperative period has very limited potential benefits and is therefore unwarranted.

Sodium-Glucose Cotransporter-2 Inhibitors for Hyperglycemia in Phosphoinositide 3-kinase Pathway Inhibition.

Purpose Phosphoinositide 3-kinase (PI3K) inhibition is used for the treatment of certain cancers, but can cause profound hyperglycemia and insulin resistance, for which sodium-glucose cotransporter-2 (SGLT2) inhibitors have been proposed as a preferred therapy. The objective of this research is to assess the effectiveness and safety of SGLT2 inhibitors for hyperglycemia in PI3K inhibition. Methods We conducted a single-center retrospective review of adults initiating the PI3k inhibitor alpelisib. Exposure to different antidiabetic drugs and adverse events including diabetic ketoacidosis (DKA) were assessed through chart review. Plasma and point-of-care blood glucoses were extracted from the electronic medical record. Change in serum glucose and the rate of DKA on SGLT2 inhibitor versus other antidiabetic drugs were examined as co-primary outcomes. Results We identified 103 patients meeting eligibility criteria with median follow-up of 85 days after starting alpelisib. When SGLT2 inhibitors were used to treat hyperglycemia, they were associated with a decrease in mean random glucose by -54 mg/dL (95% CI -99 to -8) in adjusted linear modeling. Five cases of DKA were identified, two occurring in patients on alpelisib plus SGLT2 inhibitor. Estimated incidence of DKA was: alpelisib plus SGLT2 inhibitor, 24 DKA cases per 100 patient-years (95% CI 6, 80); alpelisib with non-SGLT2 inhibitor antidiabetic drugs, 7 (95% CI 0.1, 34); alpelisib only, 4 (95% CI 0.1, 21). Conclusions SGLT2 inhibitors are effective treatments for hyperglycemia in the setting of PI3K inhibition, but given possible adverse events, SGLT2 inhibitors should be used with caution.

Instrumented difference-in-differences.

Unmeasured confounding is a key threat to reliable causal inference based on observational studies. Motivated from two powerful natural experiment devices, the instrumental variables and difference-in-differences, we propose a new method called instrumented difference-in-differences that explicitly leverages exogenous randomness in an exposure trend to estimate the average and conditional average treatment effect in the presence of unmeasured confounding. We develop the identification assumptions using the potential outcomes framework. We propose a Wald estimator and a class of multiply robust and efficient semiparametric estimators, with provable consistency and asymptotic normality. In addition, we extend the instrumented difference-in-differences to a two-sample design to facilitate investigations of delayed treatment effect and provide a measure of weak identification. We demonstrate our results in simulated and real datasets.

Rejoinder to "Instrumented difference-in-differences".

We thank all the discussants for the careful reading and insightful comments. In our rejoinder, we extend the discussion of how the assumptions of instrumented difference-in-differences (iDID) compare to the assumptions of the standard instrumental variable method. We also make additional comments on how iDID is related to the fuzzy DID. We highlight future research directions to enhance the utility of iDID, including extensions to adjust for covariate shift in two-sample iDID design, and generalization of iDID to multiple time points and a multi-valued instrumental variable for DID.

Prescriber Uncertainty as Opportunity to Improve Care of Type 2 Diabetes with Chronic Kidney Disease: Mixed Methods Study.

BACKGROUND: Over 5 million patients in the United States have type 2 diabetes mellitus (T2D) with chronic kidney disease (CKD); antidiabetic drug selection for this population is complex and has important implications for outcomes. OBJECTIVE: To better understand how providers choose antidiabetic drugs in T2D with CKD DESIGN: Mixed methods. Interviews with providers underwent qualitative analysis using grounded theory to identify themes related to antidiabetic drug prescribing. A provider survey used vignettes and direct questions to quantitatively assess prescribers' knowledge and preferences. A retrospective cohort analysis of real-world prescribing data assessed the external validity of the interview and survey findings. PARTICIPANTS: Primary care physicians, endocrinologists, nurse-practitioners, and physicians' assistants were eligible for interviews; primary care physicians and endocrinologists were eligible for the survey; prescribing data were derived from adult patients with serum creatinine data. MAIN MEASURES: Interviews were qualitative; for the survey and retrospective cohort, proportion of patients receiving metformin was the primary outcome. KEY RESULTS: Interviews with 9 providers identified a theme of uncertainty about guidelines for prescribing antidiabetic drugs in patients with T2D and CKD. The survey had 105 respondents: 74 primary care providers and 31 endocrinologists. Metformin was the most common choice for patients with T2D and CKD. Compared to primary care providers, endocrinologists were less likely to prescribe metformin at levels of kidney function at which it is contraindicated and more likely to correctly answer a question about metformin's contraindications (71% versus 41%) (p < .05). Real-world data were consistent with survey findings, and further showed low rates of use of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists (<10%) in patients with eGFR below 60 ml/min/1.73m2. CONCLUSIONS: Providers are unsure how to treat T2D with CKD and incompletely informed as to existing guidelines. This suggests opportunities to improve care.

Impact of the Affordable Care Act's Physician Payments Sunshine Act on branded statin prescribing.

OBJECTIVE: To evaluate the impact of the Affordable Care Act's Physician Payments Sunshine Act (PPSA), which mandates disclosure of industry payments to physicians, on physician prescribing of branded statins. DATA SOURCES: Administrative claims data from 2011 to 2015 from three large national commercial insurers were provided by the Health Care Cost Institute. STUDY DESIGN: We adopted a difference-in-differences and event study design, leveraging the control group of physicians in two states, MA and VT, which implemented state laws on disclosure of industry payments prior to the national PPSA. To further address potential confounding caused by differences in prescribing patterns across states, our analytical sample includes physicians practicing in border counties between the treatment (NH, NY, and RI) and control (MA and VT) states. DATA COLLECTION: We restricted our sample to physicians who had at least 50 new-fill prescription claims for statins during the five-year study period, with at least one new-fill prescription claim each year. PRINCIPAL FINDINGS: We found that the PPSA led to a 7% (p < 0.001) reduction in monthly new prescriptions of brand-name statin over the study period, with little change in generic prescribing. The reduction in branded prescriptions was concentrated among physicians with the highest tercile of drug spending pre-PPSA, with a decrease of 15% (p < 0.001) in new branded statin prescriptions. The decline was most prominent after mandated reporting of industry payments began before the payment data was published. CONCLUSIONS: The PPSA may have achieved its intended effect of reducing branded prescriptions at least in the short run, particularly among physicians most likely to have engaged in excessive or low-value prescribing of branded drugs.

Baseline haemoglobin A1c and the risk of COVID-19 hospitalization among patients with diabetes in the INSIGHT Clinical Research Network.

AIMS: To examine the association between baseline glucose control and risk of COVID-19 hospitalization and in-hospital death among patients with diabetes. METHODS: We performed a retrospective cohort study of adult patients in the INSIGHT Clinical Research Network with a diabetes diagnosis and haemoglobin A1c (HbA1c) measurement in the year prior to an index date of March 15, 2020. Patients were divided into four exposure groups based on their most recent HbA1c measurement (in mmol/mol): 39-46 (5.7%-6.4%), 48-57 (6.5%-7.4%), 58-85 (7.5%-9.9%), and ≥86 (10%). Time to COVID-19 hospitalization was compared in the four groups in a propensity score-weighted Cox proportional hazards model adjusting for potential confounders. Patients were followed until June 15, 2020. In-hospital death was examined as a secondary outcome. RESULTS: Of 168,803 patients who met inclusion criteria; 50,016 patients had baseline HbA1c 39-46 (5.7%-6.4%); 54,729 had HbA1c 48-57 (6.5-7.4%); 47,640 had HbA1c 58-85 (7.5^%-9.9%) and 16,418 had HbA1c ≥86 (10%). Compared with patients with HbA1c 48-57 (6.5%-7.4%), the risk of hospitalization was incrementally greater for those with HbA1c 58-85 (7.5%-9.9%) (adjusted hazard ratio [aHR] 1.19, 95% confidence interval [CI] 1.06-1.34) and HbA1c ≥86 (10%) (aHR 1.40, 95% CI 1.19-1.64). The risk of COVID-19 in-hospital death was increased only in patients with HbA1c 58-85 (7.5%-9.9%) (aHR 1.29, 95% CI 1.06, 1.61). CONCLUSIONS: Diabetes patients with high baseline HbA1c had a greater risk of COVID-19 hospitalization, although association between HbA1c and in-hospital death was less consistent. Preventive efforts for COVID-19 should be focused on diabetes patients with poor glucose control.

Characterization, management, and risk factors of hyperglycemia during PI3K or AKT inhibitor treatment.

PURPOSE: The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway controls insulin sensitivity and glucose metabolism. Hyperglycemia is one of the most common on-target adverse effects (AEs) of PI3K/AKT inhibitors. As several PI3K and AKT inhibitors are approved by the United States Food and Drug Administration or are being studied in clinical trials, characterizing this AE and developing a management strategy is essential. METHODS: Patients with hematologic or solid malignancies treated at Memorial Sloan Kettering Cancer Center with a PI3K or AKT inhibitor were included in this retrospective analysis. A search for patients experiencing hyperglycemia was performed. The frequency, management interventions and outcomes were characterized. RESULTS: Four hundred and ninety-one patients with 10 unique cancer types who received a PI3K or AKT inhibitor were included. Twelve percent of patients required a dose interruption, 6% of patients required a dose reduction and 2% of patients were hospitalized to manage hyperglycemia. No events occurred among patients receiving ß-, γ-, or δ- specific PI3K inhibitor. There was one case where the PI3K or AKT inhibitor was permanently discontinued due to hyperglycemia. Metformin was the most commonly used antidiabetic medication, followed by insulin, sodium-glucose transport protein 2 (SGLT2) inhibitors, and sulfonylurea. SGLT2 inhibitors were associated with the greatest reductions in blood sugar, followed by metformin. At least one case of euglycemic diabetic ketoacidosis (DKA) occurred in a patient on PI3K inhibitor and SGLT2 inhibitor. Body mass index ≥ 25 and HbA1c  ≥ 5.7 are were independently significant predictors of developing hyperglycemia. CONCLUSION: Hyperglycemia is one of the major on-target side effects of PI3K and AKT inhibitors. It is manageable with antidiabetic medications, treatment interruption and/or dose modification. We summarize pharmacological interventions that may be considered for PI3K/AKT inhibitor induced hyperglycemia. SGLT2-inhibitor may be a particularly effective second-line option after metformin but there is a low risk of euglycemic DKA, which can be deadly. To our knowledge, our report is the largest study of hyperglycemia in patients receiving PI3K/AKT inhibitors.