Primecuts – This Week In The Journals

July 16, 2012

By Mark Adelman, MD

Faculty Peer Reviewed

The U.S House of Representatives voted for the 33rd time last Wednesday to repeal the Affordable Care Act, a largely symbolic move as the prior 32 companion bills were never passed by the Senate.[1] With the realities of roughly 50 million uninsured Americans[2] and healthcare spending accounting for nearly 18% of the US GDP[3] in mind, let us review some recent publications that may improve both clinical care and runaway healthcare spending.

In an online-first publication by the Annals of Internal Medicine,[4] Smith reports on a curriculum designed by a collaboration between the Alliance of Academic Internal Medicine and the American College of Physicians, “to incorporate the principles of high-value, cost-conscious care into residency training.” Noting that medical education has historically lacked specific training in the stewardship of healthcare resources, this curriculum development committee created a series of lectures and small group activities designed to be incorporated into pre-existing resident education sessions (e.g. noon conferences and morning reports). The goal of such a curriculum is to get residents more accustomed to considering the “benefits, harms, and costs of a test or intervention as well as use of evidence-based, shared decision making.”

While some may argue that the role of the physician is to advocate for each individual patient, and so a consideration of cost should not factor into one’s clinical decision-making, I believe that cost-consciousness merely acknowledges the unavoidable fact that healthcare spending in the US is on an unsustainable trajectory. This AAIM-ACP collaboration should be commended for their recognition of a traditionally weak spot in medical education and a proposed solution that will hopefully contribute to improved care for patients nationwide in the future.

The most recent print edition of Annals includes a clinical practice guideline on packed red blood cell (PRBC) transfusion developed by the AABB (formerly known as the American Association of Blood Banks).[5] The guideline makes four major recommendations related to the use of PRBC transfusion in hospitalized, hemodynamically stable patients with anemia. Recommendation #1 is that a restrictive transfusion strategy, i.e. hemoglobin level <7 g/dL, be used for adult and pediatric ICU patients. Of note, this is the only recommendation deemed to have high-quality evidence and thus the strength of the recommendation is “strong.” Recommendation #2 also advocates for adhering to a restrictive transfusion strategy for patients with pre-existing cardiovascular disease, with a transfusion threshold of 8 g/dL in the presence of symptoms (defined as chest pain, orthostatic hypotension or tachycardia unresponsive to fluid resuscitation, or congestive heart failure). The quality of the evidence for this recommendation was moderate, making the strength of the recommendation “weak.” The AABB was unable to recommend a liberal or restrictive transfusion strategy for patients with acute coronary syndrome (recommendation #3), noting that the systematic review that preceded the development of the guideline did not identify any randomized, controlled trials (RCTs) that address this question. Recommendation #4 is that transfusion decisions be influenced by patient symptoms and not just hemoglobin concentrations. However, this is another weak recommendation based on low quality evidence, with only one identified RCT that incorporated symptoms into the decision to transfuse. Therefore, the recommendation appears to be based more on expert opinion and “conventional wisdom, based on physiologic reasoning….” The guideline authors state that if restrictive transfusion strategies were widely implemented, exposure of patients to PRBC transfusions would decrease by an average of approximately 40%. This seems like a worthy goal given the risk of complications associated with blood transfusions and the substantial resources consumed by the estimated 15 million yearly PRBC transfusions in the US.

Most women who suffer from urinary tract infections (UTIs) have likely been advised to try cranberry juice as a treatment or prophylactic measure at some point in their lives, whether by a physician, friend or family member. Wang and colleagues conducted a systematic review and meta-analysis, published in the Archives of Internal Medicine,[6] examining the evidence for the use of cranberry-containing products for the prevention of UTIs. The authors note that UTIs are a common diagnosis, with an estimated 7 million office visits, 1 million ER visits and 100,000 hospitalizations yearly in the US, with a total cost of $1.6 billion. Analyzing 10 studies with a total of nearly 1500 subjects, the authors calculated an overall relative risk of UTI in cranberry users vs. non-cranberry users of 0.62 (95% CI, 0.49-0.80). However, the studies were fairly heterogeneous (I2=43%), with much variability in populations studied, method and dose of cranberry administration and even definition of UTI. This means that the results should be interpreted with caution and further studies are warranted. However, given that cranberry consumption is a very low risk and inexpensive intervention, it seems reasonable to recommend its use for the prevention of UTIs with the caveat that its effectiveness is by no means entirely proven.

Much has been published on the possible interaction between Plavix and proton pump inhibitors (PPIs), with conflicting evidence as to whether there is a clinically relevant increase in cardiovascular events that can be attributed to a pharmacokinetic interaction between these two agents that are both metabolized by CYP2C19. A group of UK researchers led by Douglas conducted an observational study published online by BMJ that attempted to address this issue.[7] Their publication consisted of two studies with different designs; the first was a traditional cohort study but the second was a self controlled case series. The authors explain that a self controlled case series is essentially a case-control study that uses each case as its own control. In this study, incidence rate ratios for the primary outcome of composite all-cause mortality or incident MI were calculated by comparing event rates during periods of time that patients were taking both Plavix and a PPI(case period) to periods of time in which they were taking Plavix but not a PPI (control period).

In the cohort study, the adjusted hazard ratio was 1.37 (95%CI 1.27-1.48), suggesting that there is an association between Plavix-PPI co-administration and mortality and/or MI. However, in the self controlled case series there was no significant difference in the adjusted incidence rate ratio between groups (IRR 0.75, 95%CI 0.55-1.01). The authors argue that the association present in their cohort study that disappeared in the self controlled case series suggests that there is not a causal relationship between Plavix-PPI co-administration and death/MI. It is possible that patients who take Plavix and PPIs are somehow different than patients who take only Plavix and it is this difference that drives the increased risk of death/MI.

Another study related to the treatment of coronary artery disease, this time the surgical management of CAD, was published in JAMA.[8] The RED-CABG study was a RCT designed to assess the efficacy and safety of acadesine administered perioperatively to moderate-to-high risk CABG patients in reducing a composite outcome of all-cause mortality, nonfatal stroke, and severe left ventricular dysfunction (SLVD) through 28 days. Acadesine is an adenosine-regulating agent, which increases the availability of adenosine to myocardial cells. Endogenous adenosine decreases the severity of ischemia-reperfusion injury, which forms the physiologic underpinning for the use of an agent like acadesine in the peri-CABG setting. RED-CABG was projected to enroll 7500 participants, however the study was halted after enrollment of about 3000 patients when an interim analysis showed no significant difference in the primary outcome incidence rate between the intervention and placebo groups (OR, 1.01 [95% CI, 0.73-1.41]; P = .94), which failed to meet a pre-specified futility threshold. This lack of benefit is in contrast to the findings of a 1997 meta-analysis of previous trials of acadesine. The authors note that the incidence of the primary outcome (~5% in both groups) was lower than expected and may reflect more recent advances in the management of CABG patients, including methods for myocardial protection other than pharmacologic additives.

This week’s selection of articles cover a broad range of topics, dealing with clinical issues that are common in the US and thus practical areas for improving outcomes, minimizing harms and providing care in a cost-conscious way.

Other articles of note:

Ahmed S, Li Q, Liu L, Tsui AO et al. Maternal deaths averted by contraceptive use: an analysis of 172 countries. Lancet. 2012;380(9837):111-125.

Statistical modeling estimated that worldwide maternal mortality in 2008 was 342,203 deaths. An estimated 272,040 maternal deaths were prevented by contraceptive use, and satisfying the unmet need for contraception could prevent an additional 104,000 maternal deaths every year.

Aubin HJ, Farley A, Lycett D, Lahmek P, Aveyard P. Weight gain in smokers after quitting cigarettes: meta-analysis. BMJ. 2012 Jul 10;345:e4439.

Meta-analysis of 62 studies that recorded weight change from baseline in abstinent smokers. Mean weight gain was 4-5kg 12 months after smoking cessation, with most of the gain occurring within three months of quitting. 16% of subjects lost weight, and 13% gained more than 10kg.

Flaherty KT, Robert C, Hersey P et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012 Jul 12;367(2):107-14.

Open-label phase 3 RCT comparing trametinib, an oral selective BRAF inhibitor, to cytotoxic chemotherapy (dacarbazine or paclitaxel) in patients with V600E or V600K BRAF-mutated metastatic melanoma. Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group; 6 month overall survival was 81% in the trametinib group and 67% in the chemotherapy group.

Greenberger NJ, Sharma P. Update in Gastroenterology and Hepatology: Evidence Published in 2011. Ann Intern Med. 3 July 2012;157(1):44-48.

Summary of studies published in 2011 relevant to practice of gastroenterology and hepatology. Topics include esophageal disorders, PPIs, hyperemesis, mast cell disorders, treatment of C. diff infections, and pancreatitis and hepatitis.

Dr. Mark Adelman is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Robert Gianotti, MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


1. Caldwell LA. House passes health care repeal, again. CBS News. July 11, 2012.

2. US Census Bureau. Income, Poverty and Health Insurance Coverage in the United States: 2009. September 16, 2010.

3. Centers for Medicare and Medicaid Services. National Health Expenditure Data.

4. Smith CD. Teaching High-Value, Cost-Conscious Care to Residents: The Alliance for Academic Internal Medicine-American College of Physicians Curriculum. Ann Intern Med. 2012 Jul 10:E-496.

5. Carson JL, Grossman BJ, Kleinman S et al. Red Blood Cell Transfusion: A Clinical Practice Guideline From the AABB. Ann Intern Med. 2012;157(1):49-58.

6. Wang CH, Fang CC, Chen NC et al. Cranberry-Containing Products for Prevention of Urinary Tract Infections in Susceptible Populations: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2012;172(13):988-96.

7. Douglas IJ, Evans SJW, Hingorani AD et al. Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs. BMJ. 2012;345:e4388.

8. Newman MF, Ferguson TB, White JA et al. Effect of Adenosine-Regulating Agent Acadesine on Morbidity and Mortality Associated With Coronary Artery Bypass Grafting: The RED-CABG Randomized Controlled Trial. JAMA. 2012;308(2):157-164.