Annals of Internal Medicine Online First

Annals for the Ages: Annals of Internal Medicine Turns 90

Lundberg GD. — Tue, 04 Jul 2017 00:00:00 GMT

In July 2017, Annals of Internal Medicine celebrates 90 years of continuous publication. Recognizing the occasion, the editorialist provides reflections on the history and future of medical journals.

High Generic Drug Prices and Market Competition A Retrospective Cohort Study

Dave CV, Kesselheim AS, Fox ER, et al. — Tue, 04 Jul 2017 00:00:00 GMT

Background:

Prices for some generic drugs have increased in recent years, adversely affecting patients who rely on them.

Objective:

To determine the association between market competition levels and the change in generic drug prices in the United States.

Design:

Retrospective cohort study.

Setting:

Prescription claims from commercial health plans between 2008 and 2013.

Measurements:

The 5.5 years of data were divided into 11 study periods of 6 months each. The Herfindahl–Hirschman Index (HHI)—calculated by summing the squares of individual manufacturers' market shares, with higher values indicating a less competitive market—and average drug prices were estimated for the generic drugs in each period. The HHI value estimated in the baseline period (first half of 2008) was modeled as a fixed covariate. Models estimated price changes over time by level of competition, adjusting for drug shortages, market size, and dosage forms.

Results:

From 1.08 billion prescription claims, a cohort of 1120 generic drugs was identified. After adjustment, drugs with quadropoly (HHI value of 2500, indicating relatively high levels of competition), duopoly (HHI value of 5000), near-monopoly (HHI value of 8000), and monopoly (HHI value of 10 000) levels of baseline competition were associated with price changes of −31.7% (95% CI, −34.4% to −28.9%), −11.8% (CI, −18.6% to −4.4%), 20.1% (CI, 5.5% to 36.6%), and 47.4% (CI, 25.4% to 73.2%), respectively, over the study period.

Limitation:

Study findings may not be generalizable to drugs that became generic after 2008.

Conclusion:

Market competition levels were associated with a change in generic drug prices. Such measurements may be helpful in identifying older prescription drugs at higher risk for price change in the future.

Primary Funding Source:

None.

Increasing Incidence of Multiply Recurrent Clostridium difficile Infection in the United States A Cohort Study

Ma GK, Brensinger CM, Wu Q, et al. — Tue, 04 Jul 2017 00:00:00 GMT

Background:

Clostridium difficile infection (CDI), the most common health care–associated infection, often recurs. Fecal microbiota transplantation is increasingly used to treat multiply recurrent CDI (mrCDI).

Objective:

To determine whether the incidence of mrCDI is increasing in proportion to CDI and to identify risk factors for mrCDI.

Design:

Retrospective cohort study.

Setting:

United States.

Participants:

38 911 718 commercially insured patients in the OptumInsight Clinformatics Database, of whom 45 341 developed CDI.

Measurements:

Age- and sex-standardized incidence rates for CDI and mrCDI.

Results:

From 2001 to 2012, the annual incidence of CDI and mrCDI per 1000 person-years increased by 42.7% (from 0.4408 to 0.6289 case) and 188.8% (from 0.0107 to 0.0309 case), respectively. The increase in mrCDI incidence was independent of known risk factors for CDI. Those who developed mrCDI were older (median age, 56.0 vs. 49.0 years; adjusted odds ratio [aOR] per 10-year increase in age, 1.25 [95% CI, 1.21 to 1.29]) and were more likely to be female (63.8% vs. 58.7%; aOR, 1.24 [CI, 1.11 to 1.38]) and to have used antibiotics (72.3% vs. 58.8%; aOR, 1.79 [CI, 1.59 to 2.01]), proton-pump inhibitors (24.6% vs. 18.2%; aOR, 1.14 [CI, 1.01 to 1.29]), or corticosteroids (18.3% vs. 13.7%; aOR, 1.15 [CI, 1.00 to 1.32]) within 90 days of CDI diagnosis. Chronic kidney disease (10.4% vs. 5.6%; aOR, 1.49 [CI, 1.24 to 1.80]) and diagnosis in a nursing home (2.1% vs. 0.6%; aOR, 1.99 [CI, 1.34 to 2.93]) were also associated with increased risk for mrCDI.

Limitation:

The primary analyses included only commercially insured patients in the United States.

Conclusion:

Relative to CDI, mrCDI incidence has disproportionately increased, indicating a rising demand for mrCDI therapies.

Primary Funding Source:

National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Allergy and Infectious Diseases.

Fool Me Thrice: The Evolving Story of Multiply Recurrent Clostridium difficile Infection

Saini SD, Waljee AK. — Tue, 04 Jul 2017 00:00:00 GMT

Ma and colleagues report a retrospective cohort study to address gaps in our knowledge about multiply recurrent Clostridium difficile infection (mrCDI). The editorialists discuss the findings, the limitations of the study, and why a better understanding of the epidemiology of mrCDI is a critical first step toward developing a sound strategy to address this growing public health challenge.

The Association of Firearm Suicide With Mental Illness, Substance Use Conditions, and Previous Suicide Attempts

Boggs JM, Simon GE, Ahmedani BK, et al. — Tue, 04 Jul 2017 00:00:00 GMT

CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration

Cheng C, Wu T, Shang H, et al. — Tue, 27 Jun 2017 00:00:00 GMT

Chinese herbal medicine (CHM) formulas are the major components of traditional Chinese medicine (TCM) interventions. The general reporting quality of randomized controlled trials (RCTs) of CHM formulas is disappointing, although CONSORT (Consolidated Standards of Reporting Trials) Statement extensions for herbal medicinal interventions and acupuncture interventions are available. A group of TCM clinical experts, methodologists, epidemiologists, and editors has developed this CONSORT Extension for CHM Formulas (CONSORT-CHM Formulas 2017) through a comprehensive process, including publication of the draft version, solicitation of comments, revision, and finalization.The CONSORT 2010 Statement was extended by introducing the idea of TCM Pattern and the features of CHM formulas. One new checklist subitem, keywords, was added to facilitate indexing and data searching. Seven of the 25 CONSORT checklist items, namely title and abstract, background and objectives, participants, interventions, outcomes, generalizability, and interpretation, are now elaborated, and the explanation of harms specific to CHM formulas is revised. Illustrative examples and explanations are also provided. The group hopes that CONSORT-CHM Formulas 2017 can improve the reporting quality of RCTs of CHM formulas.

Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy A Systematic Review and Meta-analysis

Kołodziejczak M, Andreotti F, Kowalewski M, et al. — Tue, 27 Jun 2017 00:00:00 GMT

Background:

Implantable cardioverter-defibrillators (ICDs) have a role in preventing cardiac arrest in patients at risk for life-threatening ventricular arrhythmias.

Purpose:

To compare ICD therapy with conventional care for the primary prevention of death of various causes in adults with ischemic or nonischemic cardiomyopathy.

Data Sources:

MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, and EMBASE databases, as well as several Web sites, from 1 April 1976 through 31 March 2017.

Study Selection:

Randomized controlled trials, published in any language, comparing ICD therapy with conventional care and reporting mortality outcomes (all-cause, sudden, any cardiac, or noncardiac) in the primary prevention setting.

Data Extraction:

2 independent investigators extracted study data and assessed risk of bias.

Data Synthesis:

Included were 11 trials involving 8716 patients: 4 (1781 patients) addressed nonischemic cardiomyopathy, 6 (4414 patients) ischemic cardiomyopathy, and 1 (2521 patients) both types of cardiomyopathy. Mean follow-up was 3.2 years. An overall reduction in all-cause mortality, from 28.26% with conventional care to 21.37% with ICD therapy (hazard ratio [HR], 0.81 [95% CI, 0.70 to 0.94]; P = 0.043), was found. The magnitude of reduction was similar in the cohorts with nonischemic (HR, 0.81 [CI, 0.72 to 0.91]) and ischemic (HR, 0.82 [CI, 0.63 to 1.06]) disease, although the latter estimate did not reach statistical significance. The rate of sudden death fell from 12.15% with conventional care to 4.39% with ICD therapy (HR, 0.41 [CI, 0.30 to 0.56]), with a similar magnitude of reduction in patients with ischemic (HR, 0.39 [CI, 0.23 to 0.68]) and those with nonischemic disease (HR, 0.44 [CI, 0.17 to 1.12]). Noncardiac and any cardiac deaths did not differ significantly by treatment.

Limitation:

Heterogeneous timing of ICD placement; heterogeneous pharmacologic and resynchronization co-interventions; trials conducted in different eras; adverse events and complications not reviewed.

Conclusion:

Overall, primary prevention with ICD therapy versus conventional care reduced the incidence of sudden and all-cause death.

Primary Funding Source:

None.

Randomized Trials of Chinese Herbal Medicine: A New Extension of the CONSORT Statement

Linde K, Brinkhaus B. — Tue, 27 Jun 2017 00:00:00 GMT

This issue includes an extension of the CONSORT Statement that presents and explains recommendations for the better description of randomized trials of Chinese herbal medicine. The editorialists discuss the extension and how it will help to improve the quality, trustworthiness, and clinical relevance of trials of Chinese herbal therapies.

The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients A Pilot Randomized Trial

Vassy JL, Christensen KD, Schonman EF, et al. — Tue, 27 Jun 2017 00:00:00 GMT

Background:

Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase health care use without clinical value.

Objective:

To describe the effect on clinical care and outcomes of adding WGS to standardized family history assessment in primary care.

Design:

Pilot randomized trial. (ClinicalTrials.gov: NCT01736566)

Setting:

Academic primary care practices.

Participants:

9 primary care physicians (PCPs) and 100 generally healthy patients recruited at ages 40 to 65 years.

Intervention:

Patients were randomly assigned to receive a family history report alone (FH group) or in combination with an interpreted WGS report (FH + WGS group), which included monogenic disease risk (MDR) results (associated with Mendelian disorders), carrier variants, pharmacogenomic associations, and polygenic risk estimates for cardiometabolic traits. Each patient met with his or her PCP to discuss the report.

Measurements:

Clinical outcomes and health care use through 6 months were obtained from medical records and audio-recorded discussions between PCPs and patients. Patients' health behavior changes were surveyed 6 months after receiving results. A panel of clinician-geneticists rated the appropriateness of how PCPs managed MDR results.

Results:

Mean age was 55 years; 58% of patients were female. Eleven FH + WGS patients (22% [95% CI, 12% to 36%]) had new MDR results. Only 2 (4% [CI, 0.01% to 15%]) had evidence of the phenotypes predicted by an MDR result (fundus albipunctatus due to RDH5 and variegate porphyria due to PPOX). Primary care physicians recommended new clinical actions for 16% (CI, 8% to 30%) of FH patients and 34% (CI, 22% to 49%) of FH + WGS patients. Thirty percent (CI, 17% to 45%) and 41% (CI, 27% to 56%) of FH and FH + WGS patients, respectively, reported making a health behavior change after 6 months. Geneticists rated PCP management of 8 MDR results (73% [CI, 39% to 99%]) as appropriate and 2 results (18% [CI, 3% to 52%]) as inappropriate.

Limitation:

Limited sample size and ancestral and socioeconomic diversity.

Conclusion:

Adding WGS to primary care reveals new molecular findings of uncertain clinical utility. Nongeneticist providers may be able to manage WGS results appropriately, but WGS may prompt additional clinical actions of unclear value.

Primary Funding Source:

National Institutes of Health.

Benefits and Risks of Antithrombotic Therapy in Essential Thrombocythemia A Systematic Review

Chu DK, Hillis CM, Leong DP, et al. — Tue, 27 Jun 2017 00:00:00 GMT

Background:

Patients with essential thrombocythemia (ET) are at high risk for both thrombosis and hemorrhage.

Purpose:

To evaluate the risks and benefits of antithrombotic therapy in adults with ET.

Data Sources:

Multiple databases, including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, through 4 March 2017.

Study Selection:

Randomized and observational studies of antiplatelet or anticoagulant therapy, published in any language and reporting thrombotic or hemorrhagic events.

Data Extraction:

Two reviewers independently extracted data, assessed risk of bias, and graded certainty of evidence.

Data Synthesis:

No relevant randomized trials were identified. Twenty-four observational studies (18 comparative and 6 single-group) involving 6153 patients followed for 31 711 patient-years were reviewed; most were deemed to have high risk of bias. Most patients receiving antiplatelet therapy (3613 of 4527 [80%]) received low-dose aspirin (50 to 150 mg/d); 914 (20%) received high-dose aspirin (300 to 600 mg/d), dipyridamole, or other agents. Overall, findings were inconsistent and imprecise. The reported incidence rates of thrombosis, any bleeding, and major bleeding without antiplatelet therapy ranged from 5 to 110 (median, 20), from 3 to 39 (median, 8), and from 2 to 53 (median, 6) cases per 1000 patient-years, respectively. The reported relative risks for thrombosis, any bleeding, and major bleeding with antiplatelet therapy compared with none ranged from 0.26 to 3.48 (median, 0.74), from 0.48 to 11.04 (median, 1.95), and from 0.48 to 5.17 (median, 1.30), respectively. Certainty of evidence was rated low or very low for all outcomes.

Limitation:

No randomized trials, no extractable data on anticoagulants, lack of uniform bleeding definitions, and systematic reporting of outcomes.

Conclusion:

Available evidence about the risk–benefit ratio of antiplatelet therapy in adults with ET is highly uncertain.

Primary Funding Source:

Regional Medical Associates. (PROSPERO: CRD42015027051)

Whole-Genome Sequencing in Primary Care

Tue, 27 Jun 2017 00:00:00 GMT

Erosive Rheumatoid Arthritis After Bilateral Hand Transplantation

Adler BL, Albayda J, Shores JT, et al. — Tue, 27 Jun 2017 00:00:00 GMT

Are Antiplatelet Agents Beneficial in Essential Thrombocythemia? Maybe Yes, Probably No

Bennett JS. — Tue, 27 Jun 2017 00:00:00 GMT

Chu and colleagues report a systematic review to determine the benefits and risks of treating patients with essential thrombocythemia with antiplatelet agents. The editorialist discusses the uncertainty the review uncovers and the need for high-quality trials to definitively address this important clinical question.

CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration (Traditional Chinese Version)

Cheng C, Wu T, Shang H, et al. — Tue, 27 Jun 2017 00:00:00 GMT

This article is the traditional Chinese version of the CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration.

CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration (Simplified Chinese Version)

Cheng C, Wu T, Shang H, et al. — Tue, 27 Jun 2017 00:00:00 GMT

This article is the simplified Chinese version of the CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration.

Incorporating Whole-Genome Sequencing Into Primary Care: Falling Barriers and Next Steps

Manolio TA. — Tue, 27 Jun 2017 00:00:00 GMT

Vassy and colleagues report a pilot study of the effect of adding whole-genome sequencing (WGS) to a standardized family history assessment in primary care. The editorialist notes that the findings demonstrate that primary care physicians are capable of managing WGS findings, healthy patients tolerate this information well, and use and costs seem to increase. The unanswered question remains whether WGS will truly improve patient outcomes.

The Relationship of Health Insurance and Mortality: Is Lack of Insurance Deadly?

Woolhandler S, Himmelstein DU. — Tue, 27 Jun 2017 00:00:00 GMT

About 28 million Americans are currently uninsured, and millions more could lose coverage under policy reforms proposed in Congress. At the same time, a growing number of policy leaders have called for going beyond the Affordable Care Act to a single-payer national health insurance system that would cover every American. These policy debates lend particular salience to studies evaluating the health effects of insurance coverage. In 2002, an Institute of Medicine review concluded that lack of insurance increases mortality, but several relevant studies have appeared since that time. This article summarizes current evidence concerning the relationship of insurance and mortality. The evidence strengthens confidence in the Institute of Medicine's conclusion that health insurance saves lives: The odds of dying among the insured relative to the uninsured is 0.71 to 0.97.