Annals of Internal Medicine Current Issue

Clinical Outcomes With Rivaroxaban in Patients Transitioned From Vitamin K Antagonist Therapy A Subgroup Analysis of a Randomized Trial

Mahaffey KW, Wojdyla D, Hankey GJ, et al. — Tue, 18 Jun 2013 00:00:00 GMT

Chinese translation

Background:

In ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), a large randomized, clinical trial, rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation.

Objective:

To determine the efficacy and safety of rivaroxaban compared with warfarin among vitamin K antagonist (VKA)–naive and VKA-experienced patients.

Design:

Prespecified subgroup analysis. (ClinicalTrials.gov: NCT00403767)

Setting:

Global.

Patients:

14 264 persons with atrial fibrillation.

Measurements:

Interaction of the relative treatment effect of rivaroxaban and warfarin on stroke or systemic embolism among VKA-naive and VKA-experienced patients.

Results:

Overall, 7897 (55.4%) patients were VKA-experienced and 6367 (44.6%) were VKA-naive. The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent: Rates per 100 patient-years of follow-up were 2.32 versus 2.87 for VKA-naive patients (hazard ratio [HR], 0.81 [95% CI, 0.64 to 1.03]) and 1.98 versus 2.09 for VKA-experienced patients (HR, 0.94 [CI, 0.75 to 1.18]; interaction P = 0.36). During the first 7 days, rivaroxaban was associated with more bleeding than warfarin (HR in VKA-naive patients, 5.83 [CI, 3.25 to 10.44], and in VKA-experienced patients, 6.66 [CI, 3.83 to 11.58]; interaction P = 0.53). After 30 days, rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients (HR, 0.84 [CI, 0.74 to 0.95]) and similar bleeding in VKA-experienced patients (HR, 1.06 [CI, 0.96 to 1.17]; interaction P = 0.003).

Limitation:

The trial was not designed to detect differences in these subgroups.

Conclusion:

The efficacy of rivaroxaban in VKA-experienced and VKA-naive patients was similar to that of the overall trial. There were more bleeding events within 7 days of study drug initiation with rivaroxaban, but after 30 days, rivaroxaban was associated with less bleeding in VKA-naive patients and similar bleeding in VKA-experienced patients. This information may be useful to clinicians considering a transition to rivaroxaban for patients receiving VKA therapy.

Primary Funding Source:

Johnson & Johnson and Bayer HealthCare.

Observation Versus Initial Treatment for Men With Localized, Low-Risk Prostate Cancer A Cost-Effectiveness Analysis

Hayes JH, Ollendorf DA, Pearson SD, et al. — Tue, 18 Jun 2013 00:00:00 GMT

Chinese translation

Background:

Observation is underutilized among men with localized, low-risk prostate cancer.

Objective:

To assess the costs and benefits of observation versus initial treatment.

Design:

Decision analysis simulating treatment or observation.

Data Sources:

Medicare schedules, published literature.

Target Population:

Men aged 65 and 75 years who had newly diagnosed low-risk prostate cancer (prostate-specific antigen level <10 µg/L, stage ≤T2a, Gleason score ≤3 + 3).

Time Horizon:

Lifetime.

Perspective:

Societal.

Intervention:

Treatment (brachytherapy, intensity-modulated radiation therapy, or radical prostatectomy) or observation (active surveillance [AS] or watchful waiting [WW]).

Outcome Measures:

Quality-adjusted life expectancy and costs.

Results of Base-Case Analysis:

Observation was more effective and less costly than initial treatment. Compared with AS, WW provided 2 additional months of quality-adjusted life expectancy (9.02 vs. 8.85 years) at a savings of $15 374 ($24 520 vs. $39 894) in men aged 65 years and 2 additional months (6.14 vs. 5.98 years) at a savings of $11 746 ($18 302 vs. $30 048) in men aged 75 years. Brachytherapy was the most effective and least expensive initial treatment.

Results of Sensitivity Analysis:

Treatment became more effective than observation when it led to more dramatic reductions in prostate cancer death (hazard ratio, 0.47 vs. WW and 0.64 vs. AS). Active surveillance became as effective as WW in men aged 65 years when the probability of progressing to treatment on AS decreased below 63% or when the quality of life with AS versus WW was 4% higher in men aged 65 years or 1% higher in men aged 75 years. Watchful waiting remained least expensive in all analyses.

Limitation:

Results depend on outcomes reported in the published literature, which is limited.

Conclusion:

Among these men, observation is more effective and costs less than initial treatment, and WW is most effective and least expensive under a wide range of clinical scenarios.

Primary Funding Source:

National Cancer Institute, U.S. Department of Defense, Prostate Cancer Foundation, and Institute for Clinical and Economic Review.

Statin Toxicity From Macrolide Antibiotic Coprescription A Population-Based Cohort Study

Patel AM, Shariff S, Bailey DG, et al. — Tue, 18 Jun 2013 00:00:00 GMT

Chinese translation

Background:

Clarithromycin and erythromycin, but not azithromycin, inhibit cytochrome P450 isoenzyme 3A4 (CYP3A4), and inhibition increases blood concentrations of statins that are metabolized by CYP3A4.

Objective:

To measure the frequency of statin toxicity after coprescription of a statin with clarithromycin or erythromycin.

Design:

Population-based cohort study.

Setting:

Ontario, Canada, from 2003 to 2010.

Patients:

Continuous statin users older than 65 years who were prescribed clarithromycin (n = 72 591) or erythromycin (n = 3267) compared with those prescribed azithromycin (n = 68 478).

Measurements:

The primary outcome was hospitalization with rhabdomyolysis within 30 days of the antibiotic prescription.

Results:

Atorvastatin was the most commonly prescribed statin (73%) followed by simvastatin and lovastatin. Compared with azithromycin, coprescription of a statin with clarithromycin or erythromycin was associated with a higher risk for hospitalization with rhabdomyolysis (absolute risk increase, 0.02% [95% CI, 0.01% to 0.03%]; relative risk [RR], 2.17 [CI, 1.04 to 4.53]) or with acute kidney injury (absolute risk increase, 1.26% [CI, 0.58% to 1.95%]; RR, 1.78 [CI, 1.49 to 2.14]) and for all-cause mortality (absolute risk increase, 0.25% [CI, 0.17% to 0.33%]; RR, 1.56 [CI, 1.36 to 1.80]).

Limitations:

Only older adults were included in the study. The absolute risk increase for rhabdomyolysis may be underestimated because the codes used to identify it were insensitive.

Conclusion:

In older adults, coprescription of clarithromycin or erythromycin with a statin that is metabolized by CYP3A4 increases the risk for statin toxicity.

Primary Funding Source:

Academic Medical Organization of Southwestern Ontario.

Effectiveness and Harms of Recombinant Human Bone Morphogenetic Protein-2 in Spine Fusion A Systematic Review and Meta-analysis

Fu R, Selph S, McDonagh M, et al. — Tue, 18 Jun 2013 00:00:00 GMT

Background:

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used as a bone graft substitute in spinal fusion, which unites (fuses) bones in the spine. The accuracy and completeness of journal publications of industry-sponsored trials on the effectiveness and harms of rhBMP-2 has been called into question.

Purpose:

To independently assess the effectiveness and harms of rhBMP-2 in spinal fusion and reporting bias in industry-sponsored journal publications.

Data Sources:

Individual-patient data (IPD) from 17 industry-sponsored studies; related internal documents; and searches of MEDLINE (1996 to August 2012), other databases, and reference lists.

Study Selection:

Randomized, controlled trials (RCTs) and cohort studies of rhBMP-2 versus any control and uncontrolled studies of harms.

Data Extraction:

Effectiveness outcomes in IPD were recalculated using consistent definitions. Study characteristics and results were abstracted by 1 investigator and confirmed by another. Two investigators independently assessed quality using predefined criteria.

Data Synthesis:

Thirteen RCTs and 31 cohort studies were included. For lumbar spine fusion, rhBMP-2 and iliac crest bone graft were similar in overall success, fusion, and other effectiveness measures and in risk for any adverse event, although rates were high across interventions (77% to 93% at 24 months from surgery). For anterior lumbar interbody fusion, rhBMP-2 was associated with nonsignificantly increased risk for retrograde ejaculation and urogenital problems. For anterior cervical spine fusion, rhBMP-2 was associated with increased risk for wound complications and dysphagia. At 24 months, the cancer risk was increased with rhBMP-2 (risk ratio, 3.45 [95% CI, 1.98 to 6.00]), but event rates were low and cancer was heterogeneous. Early journal publications misrepresented the effectiveness and harms through selective reporting, duplicate publication, and underreporting.

Limitations:

Outcome assessment was not blinded, and ascertainment of harms in trials was poor. No trials were truly independent of industry sponsorship.

Conclusion:

In spinal fusion, rhBMP-2 has no proven clinical advantage over bone graft and may be associated with important harms, making it difficult to identify clear indications for rhBMP-2. Earlier disclosure of all relevant data would have better informed clinicians and the public than the initial published trial reports did.

Primary Funding Source:

Yale University and Medtronic.

Safety and Effectiveness of Recombinant Human Bone Morphogenetic Protein-2 for Spinal Fusion A Meta-analysis of Individual-Participant Data

Simmonds MC, Brown JE, Heirs MK, et al. — Tue, 18 Jun 2013 00:00:00 GMT

Background:

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used to promote fusion in spinal surgery, but its safety has been questioned.

Purpose:

To evaluate the effectiveness and safety of rhBMP-2.

Data Sources:

Individual-participant data obtained from the sponsor or investigators and data extracted from study publications identified by systematic bibliographic searches through June 2012.

Study Selection:

Randomized, controlled trials of rhBMP-2 versus iliac crest bone graft (ICBG) in spinal fusion surgery for degenerative disc disease and related conditions and observational studies in similar populations for investigation of adverse events.

Data Extraction:

Individual-participant data from 11 eligible of 17 provided trials sponsored by Medtronic (Minneapolis, Minnesota) (n = 1302) and 1 of 2 other eligible trials (n = 106) were included. Additional aggregate adverse event data were extracted from 35 published observational studies.

Data Synthesis:

Primary outcomes were pain (assessed with the Oswestry Disability Index [ODI] or Short Form-36), fusion, and adverse events. At 24 months, ODI scores were 3.5% lower (better) with rhBMP-2 than with ICBG (95% CI, 0.5% to 6.5%) and radiographic fusion was 12% higher (CI, 2% to 23%). At or shortly after surgery, pain was more common with rhBMP-2 (odds ratio, 1.78 [CI, 1.06 to 2.95]). Cancer was more common after rhBMP-2 (relative risk, 1.98 [CI, 0.86 to 4.54]), but the small number of events precluded definite conclusions.

Limitation:

The observational studies were diverse and at risk of bias.

Conclusion:

At 24 months, rhBMP-2 increases fusion rates, reduces pain by a clinically insignificant amount, and increases early postsurgical pain compared with ICBG. Evidence of increased cancer incidence is inconclusive.

Primary Funding Source:

Yale University Open Data Access Project.

Update in Rheumatology: Evidence Published in 2012

Deodhar A. — Tue, 18 Jun 2013 00:00:00 GMT

This Update summarizes studies published in 2012 that the authors consider highly relevant to the practice of rheumatology. Topics include treatment of rheumatologic disease, pharmacoepidemiology, diagnostic testing, and new practice guidelines.

What Is Our Plan for Acute Unscheduled Care?

Kocher KE, Asplin BR. — Tue, 18 Jun 2013 00:00:00 GMT

The fundamental question of where patients with acute care needs should go for unscheduled care is left inadequately answered in the debate over health care reform. This commentary discusses the burden of and an ideal system for acute unscheduled care.

A Historic Moment for Open Science: The Yale University Open Data Access Project and Medtronic

Krumholz HM, Ross JS, Gross CP, et al. — Tue, 18 Jun 2013 00:00:00 GMT

Two systematic reviews on rhBMP-2 in this issue are based on patient-level data from all clinical trials conducted by Medtronic, which were shared through the YODA Project—an unprecedented step in data sharing. The editorialists, all affiliated with the project, discuss how the Medtronic proposal unfolded and hope that it contributes to a cultural shift in thinking about data sharing.

Closing in on the Truth About Recombinant Human Bone Morphogenetic Protein-2: Evidence Synthesis, Data Sharing, Peer Review, and Reproducible Research

Laine C, Guallar E, Mulrow C, et al. — Tue, 18 Jun 2013 00:00:00 GMT

This issue includes 2 systematic reviews that use the same data to address the same question: Compared with iliac crest bone grafting, does rhBMP-2 safely improve outcomes of spinal fusion surgery? The Editors discuss how these reviews spotlight the power of evidence synthesis, data sharing, peer review, and reproducible research.

Meta-analysis of Trials of Recombinant Human Bone Morphogenetic Protein-2: What Should Spine Surgeons and Their Patients Do With This Information?

Resnick D, Bozic KJ. — Tue, 18 Jun 2013 00:00:00 GMT

There has been considerable controversy surrounding the promotion and use of rhBMP-2 for spinal fusion. In this issue, 2 meta-analyses based on patient-level trial data examine the benefits and harms associated with rhBMP-2. The editorialists discuss how these findings should guide clinical decision making and future research to define the role of rhBMP-2 in spinal surgery.

The Changing Structure of Industry-Sponsored Clinical Research: Pioneering Data Sharing and Transparency

Kuntz RE. — Tue, 18 Jun 2013 00:00:00 GMT

The 2 reviews in this issue on rhBMP-2 analyzed patient-level data from Medtronic-sponsored clinical trials. The editorialist, from Medtronic, discusses the data-sharing experience with the YODA project and why he believes that more open research is critical to achieve balanced inferences that most benefit patients and society.

Jitterbug

Cohen LG. — Tue, 18 Jun 2013 00:00:00 GMT

The rhythmic beat of once-familiar swing music jogged my memory. Was it “One O'Clock Jump” or “Cottontail”? I know I'd heard it before, many times long ago. Suddenly I remembered a patient, Gladys Spink, and smiled. It all came back.

Chlorthalidone Versus Hydrochlorothiazide

Dhalla IA, Mamdani MM, Juurlink DN. — Tue, 18 Jun 2013 00:00:00 GMT

Chlorthalidone Versus Hydrochlorothiazide

Einhorn PT, Cushman WC, Whelton PK, et al. — Tue, 18 Jun 2013 00:00:00 GMT

Chlorthalidone Versus Hydrochlorothiazide

Donzelli A. — Tue, 18 Jun 2013 00:00:00 GMT

Chlorthalidone Versus Hydrochlorothiazide

Badgett RG. — Tue, 18 Jun 2013 00:00:00 GMT

Chlorthalidone Versus Hydrochlorothiazide

DiNicolantonio JJ, O'Keefe JH, Lavie CJ. — Tue, 18 Jun 2013 00:00:00 GMT

Chlorthalidone Versus Hydrochlorothiazide

Roush GC, Holford TR, Guddati AK. — Tue, 18 Jun 2013 00:00:00 GMT

Illness in Returned Travelers

Leder K, Libman MD, Sotir MJ. — Tue, 18 Jun 2013 00:00:00 GMT

Illness in Returned Travelers

Blanc PD. — Tue, 18 Jun 2013 00:00:00 GMT

Adding aspirin to clopidogrel worsened outcomes in PCI patients receiving oral anticoagulants

Brott BC. — Tue, 18 Jun 2013 00:00:00 GMT

Adding Na/K citrate to standard hydration reduced CIN in patients having coronary angiography

Coca S. — Tue, 18 Jun 2013 00:00:00 GMT

Automated reminders and increasing intense support increased uptake of colorectal cancer screening

Fletcher RH. — Tue, 18 Jun 2013 00:00:00 GMT

Cangrelor reduced ischemic PCI complications more than clopidogrel without increasing severe bleeding

Riezebos RK, Verheugt FA. — Tue, 18 Jun 2013 00:00:00 GMT

Mediterranean diets reduced cardiovascular events more than a low-fat diet in high-risk persons

Glasziou P. — Tue, 18 Jun 2013 00:00:00 GMT

Ramipril improved walking times and QOL in peripheral artery disease and intermittent claudication

Jaar BG. — Tue, 18 Jun 2013 00:00:00 GMT

Review: Acute geriatric unit care reduces falls, delirium, and functional decline

Tinetti M. — Tue, 18 Jun 2013 00:00:00 GMT

Review: Case management does not reduce unplanned hospital admissions compared with usual care in older persons

Hirsch C. — Tue, 18 Jun 2013 00:00:00 GMT

Review: Hydroxyethyl starch increases mortality and acute kidney injury in critically ill patients

Myburgh J. — Tue, 18 Jun 2013 00:00:00 GMT

Review: Inhaled medications vary substantively in their effects on mortality in COPD

Shafazand S. — Tue, 18 Jun 2013 00:00:00 GMT

Review: Vitamin and antioxidant supplements do not prevent adverse cardiovascular events

Rembold CM. — Tue, 18 Jun 2013 00:00:00 GMT

Use of SSRIs during pregnancy was not associated with increased risk for stillbirth or neonatal mortality

Budenholzer B. — Tue, 18 Jun 2013 00:00:00 GMT

Rivaroxaban in Patients Transitioned From Vitamin K Antagonist Therapy

Tue, 18 Jun 2013 00:00:00 GMT