Industry Payments to US Physicians by Specialty and Product Type.

This study examines the distribution of payments within and across specialties and the medical products associated with the largest total payments.

Re-Analyses of 8 Historical Trials in Cardiovascular Medicine Assessing Multimorbidity Burden and Its Association with Treatment Response.

OBJECTIVE: The purpose of this study was to examine the multimorbidity burden of clinical trial participants and assess its association with treatment response. METHODS: We conducted a reanalysis of patient level data. There were 29,954 participants from 8 clinical trials containing 11 comparisons between an intervention and control condition. Patients were classified by Charlson Comorbidity Index (CCI) score. The primary outcomes were the primary study endpoints as originally specified for each trial. A Cox model that included the CCI score groups, the randomized group, and their interaction, was used to compare the primary outcome between randomized groups. The interaction term between randomized group and comorbidity index allowed the treatment effect to differ by level of comorbidity index and comprised the primary effect of interest. Hazard ratios and risk differences were reported for all comparisons. RESULTS: The mean CCI scores of trial populations ranged from 2.1 to 3.9 points, and the percentage of patients with scores ≥5 from 3% to 39%. Tests of interaction terms in models yielded P values ≤ .10 for 4/11 comparisons and ≤ .05 for 2/11 comparisons. In 3 additional comparisons, potentially important treatment variation on an absolute scale was observed despite interaction tests with P values > .10 on the relative scale. CONCLUSIONS: These trials were mainly composed of patient populations with CCI scores ≤4. Despite this, biologically plausible treatment interactions were commonly suggested. These results are hypothesis generating; confirmation of results would require larger studies or studies targeted specifically toward patients with higher levels of multimorbidity.

What Counts as a Surrogate Decision?

When patients lose decision-making capacity, others must make surrogate decisions on their behalf. What counts as a surrogate decision might seem self-evident. But as clinician-researchers in the field of advance care planning, we have found that it is not always so clear-cut. In this paper, we describe how and why this is a matter of concern, a novel approach for assessing whether a surrogate decision occurred, and findings from this assessment.

Controversies in Hypertension V: Resistant and Refractory Hypertension.

Apparent resistant hypertension, defined as uncontrolled office blood pressure despite ≥ 3 antihypertensive medications including a diuretic or use of ≥ 4 medications regardless of blood pressure, occurs in ≤ 15% of treated hypertensives. Apparent refractory hypertension, defined as uncontrolled office pressure despite use of 5 or more medications including a diuretic, occurs in ≤ 10% of resistant cases. Both are associated with increased comorbidity and enhanced cardiovascular risk. To rule out pseudo-resistant or pseudo-refractory hypertension, employ guideline-based methodology for obtaining pressure, maximize the regimen, rule out white-coat effect, and assess adherence. True resistant hypertension is characterized by volume overload and aldosterone excess, refractory by enhanced sympathetic tone. Spironolactone is the preferred agent for resistance, with lower doses. Spironolactone, potassium binders, or both, are preferred if the estimated glomerular filtration rate is below 45. If significant albuminuria, finerenone is indicated. The optimal treatment of refractory hypertension is unclear, but sympathetic inhibition (α-ß blockade, centrally acting sympathoinhibitors, or both) seems reasonable. Renal denervation has shown minimal benefit for resistance, but its role in refractory hypertension remains to be defined.

Student Perceptions of a New Course Using Argumentation in Medical Education.

Purpose: Critical thinking and the ability to engage with others of differing views in a civil manner is essential to the practice of medicine. A new format for medical student education ("Argue-to-Learn") that uses staged debates followed by small group discussions was introduced into the curriculum of first year medical school at the Penn State College of Medicine. The goal was to create a structured environment for spirited, civil discourse, and to encourage students to think critically about clinically controversial topics. This manuscript describes the development of the program, and presents comparative data on student perceptions of the first two mandatory sessions that focused on the treatment of post-menopausal osteoporosis and on COVID-19 vaccine mandates. Methods: Quantitative results were gathered from standardized post-block student surveys for each session and compared to cumulative results of all other courses included in the learning block. Post-block surveys of students include four session-evaluation questions scored on a 5 point Likert scale. Scores were compared using Student's t-test. Thematic analysis of qualitative data was performed on a single open-ended response from the same survey. Results: Compared to all other courses in the learning block, scores on each of the four questions were either the same or numerically higher for the Argue-to-Learn sessions, but none reached statistical significance. Two important qualitative themes were identified. First, students enjoyed the format, found it interesting and engaging and want more similar sessions. Second, students appreciated hearing opposing viewpoints and presenting their own viewpoints in a safe and supportive environment. Conclusion: These findings support evidence from educational scholarship outside of medicine showing argumentation as a learning tool is well received by students. Further work is needed to determine whether it improves critical thinking skills and enhances learning in medical education.

Controversies in Hypertension IV: Renal Denervation.

Renal denervation is not a cure for hypertension. Although more recent sham-controlled trials were positive, a significant minority of patients in each trial were unresponsive. The optimal patient or patients need to be defined. Combined systolic/diastolic hypertension appears more responsive than isolated systolic hypertension. It remains uncertain whether patients with comorbidities associated with higher adrenergic tone should be targeted, including obesity, diabetes, sleep apnea, and chronic kidney disease. No biomarker can adequately predict response. A key to a successful response is the adequacy of denervation, which currently cannot be assessed in real time. It is uncertain what is the optimal denervation methodology: radiofrequency, ultrasound, or ethanol injection. Radiofrequency requires targeting the distal main renal artery plus major branches and accessory arteries. Although denervation appears to be safe, conclusive data on quality of life, improved target organ damage, and reduced cardiovascular events/mortality are required before denervation can be generally recommended.

A systematic review and meta-analysis of all sham and placebo controlled trials for resistant hypertension.

INTRODUCTION: There is a lack of consensus regarding the best add on therapy for treatment of resistant hypertension (RH). This is likely secondary to a paucity of data on the comparative effectiveness of proposed therapies for RH. METHODS: Placebo-controlled and sham-controlled randomized clinical trials testing therapies for the treatment of RH were included in this meta-analysis. Therapies with two or more studies were included as subgroups in this meta-analysis. The primary outcomes being tested were 24-hr systolic blood pressure (SBP) and office SBP. RESULTS: Eight studies were identified that tested mineralocorticoid receptor antagonist (MRA) including 1,414 participants. The raw mean difference (RMD) between MRA and placebo control was statistically significant for 24-hour SBP (-10.56 mmHg; 95% confidence interval (CI) -12.82 to -8.30), 24-hour diastolic (DBP) (-5.48 mmHg; 95% CI -8.48 to -2.58), office SBP (-11.97 mmHg; 95% CI -16.41 to -7.54), and office DBP (-4.14 mmHg; 95% CI -5.62 to -2.65). Six studies were identified that tested renal denervation (RD) including 989 participants. The RMD between RD and sham control was not statistically significant for 24-hour SBP (-1.84 mmHg; 95% CI -3.92 to 0.24), 24-hour DBP (-0.66 mmHg; 95% CI -1.85 to 0.54), office SBP (-1.57 mmHg; 95% CI -6.04 to 2.89), and office DBP (-1.49 mmHg; 95% CI -3.52 to 0.55). Four studies were identified that tested endothelin receptor antagonists (ERA) including 1,193 participants. The raw mean difference (RMD) between ERA and placebo control was statistically significant for 24-hr systolic (SBP) (-7.02 mmHg; 95% CI -9.15 to -4.90, 24-hr diastolic (DBP) (-6.22 mmHg; 95% CI -7.61 to -4.82), office SBP (-5.84 mmHg; 95% CI -10.08 to -1.60), and office DBP (-3.73 mmHg; 95% CI -5.87 to -1.59). DISCUSSION: MRA lowers BP in patients with RH more than RD, which seems to have little to no effect in RH. ERAs lead to a statistically significant reduction in BP but the confidence in efficacy is limited due to the low number of studies and differences in trial population. Individual factors and their impact on treatment response in RH should be investigated in future research.

Controversies in Hypertension III: Dipping, Nocturnal Hypertension, and the Morning Surge.

A comprehensive approach to hypertension requires out-of-office determinations by home or ambulatory monitoring. The 4 phenotypes comparing office and out-of-office pressures in treated and untreated patients include normotension, hypertension, white-coat phenomena, and masked phenomena. Components of out-of-office pressure may be equally as important as mean values. Nighttime pressures are normally 10%-20% lower than daytime (normal "dipping") pressures. Abnormalities include dipping more than 20% (extreme dippers), less than 10 % (nondippers), or rising above daytime (risers) and have been associated with elevated cardiovascular risk. Nighttime pressure may be elevated (nocturnal hypertension) in isolation or together with daytime hypertension. Isolated nocturnal hypertension theoretically changes white-coat hypertension to true hypertension and normotension to masked hypertension. Pressure normally peaks in the morning hours ("morning surge") when cardiovascular events are most common. Morning hypertension may result from residual nocturnal hypertension or an exaggerated surge and has been associated with enhanced cardiovascular risk, especially in Asian populations. Randomized trials are needed to determine whether altering therapy based solely on either abnormal dipping, isolated nocturnal hypertension, or an abnormal surge is justified.

A Subgroup Meta-Analysis Comparing the Renal Denervation Sham-Controlled Randomized Trials Among Those With Resistant and Nonresistant Hypertension.

Renal denervation (RD) has been investigated as an invasive blood pressure (BP) lowering treatment for hypertension (HTN). Resistant HTN (RHTN) has been defined as uncontrolled BP despite use of 3 antihypertensive medications of different classes, including a diuretic, at maximum tolerated doses. The impact of RD on RHTN remains under investigation. Ten sham-controlled trials testing RD were included in this trial-level analysis. A prespecified subgroup analysis was conducted to test whether efficacy of RD differed in patients with and without RHTN. The primary end points were change in 24-hour ambulatory systolic (SBP) and diastolic (DBP) using raw mean difference (RMD) between sham control and RD. Ten studies (6 RHTN and 4 nonresistant HTN) were identified that included 1,544 participants (1,001 RHTN and 543 essential HTN) with cumulative mean age (±SD) of 57 years (±3). Cochran risk of bias assessment showed 69% of the domains to be at low risk of bias. The RMD for 24-hour SBP between RD and sham control was statistically significant for nonresistant HTN trials (-4.19 mm Hg; 95% confidence interval [CI] -6.07 to -2.30) but was not statistically significant for RHTN trials (-1.86 mm Hg; 95% CI - 3.89 to 0.16). Despite the numerical difference in the subgroups, the interaction between subgroups failed to reach statistical significance (p = 0.10). The RMD for 24-hour DBP between RD and sham control was statistically significant for nonresistant HTN trials (-2.60 mm Hg; 95% CI -3.79 to -1.42) but was not statistically significant for RHTN trials (-0.67 mm Hg; 95% CI -1.84 to 0.50). The interaction between subgroups was statistically significant (p = 0.02). Our analysis indicates RD is a less effective intervention for patients with RHTN. These data may be beneficial for clinicians to consider when assessing patients with RHTN for RD.

Denosumab versus Bisphosphonates for Reducing Fractures in Postmenopausal Women with Osteoporosis: A Meta-Analysis.

BACKGROUND: There are multiple classes of pharmacologic agents approved for treatment of osteoporosis, but their costs vary widely, and systematic data on their efficacy compared with the traditional standard, bisphosphonates, for reducing fractures in postmenopausal women are lacking. The objective was to perform a systematic review and meta-analysis assessing the efficacy of denosumab compared with bisphosphonates. METHODS: Researchers selected randomized controlled trials (RCTs) comparing denosumab to bisphosphonates that included information on clinical and/or osteoporotic fracture events over the follow-up period. Each clinical outcome was meta-analyzed using a fixed-effects analysis, with clinical and osteoporotic fractures as the outcomes of interest. A meta-regression was performed using change in bone mineral density (BMD) as the moderator variable. RESULTS: Seven RCTs were included. Denosumab was not associated with a reduction in clinical or osteoporotic fractures compared with bisphosphonates. There was no association between the change in BMD with denosumab and bisphosphonates and denosumab's effect on both osteoporotic and clinical fractures. DISCUSSION: Existing data do not support the use of the more expensive denosumab as a first-line agent over bisphosphonates for reduction of fractures in postmenopausal women with osteoporosis. One limitation in this study was each RCT was not individually powered for fracture incidences.

A systematic review, meta-analysis, and meta regression of the sham controlled renal denervation randomized controlled trials.

Renal denervation (RD) has been investigated as a novel blood pressure (BP) lowering treatment for hypertension. The primary objective of this meta-analysis was to assess the efficacy of RD and factors that may associate with treatment effect heterogeneity. The primary outcomes were raw mean differences (RMD) in 24-hour ambulatory, daytime ambulatory, nighttime, and office systolic BP (SBP) and diastolic BP (DBP) between sham control and RD. A prespecified subgroup analysis was performed comparing studies with follow-up less than versus greater than 4 months. If inter-study heterogeneity was found for any of the above outcomes, additional analyses were performed to assess potential moderator variables. Ten sham-controlled randomized trials were identified and included 1,544 participants, followed for a mean of 4.20 months. RD was associated with a statistically significant reduction in all SBP and DBP measures except for nighttime SBP (-2.64 mmHg; 95% confidence interval (CI) -5.84 to 0.56, p = 0.11) and nighttime DBP (- 1.21 mmHg; 95% CI -3.17 to 0.75, p = 0.23). Mild to moderate inter-study heterogeneity was identified for three outcomes (office SBP and nighttime SBP and DBP). Studies that followed patients for longer than 4 months had numerically lower reductions in most BP outcomes; however, there were no statistically significant interactions between subgroups. Compared to a sham procedure, RD was associated with statistically significant reductions in most measures of SBP and DBP that were within bounds of what would be expected from standard blood pressure lowering medications.

Beta-blocker use in patients with chronic obstructive pulmonary disease: A systematic review: A systematic review of ßB in COPD.

Beta-blockers (ßB) are a frequently used class of medications. Although ßB have many indications, those related to cardiovascular disease are among the most common and important. However, in patients with chronic obstructive pulmonary disease (COPD), ßB are used less often due to concerns about an unfavorable impact on respiratory morbidity and mortality. We performed a systematic review to assess the safety of ßB in patients with COPD. We included a total of 2 randomized controlled trials and 28 observational studies. The majority found statistically significant reductions in mortality. The two higher quality observational studies reported increased mortality with ßB. The risk of COPD exacerbations was reduced in about half of the studies. Nonetheless, there were significant biases that confounded the results. The highest quality RCT found a significant increase in severe and very severe COPD exacerbations with ßB use. In conclusion, data on the safety of ßB in patients with COPD are conflicting. However, given higher quality evidence showed harm with their use, ßB should be prescribed with caution in patients with COPD, including patients with cardiac indication for ßB.

Intrinsic Traits Such as Personality and Decision-Making Style are Predictive of Stress in Surrogate Decision-Makers.

Introduction: Despite its prominence in psychology, little is known about how personality traits play a role in the stress experiences of surrogate decision-makers. We tested the hypothesis that intrinsic traits (personality and decision-making styles) would be related to surrogates' stress in order to learn whether screening or tailoring interventions based on personality traits could help support surrogate decision-makers. Methods: This pre-specified secondary analysis evaluated data from an interventional study with dyads of patients with advanced chronic illness and their spokespersons. Measures included stress after decision-making or patient death (Impact of Events-Revised), personality (Big Five Index; BFI) and decision-making style (maximization and regret scales). Multivariate linear regressions explored the impact of personality on the stress experience; linear regressions independently modeled the impact of maximization and regret on the stress experience. Results: Of 38 spokespersons, 89.5% were women, 97.4% non-Hispanic, and 29.0% had a college degree or higher. In univariate analyses, total stress was correlated with neuroticism (r = .56, P < .01), higher scores on the regret (r = .55, P < .01) and maximization (r = .48, P < .05). In adjusted models, BFI was significantly associated with total stress (R2 = 27.08, P = .02). However, only neuroticism was independently associated with total stress. Conclusions: Personality traits, particularly neuroticism, and decision-making styles predicted heightened stress in spokespersons of patients with advanced chronic illness. If ACP interventions are intended to reduce spokesperson stress, personality and decision-making style scales may help identify spokespersons most likely to benefit from ACP interventions.

Association between statin exposure and diabetes incidence among privately-insured patients before and after applying a novel technique to control for selection bias.

INTRODUCTION: The association between statins and incident diabetes mellitus (DM) in observational studies is much larger than that reported from randomized controlled trials. We sought to assess this association using a novel design controlling for selection bias. METHODS: Using data from MarketScan, we identified a cohort of non-diabetic patients who initiated a statin and matched them to patients not taking statins. From the statin-user cohort, we identified two subgroups: patients who received statin refills for >6 months (continuers) and patients who received statin refills <6 months (discontinuers). Patients were followed for a minimum of two years to determine incident DM. RESULTS: We included 442,526 patients, divided equally between statin users and non-users. Statin use was associated with increased DM (9.9% vs. 4.4%, HR 2.2, p < 0.001). Among the 221,263 statin users, there were 194,357 continuers and 26,906 discontinuers. There was no significant difference in the incidence rate of DM between both groups (10.0% vs. 9.3%, HR 1.03, p = 0.22). CONCLUSIONS: Statin use was strongly associated with incident diabetes when users were compared to non-users but not when continuers were compared to discontinuers. Selection bias confounds the association between statin use and incident diabetes in observational studies.

Conceptualization of Surrogate Decision-making Among Spokespersons for Chronically Ill Patients.

Importance: The value of advance care planning (ACP) has been the subject of recent debate because of mixed findings. This may be, in part, because trials presume that researchers and patient spokespersons share the same understanding of the role of a surrogate decision-maker. We explored how patient surrogates conceptualized and defined surrogate decision-making vs patient advocacy. Understanding how surrogates perceive their role in decision-making is important to avoid misinterpreting the effectiveness of ACP interventions. Objective: To understand how patient spokespersons distinguish surrogate decision-making from patient advocacy. Design, Setting, and Participants: This qualitative thematic analysis of a subsample of participants from a randomized clinical trial at a tertiary medical center was conducted from September 27, 2012, to June 30, 2021. Participants (n = 36) were the designated spokespersons of adult patients with severe illness who had made a surrogate decision on behalf of the patient since the last follow-up. Analysis was performed from March 21, 2021, to February 7, 2022. Main Outcomes and Measures: Semistructured interviews examined how patient spokespersons conceptualize differences between surrogate decision-making and advocacy. Results: The study included 36 patient spokespersons (32 women [88.9%]; mean [SD] age, 62.1 [11.8] years) and found substantial variability in how the spokespersons conceptualized what it means to make a surrogate decision for another. A total of 10 spokespersons (27.8%) did not distinguish surrogate decision-making from advocacy. There were 5 definitions for both surrogate decision-making and advocacy. The 3 most common definitions of surrogate decision-making were (1) acting as the final decision-maker (18 [50.0%]), (2) doing what is best for the patient (8 [22.2%]), and (3) making decisions on behalf of patients so that their wishes are respected (6 [16.7%]). The 3 most common definitions of advocacy were (1) doing what is best for the patient (8 [22.2%]), (2) respecting patients' wishes (6 [16.7%]), and (3) providing support to the patient (6 [16.7%]). The most common pairing of definitions by an individual spokesperson involved defining surrogate decision-making as being the final decision-maker, and defining advocacy as acting in the best interest of the patient (6 [16.7%]). Conclusions and Relevance: This qualitative study found that many spokespersons perceive their roles as surrogate decision-makers differently than clinicians and researchers likely do, often conflating surrogacy with advocacy. These findings may help explain why researchers have found that ACP does not consistently improve traditional outcomes. If spokespersons do not distinguish surrogate decision-making from advocacy, then what is being reported by spokespersons and measured by clinicians and researchers may not accurately reflect the true association of ACP with outcomes.

Controversies in Hypertension II: The Optimal Target Blood Pressure.

The optimal target blood pressure in the treatment of hypertension is undefined. Whether more intense therapy is better than standard, typically <140/90 mm Hg, is controversial. The most recent American guidelines recommend ≤130/80 mm Hg for essentially all adults. There have been at least 28 trials targeting more versus less intensive therapy, including 13 aimed at reducing cardiovascular events and mortality, 11 restricted to patients with chronic kidney disease, and 4 with surrogate endpoints. We review these trials in a narrative fashion due to significant heterogeneity in targets chosen, populations studied, and primary endpoints. Most were negative, although some showed significant benefit to more intense therapy. When determining the optimal pressure for an individual patient, additional factors should be considered, including age, frailty, polypharmacy, baseline blood pressure, and the diastolic blood pressure J-curve. We discuss these modifying factors in detail. Whereas the tenet "lower is better" is generally true, one size does not fit all, and blood pressure control must be individualized.

Controversies in Hypertension I: The Optimal Assessment of Blood Pressure Load and Implications for Treatment.

The most important factor in treating hypertension is assessing an individual patient's true blood pressure load, the cornerstone being research-grade office determination. Office blood pressure should be supplemented with out-of-office measurement, including home and ambulatory monitoring (if available), which we consider complementary and not interchangeable. Controversy remains for initiation of treatment of white coat hypertension, where cardiovascular risk lies between normotension and sustained hypertension; antihypertensive therapy should be considered unless low cardiovascular risk, wherein pressures should be followed for progression to sustained hypertension. Available data do not support intensification of therapy for the white coat effect due to the similar cardiovascular risk to controlled hypertension. Given the higher cardiovascular risk of the masked effect, initiation of therapy for masked hypertension and intensification for masked uncontrolled hypertension are indicated, acknowledging the dearth of supporting data. Optimally, randomized controlled trials are needed to determine the benefit of treating the 4 incongruous phenotypes between office and out-of-office measurements, that is, those with white coat or masked effects. We make no recommendations regarding chronotherapy pending results of ongoing trials.

Assessment of Comorbidity Burden and Treatment Response: Reanalysis of the SCD-HEFT Trial.

INTRODUCTION: Comorbidity burden may be associated with treatment-effect heterogeneity (HTE) in clinical trials, which could alter the interpretation or clinical translation of results for many patients in the real world. OBJECTIVE: In this analysis, we sought to determine the distribution of multimorbidity scores in patients enrolled in SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) and tested the association between comorbidity burden and treatment efficacy for the outcome of all-cause death. METHODS: Each patient was assigned a modified Charlson Comorbidity Index (mCCI) score from 1 to 14 based on available enrollment data. We investigated the relationship between mCCI score and time to all-cause death using Cox proportional hazards models. Models were fit for quartiles of the comorbidity index, reference coding was used, with quartile 1 (Q1; mCCI score of 1-2) selected as the reference. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were reported from these models. Following the same analysis framework as the original manuscript, patients assigned to amiodarone or implantable cardioverter-defibrillator (ICD) were compared with those assigned to placebo in separate Cox models. Each model included the mCCI score in quartiles, group assignment, and an interaction term for the quartile and group assignment. HRs and corresponding 97.5% CIs were reported from these models. RESULTS: The majority of patients had an mCCI score ≤5 (75.4%), and mortality risk was associated with increasing score. The HRs for Q2 (score 3), Q3 (scores 4-5), and Q4 (scores ≥6) were 1.46 (97.5% CI 1.06-1.99), 3.03 (97.5% CI 2.35-3.90), and 4.51 (97.5% CI 3.46-5.88), respectively. For the subgroup analysis, amiodarone was not associated with a significant difference compared with placebo for individuals in Q1-Q3; however, it was associated with an increase in death for those in Q4 (HR 1.50; 97.5% CI 1.03-2.18). ICD was associated with a significant reduction in death compared with placebo for individuals in Q1 and Q3 (HR 0.42; 97.5% CI 0.20-0.84 and HR 0.70; 97.5% CI 0.50-0.97, respectively) but not for those in Q2 or Q4. Interaction testing across subgroups suggested HTE for amiodarone (p = 0.07) and ICD (p = 0.08) versus placebo across mCCI quartiles. CONCLUSIONS: Increasing comorbidity burden was associated with HTE when evaluating amiodarone and ICD compared with placebo in the SCD-HeFT trial. Our results highlight the importance of enrolling diverse patient populations in clinical trials and considering the possibility of HTE when translating results to clinical practice.