1. Adverse events.

Study ID	Morbidities	Rx group 1 N (%)	Rx group 2 N (%)	Rx group 3 N (%)	Treatment‐related mortality
Auerbach 2004	Participants with any AEs TDI group: delayed arthralgia/myalgia syndrome (2 events, grade 1) or acute hypersensitivity reaction (1 event). The acute hypersensitivity reaction occurred with a test dose (iron dextran as Dexferrum) and precluded further therapy. This event resolved completely with no residual effects. Bolus group: 8% (3/37) of participants experienced the following adverse events: delayed arthralgia/myalgia syndrome (1 event, grade 2), fatigue (1 event), or shortness of breath (1 event). Oral iron group: 2% (1/43) of participants experienced nausea (1 event).	ESAs + TDI iron N = 41	ESAs + bolus iron N = 37	ESAs + oral iron N = 43	Zero events
		3 (7)	3 (8)	1 (2)
Auerbach 2010	‐	‐	ESAs + IV iron N = 117	ESAs alone N = 121	Zero events
	Participants with any AEs	‐	104 (89)	110 (91)
	Participants with serious AEs	‐	41 (35)	45 (37)
	Participants with treatment‐related AEs	‐	14 (12)	0 (0)
	Participants with serious treatment‐related AEs	‐	3 (3)a	0 (0)
	Participants with AEs leading to study discontinuation	‐	12 (10)	14 (12)
	Cardiovascular and thromboembolic events	‐	18 (15)	19 (16)
	Embolism/thrombosis	‐	8 (7)	10 (8)
	Arrhythmias	‐	9 (8)	7 (6)
	Congestive heart failure	‐	3 (3)	1 (1)
	Myocardial infarction/artery disorders	‐	2 (2)	2 (2)
	Cerebrovascular accident	‐	1 (1)	0 (0)
	Deaths on study (any reason)b	‐	8 (7)	13 (11)
Bastit 2008	‐	‐	ESAs + IV iron N = 203	ESAs alone N = 193	Not reported
	No. of participants reporting specific AEs	‐	21 (10)	26 (13)
	Embolism/thrombosis, arterial and venous	‐	12 (6)	12 (6)
	Myocardial infarction, ischemic and coronary artery disease	‐	3 (1)	1 (1)
	Hypertension	‐	2 (1)	5 (3)
	Congestive heart failure	‐	1 (0)	3 (2)
	Cerebrovascular accident	‐	0 (0)	0 (0)
	Deaths on study (any reason)	‐	21 (10)	15 (8)
Beguin 2008	Data are not reported. Authors state that there was no difference in rates of thromboembolic events or other complications among the groups				Not reported
Bellet 2007	A total of 375 participants were enrolled in this phase III RCT. However, the number of participants randomized to each study arm is not reported. Three serious but non‐life‐threatening iron sucrose‐related AEs were observed, including 1 case of significant, transient hypotension in a female weighing 50 kg	‐	IV iron + ESAs	ESAs alone	Not reported
Henry 2007c,d	‐	‐	ESAs + IV iron N = 63	ESAs + oral iron N = 61	Not reported
	Constipation	‐	2 (3.2)	11 (18)
	Nausea	‐	2 (3.2)	3 (4.9)
	Dyspepsia	‐	1 (1.6)	3 (4.9)
	Asthenia	‐	1 (1.6)	2 (3.3)
	Anorexia	‐	0	2 (3.3)
	Abdominal pain	‐	0	2 (3.3)
	Diarrhea	‐	1 (1.6)	0
	Hypotension	‐	1 (1.6)	0
	Vasodilation	‐	1 (1.6)	0
	Angina pectoris	‐	1 (1.6)	0
	Tremor	‐	1 (1.6)	0
	Pain at injection site	‐	1 (1.6)	0
	Vomiting	‐	0	1 (1.6)
	Back pain	‐	0	1 (1.6)
	Dehydration	‐	0	1 (1.6)
	Dizziness	‐	0	1 (1.6)
	Taste perversion	‐	0	1 (1.6)
	Melena	‐	0	1 (1.6)
	Tinnitus	‐	0	1 (1.6)
Pedrazzoli 2011e	‐	‐	ESAs + IV iron N = 73	ESAs only N = 76	Zero events
	Participants with AEs	‐	55 (75.3)	49 (64.5)
	Participants with serious AEs	‐	8 (11)	10 (13.2)
	Participants with treatment‐related AEs	‐	7 (9.6)	6 (7.9)
	Vascular/thromboembolic events	‐	3 (4.1)	2 (2.6)
	Fatal AEs: all	‐	4 (5.5)	3 (3.9)
	Fatal AEs: treatment related	‐	0 (0)	0 (0)
Steensma 2011f	Worst toxicity reported (toxicities were graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events)	ESAs + IV iron N = 164	ESAs + oral iron N = 162	ESAs + placebo N = 163	Zero events
	None	12 (7)	15 (9)	22 (13)
	Mild	28 (17)	40 (25)	33 (20)
	Moderate	35 (21)	35 (22)	33 (20)
	Severe	52 (32)	42 (26)	49 (30)
	Life‐threatening	29 (18)	24 (15)	23 (14)
	Lethal (includes participants who died while on study regardless of causality)	8 (5)	6 (4)	3 (2)

^aEpisodes of transient anaphylactoid reactions occurred in two participants soon after initiating IV iron, but these participants recovered uneventfully without hospitalization; one participant in this group had enlarged uvula, lip swelling, and dyspnea (symptoms resolved).
 ^bDeaths on study or within 30 days after the last dose of study drug.
 ^cParticipants may have experienced more than one AE.
 ^dSix participants discontinued the study due to drug‐related AEs (sodium ferric gluconate complex, N = 2 (one angina, one nausea); oral iron, N = 4 (all gastrointestinal))
 ^eSeven participants, four on DA/iron and three on DA only, died during the study or within four weeks after the last administered dose of DA. Deaths were ascribed to disease progression, two cases in each group; and respiratory complications, one in the DA‐only group (infection), two in the DA/iron group (bleeding in one, acute respiratory distress syndrome in one) not related to study drugs administration.
 ^f7% (95% CI 3% to 12%) of participants in the IV iron arm discontinued study as a result of AEs versus 3% (95% CI 1% to 7%) for oral iron and 5% (95% CI 2% to 9%) for oral placebo. Study authors also stated that no individual AE was significantly more common in the IV iron arm compared with the other arms; instead, the overall difference was a result of small differences in several uncommon AEs, including dyspnea, back pain, and hypotension, which may have been caused by premedication rather than the IV iron product itself. Other AEs associated with IV iron in past studies, including myalgia, arthralgia, abdominal pain, pruritus, rash, nausea, vomiting, or fever, were not more common than with oral placebo or oral iron in this study.

AE = adverse event
 CI = confidence interval
 DA = darbepoietin
 ESA = erythropoiesis‐stimulating agent
 IV = intravenous
 RCT = randomized controlled trial
 TDI = total dose infusion