Association Between Age and Low-Density Lipoprotein Cholesterol Response to Statins: A Danish Nationwide Cohort Study: Annals of Internal Medicine: Vol 176, No 8

Background: There is large patient-to-patient variability in the low-density lipoprotein cholesterol (LDL-C) response to statin treatment. The reduction in LDL-C may depend on the age of the patient treated—particularly in older adults, who have been substantially underrepresented in randomized controlled trials. Objective: To investigate the association between age and the LDL-C reduction by statins. Design: Nationwide, register-based cohort study. Setting: Denmark, 2008 to 2018. Participants: 82 958 simvastatin or atorvastatin initiators with LDL-C measurements before and during statin use. Measurements: Statin response, defined as percentage reduction in prestatin LDL-C level, and percentage reduction differences (PRDs) according to age and simvastatin or atorvastatin dose based on a longitudinal model for LDL-C. Results: Among 82 958 statin initiators, 10 388 (13%) were aged 75 years or older. With low- to moderate-intensity statins, initiators aged 75 years or older had greater mean LDL-C percentage reductions than initiators younger than 50 years—for example, 39.0% versus 33.8% for simvastatin, 20 mg, and 44.2% versus 40.2% for atorvastatin, 20 mg. The adjusted PRD for initiators aged 75 years compared with initiators aged 50 years was 2.62 percentage points. This association was consistent for primary prevention (2.54 percentage points) and secondary prevention (2.32 percentage points) but smaller for initiators of high-intensity statins (atorvastatin, 40 mg: 1.36 percentage points; atorvastatin, 80 mg: −0.58 percentage point). Limitation: Use of administrative data, observational pre–post comparison with a moderately high proportion of missing data, lack of information on body mass index, and the mainly White study population may limit generalizability. Conclusion: Low- to moderate-intensity statins were associated with a greater reduction in LDL-C levels in older persons than younger persons and may be more appealing as initial treatment in older adults who are at increased risk for adverse events. Primary Funding Source: The Independent Research Fund Denmark, Brødrene Hartmanns Fond, and Fonden til Lægevidenskabens Fremme.

Participant Recruitment From Low- and Middle-Income Countries for Pivotal Trials of Drugs Approved by the U.S. Food and Drug Administration: A Cross-Sectional Analysis: Annals of Internal Medicine: Vol 175, No 12

Background: Many participants in clinical trials supporting U.S. Food and Drug Administration (FDA) drug approvals are recruited from outside the United States, including from low- and middle-income countries (LMICs). Where participants are recruited for pivotal trials has implications for ethical research conduct and generalizability. Objective: To describe LMIC recruitment for pivotal trials of newly approved drugs for cancer, neurologic disease, and cardiovascular disease. Design: Cross-sectional analysis. Setting: Pivotal trials of new cancer, cardiovascular, and neurologic drugs approved from 2012 to 2019 matched to ClinicalTrials.gov, FDA records, and publications. Measurements: Host countries and available per country enrollments were extracted. The primary end point was the proportion of pivotal trials enrolling participants in LMICs. The secondary end point was the proportion of pivotal trial participants contributed by LMICs for each indication area. Results: Data were obtained from 66 new drugs and 144 pivotal clinical trials. All cardiovascular approvals (12 drugs, 29 trials) and neurologic approvals (26 drugs, 54 trials) were analyzed, as well as a random sample of cancer approvals (28 of 85 drugs [33%]) matched to their pivotal trials (61 of 210 trials [29%]). Among the trials, 56% in cancer, 79% in cardiovascular disease, and 56% in neurology recruited from an LMIC. For multicountry trials, country-level enrollment figures were not available for 71 trials (55%). For those reporting per country enrollment, the percentage of participants recruited from LMICs was 8% for cancer trials, 36% for cardiovascular trials, and 17% for neurology trials. Limitations: The study was limited to FDA-approved drugs in 3 areas, including a sample of cancer drugs. Pivotal trials of nonapproved drugs or drugs for other indications were not captured. Conclusion: Most pivotal trials for FDA-approved drugs recruit from LMICs. Publications and FDA documents generally do not provide country-level data on recruitment. Primary Funding Source: None.

Effect of Calorie-Unrestricted Low-Carbohydrate, High-Fat Diet Versus High-Carbohydrate, Low-Fat Diet on Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial: Annals of Internal Medicine: Vol 176, No 1

Background: It remains unclear if a low-carbohydrate, high-fat (LCHF) diet is a possible treatment strategy for type 2 diabetes mellitus (T2DM), and the effect on nonalcoholic fatty liver disease (NAFLD) has not been investigated. Objective: To investigate the effect of a calorie-unrestricted LCHF diet, with no intention of weight loss, on T2DM and NAFLD compared with a high-carbohydrate, low-fat (HCLF) diet. Design: 6-month randomized controlled trial with a 3-month follow-up. (ClinicalTrials.gov: NCT03068078) Setting: Odense University Hospital in Denmark from November 2016 until June 2020. Participants: 165 participants with T2DM. Intervention: Two calorie-unrestricted diets: LCHF diet with 50 to 60 energy percent (E%) fat, less than 20E% carbohydrates, and 25E% to 30E% proteins and HCLF diet with 50E% to 60E% carbohydrates, 20E% to 30E% fats, and 20E% to 25E% proteins. Measurements: Glycemic control, serum lipid levels, metabolic markers, and liver biopsies to assess NAFLD. Results: The mean age was 56 years (SD, 10), and 58% were women. Compared with the HCLF diet, participants on the LCHF diet had greater improvements in hemoglobin A1c (mean difference in change, −6.1 mmol/mol [95% CI, −9.2 to −3.0 mmol/mol] or −0.59% [CI, −0.87% to −0.30%]) and lost more weight (mean difference in change, −3.8 kg [CI, −6.2 to −1.4 kg]). Both groups had higher high-density lipoprotein cholesterol and lower triglycerides at 6 months. Changes in low-density lipoprotein cholesterol were less favorable in the LCHF diet group than in the HCLF diet group (mean difference in change, 0.37 mmol/L [CI, 0.17 to 0.58 mmol/L] or 14.3 mg/dL [CI, 6.6 to 22.4 mg/dL]). No statistically significant between-group changes were detected in the assessment of NAFLD. Changes were not sustained at the 9-month follow-up. Limitation: Open-label trial, self-reported adherence, unintended weight loss, and lack of adjustment for multiple comparisons. Conclusion: Persons with T2DM on a 6-month, calorie-unrestricted, LCHF diet had greater clinically meaningful improvements in glycemic control and weight compared with those on an HCLF diet, but the changes were not sustained 3 months after intervention. Primary Funding Source: Novo Nordisk Foundation.

Pain, Analgesic Use, and Patient Satisfaction With Spinal Versus General Anesthesia for Hip Fracture Surgery: A Randomized Clinical Trial: Annals of Internal Medicine: Vol 175, No 7

Background: The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported. Objective: To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia. Design: Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505) Setting: 46 U.S. and Canadian hospitals. Participants: Patients aged 50 years or older undergoing hip fracture surgery. Intervention: Spinal or general anesthesia. Measurements: Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care. Results: A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups. Limitation: Missing outcome data and multiple outcomes assessed. Conclusion: Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia. Primary Funding Source: Patient-Centered Outcomes Research Institute.

How Would You Treat This Patient With Acute and Chronic Pain From Sickle Cell Disease?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center: Annals of Internal Medicine: Vol 175, No 4

Sickle cell disease is prevalent in large numbers of patients in the United States and has a significant global impact. Its complications span numerous organs and lead to reduced life expectancy. Acute and chronic sickle cell pain is a common cause of patient suffering. The American Society of Hematology published updated guidelines on management of acute and chronic pain from sickle cell disease in 2019. Several of the recommendations are conditional and leave specific decisions to the treating physician. These include conditional recommendations about the use of ketamine for acute pain and the initiation and discontinuation of long-term opioid therapy for chronic pain. Here, 2 hematologists discuss these guidelines and make contrasting recommendations for the management of acute and chronic pain for a patient with sickle cell disease.

Telehealth for Substance Use Disorders: A Rapid Review for the 2021 U.S. Department of Veterans Affairs and U.S. Department of Defense Guidelines for Management of Substance Use Disorders

Background: Approximately 20.4 million Americans met criteria for a substance use disorder (SUD) in 2019; however, only about 12.2% of persons with an SUD receive specialty care. Telehealth offers alternatives to traditional forms of substance use treatment. Purpose: To synthesize recent findings on the efficacy of telehealth for SUDs. Data Sources: MEDLINE, Embase, PubMed, and the Cochrane Library from January 2015 through August 2021 (English language only). Study Selection: Randomized controlled trials (RCTs) of adults with a diagnosis of SUD based on the Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases. Data Extraction: One investigator abstracted data and assessed study quality, and a second checked for accuracy. Data Synthesis: This rapid review synthesized evidence from 17 RCTs. Evidence is very uncertain that telehealth provided as videoconference therapy (1 RCT) or web-based cognitive behavioral therapy (CBT) (3 RCTs) has similar effects to in-person therapy for improving abstinence from alcohol or cannabis. Low-strength evidence suggests that web-based CBT has similar effects for improving abstinence in multiple SUDs (2 RCTs). Low-strength evidence suggests that adding supportive text messaging to follow-up care improves abstinence and amount of alcohol per day (2 RCTs) but does not improve emergency department visits or frequency of consumption (2 RCTs). Enhanced telephone monitoring likely reduces readmissions for SUD detoxification compared with usual follow-up alone (1 RCT) but does not reduce days of substance use (low-strength evidence). Limitation: Narrative synthesis, heterogeneity of telehealth interventions, no assessment of publication bias, and study methodology. Conclusion: Evidence is very uncertain that telehealth is similar to in-person care for SUD outcomes. Limited evidence suggests some benefit of adding telehealth to usual SUD care. Primary Funding Source: U.S. Department of Veterans Affairs Veterans Health Administration.

Disparities in Dolutegravir Uptake Affecting Females of Reproductive Age With HIV in Low- and Middle-Income Countries After Initial Concerns About Teratogenicity: An Observational Study: Annals of Internal Medicine: Vol 175, No 1

Background: The transition to dolutegravir-containing antiretroviral therapy (ART) in low- and middle-income countries (LMICs) was complicated by an initial safety signal in May 2018 suggesting that exposure to dolutegravir at conception was possibly associated with infant neural tube defects. On the basis of additional evidence, in July 2019, the World Health Organization recommended dolutegravir for all adults and adolescents living with HIV. Objective: To describe dolutegravir uptake and disparities by sex and age group in LMICs. Design: Observational cohort study. Setting: 87 sites that began using dolutegravir in 11 LMICs in the Asia-Pacific; Caribbean, Central and South America network for HIV epidemiology (CCASAnet); and sub-Saharan African regions of the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. Patients: 134 672 patients aged 16 years or older who received HIV care from January 2017 through March 2020. Measurements: Sex, age group, and dolutegravir uptake (that is, newly initiating ART with dolutegravir or switching to dolutegravir from another regimen). Results: Differences in dolutegravir uptake among females of reproductive age (16 to 49 years) emerged after the safety signal. By the end of follow-up, the cumulative incidence of dolutegravir uptake among females 16 to 49 years old was 29.4% (95% CI, 29.0% to 29.7%) compared with 57.7% (CI, 57.2% to 58.3%) among males 16 to 49 years old. This disparity was greater in countries that began implementing dolutegravir before the safety signal and initially had highly restrictive policies versus countries with a later rollout. Dolutegravir uptake was similar among females and males aged 50 years or older. Limitation: Follow-up was limited to 6 to 8 months after international guidelines recommended expanding access to dolutegravir. Conclusion: Substantial disparities in dolutegravir uptake affecting females of reproductive age through early 2020 are documented. Although this disparity was anticipated because of country-level restrictions on access, the results highlight its extent and initial persistence. Primary Funding Source: National Institutes of Health.

The “Black Fungus” in India: The Emerging Syndemic of COVID-19–Associated Mucormycosis

Resistance Testing for Management of HIV Virologic Failure in Sub-Saharan Africa: An Unblinded Randomized Controlled Trial: Annals of Internal Medicine: Vol 174, No 12

Background: Virologic failure in HIV predicts the development of drug resistance and mortality. Genotypic resistance testing (GRT), which is the standard of care after virologic failure in high-income settings, is rarely implemented in sub-Saharan Africa. Objective: To estimate the effectiveness of GRT for improving virologic suppression rates among people with HIV in sub-Saharan Africa for whom first-line therapy fails. Design: Pragmatic, unblinded, randomized controlled trial. (ClinicalTrials.gov: NCT02787499) Setting: Ambulatory HIV clinics in the public sector in Uganda and South Africa. Patients: Adults receiving first-line antiretroviral therapy with a recent HIV RNA viral load of 1000 copies/mL or higher. Intervention: Participants were randomly assigned to receive standard of care (SOC), including adherence counseling sessions and repeated viral load testing, or immediate GRT. Measurements: The primary outcome of interest was achievement of an HIV RNA viral load below 200 copies/mL 9 months after enrollment. Results: The trial enrolled 840 persons, divided equally between countries. Approximately half (51%) were women. Most (72%) were receiving a regimen of tenofovir, emtricitabine, and efavirenz at enrollment. The rate of virologic suppression did not differ 9 months after enrollment between the GRT group (63% [263 of 417]) and SOC group (61% [256 of 423]; odds ratio [OR], 1.11 [95% CI, 0.83 to 1.49]; P = 0.46). Among participants with persistent failure (HIV RNA viral load ≥1000 copies/mL) at 9 months, the prevalence of drug resistance was higher in the SOC group (76% [78 of 103] vs. 59% [48 of 82]; OR, 2.30 [CI, 1.22 to 4.35]; P = 0.014). Other secondary outcomes, including 9-month survival and retention in care, were similar between groups. Limitation: Participants were receiving nonnucleoside reverse transcriptase inhibitor–based therapy at enrollment, limiting the generalizability of the findings. Conclusion: The addition of GRT to routine care after first-line virologic failure in Uganda and South Africa did not improve rates of resuppression. Primary Funding Source: The President's Emergency Plan for AIDS Relief and the National Institute of Allergy and Infectious Diseases.

Evaluation and Management After Acute Left-Sided Colonic Diverticulitis: A Systematic Review: Annals of Internal Medicine: Vol 175, No 3

Background: The value of interventions used after acute colonic diverticulitis is unclear. Purpose: To evaluate postdiverticulitis colonoscopy and interventions to prevent recurrent diverticulitis. Data Sources: MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase, CINAHL, and ClinicalTrials.gov from 1 January 1990 through 16 November 2020. Study Selection: Comparative studies of interventions of interest reporting critical or important outcomes, and larger single-group studies to evaluate prevalence of colonoscopy findings and harms. Data Extraction: 6 researchers extracted study data and risk of bias. The team assessed strength of evidence. Data Synthesis: 19 studies evaluated colonoscopy. Risk for prevalent colorectal cancer (CRC) compared with the general population is unclear. Based on low-strength evidence, long-term CRC diagnosis is similar with or without colonoscopy. High-strength evidence indicates that risk for prevalent CRC is higher among patients with complicated diverticulitis and colonoscopy complications are rare. Based on high-strength evidence, mesalamine does not reduce recurrence risk (6 randomized controlled trials [RCTs]). Evidence on other nonsurgical interventions is insufficient. For patients with prior complicated or smoldering or frequently recurrent diverticulitis, elective surgery is associated with reduced recurrence (3 studies; high strength). In 19 studies, serious surgical complications were uncommon. Limitations: Few RCTs provided evidence. Heterogeneity of treatment effect was not adequately assessed. Conclusion: It is unclear whether patients with recent acute diverticulitis are at increased risk for prevalent CRC, but those with complicated diverticulitis are at increased risk. Mesalamine is ineffective in preventing recurrence; other nonsurgical treatments have inadequate evidence. Elective surgery reduces recurrence in patients with prior complicated or smoldering or frequently recurrent diverticulitis, but it is unclear which of these patients may benefit most. Primary Funding Source: Agency for Healthcare Research and Quality and American College of Physicians. (PROSPERO: CRD42020151246)