Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA

Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA Examining the evidence: A systematic review of the inclusion and analysis of older adults in randomized controlled trials

Appendix Table: Description of trials reporting significant differential treatment effects by age

Trial # Condition Prespecified Interaction # SGAs Multiple Discussed Discussed Type of age Health Comorbidity Risk SGA studied subgroups test used reported comparisons that SGAs power as variable status SGA discussed were potential SGA exploratory limitation 1 Onc; Neph All Y 10 N Y N Dichot (65) Y N N Age-specific SGA Results: In trial of temsirolimus vs. interferon vs. combination treatment for metastatic renal cell cancer, temsirolimus alone increased overall survival (primary outcome) compared to interferon alone. Combination therapy did not differ significantly from interferon. However, the effect of temsirolimus was greater among patients under age 65, while patients aged 65 and over did not appear to benefit (treatment X age interaction, p = 0.02). 2 CV All Y 18 N N N Dichot (65) Y N N Age-specific SGA Results: In trial of tolvaptan vs. placebo in patients with heart failure, there was no significant difference in primary outcome (all- cause mortality and cardiovascular death or heart failure hospitalization) in the overall population. However, older adults (age 65+ years) in the tolvaptan group had lower mortality rates (treatment X age interaction for all-cause mortality, p = 0.02) 3 Onc NS Y 9 N N N Cont N N Y Age-specific SGA Results: In trial of paclitaxel vs. paclitaxel + bevacizumab for metastatic breast cancer, combination therapy increased progression- free survival (primary outcome) but not overall survival (secondary outcome). However, effect of combination therapy declined significantly with age (bevacizumab treatment effect X age interaction, p = 0.04). 4 Onc; GI NS Y 7 N N Y Cat (4) N N Y Age-specific SGA Results: In trial of adjuvant chemotherapy for colorectal cancer, mortality (primary outcome) and recurrence (secondary outcome) were both decreased in treatment group vs. observation group. However, individuals over age 70 benefitted less from chemotherapy (heterogeneity between four age groups was not significant with p = 0.21, but test for trend over four age groups was significant with p = 0.05). 5 Neuro; M/Sk NS Not clear 12 N Y Y Dichot (-) Y Y Y Age-specific SGA Results: In trial of decompressive laminectomy vs. nonsurgical care for degenerative spondylolisthesis with spinal stenosis, the intention-to-treat analysis showed no significant effects for primary outcomes (SF-36 bodily pain and physical function scores, and Oswestry Disability Index at 6 weeks, 3 months, 6 months, 1 year, and 2 years). The as-treated analysis showed significant advantage for surgery at multiple time points. Younger participants (< 65 years), however, had “larger treatment effects in favor of surgery at 3 months (21.3 vs. 14.6 for bodily pain, P = 0.02) but not at 1 or 2 years.” 6 CV Some Y 10 N Y N Cat (3) N Y Y Age-specific SGA Results: In trial of prasugrel vs. clopidogrel in patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel reduced primary outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). A post hoc exploratory SGA was conducted to investigate higher rates of bleeding with prasugrel. In this analysis, older adults (≥ 75 years) had no net benefit from prasugrel (hazard ratio 0.99, p = 0.92). 7 Cont Dichot (60) CV All Y 5 Y Y Y Cat (5) N Y Y Age-specific SGA Results: In trial of phlebotomy vs. control for iron excess in patients with peripheral arterial disease, there were no significant differences between treatment groups for primary or secondary end-points. However, phlebotomy resulted in significant reduction in secondary endpoints (death, nonfatal myocardial infarction, or stroke) in youngest age quartile (treatment X age interaction, p = 0.0038). Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA Examining the evidence: A systematic review of the inclusion and analysis of older adults in randomized controlled trials

References for Appendix Table

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2. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) Investigators. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007 Mar 28;297(12):1319-31.

3. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76.

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5. Weinstein JN, Lurie JD, Tosteson TD, Hanscom B, Tosteson AN, Blood EA, Birkmeyer NJ, Hilibrand AS, Herkowitz H, Cammisa FP, Albert TJ, Emery SE, Lenke LG, Abdu WA, Longley M, Errico TJ, Hu SS. Surgical versus nonsurgical treatment for lumbar degenerative spondylolisthesis. N Engl J Med. 2007 May 31;356(22):2257-70.

6. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15.

7. Zacharski LR, Chow BK, Howes PS, Shamayeva G, Baron JA, Dalman RL, Malenka DJ, Ozaki CK, Lavori PW. Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease: a randomized controlled trial. JAMA. 2007 Feb 14;297(6):603-10.