Table 7. Congestive heart failure (CHF), data from observational studies and meta-analyses.

	No. of patients (TNF/ Comparator)	Baseline disease characteristics (Duration, HAQ or DAS scores)	Definition of HF	At Risk Period	Duration of follow up	Biologic Arm	Comparator Arm	Reported Incidence
Observational
Listing 2008 [58]	RA 2757/1491	Duration: 9 yrs, TNF vs. 6 yrs, DMARD DAS: 5.8 (1.2) vs. 5.1 (1.3)	Confirmed by physician and fulfillment of NYHA classification criteria	Time on drug	3 years	Etanercept, Adalimumab, Infliximab	Conventional DMARDs	Risk of de novo heart failure HR (CI) 1.66 (0.67-4.10)a, b Worsening of prevalent heart failure HR (CI) 1.18 (0.30-4.73)a, b
Curtis 2007 [59]	4018 (RA and CD); Age < 50 yrs	Not provided	Identified using diagnostic codes Adjudicated by physician review of medical records	Within 9 months of exposure to drug	18 months	Infliximab, etanercept	Non biologic DMARDs	Risk of new onset HF in Anti TNF exposed vs. unexposedc: RR 4.3 (p NS) RA RR 1.2 (p NS) CD
Cole et al 2007 [60]	103: RA patients using TNF/ 100 RA controls/ 100 non RA controls	Not provided	Identified using ICD9 codes and review of medical records	Ever received TNF	3.5 yrs	Etanercept, Adalimumab, Infliximab	1) RA control 2) Non RA control	No difference in incidence or prevalence of heart failure b/n 3 gpsd (p =0.940)
Wolfe et al 2004 [61] National Databank	13171 RA (5832 in TNF gp), 2568 OA	Duration: 14.2 (10.7) yrs TNF vs. 15.5 (11.4) yrs DMARD HAQ: 1.2 (0.7) vs. 1.0 (0.7)	Patient self report or review of medical records	Ever received TNF agent	2 yrs	Infliximab, etanercept	Non biologic DMARDs	Anti-TNF vs. No Anti-TNF (rates) All heart failure: 2.8% vs. 3.9% (p =0.03) Incident heart failure: 0.2% vs. 0.2% (p NS)
Setoguchi et al 2008 [62]	RA, age >=65 yrs 1002/5593	NA	Hospital discharge diagnosise	Filled prescriptio n duration plus 14 daysf	TNF - 1.8 yrs; MTX gp- 2.5 yrs	Etanercept, Adalimumab, Infliximab	Methotrexate	HF Hospitalization in TNF vs. MTX gp: HR (CI) 1.7 (1.07-2.69); results similar in patients with and without previous HF. In patients with previous HF, HR (CI) for death: 4.19 (1.48-11.89)
Meta-analyses
Singh 2011 [29] 60 RCTs and 46 extension studies	Any indication other than HIV: 60630 subjects	NA	NA	While on drug (duration of study)	RCTs: Median 6 months Ltes: 13 months	5 Anti-TNF agents, Abatacept, Anakinra, Rituximab, Tocilizumab	Placebo or Non Biologic DMARD	OR (CI) of CHF in biologic arm vs. placebo 0.69 (0.18-2.69)
Burmester 2009 [5] Long term safety study of 36 trials of adalimumab (RCTs, LTEs, open label)	6 Rheumatic diseases 19041 patients	NA	NA	1st dose of drug to 70 days after last dose	10 yrs	Adalimumab	None	Events/ 100 patient yrs: 0-0.23 across various diseases

^{a, b}25 incident cases of heart failure in TNF gp. 12/98 patients w/ prevalent heart failure had worsening

^cSmall number of events: : 6 in TNF exposed gp, 3 in TNF unexposed

^dSmall number of cases (n=7 in TNF gp)

^ePrevious HF: HF diagnosis in a hospital discharge summary during the 2 yrs prior to the use of TNF agents or MTX; Hospitalization w/ HF: HF as primary discharge diagnosis

^fFilling at least 1 prescription of TNF agent or MTX -> last date of prescription+ no of days supply by prescription + 14days. Patients on TNF + MTX were categorized as TNF users.