Mortality in chemotherapy trials during the active study period
		ESA arm			Control arm			ESA versus control
Subgroups	Patients	events	sample	%	events	sample	%	HR	95% CI	p value*
Patient level characteristics
Hb at baseline (continuous)										0.87
Hb at baseline (cat 1)										0.90
Hb ≤ 8 g/dL	569	52	321	16%	34	248	14%	1.20	0.78‐1.86
Hb 8‐≤ 10 g/dL	2888	188	1606	12%	156	1282	12%	1.07	0.86‐1.33
Hb 10‐≤ 12 g/dL	3748	213	2121	10%	171	1627	11%	1.10	0.90‐1.34
Hb 12‐≤ 14 g/dL	2185	119	1108	11%	100	1077	9%	1.23	0.94‐1.60
Hb >14 g/dL	555	29	286	10%	25	269	9%	0.96	0.56‐1.65
Unknown	496	4	234	2%	4	262	2%	0.76	0.19‐3.05
Hb at baseline (cat 2)										0.99
Hb ≤ 8 g/dL	569	52	321	16%	34	248	14%	1.21	0.78‐1.86
Hb 8‐≤ 9 g/dL	949	72	549	13%	59	400	15%	1.01	0.72‐1.44
Hb 9‐≤ 10 g/dL	1939	116	1057	11%	97	882	11%	1.10	0.84‐1.44
Hb 10‐≤ 11 g/dL	2074	113	1179	10%	86	895	10%	1.11	0.84‐1.47
Hb 11‐≤ 12 g/dL	1674	100	942	11%	85	732	12%	1.08	0.81‐1.45
Hb 12‐≤ 13 g/dL	1359	80	679	12%	68	680	10%	1.26	0.91‐1.74
Hb 13‐≤ 14 g/dL	826	39	429	9%	32	397	8%	1.19	0.74‐1.89
Hb >14 g/dL	555	29	286	10%	25	269	9%	0.96	0.56‐1.65
Unknown	496	4	234	2%	4	262	2%	0.77	0.19‐3.07
Malignancy type
Tumour (cat. 1)										0.18
Haematological malignancies	1832	99	1034	10%	65	798	8%	1.12	0.81‐1.54
Solid tumours	7967	464	4311	11%	379	3656	10%	1.14	0.99‐1.31
Other	600	38	314	12%	43	286	15%	0.74	0.48‐1.15
Missing / unknown	42	4	17	24%	3	25	12%	1.96	0.44‐8.81
Tumour (cat. 2)										0.15
Haematological malignancies	1832	99	1034	10%	65	798	8%	1.11	0.81‐1.53
Breast cancer	4038	209	2076	10%	152	1962	8%	1.38	1.12‐1.70
Head and neck cancer	26	1	12	8%	2	14	14%	0.63	0.06‐6.99
Lung cancer	2237	187	1172	16%	173	1065	16%	1.03	0.83‐1.26
Gastrointestinal cancer	429	32	267	12%	26	162	16%	0.81	0.48‐1.37
Gynaecological cancer	1077	28	681	4%	18	396	5%	1.06	0.59‐1.95
Genitourinary cancer	160	7	103	7%	8	57	14%	0.61	0.22‐1.72
Other	600	38	314	12%	43	286	15%	0.74	0.48‐1.15
Missing / unknown	42	4	17	24%	3	25	12%	1.92	0.43‐8.62
Sex
Male	3125	241	1720	14%	209	1405	15%	0.99	0.82‐1.19	0.14
Female	7316	364	3956	9%	281	3360	8%	1.18	1.01‐1.39
Age
Age continuous										0.57
Age categorical										0.34
< 18 years	123	0	55	0%	1	68	1%	Not estimable	Not estimable
≥18‐35 years	312	9	171	5%	8	141	6%	0.78	0.30‐2.03
≥35‐45 years	1135	45	620	7%	28	515	5%	1.34	0.83‐2.14
≥45‐55 years	2425	123	1311	9%	93	1114	8%	1.22	0.93‐1.60
≥55‐65 years	3233	175	1724	10%	172	1509	11%	0.93	0.75‐1.15
≥65‐75 years	2444	190	1359	14%	146	1085	13%	1.16	0.93‐1.44
≥75 years	758	63	430	15%	41	328	13%	1.28	0.86‐1.90
Missing / unknown	11	0	6	0%	1	5	20%	Not estimable	Not estimable
Hct levels at baseline
Hct continuous										0.57
Hct categorical										0.22
≤ 23.5%	275	29	144	20%	17	131	13%	1.61	0.88‐2.94
23.5‐≤ 29.4%	2033	118	1135	10%	109	898	12%	0.96	0.74‐1.25
29.4‐≤ 35.3%	3281	208	1882	11%	163	1399	12%	1.02	0.83‐1.25
35.3‐≤ 41.2%	1801	152	931	16%	115	870	13%	1.36	1.07‐1.73
> 41.2%	459	39	249	16%	33	210	16%	1.07	0.67‐1.71
Missing / unknown	2592	59	1335	4%	53	1257	4%	1.04	0.72‐1.52
Serum Epo at baseline
Serum Epo continuous										0.91
Serum Epo categorical										0.20
< 25 mU/ml	1032	68	608	11%	41	424	10%	1.34	0.91‐1.98
25‐<100 mU/ml	2083	110	1162	9%	114	921	12%	0.79	0.61‐1.03
100‐<200 mU/ml	518	45	314	14%	28	204	14%	1.14	0.71‐1.84
200‐<500 mU/ml	227	18	134	13%	11	93	12%	1.18	0.56‐2.51
≥ 500 mU/ml	99	8	57	14%	4	42	10%	1.01	0.30‐3.39
Missing / unknown	6482	356	3401	10%	292	3081	9%	1.18	1.01‐1.38
Performance score
ECOG categorical										0.58
ECOG 0	3025	77	1582	5%	66	1443	5%	1.23	0.89‐1.71
ECOG 1	3784	237	2105	11%	185	1679	11%	1.10	0.91‐1.34
ECOG 2	1140	137	623	22%	114	517	22%	1.07	0.84‐1.38
ECOG 3	105	15	57	26%	13	48	27%	0.98	0.46‐2.07
ECOG 4	3	1	2	50%	0	1	0%	Not estimable	Not estimable
ECOG missing / unknown	2384	138	1307	11%	112	1077	10%	1.04	0.80‐1.33
ECOG dichotomous										1.00
ECOG 0, 1, 2	7949	451	4310	10%	365	3639	10%	1.12	0.98‐1.29
ECOG 3, 4	108	16	59	27%	13	49	27%	1.12	0.54‐2.34
ECOG missing	2384	138	1307	11%	112	1077	10%	1.03	0.80‐1.33
Body mass index
≤ 19 kg/m²	607	43	292	15%	45	315	14%	0.95	0.63‐1.45	0.63
19‐≤ 25 kg/m²	4283	262	2318	11%	208	1965	11%	1.11	0.93‐1.34
25‐≤ 30 kg/m²	2698	143	1468	10%	116	1230	9%	1.01	0.79‐1.30
> 30 kg/m²	1294	60	686	9%	44	608	7%	1.32	0.89‐1.94
Missing / not reported	1559	97	912	11%	77	647	12%	1.22	0.90‐1.65
History of thromboembolic events
Yes	375	27	207	13%	29	168	17%	0.76	0.45‐1.28	0.14
No	6292	400	3469	12%	320	2823	11%	1.14	0.98‐1.32
Missing / not reported	3774	178	2000	9%	141	1774	8%	1.08	0.86‐1.35
History of cardiovascular events
Yes	2319	161	1295	12%	126	1024	12%	1.11	0.88‐1.41	0.93
No	5050	266	2721	10%	223	2329	10%	1.10	0.92‐1.31
Missing / not reported	3072	178	1660	11%	141	1412	10%	1.08	0.86‐1.35
History of hypertension
Yes	1396	111	798	14%	81	598	14%	1.18	0.89‐1.57	0.61
No	5271	316	2878	11%	268	2393	11%	1.08	0.92‐1.28
Missing / not reported	3774	178	2000	9%	141	1774	8%	1.08	0.86‐1.35
History of diabetes mellitus
Yes	430	36	219	16%	37	211	18%	1.01	0.64‐1.61	0.74
No	5149	350	2786	13%	286	2363	12%	1.10	0.94‐1.29
Missing / not reported	4862	219	2671	8%	167	2191	8%	1.12	0.91‐1.37
Geographical region
Northern America	2083	92	1088	8%	95	995	10%	0.95	0.71‐1.26	0.35
Northern, Western & Southern Europe	6082	341	3342	10%	267	2740	10%	1.05	0.90‐1.24
Eastern Europe	1413	135	734	18%	98	679	14%	1.34	1.03‐1.73
Australia & New Zealand	286	14	184	8%	7	102	7%	1.59	0.64‐3.95
Other	189	13	106	12%	13	83	16%	0.90	0.42‐1.94
Missing / not reported	388	10	222	5%	10	166	6%	1.02	0.42‐2.45
Tumour stage
Metastatic / advanced	6054	491	3325	15%	388	2729	14%	1.16	1.01‐1.32	0.61
Not metastatic / not advanced	2902	25	1491	2%	24	1411	2%	1.00	0.57‐1.75
Missing / not reported	1485	89	860	10%	78	625	12%	0.82	0.60‐1.12
Planned Hb ceiling
Planned Hb ceiling (cat 1)										0.28
≤Hb 13.0 g/dL	1631	47	841	6%	49	790	6%	0.83	0.56‐1.25
Hb 13.0 ‐ ≤15.0 g/dL	8451	523	4630	11%	415	3821	11%	1.14	1.00‐1.30
Hb >15.0 g/dL	280	20	150	13%	21	130	16%	0.90	0.48‐1.67
Other	79	15	55	27%	5	24	21%	1.43	0.52‐3.93
Planned Hb ceiling (cat 2)										0.38
≤Hb 13.0 g/dL	1631	47	841	6%	49	790	6%	0.83	0.56‐1.25
Hb 13.0 – ≤14.0 g/dL	5930	323	3200	10%	277	2730	10%	1.10	0.93‐1.29
Hb 14.0 – ≤15.0 g/dL	2521	200	1430	14%	138	1091	13%	1.22	0.98‐1.52
>Hb 15.0 g/dL	280	20	150	13%	21	130	16%	0.90	0.48‐1.67
Other	79	15	55	27%	5	24	21%	1.43	0.52‐3.93
Study level characteristics
Iron supplementation
Fixed iron supplementation	1904	40	947	4%	40	957	4%	1.00	0.64‐1.55	0.52
Iron supplementation as needed	8313	549	4620	12%	429	3693	12%	1.12	0.99‐1.28
Other	224	16	109	15%	21	115	18%	0.79	0.41‐1.51
Planned ESA treatment duration
up to 8 weeks	143	3	114	3%	2	29	7%	0.38	0.06‐2.30	0.20
9‐16 weeks	3823	183	2075	9%	167	1748	10%	1.01	0.82‐1.25
> 17 weeks	2280	252	1184	21%	192	1096	18%	1.27	1.05‐1.53
Until end of chemo‐ or radiotherapy	4195	167	2303	7%	129	1892	7%	1.00	0.79‐1.26
Planned weekly ESA dosage
< 100 µg Darbepoetin or < 40000 IU Epoetin	3733	208	2023	10%	174	1710	10%	0.96	0.78‐1.18	0.29
<= 100 µg Darbepoetin or = 40000 IU Epoetin	2200	179	1101	16%	144	1099	13%	1.29	1.04‐1.61
> 100 µg Darbepoetin or > 40000 IU Epoetin	1998	86	987	9%	76	1011	8%	1.11	0.82‐1.51
Other	2510	132	1565	8%	96	945	10%	1.08	0.83‐1.42
Planned frequency of ESA application
Three times per week or more frequent	5016	267	2853	9%	210	2163	10%	0.97	0.81‐1.17	0.05
Once per week	3067	242	1528	16%	185	1539	12%	1.35	1.12‐1.64
Every second week or less frequent	1540	25	886	3%	21	654	3%	0.92	0.51‐1.68
Other	818	71	409	17%	74	409	18%	0.93	0.67‐1.29
Placebo controlled trial
Yes	5473	379	2996	13%	307	2477	12%	1.13	0.97‐1.32	0.53
No	4968	226	2680	8%	183	2288	8%	1.05	0.86‐1.28
Randomisation
Adequate	3258	244	1693	14%	202	1565	13%	1.11	0.92‐1.34	0.88
Unclear	7183	361	3983	9%	288	3200	9%	1.09	0.93‐1.28
Concealment of allocation
Adequate	8252	545	4501	12%	423	3751	11%	1.15	1.01‐1.30	0.07
Unclear	2189	60	1175	5%	67	1014	7%	0.81	0.57‐1.16
Endpoint survival
Primary endpoint	2731	221	1352	16%	177	1379	13%	1.29	1.06‐1.57	0.11
Secondary endpoint	3222	189	1730	11%	147	1492	10%	1.04	0.84‐1.30
Safety /adverse events	4488	195	2594	8%	166	1894	9%	0.96	0.78‐1.18
Year of last patient randomized
1990‐1994	1057	65	650	10%	48	407	12%	0.86	0.59‐1.26	0.16
1995‐1999	1725	95	1001	9%	70	724	10%	0.96	0.70‐1.32
2000‐2004	6112	374	3263	11%	298	2849	10%	1.22	1.05‐1.43
2005‐2006	1547	71	762	9%	74	785	9%	0.93	0.67‐1.29
Source of data
Manufacturer	8851	587	4889	12%	467	3962	12%	1.12	0.99‐1.26	0.18
Clinical study group	1590	18	787	2%	23	803	3%	0.73	0.39‐1.36
*P value for likelihood‐ratio test, patients with missing data are excluded from the test, analysis based on one‐stage Cox fixed‐effects model stratified by study ESA= erythropoiesis‐stimulating agents