Primecuts – This Week in the Journals

April 3, 2018

PrimeCuts 9 min read

By Maya Madhavan, MD

Peer Reviewed

Last week, over a people million took to the streets to march for gun control as part of the March for Our Lives movement. It was noted to be one of the biggest youth protests since the Vietnam War1. Across the nation, medical students and housestaff also participated in institution wide protests and discussions, as many consider gun-related violence to be a public health crisis. Let’s take a look at what else went on in the medical community over the last week. 

Long Term Serum Potassium Levels Associated with Mortality after Acute Decompensated Heart Failure Exacerbation

Heart failure is often associated with derangements in serum potassium levels, which can be either from disease related comorbidities or iatrogenic due to the frequent use of renin-angiotensin-aldosterone system blockers and diuretics. Prior studies have addressed the association between both hypo and hyperkalemia and mortality in heart failure patients2-3 but only use a single measurement and do not account for the fluctuations in serum potassium that are seen in these patients over time.

A study recently published in Circulation4 aimed to address the prognostic value of long term serum potassium monitoring in patients with heart failure. The single center study looked at over 2000 patients discharged after an admission for acute decompensated heart failure. Patients both with reduced and preserved ejection fraction were included. Patients who died during admission or did not follow up were excluded.  Potassium levels were measured at discharge and at subsequent outpatient follow up visits or admissions. The patients were followed until death or cardiac transplant with a median follow up of 2.79 years. The primary outcome was all-cause mortality.

The authors found a U shaped relationship between a variable (Kcumulative) that accounted for long term changes in serum potassium and all-cause mortality, with values of Kcumulative at both ends of the range predicting higher mortality risk. At both extremes, a Kcumulative value of 2.5 and 6.0 corresponded to a hazard ratio for all-cause mortality of 7.09 (95% CI, 2.31–21.78) and 1.67 (95% CI, 1.12–2.496) respectively. Similar U shaped curves were observed for cardiovascular and heart failure related mortality. When sudden death was used as an endpoint the hazard ratio increased as Kcumulative increased. When patients were sorted into broad categories of hypo and hyperkalemia using normokalemia as a reference, both were associated with increased all-cause mortality. The authors also found that patients who were able to correct their potassium derangements had a significantly lower risk of mortality than patients who remained persistently hypo/hyperkalemic.

The study is limited primarily by its nature as an observational study. Although the data was adjusted for several clinical variables, for example, presence of renal dysfunction, other traits intrinsic to the hypo-, normo-, and hyperkalemic groups could explain some of the differences in mortality. Nevertheless, the data does support the clinical utility of maintaining long-term normokalemia in patients who have been hospitalized for an acute heart failure exacerbation.

Cardiovascular Risk of Febuxostat vs. Allopurinol for Treatment of Gout

Patients with gout are known to be at a significantly higher risk of cardiovascular events and chronic disease than patients without gout5. Febuxostat is a medication used in gout patients that has a greater effect than allopurinol at reducing uric acid levels6, however has been shown in prior trials to be associated with a somewhat higher rate of cardiovascular events than allopurinol7-8.

Given this prior data, CARES, a randomized, multi-center, double-blinded trial aimed to determine whether febuxostat is non-inferior to allopurinol regarding the risk of cardiovascular events in patients with gout and co-morbid cardiovascular disease9. Inclusion criteria included a diagnosis of gout with a serum urate level of at least 7.0 mg/dL or 6.0 mg/dL with inadequately controlled disease after a washout from previous therapy, along with a history of major cardiovascular disease. Over 6000 patients were randomized to either allopurinol or febuxostat and stratified by renal function to determine dosing. Doses were subsequently adjusted based on serum urate levels. The median duration of follow-up in the febuxostat and allopurinol groups were 968 days and 942 days respectively.

The primary endpoint for the study was a composite of first occurrence of cardiovascular events including cardiovascular death, nonfatal MI and strokes, or urgent revascularization for unstable angina. Febuxostat was found to be non-inferior to allopurinol for this endpoint (HR 1.03 (0.87-1.23), P=0.002 for noninferiority), as well as for nonfatal MI, stroke and unstable angina and all events composited. However, febuxostat had a higher risk for cardiovascular death and death from any cause (Number needed to harm 91 and 71 respectively).

One limitation of this study was that the analysis carried out was a modified intention-to-treat analysis, however in both arms a large number of patients discontinued treatment or follow-up. The authors speculate on what the results may be for a per-protocol analysis but do not include the numbers which could affect the major results. Notably the trial is also industry funded. The results warrant clinicians weighing the risks of potential increased risk of death with benefits of treatment with febuxostat in their patients at high risk for cardiovascular death.

Extended Versus Bolus Infusions of B-lactams for Febrile Neutropenia

Broad spectrum B-lactam antibiotics are the initial mainstay of treatment of neutropenic patients with new fever and are critical for reduction in mortality10. These antibiotics are typically administered as a bolus; however recent data suggests that using an extended or continuous infusion rather than a bolus is associated with higher rates of achieving a target concentration that exceeds the minimum inhibitory concentration of the bacteria11-12.

A single center, unblinded trial in Clinical Infectious Diseases aimed to compare clinical outcomes in patients who were randomized to extended (4 hour) versus bolus infusions of zosyn or ceftazidime for febrile neutropenia13. Inclusion criteria included patients 18 years or older who were undergoing hematopoietic cell transplantation or consolidation chemotherapy for acute leukemia. Exclusion criteria included being scheduled for outpatient follow-up while neutropenic, receiving maintenance chemotherapy, creatinine clearance of less than 40 ml/min, and being infected or colonized with bacteria resistant to the antibiotics studied up to 30 days prior to enrollment. Additional antibiotics were added on as clinically indicated.

The primary endpoint in this trial was “overall treatment response” on day 4, including fever resolution, sterile cultures, resolving symptoms of infection and lack of changes to the antibiotic regimen. In the intention-to-treat analysis, this endpoint was attained in 55.1% of the bolus arm versus 74.4% of the extended arm (ARR 19.3%, 95% CI 1.4%-37.1% with NNT of 5, P=0.044). Similar data was obtained in the per-protocol analysis. The authors also found a significant increase in this endpoint for patients with a documented pulmonary infiltrate. Secondary endpoints such as need for pressors, length of stay and rates of C diff and AKI did not significantly differ.

Major limitations of this trial included the low sample size at a single center (105 patients in the ITT analysis), with a relatively narrow type of patient population, warranting further investigation. However, this intervention appears promising as a relatively simple, low-risk and cost-effective way to improve outcomes for febrile neutropenia.

Do E-Cigarettes Help Patients to Quit Smoking?

E-cigarettes are battery operated devices that users can inhale a nicotine aerosol from, thus avoiding the toxic effects of combustion associated with traditional cigarettes. Prior studies have shown that cigarette smokers who manage to completely switch to e-cigarettes can reduce their risks related to tobacco use14 but it is unclear whether e-cigarettes are effective at helping patients to quit smoking.

Helping HAND 2, is a 3 site randomized controlled trial that randomized patients who planned to quit smoking after discharge from a hospital to either a standard of care smoking cessation program or the intervention arm, which included access to a free 30 day supply of a FDA approved smoking cessation pharmacotherapy. Observational data that analyzed self-reported e-cigarette use among the participants of this trial was recently published in the Annals of Internal Medicine15. E-cigarette use was self-reported at 1 and 3 months post-discharge, and success at tobacco abstinence quantified using saliva nicotine metabolites or measurement of expired carbon monoxide to differentiate nicotine from e-cigarettes from traditional cigarettes.

The authors found that patients who self-reported e-cigarette use in the 3 months after discharge were less likely to be abstinent from smoking (10.1% vs. 26.6%; Absolute risk difference, −16.5% [95% CI, −23.3% to −9.6%])), corresponding to a NNH of 6. There was also a significantly greater risk of failure to quit smoking among e-cigarette users in the intervention arm compared to the standard of care arm.

This secondary analysis of a RCT was significantly limited in that the patients were not randomized to e-cigarette use, and traits inherent to the choice to use e-cigarettes could also explain lack of success with smoking cessation. Thus, clinicians cannot conclude that e-cigarette use makes it harder to stop smoking. However, the authors did perform an analysis that indicated that a large confounding effect would be needed to remove the results observed. Clinicians might use this data in practice to counsel patients that there isn’t yet evidence to suggest that e-cigarettes can help them to stop smoking.

Minicuts:

A double-blind, multi-center randomized controlled trial (EXPAND) recently published in The Lancet found that siponimod is the first therapy to show superiority over placebo in reducing disability progression in patients with secondary progressive multiple sclerosis16.

A cohort multicenter study published in the British Medical Journal found a small increase in in-hospital mortality for patients admitted for acute MI initiated on haldol compared to those initiated on atypical antipsychotics for management of delirium.17

A small phase 2 trial published in the New England Journal of Medicine showed that the combination of ibrutinib and venetoclax could improve outcomes for patients with mantle-cell lymphoma beyond outcomes observed with monotherapy of either drug18.

Dr. Maya Madhavan, is a 1st year internal medicine resident at NYU Langone Health.

Peer reivewed by Ian Henderson, MD, editor, Clinical Correlations and chief resident in internal medicine, NYU Langone Health.

Image courtesy of Wikimedia Commons

References:

  1. Lopez, German. “It’s official: March for Our Lives was one of the biggest youth protests since the Vietnam War” . Vox. Mar 26, 2018. https://www.vox.com/policy-and-politics/2018/3/26/17160646/march-for-our-lives-crowd-size-count
  2. Alper AB, Campbell RC, Anker SD, Bakris G, Wahle C, Love TE, Hamm LL, Mujib M, Ahmed A. A propensity-matched study of low serum potassium and mortality in older adults with chronic heart failure. Int J Cardiol. 2009;137:1–8.
  3. Ahmed MI, Ekundayo OJ, Mujib M, Campbell RC, Sanders PW, Pitt B, Perry GJ, Bakris G, Aban I, Love TE, Aronow WS, Ahmed A. Mild hyperkalemia and outcomes in chronic heart failure: a propensity matched study. Int J Cardiol. 2010;144:383–388.
  4. Núñez J, Bayés-Genís A, Zannad F, Rossignol P, Núñez E, Bodí V, Miñana G, Santas E, Chorro FJ, Mollar A, Carratalá A, Navarro J, Górriz JL, Lupón J, Husser O, Metra M, Sanchis J. Long-Term Potassium Monitoring and Dynamics in Heart Failure and Risk of Mortality. Circulation. 2018 Mar 27;137(13):1320-1330.
  5. Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation 2007; 116:894-900
  6. Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum 2008;59:1540-8.
  7. Schumacher HR Jr, Becker MA, Lloyd E, MacDonald PA, Lademacher C. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford) 2009;48: 188-94
  8. White WB, Chohan S, Dabholkar A, Hunt B, Jackson R. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities. Am Heart J 2012;164:14-20.
  9. White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, Hunt B, Castillo M, Gunawardhana L, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018 Mar 29;378(13):1200-1210.
  10. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52: 427-431.
  11. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, et al. Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med 2016; 42: 1535-1545.
  12. Abdul-Aziz MH, Lipman J, Akova M, et al. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J Antimicrob Chemother 2016; 71: 196-207.
  13. Ram R, Halavy Y, Amit O, Paran Y, Katchman E, Yachini B, Kor S, Avivi I, Ben-Ami R. Extended versus Bolus Infusion of Broad Spectrum β-Lactams for Febrile Neutropenia: an Unblinded Randomized Trial, Clinical Infectious Diseases. 2018 28 Mar. https://doi.org/10.1093/cid/ciy258
  14. Bhatnagar A, Whitsel LP, Ribisl KM, Bullen C, Chaloupka F, Piano MR et al, American Heart Association Advocacy Coordinating Committee, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, and Council on Quality of Care and Outcomes Research. Electronic cigarettes: a policy statement from the American Heart Association. Circulation. 2014; 130:1418-36.
  15. Rigotti NA, Chang Y, Tindle HA, Kalkhoran SM, Levy DE, Regan S, Kelley JHK, Davis EM, Singer DE. Association of E-Cigarette Use With Smoking Cessation Among Smokers Who Plan to Quit After a Hospitalization: A Prospective Study. Ann Intern Med. 2018 Mar 27. doi: 10.7326/M17-2048. [Epub ahead of print]
  16. Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, Vermersch P, Arnold DL, Arnould S, Scherz T, Wolf C, Wallström E, Dahlke F, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018 Mar 22. pii: S0140-6736(18)30475-6. doi: 10.1016/S0140-6736(18)30475-6. [Epub ahead of print]
  17. Park Y, Bateman BT, Kim DH, Hernandez-Diaz S, Patorno E, Glynn RJ, Mogun H, Huybrechts KF. Use of haloperidol versus atypical antipsychotics and risk of in-hospital death in patients with acute myocardial infarction: cohort study. BMJ. 2018 Mar 28;360:k1218. doi: 10.1136/bmj.k1218.
  18. Tam CS, Anderson MA, Pott C, Agarwal R, Handunnetti S, Hicks RJ, Burbury K, Turner G, Di Iulio J, Bressel M, Westerman D, Lade S, Dreyling M, Dawson SJ, Dawson MA, Seymour JF, Roberts AW. Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N Engl J Med. 2018 Mar 29;378(13):1211-1223.