Assessing the use of observational methods and real-world data to emulate ongoing randomized controlled trials.

BACKGROUND/AIMS: There has been growing interest in better understanding the potential of observational research methods in medical product evaluation and regulatory decision-making. Previously, we used linked claims and electronic health record data to emulate two ongoing randomized controlled trials, characterizing the populations and results of each randomized controlled trial prior to publication of its results. Here, our objective was to compare the populations and results from the emulated trials with those of the now-published randomized controlled trials. METHODS: This study compared participants' demographic and clinical characteristics and study results between the emulated trials, which used structured data from OptumLabs Data Warehouse, and the published PRONOUNCE and GRADE trials. First, we examined the feasibility of implementing the baseline participant characteristics included in the published PRONOUNCE and GRADE trials' using real-world data and classified each variable as ascertainable, partially ascertainable, or not ascertainable. Second, we compared the emulated trials and published randomized controlled trials for baseline patient characteristics (concordance determined using standardized mean differences <0.20) and results of the primary and secondary endpoints (concordance determined by direction of effect estimates and statistical significance). RESULTS: The PRONOUNCE trial enrolled 544 participants, and the emulated trial included 2226 propensity score-matched participants. In the PRONOUNCE trial publication, one of the 32 baseline participant characteristics was listed as an exclusion criterion on ClinicalTrials.gov but was ultimately not used. Among the remaining 31 characteristics, 9 (29.0%) were ascertainable, 11 (35.5%) were partially ascertainable, and 10 (32.2%) were not ascertainable using structured data from OptumLabs. For one additional variable, the PRONOUNCE trial did not provide sufficient detail to allow its ascertainment. Of the nine variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 6 (66.7%). The primary endpoint of time from randomization to the first major adverse cardiovascular event and secondary endpoints of nonfatal myocardial infarction and stroke were concordant between the emulated trial and published randomized controlled trial. The GRADE trial enrolled 5047 participants, and the emulated trial included 7540 participants. In the GRADE trial publication, 8 of 34 (23.5%) baseline participant characteristics were ascertainable, 14 (41.2%) were partially ascertainable, and 11 (32.4%) were not ascertainable using structured data from OptumLabs. For one variable, the GRADE trial did not provide sufficient detail to allow for ascertainment. Of the eight variables that were ascertainable, values in the emulated trial and published randomized controlled trial were discordant for 4 (50.0%). The primary endpoint of time to hemoglobin A1c ≥7.0% was mostly concordant between the emulated trial and the published randomized controlled trial. CONCLUSION: Despite challenges, observational methods and real-world data can be leveraged in certain important situations for a more timely evaluation of drug effectiveness and safety in more diverse and representative patient populations.

Emulating the GRADE trial using real world data: retrospective comparative effectiveness study.

OBJECTIVE: To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A1c (HbA1c). DESIGN: Observational study. SETTING: OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019. PARTICIPANTS: Adults with type 2 diabetes and HbA1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine. MAIN OUTCOME MEASURES: The primary outcome was time to HbA1c ≥7.0%. Secondary outcomes were time to HbA1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression. RESULTS: 8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes. CONCLUSIONS: In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.

Heart Failure Population with Therapeutic Response to Sacubitril/Valsartan, Spironolactone and Candesartan: FDA Perspective.

Sacubitril/valsartan was approved by the Food and Drug Administration in 2015 to reduce the risk of cardiovascular death and hospitalization for heart failure (HHF) in patients with chronic heart failure with reduced ejection fraction defined as left ventricular ejection fraction (LVEF) ≤ 40%. This approval was based on PARADIGM-HF trial. Subsequently, PARAGON-HF was conducted to support a claim for sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF), defined as LVEF ≥ 45%. PARAGON-HF failed to meet the pre-defined threshold for statistical significance for the primary composite endpoint. However, analysis of the primary endpoint by LVEF as a continuous variable demonstrated that sacubitril/valsartan was efficacious in patients with mildly abnormal LVEF similar to patients with LVEF ≤ 40% evaluated in PARADIGM-HF. This led to a broader indication for sacubitril/valsartan-"to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat." This article describes the rationale for a revised indication for sacubitril/valsartan, emphasizes the need to go beyond a dichotomous classification of HF based on a traditional LVEF cut-off and clarifies that the product label for sacubitril/valsartan does not refer to HFpEF.

Risk of Covid-19-Related Hospitalization and More Severe Outcomes in Medicare Beneficiaries Treated with Renin-Angiotensin-Aldosterone System Inhibitors for Hypertension.

BACKGROUND: There are theoretical concerns that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could increase the risk of severe Covid-19. OBJECTIVE: To determine if ACEIs and ARBs are associated with an increased risk of Covid-19 hospitalization overall, or hospitalization involving intensive care unit (ICU) admission, invasive mechanical ventilation, or death. DESIGN: Observational case-control study. PARTICIPANTS: Medicare beneficiaries aged ≥ 66 years with hypertension, treated with ACEIs, ARBs, calcium channel blockers (CCBs), or thiazide diuretics. MAIN MEASURES: Adjusted odds ratios (OR) and 95% confidence intervals (CI) for the outcomes of Covid-19 hospitalization, or hospitalization involving ICU admission, invasive mechanical ventilation, or death. RESULTS: A total of 35,300 cases of hospitalized Covid-19 were matched to 228,228 controls on calendar date and neighborhood of residence. The median age of cases was 79 years, 57.4% were female, and the median duration of hospitalization was 8 days (interquartile range 5-12). ACEIs and ARBs were associated with a slight reduction in Covid-19 hospitalization risk compared with treatment with other first-line antihypertensives (OR for ACEIs 0.95, 95% CI 0.92-0.98; OR for ARBs 0.94, 95% CI 0.90-0.97). Similar results were obtained for hospitalizations involving ICU admission, invasive mechanical ventilation, or death. There were no meaningful differences in risk for ACEIs compared with ARBs. In an analysis restricted to monotherapy with a first-line agent, CCBs were associated with a small increased risk of Covid-19 hospitalization compared with ACEIs (OR 1.09, 95% CI 1.04-1.14), ARBs (OR 1.10, 95% CI 1.05-1.15), or thiazide diuretics (OR 1.11, 95% CI 1.03-1.19). CONCLUSIONS: ACEIs and ARBs were not associated with an increased risk of Covid-19 hospitalization or with hospitalization involving ICU admission, invasive mechanical ventilation, or death. The finding of a small increased risk of Covid-19 hospitalization with CCBs was unexpected and could be due to residual confounding.

Real-world Cardiovascular Outcomes Associated With Degarelix vs Leuprolide for Prostate Cancer Treatment.

Importance: With a growing interest in the use of real-world evidence for regulatory decision-making, it is important to understand whether real-world data can be used to emulate the results of randomized clinical trials. Objective: To use electronic health record and administrative claims data to emulate the ongoing PRONOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease). Design, Setting, and Participants: This retrospective, propensity-matched cohort study included adult men with a diagnosis of prostate cancer and cardiovascular disease who initiated either degarelix or leuprolide between December 24, 2008, and June 30, 2019. Participants were commercially insured individuals and Medicare Advantage beneficiaries included in a large US administrative claims database. Exposures: Degarelix or leuprolide. Main Outcomes and Measures: The primary end point was time to first occurrence of a major adverse cardiovascular event (MACE), defined as death due to any cause, myocardial infarction, or stroke, analogous to the PRONOUNCE trial. Secondary end points were time to death due to any cause, myocardial infarction, stroke, and angina. Cox proportional hazards regression was used to evaluate primary and secondary end points. Results: A total of 32 172 men initiated degarelix or leuprolide for prostate cancer; of them, 9490 (29.5%) had cardiovascular disease, and 7800 (24.2%) met the PRONOUNCE trial eligibility criteria and were included in this study. Overall, 165 participants (2.1%) were Asian, 1390 (17.8%) were Black, 663 (8.5%) were Hispanic, and 5258 (67.4%) were White. The mean (SD) age was 74.4 (7.4) years. Among 2226 propensity score-matched patients, no significant difference was observed in the risk of MACE for patients taking degarelix vs those taking leuprolide (10.18 vs 8.60 events per 100 person-years; hazard ratio [HR], 1.18; 95% CI, 0.86-1.61). Degarelix was associated with a higher risk of death from any cause (HR, 1.48; 95% CI, 1.01-2.18) but not of myocardial infarction (HR, 1.16; 95% CI, 0.60-2.25), stroke (HR, 0.92; 95% CI, 0.45-1.85), or angina (HR, 1.36; 95% CI, 0.43-4.27). Conclusions and Relevance: In this emulation of a clinical trial of men with cardiovascular disease undergoing treatment for prostate cancer, degarelix was not associated with a lower risk of cardiovascular events than leuprolide. Comparison of these data with PRONOUNCE trial results, when published, will help enhance our understanding of the appropriate role of using real-world data to emulate clinical trials.

Characteristics and resolution of hypertension in obese African American bariatric cohort.

Weight reduction continues to be first-line therapy in the treatment of hypertension (HTN). However, the long-term effect of bariatric malabsorptive surgical techniques such as Roux-en-Y Gastric Bypass (RYGB) surgery in the management of hypertension (HTN) is less clear. African Americans (AA) are disproportionately affected by obesity and hypertension and have inconsistent outcomes after bariatric surgery (BS). Despite a plethora of bariatric literature, data about characteristics of a predominantly AA bariatric hypertensive cohort including hypertension in obese (HIO) are scarce and underreported. The aims of this study were, (1) to describe the preoperative clinical characteristics of HIO with respect to HTN status and age, and (2) to identify predictors of HTN resolution one year after RYGB surgery in an AA bariatric cohort enrolled at the Howard University Center for Wellness and Weight Loss Surgery (HUCWWS). In the review of 169 AA bariatric patients, the average BMI was 48.50 kg/m2 and the average age was 43.86 years. Obese hypertensive patients were older (46 years vs. 37.89 years; p < .0001); had higher prevalence of diabetes mellitus (DM, 43.09% vs. 10.87%; p < .0001) and dyslipidemia (38.2% vs. 13.04%; p 0.002). Hypertensive AA who were taking ≥ 2 antihypertensive medications prior to RYGB were 18 times less likely to experience HTN resolution compared to hypertensive AA taking 0-1 medications, who showed full or partial response. Also, HIO was less likely to resolve after RYGB surgery in patients who needed ≥ 2 antihypertensive medications prior to surgical intervention.

An Invasive Case of Left-Sided Endocarditis Caused by Pseudomonas aeruginosa in a Patient with History of Intravenous Drug Abuse.

Infective endocarditis, caused by Pseudomonas aeruginosa, is rarely seen in clinical practice. It has been reported mainly in intravenous drug abusers (IVDA). We present a case of a 63-year-old male who presented with abdominal pain and fever. Computed tomography (CT) abdomen showed splenic and renal infarct. The blood culture grew Pseudomonas aeruginosa. A transthoracic echocardiogram showed aortic insufficiency with 13 mm mobile vegetation. The patient was started on ceftazidime and tobramycin and, later on, surgery was done for aortic valve replacement. His stay was complicated by multiple hemorrhagic emboli in the brain. This case highlights the importance of the early diagnosis and management of infective endocarditis caused by Pseudomonas aeruginosa.