Primecuts – This Week In The Journals

February 9, 2015

By Shyam Amin, MD

Peer reviewed

In the news…

Congratulations to the New England Patriots and their fans for a thrilling Super Bowl victory this past week. A full ten years since their last Super Bowl win, Tom Brady and Bill Belichick are champions once again in a truly memorable game that featured an historic fourth quarter comeback and a wild final Seahawks drive that was ultimately thwarted by the unlikeliest of heroes.

In health-related news, an investigation led by the New York State attorney general’s office has revealed that several major retailers might be selling fraudulent and mislabeled herbal and dietary supplements [1]. The dietary supplement industry has rapidly grown over the past 10 years and is now a $13 billion a year business, producing supplements consumed by nearly half of all Americans. Unlike with the pharmaceutical industry, the FDA does not have the legal authority to approve or deny marketing of supplements based on safety or effectiveness and does not typically oversee the contents of supplements in the same manner as it does pharmaceuticals.

The attorney general’s investigation analyzed a small sample of store-brand supplements from retailers including GNC, Target, Walgreens, and Walmart and found that a majority of the samples tested did not contain the herb or supplement on its label in any detectable quantity. Instead the supplements contained various fillers such as powdered rice, beans, legumes, or wheat. Moreover, these products do not pose a negligible risk to patients – there have been reports of hepatitis and liver failure attributed to supplements, among other risks [2].

The New York State attorney general has sent cease-and-desist letters to these four retailers specifically targeting those supplements that were tested. It remains to be seen if further action or investigation into the supplement industry will come. In the meantime, it remains critically important for healthcare providers to thoroughly counsel and educate patients regarding the risks and benefits of taking these supplements.

On to the journals…

Tenofovir-Based Preexposure Prophylaxis for HIV Infection among African Women

As the effectiveness of antiretroviral therapy progresses in treating HIV, there has been much research into pre-exposure prophylaxis (PrEP) to prevent HIV transmission. Daily PrEP with both tenofovir alone and in combination with emtricitabine has been shown to reduce HIV transmission by at least 50% in MSM, heterosexuals, and in IV drug users with greater effectiveness in subjects with high adherence to the regimen [3]. Investigators have also attempted to evaluate the effectivess of PrEP in African women, a population with the highest incidence of HIV – however, in one study [4], daily Truvada-based PrEP was found to be ineffective in preventing HIV transmission, in large part due to low adherence rates of less than 40%.

The New England Journal of Medicine published a new study on pre-exposure prophylaxis for African women[5], using tenofovir-based regimens in both oral and vaginal gel forms. Under the study protocol, subjects were offered monthly HIV tests and interviews, quarterly blood testing, twice-yearly pelvic examinations, and they were given a small reimbursement for travel expenses and for missing work. Adherence was monitored by blood testing and by in-clinic counts of empty pill bottles and gel containers.

The results again showed that none of the tenofovir-based regimens were effective in reducing HIV-1 transmission. For oral tenofovir alone, the effectiveness was -49.0% (hazard ratio 1.49, 95% CI 0.97 to 2.29); for oral tenofovir-emtricitabine, the effectiveness was -4.4% (hazard ratio 1.04, 95% CI 0.73 to 1.49); and for tenofovir vaginal cream, the effectiveness was 14.5% (hazard ratio 0.85, 95% CI 0.61 to 1.21). Concerningly, despite subjects consistently returning empty pill bottles and gel containers, adherence as detected by measurement of serum tenofovir levels was detected at 30%, 29%, and 25% for the respective groups. Further discussion [6] suggests subjects may have chosen not to take the medications for fear of side effects and of stigma associated with taking HIV medications; additionally, subjects may have falsely reported compliance in order to continue receiving routine health screenings and small stipends.

This study confirms what was already known – that HIV PrEP with poor adherence does not work – and further emphasizes the need to find new delivery methods for PrEP to this highest-risk population, whether through increased awareness and education to support daily HIV medication use or through alternate long-acting agents like once-monthly vaginal rings.

What Is the Role of Tiotropium in Asthma?

Maintenance therapy for asthma is classically treated with a stepwise approach, including intermittent short-acting beta agonists, inhaled corticosteroids (ICS), and long-acting beta agonists (LABAs). The role of short-acting anticholinergic agents is proven in acute asthma exacerbations [7]; however, the role of long-acting anticholinergic agents in the long-term management of asthma is not as well-established.

Rodrigo et al. performed a meta-analysis, published in Chest[8], compiling all available data on the effect of tiotropium use in adolescent and adult subjects with asthma. Thirteen randomized, placebo-controlled studies were included, tallying almost 5000 patients that were divided into severity of asthma (mild, moderate, and severe). The primary outcomes of included studies were peak and trough FEV1 and morning and evening peak flow; secondary outcomes included frequency of exacerbations and quality-of-life questionnaires.

The results were generally in favor of tiotropium use across all stages of asthma. Tiotropium use was associated with significantly improved lung function when used as a sole add-on to ICS and was non-inferior to LABAs as add-on to ICS monotherapy. Furthermore, the addition of tiotropium to combined ICS/LABA therapy among severe asthmatics was shown to significantly improve pulmonary function and reduce rate of asthma exacerbations (relative risk 0.70, 95% CI 0.53 to 0.94). No significant increase in adverse events was reported.

These results support the use of tiotropium in asthma, either as a replacement for LABAs in patients with moderate asthma that cannot tolerate LABA therapy or in addition to combination ICS/LABA regimens in moderate to severe asthma.

Use and Outcomes Associated with Bridging During Anticoagulation Interruptions in Patients with Atrial Fibrillation

For patients with atrial fibrillation (AF), anticoagulation can significantly reduce the risk of stroke. When patients with AF on anticoagulation undergo procedures that require cessation of oral anticoagulants, a decision has to be made whether to provide bridging anticoagulation with either unfractionated or low molecular weight heparins. However, the effectiveness of bridging anticoagulation in these scenarios had not previously been well-studied.

In Circulation [9], a recent observational registry study compared outcomes in patients with AF that had been bridged to patients that had not been bridged while holding oral anticoagulation in anticipation of a procedure. The study analyzed the ORBIT-AF registry of patients on oral anticoagulation for AF and identified 2200 patients in which 2803 overall interruptions of anticoagulation occurred for procedures. Among these interruptions, bridging anticoagulation was used in 24% of cases – these were compared to the remaining cases in which no bridge was used. Of note, although the CHADS and CHADS-VASc score were slightly higher in bridged patients, the proportion of patients with scores >2 was not significantly different in both groups.

The results showed an expected increased risk of bleeding events in bridged compared to non-bridged patients (5.0% vs 1.3%, adjusted OR 3.84, p < 0.0001). However, there was also a significantly higher incidence of the composite end-point (myocardial infarction, stroke or systemic embolism, major bleeding, hospitalization, or death within 30 days) in the bridged compared to non-bridged patients even after adjusting for multiple confounders (13% vs 6.3%, adjusted OR 1.94, p = 0.0001). The increased bleeding risk contributed most to the rate of the composite end-point in patients with bridging anticoagulation, but still each of the individual components trended towards worse outcomes with bridging.

Based on this observational study, the routine use of bridging anticoagulation cannot be recommended and in fact may be harmful in patients at less risk for embolic disease. In high-risk patients that require continuous anticoagulation, the results of this study suggest it may in fact be better to continue oral anticoagulation without interruption if the procedure can be performed on oral anticoagulants rather than bridging with alternate anticoagulants. In patients that do require interruptions in oral anticoagulation, there may be less of a role for bridging anticoagulants in patients with relatively low risk of embolic events. However, additional studies are required to support the results of this observational study.

Symptom Trends in the Last Year of Life from 1998 to 2010

Despite increased attention and drive to improve end-of-life care throughout the country, a study published in the Annals of Internal Medicine [10] suggests there is still much room to go. The study used data from the Health and Retirement Study, which is a nationwide cohort of adults aged 51 or older that has been followed since 1992 with serial interviews. Upon a participant’s death, the HRS staff interviewed a proxy informant familiar with the participant to assess the participant’s symptoms during the last year of life, including pain, depression, confusion, severe fatigue, and incontinence.

This study compared post-mortem interviews from 1998 to 2010. Over this time frame, several symptoms were found to be more prevalent in 2010. Reports of pain have increased by 11.9% (95% CI 3.1% to 21.4%), reports of depression have increased by 26.6% (95% CI 14.5% to 40.1%), and rates of confusion have increased by 31.3% (95% CI 18.6% to 45.1%).These effects were seen in multiple disease categories including sudden death, congestive heart failure, or chronic lung disease. This studies highlights that while significant efforts have expanded the role of palliative and end-of-life care, there is still significant room to go.

Lastly, a few quick hits…

In the New England Journal of Medicine [11], a new device was studied in patients with refractory angina despite optimal medical therapy. The device is a coronary-sinus reducing device, designed to increase pressure in the coronary sinus. In this small clinical trial, implantation of the device showed significant improvements in symptoms and quality of life.

In Circulation [12], a new study in angioplasty for peripheral arterial disease compared drug-coated balloon to standard percutaneous transluminal angioplasty. The DCB arm showed very significant improvement in primary patency compared to standard PTA (82.2% vs 52.4%, p < 0.001) and significantly lower rates of target lesion revascularization (2.4% vs 20.6%, p < 0.001).

Finally, over the past two years as part of the Affordable Care Act, Medicaid reimbursements for primary care were increased to match Medicare levels in an effort to expand access to care. A study in the New England Journal of Medicine [13] analyzed the effects of increased reimbursement on access to care and waiting time for appointments for Medicaid enrollees. The results found an overall increase in availability of primary care appointments after increased reimbursements – indeed, the states with the largest increases in availability also had the most significant increase in reimbursement. Furthermore, no significant increase in waiting times was seen. Unfortunately, despite these improvements, the reimbursement increase expired at the end of 2014 in most states.

Shyam Amin, MD is a third year resident at NYU Langone Medical Center

Peer Reviewed by Mark H. Adelman, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


[1] O’Connor, A. New York Attorney General Targets Supplements at Major Retailers. New York Times. Feb 3 2015.

[2] Acute hepatitis and liver failure following the use of a dietary supplement intended for weight loss or muscle building — May-October 2013. MMWR Morb Mortal Wkly Rep 2013; 62:817-819.

[3] McGowan I. An Overview of Antiretroviral Pre-Exposure Prophylaxis of HIV Infection. Am J Reprod Immunol. 2014 Jun; 71 (6): 624-30.

[4] Van Damme L, Corneli A, Ahmed K, et al. Preexposure Prophylaxis for HIV Infection among African Women. N Engl J Med. 2012 Aug 2; 367 (5): 411-22.

[5] Marrazzo JM, et al. Tenofovir-based Preexposure Prophylaxis for HIV Infection among African Women. N Engl J Med. 2015 Feb 5; 372 (6): 509-18.

[6] Saag MS. Preventing HIV in Women—Still Trying to Find their Voice. N Engl J Med. 2015 Feb 5; 372 (6): 564-6.

[7] Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the Treatment of Children and Adults with Acute Asthma: a Systematic Review with Meta-Analysis. Thorax. 2005 Sept; 60 (9): 740-6.

[8] Rodrigo GJ, Castro-Rodriguez JA. What Is the Role of Tiotropium in Asthma? A Systematic Review with Meta-analysis. Chest. 2015 Feb; 147 (2): 388-96.

[9] Steinberg BA, et al. Use and Outcomes Associated with Bridging during Anticoagulation Interruptions in Patients with Atrial Fibrillation. Circulation. 2015 Feb 3; 131(5): 488-94.

[10] Singer AE, et al. Symptom Trends in the Last Year of Life from 1998-2010. Ann Intern Med. 2015 Feb 3; 162 (3): 175-83.

[11] Verheye S, et al. Efficacy of a Device to Narrow the Coronary Sinus in Refractory Angina. N Engl J Med. 2015 Feb 5; 372 (6): 519-27.

[12] Tepe G, et al. Drug-Coated Balloon Versus Standard Percutaneous Transluminal Angioplasty for the Treatment of Superficial Femoral and Popliteal Peripheral Artery Disease. Circulation. 2015 Feb 3; 131 (5): 495-502.

[13] Polsky D, et al. Appointment Availability after Increases in Medicaid Payments for Primary Care. N Engl J Med. 2015 Feb 5; 372 (6): 537-45.