Primecuts – This Week in the Journals

February 13, 2018

PrimeCuts 8 min read

By Sharine Wittkopp, MD

Peer Reviewed

Winter Games are warming up Pyeongchang despite frigid temperatures. Braving 11-degree weather, the US Olympic team is the largest team any nation has ever brought to a winter Olympic games.1 Perhaps they can huddle together for warmth.

Speaking of global warming, the EPA has recently replaced its top scientific advisors under a new rule banning researchers who receive EPA funding from serving in advisory positions, opening the door for industry scientists whose backers have the most to gain from weakening environmental policies.2 Some day we may all breathe easier knowing that unbiased science is informing environmental policy, but for now we wait with bated breath.

In the meantime, some medical news…  

COPD exacerbations decreased with inhaled triple therapy 

The Global Initiative for Chronic Obstructive Lung Disease report predicts that COPD will be the third leading cause of death in the world by 20203. The mainstay of treatment for this disease is inhaled medications including long-acting bronchodilators (antimuscarinics [LAMA], β2 agonists [LABA] or both) with or without corticosteroids, with the main therapeutic goal of preventing exacerbations. Previous studies have evaluated triple therapy (and dual bronchodilation) compared to monotherapy, but have not directly compared triple therapy with dual therapy.

The TRIBUTE study4, recently published in Lancet, aimed to directly compare triple therapy comprised of LAMA, LABA and corticosteroid in a single inhaler, with single-inhaler dual therapy of LAMA and LABA. TRIBUTE was randomized, parallel-group, double-blind, double-dummy active controlled phase 3b study of 1532 current or former smokers >40 years of age with COPD diagnosis, FEV1 less than 50% and at least one moderate or severe COPD exacerbation within the previous year. Patients were excluded if they were already prescribed inhaled corticosteroids for concurrent diagnosis of asthma, or if they had used inhaled triple therapy in the previous 2 months. After a 2 week run-in period on dual therapy consisting of 85 μg indacaterol plus 43 μg glycopyrronium (IND/G), patients received 52 weeks of either one inhalation of IND/G daily or twice daily triple therapy consisting of 87 μg beclometasone dipropionate, 5 μg formoterol fumarate and 9 μg glycopyrronium; placebos were dry-powder inhalation either once or twice daily. Key results from this study include an adjusted rate ratio for moderate to severe COPD exacerbations for patients on triple therapy of 0.848 (95% CI 0.723-0.995; p=0.043) from the intention-to-treat analysis. However, this rate ratio did not retain significance on a per-protocol analysis (0.849, 95%CI 0.721-1.000; p=0.050). The use of rescue medication did not significantly differ between groups. Adverse events were also similar between groups; the main adverse event monitored was pneumonia, which occurred in 4% of each group during the study period.

This study fills a gap in the knowledge of COPD treatments by providing a head-to-head trial of triple therapy versus dual therapy in preventing COPD exacerbations. While the study did not test the same LABA and LAMA, TRIBUTE stills provide useful information that a triple-therapy single inhaler may aid in prevention of moderate to severe exacerbations in a population of adult current or former smokers.

Improved progression-free survival with Daratumumab in first-line treatment for multiple myeloma 

A malignancy of terminally differentiated plasma cells, multiple myeloma (MM) is the second most common hematologic malignancy in the United States.5 While survival rates are improving6, the disease remains incurable.7 Given that the most common regimens for elderly are only associated with progression-free survival of 18 to 24 months, there remains room for improvement in these treatments.

Daratumumab is a fully human monoclonal antibody that targets CD38 epitope abundant on plasma cells and has been used in treatment of refractory multiple myeloma.8 The ALCYONE trial is an ongoing study of patients with newly diagnosed MM, who were ineligible for stem-cell transplant, comparing a standard therapy (melphalan, prednisone and bortezomib) versus standard therapy plus daratumumab. The trial is an open-label randomized trial of 706 patients in 25 countries who had recently diagnosed, untreated multiple myeloma of varying stage. In the patients randomized to the daratumumab group, the rate of death or disease progression was 25.1% versus 40.2% in the control group; the hazard ratio for disease progression or death was 0.50 (95% confidence interval 0.38-0.65, p<0.001). Subgroup analysis showed consistent rates of progression-free survival across all subgroups. A secondary aim of the study was to evaluate safety of the standard treatment plus daratumumab versus standard alone. Pneumonia was the most common adverse event and occurred at a higher rate in the daratumumab group versus standard therapy alone (10.1% versus 3.1%); however, rates of discontinuation secondary to infections were similar in both groups suggesting these pneumonias were manageable. This interim analysis of the ongoing ALCYONE trial demonstrates significantly longer progression-free survival with standard therapy plus daratumumab compared to standard therapy alone among patients with newly diagnosed MM who were ineligible for stem-cell transplantation.7

Decreased in-hospital mortality after ICH on NOAC versus warfarin 

Non-vitamin K antagonist oral anticoagulants (NOACs) are highly-specific inhibitors to coagulation factors whose use has skyrocketed in preventing stroke in patients with atrial fibrillation. NOACs have shown favorable safety profiles when compared to warfarin, but continue to have an annual risk of intracerebral hemorrhage (ICH) of approximately 0.05%.9-12 Given there is significantly different pharmacology between NOACs and vitamin K antagonists (VKAs)13, it is likely that the outcomes associated with ICH while on NOACs differ from those associated with ICH on VKAs.

JAMA recently published a retrospective cohort study evaluating mortality after ICH in patients taking either NOACs or warfarin.14 The study included 141311 patients from 1662 hospitals in the AHA/ASA Get With The Guidelines-Stroke registry. Patients were excluded if taking 3 or more antiplatelet agents, 2 or more oral anticoagulants. The study found that patients taking either warfarin or NOACs had higher in-hospital mortality versus those not on oral anticoagulants. However compared to warfarin, those taking NOACs had a lower risk of overall in-hospital mortality (Adjusted risk difference  -5.7% [97.5% confidence interval -7.3% to -4.2%]. Patients on NOACs had better functional outcomes at discharge and were more likely to be discharged home than patients taking warfarin. Because patients on warfarin had variable INR, mortality rates were compared between NOAC users and warfarin users with therapeutic INR. This subgroup analysis also showed lower in-hospital mortality for NOAC users than for patients with therapeutic INR on warfarin [ADR -6.1%, 97.5% confidence interval -8.2% to -4.0%]. This study adds to the growing literature supporting the lower rates of adverse events with use of NOACs. Thus, despite the lack of reversal agents, NOACs may be associated with lower rates of in-hospital mortality and better functional outcomes among patients who sustain ICH on oral anticoagulants.

Association of Trimethoprim with acute kidney injury and hyperkalemia

Trimethoprim/Sulfamethoxazole (TMP/SMX) is the fourth most commonly prescribed antibiotic in the United States.15 It has known risk of acute kidney injury (AKI) and hyperkalemia;16 however, it is unclear which component of this medication is associated with these adverse effects. In the United Kingdom, trimethoprim alone is more commonly used owing to the limited and specific licensing indications for TMP/SMX, presenting an opportunity to evaluate the individual component trimethoprim for its adverse effects.

A recent study in BMJ evaluated antibiotics prescribed for UTI in a cohort study of adults >65 years of age.17 The study investigated rates of AKI, hyperkalemia, and death within 14 days of initiation of trimethoprim, amoxicillin, cefalexin, ciprofloxacin and nitrofurantion for UTI among 178238 individuals treated between 1997 and 2015. After adjusting for numerous confounders, trimethoprim was associated with the highest odds of AKI (AOR 1.72, 95% confidence interval 1.31-2.24) and hyperkalemia (AOR 2.27, 1.49-3.45) compared to amoxicillin. Ciprofloxacin also had increased odds of AKI (1.48, 1.03-2.13). In a sensitivity analysis, trimethoprim use for all indications (as opposed to just UTI) was associated with increased odds of AKI by 2.36 (95% confidence interval 2.22-2.51) versus amoxicillin. Limiting analysis to users of renin-angiotensin system blockers increased estimates only slightly (AOR 1.92, 95% CI 1.29-2.87). Trimethoprim did not have elevated odds of death within 14 days of initiation versus amoxicillin. The authors did not directly compare trimethoprim with TMP/SMX. While sulfonamide antibiotics (including sulfamethoxazole) have been implicated in AKI previously, this study showed the trimethoprim component alone was associated with AKI and hyperkalemia in patients over 65 years of age being treated for UTI. 

Minicuts

A recent RCT of prazosin versus placebo was undertaken to evaluated effects on PTSD-related nightmares but showed no significant difference in sleep quality or recurrent distressing dreams.18 Some suggest this may simple be a failure to appropriately identify clinical subtypes that are amenable to treatment given that these results are starkly different to those previously published.19

Mycobacterium tuberculosis (Mtb) has proven challenging to prevent and treat partially owing to its ability to infect alveolar macrophages. A recent animal study suggests intercepting Mtb infection at its earliest stages may be possible using a cytomegalovirus-based vaccine.20 While such a vaccine would not prevent infection altogether it has the potential to decrease transmission and thereby reduce disease incidence.

While already anecdotally clear, JAMA recently published a study of the relationship between income and life expectancy over time and geography.21 Not surprisingly, the authors found higher income was associated with greater longevity. Interestingly, though these differences increased over time and were subject to substantially regional variation.

Dr. Sharine Wittkopp, is a 2nd year internal medicine resident at NYU Langone Health

Peer reviewed by Kevin Hauck, attending physician, NYU Langone Health

References

 

  1. https://www.npr.org/sections/thetorch/2018/02/09/583565914/bigger-than-ever-and-more-diverse-team-usa-at-the-2018-winter-olympics. In.
  1. https://www.huffingtonpost.com/entry/epa-science-advisers-replaced_us_59fa2b75e4b0b0c7fa37bd17?utm_hp_ref=trump-administration. In.
  1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for prevention, diagnosis and management of COPD, 2018.
  1. Papi A, Vestbo J, Fabbri L, Corradi M, Prunier H, Cohuet G et al Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. The Lancet; doi https://doi.org/10.1016/S0140-6736(18)30206-X.
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  1. Kumar SK, Rajkumar V, Kyle RA, van Duin M, Sonneveld P, Mateos MV et al Multiple myeloma. Nat Rev Dis Primers 2017; 3: 17046.
  1. Mateos M-V, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S et al Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. New England Journal of Medicine 2017; 378: 518-528.  https://www.ncbi.nlm.nih.gov/pubmed/29231133
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  1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.  https://www.ncbi.nlm.nih.gov/pubmed/19717844
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  1. Inohara T, Xian Y, Liang L, et al. Association of intracerebral hemorrhage among patients taking non–vitamin k antagonist vs vitamin k antagonist oral anticoagulants with in-hospital mortality. JAMA 2018; 319: 463-473.
  1. Center for Disease Dynamics Economics and Policy. The state of the world’s antibiotics 2015, 2015.  https://www.cddep.org/publications/state_worlds_antibiotics_2015/
  1. Fraser TN, Avellaneda AA, Graviss EA, Musher DM Acute kidney injury associated with trimethoprim/sulfamethoxazole. J Antimicrob Chemother 2012; 67: 1271-1277.
  1. Crellin E, Mansfield KE, Leyrat C, Nitsch D, Douglas IJ, Root A et al Trimethoprim use for urinary tract infection and risk of adverse outcomes in older patients: cohort study. BMJ 2018; 360.
  1. Raskind MA, Peskind ER, Chow B, Harris C, Davis-Karim A, Holmes HA et al Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans. New England Journal of Medicine 2018; 378: 507-517.
  1. Ressler KJ Alpha-Adrenergic Receptors in PTSD — Failure or Time for Precision Medicine? New England Journal of Medicine 2018; 378: 575-576.
  2. Carpenter SM, Behar SM A new vaccine for tuberculosis in rhesus macaques. Nature Medicine 2018; 24: 124. https://www.nature.com/articles/nm.4488
  3. Chetty R, Stepner M, Abraham S, et al. The association between income and life expectancy in the united states, 2001-2014. JAMA 2016; 315: 1750-1766.