Primecuts – This Week In The Journals

March 25, 2014

By Nicole Van Groningen, MD

Peer reviewed

At 12:57 pm last Thursday, the sun passed the celestial equator, marking the Vernal Equinox. What has spring meant to New Yorkers so far? Mother nature offered an impressive 3-day stretch of near-50 degree weather. The Eastern Phoebe, a drab-colored songbird thought to herald the beginning of spring, has been spotted in the city. And in Bowling Green, urban shaman and eco-ceremonialist Donna Henes conducted her 39th consecutive ritual of standing eggs on their ends, an ancient practice done to salute the new season.

If you find these local events sub-inspirational, another new beginning made national news this week: Starbucks and Oprah Winfrey announced a partnership in creating a new tea with an ingenious name: “the Oprah chai.”

Almost as groundbreaking, the New England Journal of Medicine punctuated the week of the Equinox with the a publication that defines “a new era of sepsis management” [1]. This comes over a decade after Rivers et al. transformed sepsis management by demonstrating improved outcomes using Early Goal Directed Therapy (EGDT), a 6 hour protocol that employed invasive measurements of hemodynamics to guide resuscitation [2]. Investigators of this week’s ProCESS trial re-examined the utility of a protocol-based approach in treating sepsis [3]. The study, which enrolled 1341 patients in suspected septic shock from 31 centers, randomized each patient in a 1:1:1 ratio to receive protocol-based EGDT, protocol-based standard care, and usual care within 2 hours of recognition of shock and within 12 hours of arrival to the ED. Patients randomized to EGDT all underwent central venous catheter placement and were treated based on targets in Rivers’ algorithm: central venous pressure, mean arterial pressure, and mixed venous oxygen saturation. The amount and timing of volume resuscitation was specifically dictated in this treatment group. Protocol-based standard therapy was developed through a review of the literature as well as the input of expert physicians, and patients in this group were treated according to targets requiring less invasive measurement techniques, such as systolic blood pressure and clinical and laboratory signs of hypoperfusion. In the usual care group, the bedside providers directed all care without any direction from study coordinators.

The primary outcome of 60-day mortality did not differ among the three groups (21% in EGDT, 18% in protocol-based standard care, and 19% in usual care; 95% confidence interval [CI], 0.82 to 1.31; p=0.83), with comparably insignificant differences in 90-day and 1-year mortality rates. These findings suggest that, despite its widespread use, a protocol based on invasive hemodynamic monitoring does not significantly improve outcomes in septic shock compared to less invasive approaches. Similar to research that found the use of pulmonary artery catheters did not improve mortality, this study has the potential to alter our current standards of care and management by suggesting that invasive hemodynamic monitoring is not a requirement for the management of septic shock. Early recognition of sepsis, as well as cornerstone interventions – the rapid infusion of intravenous fluids, early broad spectrum antibiotics, and prompt source control – have a greater impact on survival than the use of invasive monitoring to guide such therapies.

Also new this week, investigators of the ADJUST-PE Study may be able to ease the woes of practitioners suffering the frustrations of elevated D-dimers. Based on evidence that D-Dimer levels tend to increase with age, the authors propose an age-adjusted cutoff of ‘10 times age’ in patients over 50 (the cut-off for those below 50 remains 500) [4,5]. In this prospective, multi-center European study, age adjusted D-dimer testing was performed on those categorized as “low-risk” for pulmonary embolism (PE) based on the Revised Geneva Score or the 2-Level Wells Score (87.2% of the initial 3346 patients enrolled). The primary outcome, failure rate of the age-adjusted D-dimer, was determined by the rate of symptomatic thromboembolic events diagnosed over a 3-month follow-up period in those with a negative age-adjusted D-Dimer. In patients over 50 with a D-Dimer level between 500 and their age-adjusted cutoff (those who would previously been classified as “positive”), the failure rate was 0.3% (95% CI, 0.1% – 1.7%) – about that observed after a negative pulmonary angiography result. In those over the age of 75, using the age adjusted D-Dimer did not lead to any false negative findings based on the follow-up period.

Overall, the age-adjusted cut off led to an 11.6% absolute increase and a 41.2% relative increase in the proportion of negative D-dimer results. There were some limitations to this study, however, such as the use of two different probability assessment scores, varying D-dimer assays among the medical centers, and the lack of a control group with randomization. Regardless, the study’s findings, echoed by several retrospective studies of similar design, suggest that adoption of an age-adjusted D-Dimer cutoff could amplify the diagnostic yield (number needed to test), and decrease the costs and morbidity associated with computed tomogrpahy angiograms performed as a result of false-positive D-dimers.

Warfarin continued to lose grip as the leader of the oral anticoagulants this week, with the publication of a study that provided clearer definition of new oral anticoagulants’ (NOACs) role in stroke prevention in patients with atrial fibrillation. The study, published in The Lancet, became the first meta-analysis to date to include all 4 of the phase 3 randomized trials comparing NOAC’s (dabigatran, rivaroxaban, apixaban, and edoxaban) to warfarin in atrial fibrillation [6]. Overall, there were 42,411 patients receiving NOACs and 29,272 receiving warfarin. The authors found that NOAC’s significantly reduced the incidence of stroke or systemic embolic events by 19% compared with warfarin (relative risk [RR] 0.89, 95% CI .73-.99; p<0.0001), which was primarily attributable to a 50% reduction in hemorrhagic stroke (RR 0.49, 0.38–0.64; p<0.0001, number-needed-to-treat of 218).

Although NOAC’s safety profile remains limited by a higher risk of gastrointestinal bleeding (RR 1.25, 95% CI 1.01-1.55; p=0.04), it was also associated with a significant decrease in all-cause mortality (RR 0.9, 95% CI 0.85-0.95, p = 0.003) as well as intracranial hemorrhage (RR 0.48, 0.39-0.59; p<0.0001), a devastating complication of systemic anticoagulation. Importantly, these efficacy and safety findings were consistently significant across subgroup analyses, including the elderly and those with renal dysfunction. Although the individual studies used in the meta-analysis were powered only to evaluate the primary outcome and treatment effect of NOACs, this meta-analysis pooled sufficient patient data to provide reassurance of efficacy and safety, which is preserved even for higher-risk groups.

Also in the Lancet this week, another study adds to the list of statins’ benefits, this time in patients with multiple sclerosis. Included in this multi-center, prospective randomized controlled trial were 140 patients with secondary progressive multiple sclerosis – a form of the disease for which immunomodulatory and neuroprotective therapies have failed – in which half of participants received simvastatin (80mg daily for two years), while the other half received placebo [7]. Brain volume was measured with magnetic resonance imaging at 0, 12, and 25 months to determine rate of whole brain atrophy per year, the study’s primary endpoint. Patients treated with simvastatin had a significantly decreased rate of brain atrophy (0.288% per year) compared to those treated with placebo (0.584% per year), translating to an adjusted relative reduction of roughly 40%. Two secondary clinical outcomes, the expanded disability status scale (EDSS) and the multiple sclerosis impact scale 29 (MSIS-29), also showed small but statistically significant improvements in functional status of those treated with statins. There was no significant difference, however, in rate of new or enlarging lesion formation, or in the rate of relapse. Still, the authors invite further exploration of the topic, theorizing that the cell-protective properties of statins and improvement of cerebrovascular hemodynamics led to positive results.


Other noteworthy reads this week:

A target mean arterial pressure of 80 to 85 mmg Hg did not improve outcomes in septic patients when compared to the traditional target of 65 to 70 mmHg. Both 28-day and 90-day mortality were similar in both groups, as was median intensive care unit stay [8].

In the Lancet Global Health, researchers presented a novel campaign to promote hand washing in developing countries that centered on emotional drivers of behavior through pictures, videos, and performances. The implementation of these interventions in Indian villages resulted in substantial increases in hand washing rates compared to traditional campaigns that focus on increasing knowledge [9].

An FDA advisory panel voted unanimously to recommend that a DNA test for the human papilloma virus should replace the pap smear as first line screening for cervical cancer, as reported by the British Medical Journal [10].

A peripheral blood test for Alzheimer’s disease may be on the horizon. In a Nature Medicine letter, researchers describe a set of 10 biomarkers that predict phenoconversion to either mild cognitive impairment or Alzheimer’s disease with over 90% accuracy within a 2-3 year period [11].

Dr. Nicole Van Groningen is a 1st year internal medicine resident at NYU Langone Medical Center

Peer reviewed by Gregory Schrank, MD, Contributing Editor, Clinical Correlations

Image courtesy of Wikimedia Commons



1. Lilly CM. The ProCESS Trial – A New Era of Sepsis Management. N Engl J Med. 2014 Mar 18. [Epub ahead of print].

2. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med2001;345:1368-1377.

3. The ProCESS Investigators. A Randomized Trial of Protocol-Based Therapy for Early Septic Shock. New Engl J Med 2014 March 18 [Epub ahead of print].

4. Tardy B, Tardy-Poncet B, Viallon A, et al. Evaluation of D-dimer ELISA test in elderly patients with suspected pulmonary embolism. Thromb Haemost. 1998;79(1):38-41

5. Righini M, Van Es J, Roy PM et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA. 2014 Mar 19;311(11):1117-24.

6. Ruff CT, Guigliano RP, Braunwald E et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. Lancet. 2014 Mar 15;383(9921):955-62.

7. Chataway J, Shuerer N, Ali A et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomized, placebo-controlled, phase 2 trial. The Lancet, Early Online Publication, 19 March 2014.

8. Asfar P, Meziani F, Hamel JF et al. High versus Low Blood-Pressure Target in Patients with Septic Shock. N Engl J Med. 2014 March 18. [Epub ahead of print]

9. Biran A, Schmidt WP, Varadharajan KS. Effect of a behaviour-change intervention on handwashing with soap in India (SuperAmma): a cluster-randomised trial. The Lancet Global Health. 1 March 2013. Vol. 2, Issue 3, pages e145-e154.

10. McCarthy M. FDA panel recommends DNA test as first line cervical cancer screening test. BMJ 2014; 348:g2164.

11. Mapstone M, Cheema AK, Flandaca MS et al. Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. 2014 Mar 9. [Epub ahead of print].