Primecuts – This Week In The Journals

September 1, 2015

alison-parker-adam-ward-split-large-169By Ofole Mgbako, MD

Peer Reviewed 

This past week marked 10 years since Hurricane Katrina and President Obama visited the Lower Ninth Ward in New Orleans. The president described the hurricane as “a natural disaster” that became “a man-made disaster…a failure of government to look out for its own citizens.” While important progress has been made, the region still faces many economic problems – about one-third of the population and 40% of children live below the poverty line – and over 100,000 African Americans who left the city have not yet been able to return [1].

In other news, in what has become a disturbing trend of horrific episodes of gun violence, reporter Alison Parker and cameraman Adam Ward were shot and killed, while one local official was wounded, on live television in Moneta, Virginia. The gunman disturbingly posted video of the killing to social media prior to taking his own life, prompting another public debate about gun control.

Meanwhile in this week’s Primecuts, researchers examined the benefit of immediate initiation of antiretroviral therapy versus delayed initiation in asymptomatic HIV patients, the efficacy of perioperative bridging of anticoagulation in atrial fibrillation, outcomes following epidural steroid injection in radiculopathy and spinal stenosis, and the impact of physical activity on cognition in elderly adults.

Immediate initiation of antiretroviral therapy in early asymptomatic HIV infection improves AIDS-related outcomes.  

The CD4+ count threshold at which asymptomatic patients should initiate antiretroviral therapy (ART) following HIV diagnosis has changed over time. Recent studies have shown a clear benefit for initiation of ART in patients with a CD4+ count of 350 cells per cubic millimeter and below, and randomized control trials have established the benefit of early initiation of ART in patients with CD4+ count less than 500 cells per cubic millimeter [2]. The SMART trial examined the impact of immediate initiation of ART in asymptomatic patients with CD4+ count greater than 500 cells per cubic millimeter versus delayed initiation of ART. The delayed initiation group had ART started when their CD4+ count dropped below 350 cells per cubic millimeter, they developed an AIDS-related event or had another reason to start ART.

In this international multicenter randomized control trial, 4685 patients with an initial median CD4+ count of 651 cells per cubic millimeter from over 200 sites in 35 countries were randomized to immediate versus delayed initiation of ART (tenofovir, emtricitabine, and efavirenz). The authors used a composite primary end point that included any serious AIDS-related event, serious non-AIDS related event, and death from any cause. The results yielded a hazard ratio of 0.43 (95% confidence interval [CI], 0.30 to 0.62; P<0.001) for delayed initiation of ART. Breaking down the composite primary end point into its components, they found statistically significant reduction in serious AIDS-related events (HR 0.28, 95% CI, 0.15 to 0.50; P<0.001), particularly tuberculosis and Kaposi’s sarcoma, as well as serious non-AIDS related events (HR 0.61, 95% CI, 0.38 to 0.97; P=0.04), particularly non-AIDS cancers. In terms of secondary end points, there was a statistically significant reduction in the rate of bacterial infections in the immediate initiation arm [3]. This well-designed multinational study provides strong support for an international standard for immediate ART initiation in early asymptomatic HIV infection. It shows that early antiretroviral therapy is both safe in terms of minimal adverse effects from ART and provides long-term benefits other than protection against AIDS-defining illnesses.

Bridging anticoagulation with low molecular weight heparin in patients with atrial fibrillation undergoing minor elective surgery shows little clinical benefit. 

Patients with atrial fibrillation on warfarin undergoing an elective procedure stop anticoagulation 5 days prior to intervention and may take up to two weeks after hemostasis to achieve therapeutic INR. Clinicians often use bridging anticoagulation therapy to shorten this time when patients are theoretically at greater risk for arterial thromboembolism.

The BRIDGE trial was a randomized, double-blinded, placebo-controlled non-inferiority trial that recruited patients undergoing various gastrointestinal, cardiothoracic and orthopedic procedures. They randomized 1884 patients to bridging anticoagulation with dalteparin versus no bridging anticoagulation (matching placebo). The mean age of patients was 71.7, they were mostly white males with a mean CHADS2 score of 2.3. They found an incidence of 0.3% in the bridging group versus 0.4% in the placebo group (95% CI, −0.6 to 0.8; P=0.01 for noninferiority; P=0.73 for superiority). Comparing major bleeding in the bridging group (3.2%) with placebo (1.3%) yielded a relative risk of 0.41 (95% CI, 0.20 to 0.78; P=0.005 for superiority. There were also no significant differences in acute myocardial infarction, deep venous thromboembolism or death [4]. These findings support previous observational studies, as well as the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study, showing no difference in arterial thromboembolism while putting patients at risk for major bleeding perioperatively [5]. These significant findings may provide more clarity for clinicians in foregoing bridging anticoagulation. 

Steroid injections may not help patients with long-term pain control or slowing progression to surgery in patients with back pain.

Epidural corticosteroid injections are commonly used to provide pain relief in patients with low back pain due to radiculopathy, as well as spinal stenosis. Previous trials have shown conflicting evidence regarding the effects on steroid injections on long-term pain control and functional status. Clinical practice guidelines for the use of steroid injections also vary. A review in the Annals of Internal Medicine examined all randomized placebo-controlled trials for steroid use in radiculopathy or spinal stenosis and looked at pain, function, composite outcomes, and subsequent surgery. Thirty trials compared steroids to placebo for radiculopathy, ranging from 26 to 239 participants, while 8 trials met criteria for the same comparison in spinal stenosis, ranging from 29 to 386 participants for follow-up periods ranging from 1 week to 3 years. Results showed statistically significant short term (5 days to 2 weeks) pain control in radiculopathy, however only 6 trials met a moderate strength of evidence while others had issues with consistence and precision. There was no significant benefit in long-term pain, functionality or surgery risk. Studies for spinal stenosis showed no benefit in short-term or long-term outcomes. Results were similar in cases of spinal stenosis. This review provides important clarity for the role of steroid injections in the management of back pain, however the heterogeneity among the trials calls for more well-designed placebo-controlled RCTs in the future [6]. 

Does increased physical activity improve cognitive outcomes or lower risk of dementia in the elderly?

The 24-month LIFE trial published in JAMA this week explored the effect of a physical activity program on improving long-term cognition in the elderly. Participants were in their mid-70s at enrollment and the majority were college-educated women with no significant sognitive impairment by mini-mental status exam at baseline. They were randomized to a physical activity intervention, which involved moderate-intensity aerobic exercise and strength/balance training sessions multiple days per week, or a health education program. Results showed no major differences in global or domain-specific cognitive scores at 24 months, which evaluated such indicators as executive function and delayed recall. However, a subgroup analysis showed some statistically significant benefit for executive function in the intervention arm in patients over 80 years old or who had a lower baseline of physical function. There was also no difference in mild cognitive impairment or dementia. While this randomized control trial was the longest and largest study of its kind, future studies would ideally assess a longer period of time, as well as surrogate markers like functional MRI or beta-amyloid levels in the cerebrospinal fluid.


In patients with relapsed or refractory multiple myeloma, daratumumab, an anti-CD38 monoclonal antibody, showed promising phase 1-2 results [8]

A population cohort study looks at the dose and duration of aspirin and other NSAIDs in reduction of colorectal cancer [9]

Lastly, a new study showed the potential efficacy of combination therapy ambrisentan plus tadalafil versus monotherapy in pulmonary arterial hypertension [10]

Dr. Ofole Mgbako is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Matthew Dallos, MD, Medicine, NYU Langone Medical Center

Image courtesy of CNN News


  1. For Hurricane Katrina anniversary, Obama cites inequities ‘brewing for decades’. CNN August 28, 2015.
  2. Grinsztejn B, Hosseinipour MC, Ribaudo HJ, et al. Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infect Dis 2014;14:281-290.
  3. The INSIGHT START Study Group. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med 2015; 373:795-807.
  4. Douketis JD, Spyropoulos AC, et al. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med 2015; 373:823-833.
  5. Healey JS, Eikelboom J, Douketis J, et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 2012;126:343-348.
  6. Chou R, Hashimoto R, Friedly J, Fu R, Bougatsos C, et al. Epidural Corticosteroid Injections for Radiculopathy and Spinal Stenosis: A Systematic Review and Meta-analysis. Ann Intern Med. 2015.
  7. Sink KM, Espeland MA, Castro CM, et al. Effect of a 24-Month Physical Activity Intervention vs Health Education on Cognitive Outcomes in Sedentary Older Adults: The LIFE Randomized Trial. JAMA. 2015;314(8):781-90.
  8. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. Published online August 26, 2015.
  9. Low-Dose Aspirin or Nonsteroidal Anti-inflammatory Drug Use and Colorectal Cancer Risk: A Population-Based, Case–Control Study. Ann Intern Med. Published online 25 August 2015.  
  10. Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015; 373:834-844.