Primecuts – This Week in the Journals

November 8, 2019


By Alvaro Vargas

Peer Reviewed

With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.

Gilteritinib or Chemotherapy for Relapsed for Refractory FLT3-Mutated AML [1]

Outcomes in relapsed or refractory acute myeloid leukemia (AML) with unfavorable cytogenetic risk status are poor [2]. One of these cytogenetic markers is the FMS-like tyrosine kinase 3 (FLT3), a cytokine receptor tyrosine kinase that is present in about 30% of patients with AML [3].

This international, multicenter phase 3 trial [1], randomized 247 patients with relapsed or refractory FLT3+ AML in a 2:1 fashion to gilteritinib, an oral and selective FLT3 inhibitor, or salvage chemotherapy. Results showed gilteritinib was superior to salvage chemotherapy in both the primary endpoints, overall survival (9.3 months vs. 5.6 months; HR for death 0.65, 95% CI 0.49-0.83) and full remission with full or partial hematologic recovery (34% vs. 15.3%; risk difference 18.6 percentage points, 95% CI 9.8-27.4).  These results are consistent with a similarly designed trial [4], which also showed advantage of FLT3-directed therapy compared to salvage chemotherapy, however outcomes with this other agent (quizartinib) were not as robust and in contrast to gilteritinib, quizartinib is only used for one of the FLT3 variants.

Authors do warn that although these results are promising, they should not be overinterpreted, as there are important limitations, such as the relatively small sample size (especially for subgroup analysis) and the fact that very few subjects received FLT3-directed therapy during induction. Nonetheless, we might indeed be witnessing an “AML therapeutic revolution” [5].

Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism [6]

Subclinical hypothyroidism is defined by increased thyroid-stimulating hormone (TSH) and normal free thyroxine levels (FT4). Previous literature [7] and current guidelines [8,9] recommend against the treatment of subclinical hypothyroidism, however adults 80 years and older have been underrepresented in previous studies [7].

To investigate whether adults 80 years or older would benefit from treatment, authors in this study [6] combined data from two randomized, double-blinded, placebo-controlled parallel-group clinical trials: the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial [10], and the Thyroid Hormone Replacement for Untreated Adults With Subclinical Hypothyroidism Trial (TRUST) [11] . A total of 251 participants (TSH range 4.6-17.6 mIU/L) were randomized in a 1:1 fashion to levothyroxine treatment or placebo. The co-primary outcomes were Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire scores for the domains of hypothyroid symptoms and tiredness. This questionnaire ranges from 0-100 (higher scores mean more symptoms), and the minimal score difference for clinical importance is 9 [12].

At 1 year, hypothyroid symptoms scores between the intervention and placebo arm were not significantly different (scores decreased from 21.7 at baseline to 19.3 in the levothyroxine group, and 19.8 to 17.4 in the placebo group; p=0.53). Similarly, tiredness scores were not statistically different and increased from 25.5 to 28.2 in the levothyroxine group and 25.1 to 28.7 in the placebo group (p=0.96).

Despite some limitations, such as the lack of a pre-specified subgroup analysis in the high-symptom-burden group and more severely elevated TSH (values ranged from 4.6-12.5 mIU/L in the levothyroxine group), authors concluded that adults 80 years or older with subclinical hypothyroidism should not be routinely treated with levothyroxine.

The Cost-Effectiveness of Cognitive Behavioral Therapy Versus Second-Generation Antidepressants for Initial Treatment of Major Depressive Disorder in the United States: A Decision Analytic Model [13]

For several years, the first-line treatment for major depressive disorder (MDD) has been pharmacologic therapy with second-generation antidepressants (SGAs) or cognitive behavioral therapy (CBT) [14]. Despite this, it is estimated that fewer than a quarter of patients receive CBT [15]. One factor that could account for the underuse of CBT is cost, as a single CBT session costs more than $100 [16], compared to commonly used SGAs, which cost less than $100 per year [17].

To further assess the cost-effectiveness of SGAs compared to CBT as initial treatment modality, authors used a previously described decision analytic model [18] to simulate the clinical and economic outcomes [13]. Authors’ methodology was consistent with the 2013 Consolidation Health Economic Evaluation Reporting Standards [19]. Results showed that there does not appear to be a substantial economic difference between SGAs and CBT, although the 1-year analysis favored SGAs (64-77% chance of being preferred) and the 5-year analysis favored CBT (73-77% chance of being preferred).

Authors did note a strong trend towards long-term savings with CBT, which despite not being statistically significant, could result in more than $1.5 billion in savings at 5 years. In short, authors concluded that given their clinical and economic similarities, the decision between SGAs and CBT for the initial treatment of MDD should continue to rely on patient-centered discussions that include preferences, CBT availability, and ability to afford up-front costs.

Minicuts

Serious Illness Treatment Preferences for Older Adults with Advanced CKD [20]

This study asked 382 participants 60 years or older with non-dialysis-dependent chronic kidney disease (CKD) stage 4 or 5 to answer what would be important to them in case they had a serious illness. Among them, 20% answered “live as long as possible,” compared to 33% for “focus on comfort.” One third of those who wanted to “focus on comfort” reported that “a life on dialysis would not be worth living,” compared to 5% of those who answered “live as long as possible” (p<0.001).

Nintedanib in Progressive Fibrosing Interstitial Lung Diseases [21]

Nintedanib, an inhibitor of tyrosine kinase, has been shown to improve outcomes in idiopathic pulmonary fibrosis [22]. In this double-blinded, placebo-controlled, phase 3 trial that included 663 patients [21], nintedanib was tested in a broad range of fibrosing lung diseases and was found to slow down the decline of the functional vital capacity (FVC) from 187.8ml per year to 80.8ml per year (p<0.001).

Incident Type 2 Diabetes in OSA and Effect of CPAP Treatment: A Retrospective Clinic Cohort Study [23]

This retrospective cohort study used data from 1,206 subjects to correlate obstructive sleep apnea (OSA) severity and continuous positive airway pressure (CPAP) adherence with the incidence of type 2 diabetes (T2D). At a median follow-up of 7.3 years, investigators found that moderate and severe OSA increased the risk of T2D incidence (HR 2.01, 95% CI 1.06-3.81 for moderate; HR 2.62, 95% CI 1.40-4.93 for severe). The third of patients who used CPAP regularly appeared to have a lower T2D incidence, 3.41 versus 1.61 per 100 person-years.

Physician and Trainee Experiences With Patient Bias [24]

This qualitative study that included 50 participants (11 hospitalists, 26 internal medicine residents, and 13 students) aimed to explore episodes of biased behaviors from patients towards physicians and trainees. It found that there is a wide range of biased behaviors that participants were exposed to including explicit racist, sexist, and homophobic comments, as well as more subtle microaggressions such as “jokes.” Uniformly, participants agreed that further training on how to respond in these situations, along with clear institutional policies, would be beneficial.

Dr. Alvaro Vargas is a third-year resident in internal medicine at NYU Langone Health

Peer reviewed by Christian Torres, MD, chief resident, internal medicine, NYU School of Medicine

Image courtesy of Wikimedia Commons

References

[1] Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019;381:1728-1740. https://www.nejm.org/doi/full/10.1056/NEJMoa1902688

[2] Litzow MR, Othus M, Cripe LD, et al. Failure of three novel regimens to improve outcome for patients with relapsed or refractory acute myeloid leukaemia: a report from the Eastern Cooperative Oncology Group. Br J Haematol 2010; 148: 217-25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809127/

[3] Megías-Vericat JE, Martínez-Cuadrón D, Sanz MA, Montesinos P. Salvage regimens using conventional chemotherapy agents for relapsed/refractory adult AML patients: a systematic literature review. Ann Hematol 2018; 97: 1115-53. https://www.ncbi.nlm.nih.gov/pubmed/29680875

[4] Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019;20:984-997. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30150-0/fulltext

[5] Jan Philipp Bewersdorf, Maximilian Stahl & Amer M. Zeidan (2019) Are we witnessing the start of a therapeutic revolution in acute myeloid leukemia?, Leukemia & Lymphoma, 60:6, 1354-1369. https://www.ncbi.nlm.nih.gov/pubmed/30652518

[6] Mooijaart SP, Du Puy RS, Stott DJ, et al. Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism. JAMA. Published online October 30, 2019. https://jamanetwork.com/journals/jama/fullarticle/2753909

[7] Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007;(3):CD003419. https://www.cochrane.org/CD003419/ENDOC_thyroid-hormone-replacement-for-subclinical-hypothyroidism

[8] Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988-1028. https://journals.aace.com/doi/abs/10.4158/EP12280.GL

[9] Pearce SH, Brabant G, Duntas LH, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2(4):215-228. https://www.eurothyroid.com/files/download/ETA-Guideline-Management-of-Subclinical-Hypothyroidism.pdf

[10] Du Puy RS, Postmus I, Stott DJ, et al. Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over. BMC Endocr Disord. 2018;18(1):67. http://eprints.gla.ac.uk/171015/

[11] Stott DJ, Gussekloo J, Kearney PM, et al. Study protocol; thyroid hormone replacement for untreated older adults with subclinical hypothyroidism: a randomised placebo controlled trial (TRUST). BMC Endocr Disord. 2017;17(1):6. https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-017-0156-8

[12] Watt T, Hegedüs L, Groenvold M, et al. Validity and reliability of the novel thyroid-specific quality of life questionnaire, ThyPRO. Eur J Endocrinol. 2010;162(1):161-167. https://eje.bioscientifica.com/view/journals/eje/162/1/161.xml

[13] Ross EL, Vijan S, Miller EM, et al. The Cost-Effectiveness of Cognitive Behavioral Therapy Versus Second-Generation Antidepressants for Initial Treatment of Major Depressive Disorder in the United States: A Decision Analytic Model. Ann Intern Med. 2019. https://annals.org/aim/article-abstract/2753801/cost-effectiveness-cognitive-behavioral-therapy-versus-second-generation-antidepressants-initial

[14] Qaseem A, Barry MJ, Kansagara D; Clinical Guidelines Committee of the American College of Physicians. Nonpharmacologic versus pharmacologic treatment of adult patients with major depressivev disorder. A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2016;164:350-9. https://annals.org/aim/fullarticle/2490527/nonpharmacologic-versus-pharmacologic-treatment-adult-patients-major-depressive-disorder-clinical

[15] Olfson M, Blanco C, Marcus SC. Treatment of adult depression in the United States. JAMA Intern Med. 2016;176:1482-91. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2546155

[16] Centers for Medicare & Medicaid Services. Physician fee schedule. Accessed at www.cms.gov/apps/physician-fee-schedule/ on 17 July 2017

[17] Trevin˜o LA, Ruble MW, Trevin˜o K, et al. Antidepressant medication prescribing practices for treatment of major depressive disorder. Psychiatr Serv. 2017;68:199-202. https://ps.psychiatryonline.org/doi/full/10.1176/appi.ps.201600087?url_ver=Z39.88 2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&

[18] Ross EL, Zivin K, Maixner DF. Cost-effectiveness of electroconvulsive therapy vs pharmacotherapy/psychotherapy for treatmentresistant depression in the United States. JAMA Psychiatry. 2018;75: 713-22. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/10.1001/jamapsychiatry.2018.0768

[19] Husereau D, Drummond M, Petrou S, et al; ISPOR Health Economic Evaluation Publication Guidelines-CHEERS Good Reporting Practices Task Force. Consolidated health economic evaluation reporting standards (CHEERS)—explanation and elaboration: a report of the ISPOR health economic evaluation publication guidelines good reporting practices task force. Value Health. 2013;16:231-50. https://www.valueinhealthjournal.com/article/S1098-3015(13)00022-3/fulltext?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1098301513000223%3Fshowall%3Dtrue

[20] Nicolas Awad Baddour, Edward D. Siew, Cassianne Robinson-Cohen, Huzaifah Salat, Olivia J. Mason, Thomas G. Stewart, Mohana Karlekar, Maie H. El-Sourady, Loren Lipworth, Khaled Abdel-Kader JASN Nov 2019, 30 (11) 2252-226. https://jasn.asnjournals.org/content/30/11/2252

[21]. Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. New England Journal of Medicine. 2019;381:1718-1727.  https://www.nejm.org/doi/full/10.1056/NEJMoa1908681

[22] Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365: 1079-87. https://www.nejm.org/doi/full/10.1056/NEJMoa1103690

[23]. Xu, Pei Hang et al. Incident Type 2 Diabetes in OSA and Effect of CPAP Treatment, CHEST, Volume 156, Issue 4, 743-753. https://journal.chestnet.org/article/S0012-3692(19)31119-5/pdf

[24] Wheeler M, de Bourmont S, Paul-Emile K, et al. Physician and Trainee Experiences With Patient Bias. JAMA Intern Med. Published online October 28, 2019. https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2753424

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