Primecuts – This Week In the Journals

July 14, 2014

By Kimberly Skrobarcek, MD

Peer Reviewed

As the world is seemingly captivated by German’s victory in overtime of the World Cup final game, more and more of our television commercials and advertisements seem to be caught up in the frenzy as well. One Hyundai commercial in particular highlights the emotional connection we feel with the joy of a victory, maybe even prompting the start of a family [1]. With this in mind, we turn to an exciting new study that could prove very important in the battle with infertility.

New treatment for Infertility in the Polycystic Ovary Syndrome

The New England Journal of Medicine published a study looking at whether letrozole (an aromatase inhibitor) or clomiphene (a selective estrogen-receptor modulator) would result in improved pregnancy outcomes in women with polycystic ovarian syndrome (PCOS) and ovulatory dysfunction [2]. This double-blind, multicenter trial randomly assigned 750 women ages 18-40 years with PCOS, normal anatomy, and male partners with adequate sperm count, to receive either letrozole or clomiphene while having regular intercourse with intent of conception. The primary endpoint was live births during the treatment period. Results showed that women who received letrozole had more cumulative live births (27.5% vs 19.1%, p= 0.007) without significant differences in overall congenital anomalies, pregnancy loss, or twin pregnancies. Clomiphene was associated with higher incidence of hot flushes, while letrozole was associated with higher incidence of fatigue and dizziness. This makes letrozole a potentially more attractive first line treatment for infertility in PCOS. Even so, there were four major congenital anomalies in the letrozole group and only one in the clomiphene group, data which was not significant in this small study but will need to be better explored in a larger trial before the standard of care can change.

New treatment practices for tobacco cessation

All women who are pregnant should do their best to avoid tobacco, and this week the Journal of the American Medical Association (JAMA) offered some new evidence to help in that challenge. The efficacy and safety of combined nicotine replacement therapy (NRT) with varenicline versus varenicline alone for smoking cessation was evaluated in a randomized control trial [3]. Over 400 smokers were randomized to begin either nicotine or placebo patches 2 weeks before a target quit date (TQD) and to continue their use for 12 weeks after the TQD. Varenicline was then started in both groups 1 week prior to the TQD and continued concomitantly with the placebo or patch for the duration of the therapy, with an additional patch free week (week 13), during which varenicline was tapered off. The primary end point was abstinence at 12 weeks with secondary end points of abstinence at 6 months, 24 months, and adverse events. Abstinence rates for the combination group were higher at both 12 weeks (OR 1.85, 95%CI 1.19-2.89, p=0.007) and 24 weeks (OR 1.98, 95% CI 1.25-3.14, p=0.004). The study concluded that 6-7 patients would need to be treated with both NRT and varenicline for one person to benefit. The combination group did have increased incidence of nausea, sleep disturbance, skin reactions, constipation, and depression; although only skin reactions were statistically significant. While these results lead to the conclusion that combination therapy with varenicline and NRT is both safe and more effective than varenicline alone, the study’s relatively healthy population raises concerns over the relevancy of its findings to more chronically ill patients.

Obstructive Sleep Apnea (OSA) and its association with cardiovascular risk factors in perimenopausal Women

Continuing on the topic of women’s health, much is still unknown about how the perimenopausal period contributes to cardiac risk. Studies, largely conducted in men, have shown that obstructive sleep apnea (OSA) is a risk factor for cardiovascular disease, but there has been little definitive data to address this question in women. CHEST contributes to this debate with the recent publication of a cross sectional study evaluating perimenopausal women without current cardiac disease for evidence of obstructive sleep apnea, hypertension, and arterial stiffness [4]. All women underwent 24 hour ambulatory blood pressure monitoring, arterial stiffness evaluation by pulse wave velocity (PWV), and a portable sleep study. OSA was diagnosed in 40.1% of all participants with 11.1% of all participants having moderate to severe disease. These women were also found to have a higher prevalence of hypertension (84% vs 69%, p<0.01) and arterial stiffness (pulse wave velocity, 11.5 m/s vs 9.5 m/s, p<0.001). This study suggests that OSA is an underdiagnosed disease in this population, possibly because of the strange absence of excessive daytime sleepiness in these women, which can be a common presenting symptom. Unfortunately, due to the cross sectional nature of this study, we are unable to infer any causality other than an association between OSA and cardiovascular parameters. Additional studies are needed to reduce confounding and produce more evidence to support this claim. Also efforts should be made to identify an applicable method of screening for OSA in this population.

Delaying antiretroviral therapy (ART) for newly diagnosed HIV patients with tuberculosis

We now move on to discuss HIV and tuberculosis, two diseases that do not discriminate against gender. Current WHO guidelines recommend early initiation of antiretroviral therapy (ART) of all HIV patients with tuberculosis regardless of CD4 count [5]. This strategy puts patients at risk for toxic effects, drug interactions, risk of antiretroviral resistance, and compliance challenges with increased pill burden. Questioning if early treatment regardless of CD4 is really necessary, The Lancet Infectious Disease published a trial comparing early versus delayed initiation of ART in HIV positive patients with CD4 counts greater than 220 cells per µL [6]. The study, which was done at 26 treatment centers in South Africa, Tanzania, Uganda, and Zambia enrolled patients with newly diagnosed smear positive, culture confirmed tuberculosis who already tolerated 2 weeks of tuberculosis therapy with Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol. One thousand six hundred and seventy five patients were enrolled in this randomized, placebo controlled trial and were either started on ART after 2 weeks or after 6 months of tuberculosis treatment. After two months of treatment with the aforementioned 4 drug regimen, patients were changed to the standard 4 months of Rifampicin and Isoniazid. The primary outcome was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment. Failure of tuberculosis treatment was defined as sputum-positive tuberculosis culture at 6 months after the completion of tuberculosis treatment. The primary outcome was reached by 8.5% in the early group and 9.2% in the delayed group [RR 0.91, CI 0.64-1.3, p=0.9]. The mortality [RR 1.4, p=0.23], severe adverse events [18% vs 21%, p=0.37], and rates of immune reconstitution syndrome [10% vs 10%, p=0.56] did not differ significantly between the two groups. These results demonstrate that if no difference exists among these end points, it may be beneficial to delay treatment to avoid the aforementioned risks associated with early treatment in this high CD4 count population.

Also in the journal this week:

On the heels of a CDC statement detailing the Ebola outbreak in Sierra Leone [7], The Lancet published a call to action against the virus [8].

– The Lancet also released an article showing safety and efficacy of insulin pump treatment compared with multiple daily injections in uncontrolled type 2 diabetics [9].

– JAMA provides a guide on how to read and apply the results of systematic review and meta-analysis to patient care [10].

NEJM published the results of two phase 3 trials demonstrating the efficacy of Secukinumab, a new immunoglobulin antibody targeting interleukin-17a, for the treatment of moderate to severe plaque psoriasis [11].

Dr. Kimberly Skrobarcek, is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Jessica Taff, chief resident at NYU Langone Medical Center


1. Hyundai 2014 FIFA World Cup #BecauseFutbol Baby Boom.

2. Richard S. Legro MD, Robert G. Brzyski MD/PhD, Michael P. Diamon, et al. Letrozole versus Clomiphene for Infertility in the Polycystic Ovary Syndrome. N Engl J Med. 2014; 371:119-129. July 10,2014. DOI: 10.1056/NEJMoa1313517.

3. Coenraad F. N. Koegelenberg MD/PhD, Firdows Noor MD, Eric D. Bateman MD/PhD, et al. Efficacy of Varenicline Combined with Nicotine Replacement Therapy vs Varenicline Alone for Smoking Cessation. JAMA. 2014; 312(2):155-161. doi:10.1001/jama.2014.7195

4. Rodrigo P Pedrosa MD/PhD, Isly ML Barros MD, Luciano F Drager MD/PhD, et al. OSA is Common and Independently Associated with Hypertension and Increased Arterial Stiffness in Consecutive Perimenopausal Women. Chest. 2014; 146(1):66-72. doi:10.1378/chest.14-0097

5. WHO policy on collaborative TB/HIV activities: guidelines for national programmes and other stakeholders. 2012.

6. Sayoki G Mfinanga PhD, Bruce J Kirenga MMed, Duncan M Chanda MD, et al. Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomized, placebo-controlled trial. Lancet Infect Dis.2014;14:563-571.

7. Meredith G Dixon MD, Ilana J Schafer DVM. Ebola Viral Disease Outbreak- West Africa, 2014. CDC Morbitidy and Mortality Weekly Report. 63(25);548-551. June 27, 2014.

8. Rashid Ansumana, Jesse Bonwitt, David A Stenger, Kathryn H Jacobsen. Ebola in Sierra Leone: a call for action. The Lancet. July 4, 2014. DOI: 10.1016/S0140-6736(14)61119-3

9. Yves Reznik MD, Ohad Cohen MD, Ronnie Aronson MD, et al. Insulin pump treatment compared with multiple daily injections for treatment of type 2 diabetes (OpT2mise): a randomized open-label controlled trial. The Lancet. July 2, 2014. DOI: 10.1016/S0140-6736(14)61037-0

10. Mohammad Hassan Murad MD/MPH, Victor M Montori MD/MSc, John P A Ioannidis MD, et al. How to Read a Systematic Review and Meta-Analysis and Apply the results to Patient Care: Users’ Guides to the Medical Literautre. JAMA. 2014;312(2):171-179. doi:10.1001/jama.2014.5559.

11. Richard G Langley MD, Boni E Elewski MD, Mark Lebwohl MD, et al. Secukinumab in Plaque Psoriasis- Results of Two Phase 3 Trials. N Engl J Med. July 9,2014. DOI: 10.1056/NEJMoa1314258