Primecuts – This Week In The Journals

November 4, 2013

By Cindy Fei, MD

Faculty Peer Reviewed

Online enrollment continues at the website in accordance with the rollout of the Affordable Care Act and its January 1, 2014 deadline for mandated individual health insurance coverage. The recent opening of the online marketplace for health care insurance plans on October 1 was marred by frequent website blackouts, errors due to high-user demand and technical problems. Known colloquially as ObamaCare, the Affordable Care Act requires everyone to have health insurance by the beginning of next year, and provides access to subsidies to facilitate purchase of insurance plans. As part of its broad-sweeping effects, the Affordable Care Act also aims to switch medical care from a fee-for-service model to value-based care, emphasizing quality, cost-effectiveness and reinforcing our reliance on evidence-based medicine. With this in mind, let’s look at some recently published articles and how they fall into the current realm of evidence.

A recent article from JAMA examined the role of a short-acting beta-blocker in patients with septic shock. [1] The randomized, open-label, phase 2 study used esmolol infusion compared with conventional management as a means to reverse the catecholamine surge associated with tachycardia, cardiac dysfunction, and adverse outcomes. The study enrolled 154 intensive care unit patients at the University of Rome Hospital in septic shock on pressors with a heart rate greater than 95 despite appropriate fluid resuscitation. The primary outcome in the intention-to-treat analysis was the ability to titrate the esmolol drip to a heart rate between 80-94 over 96 hours, which not surprisingly was achieved in the esmolol group with a mean reduction of 18 beats/min (p <0.001). Important secondary outcomes included 28-day mortality and norepinephrine requirements, which proved to be statistically significant with a reduction in short-term mortality from 80% in the control group to 49% in the esmolol intervention group (p <0.001), along with a statistically significant reduction in pressor requirements and increased stroke volume index of 4 vs 1 mL/m2 in the control group (p = 0.02). This article highlights the benefits of reversing catecholamine-induced tachycardia in septic shock and suggests an important adjunct treatment target in the management of sepsis. Despite the single-center and open-label nature of the study, as well as the less-than-bold primary outcome, the impressive mortality data and favorable hemodynamic variables should propel further investigation.

Another critical care article from JAMA compared crystalloid versus colloid fluid resuscitation in newly admitted patients with severe hypovolemic shock in the intensive care unit.[2] The multinational, open-label trial allowed individual discretion regarding specific type of colloid or crystalloid administered within each class, with the majority in each group receiving hydroxyethyl starch (68%) or normal saline (85%). The intention-to-treat analysis showed no difference in the primary outcome of 28-day mortality for colloid versus crystalloid resuscitation (25.5% vs 27%, RR 0.96, p=0.26). However, mortality trends favored colloids in the secondary outcome of 90-day mortality (30.7% vs 34.2%, RR 0.92, p=0.03) as well as ICU mortality (25.1% vs 28.1%, RR 0.92, p=0.06). Prior studies had compared specific agents, such as albumin versus normal saline in the SAFE trial [3], and hydroxyethyl starch versus normal saline in the CHEST trial [4], with hydroxyethyl starch associated with increased acute renal failure or greater need for renal replacement therapy. However, the current trial did not show the same association, perhaps due to exclusion of patients with severe chronic kidney failure and maximal limits for hydroxyethyl starch. This study provides valuable information but it does not seem likely that it will end the debate over crystalloid versus colloid resuscitation.

The NEJM published the European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) trial on peri-procedural bivalirudin during primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) [5]. This study follows the 2008 HORIZONS-AMI trial, which showed bivalirudin’s mortality benefit as compared to heparin and glycoprotein IIb/IIIa blockers [6]. In a multicenter, randomized, open-label trial of 2198 patients presenting with STEMI to an ambulance or non-PCI equipped institution, subjects were assigned to early bivalirudin versus heparin infusion with optional use of glycoprotein IIb/IIIa blockers. In the intention-to-treat analysis, bivalirudin reduced the primary outcome of composite 30-day all-cause mortality or non-coronary artery bypass graft (CABG)-related major bleeding, to 5.1%, compared with 8.5% in the control heparin group (RR 0.6, p = 0.001). This difference was driven by less frequent non-CABG bleeding in the bivalirudin group, as all-cause mortality was similar. However, early stent thrombosis within 24 hours of PCI was more common in the bivalirudin group, a finding mirrored in the original HORIZONS-AMI trial. The current study was unable to reproduce the mortality benefit with bivalirudin seen in the original study, but did reinforce a reduced bleeding risk in conjunction with increased acute stent thrombosis risk.

In other cardiac news from Brazil, the Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE) trial in JAMA compared a conventional versus shorter course of dual antiplatelet therapy after PCI with a second-generation drug-eluting stent [7]. The open-label, randomized study of over 3000 patients presenting with low-risk acute coronary syndrome or stable angina compared 12 versus 3 months of aspirin 100-200mg daily and clopidogrel 75mg daily. The intention-to-treat analysis established non-inferiority between the two groups in the primary composite outcome of all-cause mortality, myocardial infarction, stroke, or major bleeding over 1 year (shorter course 6% vs longer course 5.8%, p = 0.002 for non-inferiority), without increased risk of early or delayed stent thrombosis (0.8% vs 0.8%, p = 0.86). The per-protocol analysis also demonstrated non-inferiority for the primary outcome (shorter course 5.1% vs longer course 4.9%, p = 0.001 for non-inferiority). No statistically significant difference in major bleed or any bleeding was found. These findings echo prior studies (EXCELLENT[5] [8], PRODIGYix, RESETx) that also espoused no difference between shorter (3-6 month) versus longer (12-24 month) duration of dual antiplatelet therapy for various first and second-generation drug-eluting stents. However, this most recent study may have been underpowered to detect ischemic events, bleeding rates, and stent thrombosis.

Other articles of note

The American College of Physicians (ACP) released new guidelines for management of early chronic kidney disease stages 1-3, including four main recommendations. [11]  The ACP strongly recommended that angiotensin-converting-enzyme inhibitors (ACEi) or angiotension II-receptor blockers (ARB) be used in concomitant hypertension, and that statins be used in concomitant dyslipidemia to reduce all-cause mortality. The ACP also recommended against screening for chronic kidney disease in asymptomatic individuals, as well as against proteinuria screening in patients already on ACEi/ARB.

The Lancet published a multi-center phase 3 clinical trial that compared linagliptin, a once-daily oral dipeptidyl peptidase-4 (DPP4) inhibitor, to placebo in elderly type 2 diabetics already on metformin, sulfonylureas, and/or basal insulin. Linagliptin was found to reduce glycosylated hemoglobin A1c by 0.61% (p <0.0001) after 24 weeks, without increased risk of hypoglycemia or other adverse side effects. [12]

A systematic review and meta-analysis from the British Medical Journal compared different classes of antihypertensive blood pressure medications in diabetics. Drawing from 63 randomized clinical trials, the investigators confirmed angiotensin-converting enzyme inhibitors (ACEi) as the first-line drug to reduce mortality, and suggested combination ACEi and calcium-channel blocker as the best dual therapy for mortality benefit. [13]

The Archives of Internal Medicine published a short piece describing the weekly rhythms of smoking cessation, with online Google searches for smoking cessation peaking on Monday then declining throughout the week to reach its nadir on Saturday. [14] The article suggested that knowledge of this trend may help smoking cessation efforts target patients during their receptive period.

Dr. Cindy Fei is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Arnab Ghosh, MD, a 3rd year resident at NYU Langone Medical Center


1. Morelli A, Ertmer C, Westphal M, et al. Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock: A Randomized Clinical Trial. JAMA. 2013;310(16):1683-1691.

2. Annane D, Siami S, Jaber S, Martin C, et al. Effects of Fluid Resuscitation With Colloids vs Crystalloids on Mortality in Critically Ill Patients Presenting With Hypovolemic Shock: The CRISTAL Randomized Trial. JAMA 2013

3. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. NEJM 2004; 350(22): 2247-2256.

4. Myburgh JA, Finfer S, Bellomo R Hydroxyethyl starch or saline for fluid resuscitation in intensive care. NEJM 2012; 367(20): 1901-1911.

5.  Steg PG, van ‘t Hof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. NEJM 2013.

6.  Stone G, Witzenbichler B, Guagliumi G, et al. Bivalirudin during Primary PCI in Acute Myocardial Infarction. NEJM 2008;358:21: 2218-230.

7.  Feres F, Costa RA, Abizaid A, et al. Three vs Twelve Months of Dual Antiplatelet Therapy After Zotarolimus-Eluting StentsThe OPTIMIZE Randomized Triail. JAMA

8.  Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012;125(3): 505-513.

9.  Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125(16): 2015-2026.

10.  Kim BK, Hong MK, Shin DH, et al; RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012;60(15):1340-1348.

11.  Qaseem A, Hopkins RH, Sweet DE, et al. Screening, Monitoring, and Treatment of Stage 1 to 3 Chronic Kidney Disease: A Clinical Practice Guideline From the Clinical Guidelines Committee of the American College of Physicians. Annals of Internal Medicine. 2013 Oct:.

12.  Barnett AH, Huisman H, Jones R, et al. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 2013;382:26: 1413-1423.

13.  Wu H, Huang J, Lin H, et al. Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and bayesian network meta-analysis. BMJ 2013;347:f6008.

14.  Ayers JW, Althouse BM, Johnson M, et al. Circaseptan (Weekly) Rhythms in Smoking Cessation Considerations. JAMA Internal Medicine. 2013