RED-HF™ Trial - Reduction of Events With Darbepoetin Alfa in Heart Failure Trial

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00358215
• Collaborator: (none)
• Enrollment: 2,278
• Locations: 754
• Arms: 2
• Actual Duration (Months): 76.4
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of the study is to determine the efficacy of treatment of anemia with darbepoetin alfa compared to placebo on the composite of time to death from any cause or first hospital admission for worsening heart failure in patients with symptomatic left ventricular systolic dysfunction and anemia.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure; Anemia; Cardiovascular Disease; Ventricular Dysfunction; Congestive Heart Failure	Drug: Darbepoetin alfa; Drug: Placebo	Phase 3

Detailed Description

Several epidemiological studies have demonstrated an association between HF and anemia and correlation of increased risk for mortality and hospitalization with low hemoglobin in patients with HF. Earlier single-center interventional studies suggest that meaningful clinical benefits may be achieved by raising hemoglobin concentration in patients with symptomatic HF and anemia. Data from Amgen's completed phase 2 multi-center studies support this hypothesis and show that darbepoetin alfa is well tolerated in patients with symptomatic left ventricular systolic dysfunction and anemia and effectively raises hemoglobin. The pivotal phase 3 Study 20050222 RED-HF Trial is evaluating the effect of treatment with darbepoetin alfa on the composite risk of all-cause mortality or hospitalization for worsening HF in patients with symptomatic left ventricular systolic dysfunction and anemia. This study also evaluates the effect of darbepoetin alfa treatment on all-cause death, on cardiovascular death or hospitalization for worsening HF, and on patient-reported quality-of-life outcomes.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2278 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy and Safety of Darbepoetin Alfa Treatment on Mortality and Morbidity in Heart Failure (HF) Subjects With Symptomatic Left Ventricular Systolic Dysfunction and Anemia
• Actual Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Oct 11, 2012
• Actual Study Completion Date: Oct 11, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Darbepoetin alfa Starting dose of 0.75 µg/kg subcutaneously every 2 weeks until hemoglobin concentrations reach 13.0 g/dL on 2 consecutive visits, then monthly dosing, titrated to achieve hemoglobin target of 13.0 g/dL, not to exceed 14.5 g/dL.	Drug: Darbepoetin alfa; Administered by subcutaneous injection; Other Names: Aranesp®
Placebo Comparator: Placebo Participants received dose and administration schedule (every 2 weeks or once a month) changes that simulated the changes for participants receiving darbepoetin alfa.	Drug: Placebo; Placebo subcutaneous injection

Outcome Measures

Primary Outcome Measures

1. Time to All Cause Death or First Hospitalization for Worsening Heart Failure [From randomization to the end of study; maximum time on study was 73 months]

   Time to death from any cause or first hospital admission for worsening heart failure (adjudicated by the Clinical Endpoint Committee), whichever occurred first, estimated by Kaplan-Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first.

Secondary Outcome Measures

1. Time to Death From Any Cause [From randomization to the end of study; maximum time on study was 73 months]

   Time from randomization to death due to any cause, estimated by the Kaplan-Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first.

2. Time to Cardiovascular Death or First Hospital Admission for Worsening Heart Failure [From randomization to the end of study; maximum time on study was 73 months]

   Time to cardiovascular death or first hospital admission for worsening heart failure, whichever occured first, estimated using the Kaplan Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first.

3. Change From Baseline to Month 6 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score [Baseline and Month 6]

   The KCCQ is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Least squares means were calculated from a mixed effects model estimating treatment effect adjusted for region, type of device, and Baseline KCCQ score.

4. Change From Baseline to Month 6 in KCCQ Symptom Frequency Score [Baseline and Month 6]

   The KCCQ is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Least squares means were calculated from a mixed effects model estimating treatment effect adjusted for region, type of device, and Baseline KCCQ score.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Heart failure of at least 3 months duration and of New York Heart Association (NYHA) class II, III, or IV

• hemoglobin between 9.0 g/dL and 12.0 g/dL

• left ventricular ejection fraction equal to or less than 40%

Exclusion Criteria:

• Transferrin saturation (Tsat) < 15%

• Blood pressure > 160/100 mm Hg

• Heart failure primarily due to valvular heart disease or clinically significant valvular heart disease that might lead to surgical correction within 12 months of randomization

• Recipient of a major organ transplant or receiving renal replacement therapy

• Serum creatinine > 3.0 mg/dL (> 265 µmol/L)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35211
2	Research Site	Birmingham	Alabama	United States	35294
3	Research Site	Huntsville	Alabama	United States	35801
4	Research Site	Mobile	Alabama	United States	36608
5	Research Site	Gilbert	Arizona	United States	85296
6	Research Site	Mesa	Arizona	United States	85206
7	Research Site	Scottsdale	Arizona	United States	85251
8	Research Site	Tucson	Arizona	United States	85723
9	Research Site	Little Rock	Arkansas	United States	72204
10	Research Site	Little Rock	Arkansas	United States	72205
11	Research Site	Anaheim	California	United States	92801
12	Research Site	Buena Park	California	United States	90621
13	Research Site	Corona	California	United States	92879
14	Research Site	Culver City	California	United States	90232
15	Research Site	Downey	California	United States	90241
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17	Research Site	Lancaster	California	United States	93534
18	Research Site	Larkspur	California	United States	94939
19	Research Site	Loma Linda	California	United States	92354
20	Research Site	Long Beach	California	United States	90822
21	Research Site	Los Angeles	California	United States	90017
22	Research Site	Los Angeles	California	United States	90024
23	Research Site	Los Angeles	California	United States	90033-1026
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53	Research Site	Jupiter	Florida	United States	33458
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136	Research Site	Saint Louis	Missouri	United States	63110
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139	Research Site	Missoula	Montana	United States	59802
140	Research Site	Grand Island	Nebraska	United States	68803
141	Research Site	Lincoln	Nebraska	United States	68506
142	Research Site	Lincoln	Nebraska	United States	68526
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148	Research Site	Summit	New Jersey	United States	07902
149	Research Site	Westwood	New Jersey	United States	07675
150	Research Site	Albuquerque	New Mexico	United States	87131
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152	Research Site	Bronx	New York	United States	10467
153	Research Site	Buffalo	New York	United States	14221
154	Research Site	Cortlandt Manor	New York	United States	10567
155	Research Site	Flushing	New York	United States	11355
156	Research Site	Garden City	New York	United States	11530
157	Research Site	Johnson City	New York	United States	13790
158	Research Site	Kingston	New York	United States	12401
159	Research Site	New York	New York	United States	10001
160	Research Site	New York	New York	United States	10016
161	Research Site	New York	New York	United States	10019
162	Research Site	New York	New York	United States	10021
163	Research Site	New York	New York	United States	10029
164	Research Site	New York	New York	United States	10032
165	Research Site	Rochester	New York	United States	14618
166	Research Site	Staten Island	New York	United States	10305
167	Research Site	Syracuse	New York	United States	13210
168	Research Site	Troy	New York	United States	12180
169	Research Site	West Islip	New York	United States	11795
170	Research Site	Williamsville	New York	United States	14221
171	Research Site	Asheville	North Carolina	United States	28803
172	Research Site	Burlington	North Carolina	United States	27215
173	Research Site	Chapel Hill	North Carolina	United States	27599
174	Research Site	Charlotte	North Carolina	United States	28204
175	Research Site	Durham	North Carolina	United States	27705
176	Research Site	Gastonia	North Carolina	United States	28054
177	Research Site	Greensboro	North Carolina	United States	27403
178	Research Site	New Bern	North Carolina	United States	28562
179	Research Site	Winston-Salem	North Carolina	United States	27103
180	Research Site	Winston-Salem	North Carolina	United States	27157
181	Research Site	Akron	Ohio	United States	44307
182	Research Site	Canton	Ohio	United States	44710
183	Research Site	Cincinnati	Ohio	United States	45267
184	Research Site	Cleveland	Ohio	United States	44106
185	Research Site	Cleveland	Ohio	United States	44109
186	Research Site	Cleveland	Ohio	United States	44195
187	Research Site	Dayton	Ohio	United States	45414
188	Research Site	Garfield Heights	Ohio	United States	44125
189	Research Site	Mayfield Heights	Ohio	United States	44124
190	Research Site	Sandusky	Ohio	United States	44870
191	Research Site	Toledo	Ohio	United States	43606
192	Research Site	Oklahoma City	Oklahoma	United States	73104
193	Research Site	Oklahoma City	Oklahoma	United States	73109
194	Research Site	Oklahoma City	Oklahoma	United States	73112
195	Research Site	Oklahoma City	Oklahoma	United States	73120
196	Research Site	Tulsa	Oklahoma	United States	74104
197	Research Site	Bend	Oregon	United States	97701
198	Research Site	Hillsboro	Oregon	United States	97123
199	Research Site	Portland	Oregon	United States	97213
200	Research Site	Allentown	Pennsylvania	United States	18106
201	Research Site	Hershey	Pennsylvania	United States	17033
202	Research Site	Lancaster	Pennsylvania	United States	17603
203	Research Site	Philadelphia	Pennsylvania	United States	19102
204	Research Site	Philadelphia	Pennsylvania	United States	19104
205	Research Site	Philadelphia	Pennsylvania	United States	19107
206	Research Site	Philadelphia	Pennsylvania	United States	19140
207	Research Site	Philadelphia	Pennsylvania	United States	19141
208	Research Site	Pittsburgh	Pennsylvania	United States	15212
209	Research Site	Pittsburgh	Pennsylvania	United States	15213
210	Research Site	Pittsburgh	Pennsylvania	United States	15224
211	Research Site	Sayre	Pennsylvania	United States	18840
212	Research Site	Wyomissing	Pennsylvania	United States	19610
213	Research Site	Pawtucket	Rhode Island	United States	02860
214	Research Site	Anderson	South Carolina	United States	29621
215	Research Site	Charleston	South Carolina	United States	29401
216	Research Site	Charleston	South Carolina	United States	29403
217	Research Site	Columbia	South Carolina	United States	29204
218	Research Site	Orangeburg	South Carolina	United States	29115
219	Research Site	Spartanburg	South Carolina	United States	29303
220	Research Site	Chattanooga	Tennessee	United States	37404
221	Research Site	Germantown	Tennessee	United States	38138
222	Research Site	Jackson	Tennessee	United States	38305
223	Research Site	Memphis	Tennessee	United States	38104
224	Research Site	Memphis	Tennessee	United States	38120
225	Research Site	Nashville	Tennessee	United States	37203
226	Research Site	Nashville	Tennessee	United States	37232-8802
227	Research Site	Tullahoma	Tennessee	United States	37388
228	Research Site	Beaumont	Texas	United States	77702
229	Research Site	Dallas	Texas	United States	75216
230	Research Site	Dallas	Texas	United States	75226
231	Research Site	Dallas	Texas	United States	75230
232	Research Site	Dallas	Texas	United States	75231
233	Research Site	Dallas	Texas	United States	75390
234	Research Site	Galveston	Texas	United States	77555
235	Research Site	Houston	Texas	United States	77004
236	Research Site	Houston	Texas	United States	77030
237	Research Site	Houston	Texas	United States	77074
238	Research Site	Lubbock	Texas	United States	79410
239	Research Site	Odessa	Texas	United States	79763
240	Research Site	San Antonio	Texas	United States	78217
241	Research Site	Tyler	Texas	United States	75708
242	Research Site	Salt Lake City	Utah	United States	84148
243	Research Site	Annandale	Virginia	United States	22003
244	Research Site	Midlothian	Virginia	United States	23114
245	Research Site	Richmond	Virginia	United States	23249
246	Research Site	Roanoke	Virginia	United States	24014
247	Research Site	Bellingham	Washington	United States	98225
248	Research Site	Kirkland	Washington	United States	98034
249	Research Site	Seattle	Washington	United States	98195
250	Research Site	Tacoma	Washington	United States	98405
251	Research Site	Beloit	Wisconsin	United States	53511
252	Research Site	Madison	Wisconsin	United States	53707
253	Research Site	Madison	Wisconsin	United States	53792
254	Research Site	Milwaukee	Wisconsin	United States	53215
255	Research Site	Adrogue	Buenos Aires	Argentina	1836
256	Research Site	Bahia Blanca	Buenos Aires	Argentina	8000
257	Research Site	Capital Federal	Buenos Aires	Argentina	C1408INH
258	Research Site	Capital Federal	Buenos Aires	Argentina	C1426ANZ
259	Research Site	Ciudad Autonoma de Buenos Aires	Buenos Aires	Argentina	1425
260	Research Site	Ciudad Autónoma de Buenos Aires	Buenos Aires	Argentina	1118
261	Research Site	Coronel Suarez	Buenos Aires	Argentina	7540
262	Research Site	La Plata	Buenos Aires	Argentina	1900
263	Research Site	Mar del Plata	Buenos Aires	Argentina	B7600FZN
264	Research Site	Quilmes	Buenos Aires	Argentina	B1878GEG
265	Research Site	San Martin	Buenos Aires	Argentina	1650
266	Research Site	Cordoba	Córdoba	Argentina	X5016KEH
267	Research Site	Cipolletti	RÃ-o Negro	Argentina	R8324EMD
268	Research Site	Rosario	Santa Fe	Argentina	S2000CVD
269	Research Site	Buenos Aires		Argentina	1155
270	Research Site	Buenos Aires		Argentina	B1708KCH
271	Research Site	Buenos Aires		Argentina	C1181ACH
272	Research Site	Buenos Aires		Argentina	C1280AEB
273	Research Site	Buenos Aires		Argentina	C1405BCH
274	Research Site	Buenos Aires		Argentina	C1416DRJ
275	Research Site	Capital Federal		Argentina	C1221ADC
276	Research Site	Cordoba		Argentina	5000
277	Research Site	Cordoba		Argentina	X5004CDT
278	Research Site	Corrientes		Argentina	W3400AMZ
279	Research Site	Mendoza		Argentina	5500
280	Research Site	Salta		Argentina	A4406CLA
281	Research Site	Santa Fe		Argentina	3000
282	Research Site	Camperdown	New South Wales	Australia	2050
283	Research Site	Coffs Harbour	New South Wales	Australia	2450
284	Research Site	Concord	New South Wales	Australia	2139
285	Research Site	Gosford	New South Wales	Australia	2250
286	Research Site	New Lambton Heights	New South Wales	Australia	2305
287	Research Site	Randwick	New South Wales	Australia	2031
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292	Research Site	Geelong	Victoria	Australia	3220
293	Research Site	Heidelberg	Victoria	Australia	3084
294	Research Site	Parkville	Victoria	Australia	3052
295	Research Site	Prahran	Victoria	Australia	3181
296	Research Site	Nedlands	Western Australia	Australia	6009
297	Research Site	Innsbruck		Austria	6020
298	Research Site	Linz		Austria	4010
299	Research Site	Linz		Austria	4021
300	Research Site	Salzburg		Austria	5020
301	Research Site	Wels		Austria	4600
302	Research Site	Wien		Austria	1090
303	Research Site	Wien		Austria	1150
304	Research Site	Aalst		Belgium	9300
305	Research Site	Antwerpen		Belgium	2020
306	Research Site	Antwerpen		Belgium	2060
307	Research Site	Bonheiden		Belgium	2820
308	Research Site	Brugge		Belgium	8000
309	Research Site	Brussel		Belgium	1090
310	Research Site	Bruxelles		Belgium	1070
311	Research Site	Genk		Belgium	3600
312	Research Site	Gent		Belgium	9000
313	Research Site	Hasselt		Belgium	3500
314	Research Site	Huy		Belgium	4500
315	Research Site	Leuven		Belgium	3000
316	Research Site	Roeselare		Belgium	8800
317	Research Site	Turnhout		Belgium	2300
318	Research Site	Salvador	Bahia	Brazil	40144-900
319	Research Site	Fortaleza	Ceará	Brazil	60864-194
320	Research Site	Goiania	Goiás	Brazil	74605-050
321	Research Site	Belo Horizonte	Minas Gerais	Brazil	30110-908
322	Research Site	Curitiba	Paraná	Brazil	80010-030
323	Research Site	Recife	Pernambuco	Brazil	50100-060
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325	Research Site	Porto Alegre	Rio Grande Do Sul	Brazil	90035-903
326	Research Site	Porto Alegre	Rio Grande Do Sul	Brazil	90620-001
327	Research Site	Campinas	São Paulo	Brazil	13059-740
328	Research Site	Riberão Preto	São Paulo	Brazil	14048-900
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330	Research Site	Sao Paulo	São Paulo	Brazil	05403-900
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332	Research Site	Rio de Janeiro		Brazil	20020-020
333	Research Site	Rio de Janeiro		Brazil	20551-030
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336	Research Site	Dimitrovgrad		Bulgaria	6400
337	Research Site	Haskovo		Bulgaria	6300
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340	Research Site	Plovdiv		Bulgaria	4002
341	Research Site	Plovdiv		Bulgaria	4003
342	Research Site	Rouse		Bulgaria	7002
343	Research Site	Sofia		Bulgaria	1202
344	Research Site	Sofia		Bulgaria	1233
345	Research Site	Sofia		Bulgaria	1309
346	Research Site	Sofia		Bulgaria	1431
347	Research Site	Sofia		Bulgaria	1527
348	Research Site	Sofia		Bulgaria	1606
349	Research Site	Varna		Bulgaria	9010
350	Research Site	Veliko Tarnovo		Bulgaria	5000
351	Research Site	Calgary	Alberta	Canada	T2E 7C5
352	Research Site	Edmonton	Alberta	Canada	T6G 2B7
353	Research Site	Edmonton	Alberta	Canada	T6K 4C1
354	Research Site	Campbell River	British Columbia	Canada	V9W 5Y4
355	Research Site	Surrey	British Columbia	Canada	V3V 1Z2
356	Research Site	Winnipeg	Manitoba	Canada	R3C 0N2
357	Research Site	Winnipeg	Manitoba	Canada	R3T 2E8
358	Research Site	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
359	Research Site	Halifax	Nova Scotia	Canada	B3H 3A7
360	Research Site	Ajax	Ontario	Canada	L1S 7K8
361	Research Site	Cambridge	Ontario	Canada	N1R 7R1
362	Research Site	Hamilton	Ontario	Canada	L8L 2X2
363	Research Site	Kingston	Ontario	Canada	K7L 1C2
364	Research Site	London	Ontario	Canada	N6A 5A5
365	Research Site	Mississauga	Ontario	Canada	L5B 4A2
366	Research Site	North York	Ontario	Canada	M2K 2W2
367	Research Site	Ottawa	Ontario	Canada	K1Y 4W7
368	Research Site	Scarborough	Ontario	Canada	M1E 5E9
369	Research Site	Scarborough	Ontario	Canada	M1P 2V5
370	Research Site	Toronto	Ontario	Canada	M5B 1W8
371	Research Site	Toronto	Ontario	Canada	M5G 1X5
372	Research Site	Toronto	Ontario	Canada	M5G 2C4
373	Research Site	Montreal	Quebec	Canada	H1T 2M4
374	Research Site	Montreal	Quebec	Canada	H2W 1T7
375	Research Site	Montreal	Quebec	Canada	H2W 1T8
376	Research Site	Montreal	Quebec	Canada	H3A 1A1
377	Research Site	Montreal	Quebec	Canada	H3G 1A4
378	Research Site	Sherbrooke	Quebec	Canada	J1H 5N4
379	Research Site	St-Jérôme	Quebec	Canada	J7Z 5T3
380	Research Site	Regina	Saskatchewan	Canada	S4P 3X3
381	Research Site	Saskatoon	Saskatchewan	Canada	S7H 5H9
382	Research Site	Rancagua	Cachapoal	Chile	2841959
383	Research Site	La Serena	Elqui	Chile	1731295
384	Research Site	San Miguel	Santiago	Chile	8900085
385	Research Site	Osorno		Chile
386	Research Site	Santiago		Chile	7500922
387	Research Site	Santiago		Chile	8320000
388	Research Site	Santiago		Chile	8330032
389	Research Site	Santiago		Chile
390	Research Site	Temuco		Chile	4781151
391	Research Site	Vina del Mar		Chile
392	Research Site	Benesov		Czechia	256 01
393	Research Site	Brno		Czechia	656 91
394	Research Site	Ceske Budejovice		Czechia	370 87
395	Research Site	Jihlava		Czechia	586 01
396	Research Site	Karlovy Vary		Czechia	360 01
397	Research Site	Pardubice		Czechia	530 02
398	Research Site	Praha 10		Czechia	100 34
399	Research Site	Praha 10		Czechia	108 00
400	Research Site	Praha 1		Czechia	110 00
401	Research Site	Praha 2		Czechia	120 00
402	Research Site	Praha 2		Czechia	128 08
403	Research Site	Pribram 8		Czechia	261 01
404	Research Site	Tabor		Czechia	390 03
405	Research Site	Usti nad Labem		Czechia	401 13
406	Research Site	Fredericia		Denmark	7000
407	Research Site	Frederiksberg		Denmark	2000
408	Research Site	Frederikshavn		Denmark	9900
409	Research Site	Glostrup		Denmark	2600
410	Research Site	Hellerup		Denmark	2900
411	Research Site	Herlev		Denmark	2730
412	Research Site	Horsens		Denmark	8700
413	Research Site	Hvidovre		Denmark	2650
414	Research Site	København S		Denmark	2300
415	Research Site	København Ø		Denmark	2011
416	Research Site	Køge		Denmark	4600
417	Research Site	Odense		Denmark	5000
418	Research Site	Roskilde		Denmark	4000
419	Research Site	Svendborg		Denmark	5700
420	Research Site	Pärnu		Estonia	80010
421	Research Site	Tallinn		Estonia	10138
422	Research Site	Tallinn		Estonia	10617
423	Research Site	Tallinn		Estonia	13419
424	Research Site	Espoo		Finland	00029
425	Research Site	Helsinki		Finland	00260
426	Research Site	Lahti		Finland	15110
427	Research Site	Seinajoki		Finland	60100
428	Research Site	Bron		France	69500
429	Research Site	Caen Cedex 14		France	14033
430	Research Site	Cholet Cedex		France	49325
431	Research Site	Créteil Cedex		France	94010
432	Research Site	Douai Cedex		France	59507
433	Research Site	Grenoble Cedex 9		France	38043
434	Research Site	Lille Cedex		France	59037
435	Research Site	Montfermeil		France	93370
436	Research Site	Montpellier cedex 05		France	34295
437	Research Site	Nice Cedex 01		France	06002
438	Research Site	Paris Cedex 13		France	75651
439	Research Site	Paris		France	75010
440	Research Site	Pessac Cedex		France	33604
441	Research Site	Poitiers		France	86000
442	Research Site	Pontoise Cedex		France	95301
443	Research Site	Rouen Cedex		France	76031
444	Research Site	Saint Herblain		France	44800
445	Research Site	Strasbourg		France	67091
446	Research Site	Toulouse Cedex 09		France	31403
447	Research Site	Vandoeuvre-les-Nancy		France	54511
448	Research Site	Bad Tölz		Germany	83646
449	Research Site	Berlin		Germany	10787
450	Research Site	Berlin		Germany	12200
451	Research Site	Berlin		Germany	13353
452	Research Site	Bochum		Germany	44789
453	Research Site	Bremen		Germany	28277
454	Research Site	Frankfurt		Germany	60594
455	Research Site	Georgsmarienhütte		Germany	49124
456	Research Site	Göttingen		Germany	37075
457	Research Site	Hamburg		Germany	20148
458	Research Site	Hamburg		Germany	20246
459	Research Site	Hannover		Germany	30625
460	Research Site	Heidelberg		Germany	69115
461	Research Site	Heidelberg		Germany	69120
462	Research Site	Homburg		Germany	66421
463	Research Site	Ingelheim		Germany	55218
464	Research Site	Köln		Germany	50924
465	Research Site	Lahr		Germany	77933
466	Research Site	Leipzig		Germany	04289
467	Research Site	Mainz		Germany	55131
468	Research Site	Marburg		Germany	35037
469	Research Site	Nürnberg		Germany	90402
470	Research Site	Schwedt		Germany	16303
471	Research Site	Stuttgart		Germany	70376
472	Research Site	Witten		Germany	58455
473	Research Site	Hong Kong		Hong Kong
474	Research Site	New Territories		Hong Kong	00000
475	Research Site	Bekescsaba		Hungary	5600
476	Research Site	Budapest		Hungary	1027
477	Research Site	Budapest		Hungary	1075
478	Research Site	Budapest		Hungary	1096
479	Research Site	Budapest		Hungary	1106
480	Research Site	Budapest		Hungary	1115
481	Research Site	Budapest		Hungary	1135
482	Research Site	Debrecen		Hungary	4032
483	Research Site	Gyor		Hungary	9023
484	Research Site	Kalocsa		Hungary	6300
485	Research Site	Kecskemet		Hungary	6000
486	Research Site	Sopron		Hungary	9400
487	Research Site	Szeged		Hungary	6720
488	Research Site	Szekesfehervar		Hungary	8000
489	Research Site	Szekszard		Hungary	7100
490	Research Site	Szolnok		Hungary	5000
491	Research Site	Veszprem		Hungary	8200
492	Research Site	Zalaegerszeg		Hungary	8900
493	Research Site	Hyderabad	Andhra Pradesh	India	500 001
494	Research Site	Hyderabad	Andhra Pradesh	India	500 033
495	Research Site	Hyderabad	Andhra Pradesh	India	500 063
496	Research Site	New Delhi	Delhi	India	110 025
497	Research Site	New Delhi	Delhi	India	110 029
498	Research Site	Ahmedabad	Gujarat	India	380 006
499	Research Site	Ahmedabad	Gujarat	India	380 060
500	Research Site	Ahmedabad	Gujarat	India	382 428
501	Research Site	Gurgaon	Haryana	India	122 001
502	Research Site	Bangalore	Karnataka	India	560 034
503	Research Site	Bangalore	Karnataka	India	560 054
504	Research Site	Mumbai	Maharashtra	India	400 022
505	Research Site	Nagpur	Maharashtra	India	400 012
506	Research Site	Nashik	Maharashtra	India	422 005
507	Research Site	Pune	Maharashtra	India	411 001
508	Research Site	Pune	Maharashtra	India	411 004
509	Research Site	Pune	Maharashtra	India	411 006
510	Research Site	Pune	Maharashtra	India	411 011
511	Research Site	Pune	Maharashtra	India	411 016
512	Research Site	Pune	Maharashtra	India	411 033
513	Research Site	Ludhiana	Punjab	India	141 001
514	Research Site	Bikaner	Rajasthan	India	334 003
515	Research Site	Chennai	Tamil Nadu	India	600 006
516	Research Site	Chennai	Tamil Nadu	India	600 037
517	Research Site	Chennai	Tamil Nadu	India	600 081
518	Research Site	Coimbatore	Tamil Nadu	India	641 004
519	Research Site	Coimbatore	Tamil Nadu	India	641 014
520	Research Site	Madurai	Tamil Nadu	India	625 020
521	Research Site	Lucknow	Uttar Pradesh	India	226 014
522	Research Site	Mumbai		India	400 020
523	Research Site	Askelon		Israel	78278
524	Research Site	Beer Sheva		Israel	84101
525	Research Site	Beer Yaakov		Israel	70300
526	Research Site	Givatayim		Israel	53583
527	Research Site	Hadera		Israel	38100
528	Research Site	Haifa		Israel	34362
529	Research Site	Holon		Israel	58100
530	Research Site	Jerusalem		Israel	91031
531	Research Site	Jerusalem		Israel	91200
532	Research Site	Kfar Saba		Israel	44281
533	Research Site	Safed		Israel	13100
534	Research Site	Tel-Aviv		Israel	64239
535	Research Site	Arezzo		Italy	52100
536	Research Site	Bergamo		Italy	24128
537	Research Site	Cesenatico (FC)		Italy	47042
538	Research Site	Cetraro CS		Italy	87022
539	Research Site	Cortona AR		Italy	52044
540	Research Site	Eboli		Italy	84025
541	Research Site	Ferrara		Italy	44100
542	Research Site	Forlì		Italy	47100
543	Research Site	Milano		Italy	20138
544	Research Site	Napoli		Italy	80131
545	Research Site	Oliveto Citra SA		Italy	84020
546	Research Site	Palermo		Italy	90126
547	Research Site	Palmanova UD		Italy	33057
548	Research Site	Pavia		Italy	27100
549	Research Site	Roma		Italy	00152
550	Research Site	Roma		Italy	00184
551	Research Site	Rozzano MI		Italy	20089
552	Research Site	San Bonifacio VR		Italy	37047
553	Research Site	Torino		Italy	10126
554	Research Site	Trento		Italy	38100
555	Research Site	Udine		Italy	33100
556	Research Site	Daugavpils		Latvia	5417
557	Research Site	Ogre		Latvia	5001
558	Research Site	Rezekne		Latvia	4600
559	Research Site	Riga		Latvia	1002
560	Research Site	Riga		Latvia	1006
561	Research Site	Riga		Latvia	1012
562	Research Site	Riga		Latvia	1038
563	Research Site	Alytus		Lithuania	62114
564	Research Site	Kaunas		Lithuania	44320
565	Research Site	Kaunas		Lithuania	49155
566	Research Site	Kaunas		Lithuania	50009
567	Research Site	Klaipeda		Lithuania	92288
568	Research Site	Siauliai		Lithuania	76231
569	Research Site	Vilnius		Lithuania	01113
570	Research Site	Vilnius		Lithuania	08314
571	Research Site	Vilnius		Lithuania	08661
572	Research Site	Vilnius		Lithuania	10309
573	Research Site	Mexico City	Distrito Federal	Mexico	14080
574	Research Site	Guadajalara	Jalisco	Mexico	44100
575	Research Site	Guadalajara	Jalisco	Mexico	44340
576	Research Site	Guadalajara	Jalisco	Mexico	44380
577	Research Site	Monterrey	Nuevo León	Mexico	64000
578	Research Site	San Luis Potosi	San Luis PotosÃ-	Mexico	78240
579	Research Site	Xalapa	Veracruz	Mexico	91140
580	Research Site	Merida	Yucatán	Mexico	97000
581	Research Site	Baja California		Mexico	21397
582	Research Site	Distrito Federal		Mexico	06760
583	Research Site	's Hertogenbosch		Netherlands	5211 RW
584	Research Site	Alkmaar		Netherlands	1815 JD
585	Research Site	Almelo		Netherlands	7609 PP
586	Research Site	Amsterdam		Netherlands	1091 AC
587	Research Site	Arnhem		Netherlands	6815 AD
588	Research Site	Assen		Netherlands	9401 RK
589	Research Site	Blaricum		Netherlands	1261 AN
590	Research Site	Breda		Netherlands	4818 CK
591	Research Site	Delft		Netherlands	2625 AD
592	Research Site	Den Haag		Netherlands	2512 VA
593	Research Site	Deventer		Netherlands	7416 SE
594	Research Site	Eindhoven		Netherlands	5623 EJ
595	Research Site	Enschede		Netherlands	7513 ER
596	Research Site	Groningen		Netherlands	9713 GZ
597	Research Site	Haarlem		Netherlands	2035 RC
598	Research Site	Harderwijk		Netherlands	3844 DG
599	Research Site	Heerlen		Netherlands	6419 PC
600	Research Site	Hilversum		Netherlands	1213 XZ
601	Research Site	Hoorn		Netherlands	1625 HV
602	Research Site	Nijmegen		Netherlands	6532 SZ
603	Research Site	Rotterdam		Netherlands	3045 PM
604	Research Site	Rotterdam		Netherlands	3083 AN
605	Research Site	Sneek		Netherlands	8601 ZK
606	Research Site	Tiel		Netherlands	4002 WP
607	Research Site	Tilburg		Netherlands	5042 AD
608	Research Site	Zwijndrecht		Netherlands	3331 LZ
609	Research Site	Arendal		Norway	4809
610	Research Site	Gjettum		Norway	1309
611	Research Site	Kristiansand		Norway	4604
612	Research Site	Oslo		Norway	0407
613	Research Site	Skien		Norway	3710
614	Research Site	Stavanger		Norway	4095
615	Research Site	Ã…lesund		Norway	6026
616	Research Site	Bialystok		Poland	15-276
617	Research Site	Gdansk		Poland	80-952
618	Research Site	Gdynia		Poland	81-423
619	Research Site	Gdynia		Poland	81-519
620	Research Site	Katowice		Poland	40-635
621	Research Site	Krakow		Poland	30-092
622	Research Site	Krakow		Poland	31-202
623	Research Site	Lublin		Poland	20-954
624	Research Site	Stalowa Wola		Poland	37-450
625	Research Site	Tarnow		Poland	33-100
626	Research Site	Walbrzych		Poland	58-309
627	Research Site	Warszawa		Poland	01-211
628	Research Site	Warszawa		Poland	01-809
629	Research Site	Warszawa		Poland	03-242
630	Research Site	Warszawa		Poland	04-238
631	Research Site	Warszawa		Poland	04-628
632	Research Site	Wroclaw		Poland	50-981
633	Research Site	Zabrze		Poland	41-800
634	Research Site	Zielona Gora		Poland	65-046
635	Research Site	Coimbra		Portugal	3000-075
636	Research Site	Faro		Portugal	8000-386
637	Research Site	Lisboa		Portugal	1449-005
638	Research Site	Lisbon		Portugal	1169-024
639	Research Site	San Juan		Puerto Rico	00935
640	Research Site	Arad		Romania	310031
641	Research Site	Bacau		Romania	600114
642	Research Site	Brasov		Romania	500157
643	Research Site	Bucuresti		Romania	011461
644	Research Site	Bucuresti		Romania	021659
645	Research Site	Bucuresti		Romania	022328
646	Research Site	Bucuresti		Romania	030171
647	Research Site	Iasi		Romania	700111
648	Research Site	Oradea		Romania	410169
649	Research Site	Sibiu		Romania	550245
650	Research Site	Targu Mures		Romania	540103
651	Research Site	Targu Mures		Romania	540136
652	Research Site	Timisoara		Romania	300041
653	Research Site	Timisoara		Romania	300310
654	Research Site	Moscow		Russian Federation	107014
655	Research Site	Moscow		Russian Federation	109263
656	Research Site	Moscow		Russian Federation	115093
657	Research Site	Moscow		Russian Federation	115516
658	Research Site	Moscow		Russian Federation	117292
659	Research Site	Moscow		Russian Federation	117513
660	Research Site	Moscow		Russian Federation	119435
661	Research Site	Moscow		Russian Federation	119620
662	Research Site	Moscow		Russian Federation	119992
663	Research Site	Moscow		Russian Federation	121359
664	Research Site	Moscow		Russian Federation	121552
665	Research Site	Moscow		Russian Federation	125206
666	Research Site	Moscow		Russian Federation	125315
667	Research Site	Moscow		Russian Federation	127018
668	Research Site	Moscow		Russian Federation	127473
669	Research Site	Moscow		Russian Federation	127644
670	Research Site	Moscow		Russian Federation	129090
671	Research Site	Saint Petersburg		Russian Federation	192242
672	Research Site	Saint Petersburg		Russian Federation	197022
673	Research Site	Sankt-Petersburg		Russian Federation	194156
674	Research Site	St Petersburg		Russian Federation	198205
675	Research Site	St. Petersburg		Russian Federation	194017
676	Research Site	St. Petersburg		Russian Federation	199106
677	Research Site	Volgograd		Russian Federation	400008
678	Research Site	Bardejov		Slovakia	085 01
679	Research Site	Bratislava		Slovakia	811 00
680	Research Site	Kosice		Slovakia	040 22
681	Research Site	Levice		Slovakia	934 48
682	Research Site	Lucenec		Slovakia	984 01
683	Research Site	Nitra		Slovakia	949 01
684	Research Site	Nitra		Slovakia	950 01
685	Research Site	Presov		Slovakia	080 01
686	Research Site	Zilina		Slovakia	012 07
687	Research Site	Boksburg	Gauteng	South Africa	1459
688	Research Site	Johannesburg	Gauteng	South Africa	2157
689	Research Site	Johannesburg	Gauteng	South Africa	2193
690	Research Site	Pretoria	Gauteng	South Africa	0002
691	Research Site	Soweto	Gauteng	South Africa	2013
692	Research Site	Durban	KwaZulu-Natal	South Africa	4001
693	Research Site	Durban	KwaZulu-Natal	South Africa	4052
694	Research Site	Durban	KwaZulu-Natal	South Africa	4068
695	Research Site	Parow	Western Cape	South Africa	7505
696	Research Site	Somerset West	Western Cape	South Africa	7130
697	Research Site	Worcester	Western Cape	South Africa	6850
698	Research Site	Cape Town		South Africa	7405
699	Research Site	Cape Town		South Africa	7530
700	Research Site	Córdoba	AndalucÃ-a	Spain	14004
701	Research Site	Granada	AndalucÃ-a	Spain	18014
702	Research Site	Málaga	AndalucÃ-a	Spain	29010
703	Research Site	Oviedo	Asturias	Spain	33006
704	Research Site	Santander	Cantabria	Spain	39008
705	Research Site	Badalona	Cataluña	Spain	08916
706	Research Site	Barcelona	Cataluña	Spain	08003
707	Research Site	Barcelona	Cataluña	Spain	08035
708	Research Site	Barcelona	Cataluña	Spain	08036
709	Research Site	Barcelona	Cataluña	Spain	08041
710	Research Site	Sabadell	Cataluña	Spain	08208
711	Research Site	Tarragona	Cataluña	Spain	43007
712	Research Site	Valencia	Comunidad Valenciana	Spain	46014
713	Research Site	Santiago de Compostela	Galicia	Spain	15706
714	Research Site	Majadhonda	Madrid	Spain	28222
715	Research Site	El Palmar	Murcia	Spain	30120
716	Research Site	Galdakao	PaÃ-s Vasco	Spain	48960
717	Research Site	Madrid		Spain	28034
718	Research Site	Madrid		Spain	28041
719	Research Site	Madrid		Spain	28046
720	Research Site	Danderyd		Sweden	182 88
721	Research Site	Göteborg		Sweden	413 45
722	Research Site	Göteborg		Sweden	416 85
723	Research Site	Linköping		Sweden	581 85
724	Research Site	Malmö		Sweden	205 02
725	Research Site	Mölndal		Sweden	431 80
726	Research Site	Stockholm		Sweden	112 81
727	Research Site	Sundsvall		Sweden	851 56
728	Research Site	Umeå		Sweden	901 85
729	Research Site	Uppsala		Sweden	751 85
730	Research Site	Ã-rebro		Sweden	701 85
731	Research Site	Lugano		Switzerland	6900
732	Research Site	St. Gallen		Switzerland	9007
733	Research Site	Barnet		United Kingdom	EN5 3DJ
734	Research Site	Belfast		United Kingdom	BT12 6BA
735	Research Site	Birmingham		United Kingdom	B757RR
736	Research Site	Bradford		United Kingdom	BD9 6RJ
737	Research Site	Bridlington		United Kingdom	YO164QP
738	Research Site	Cottingham		United Kingdom	HU16 5JQ
739	Research Site	Coventry		United Kingdom	CV2 2DX
740	Research Site	Glasgow		United Kingdom	G12 8TA
741	Research Site	Glasgow		United Kingdom	G51 4TF
742	Research Site	Harrow		United Kingdom	HA1 3UJ
743	Research Site	Kirkcaldy		United Kingdom	KY2 5AH
744	Research Site	Leeds		United Kingdom	LS1 3EX
745	Research Site	Leeds		United Kingdom	LS9 7TF
746	Research Site	Leicester		United Kingdom	LE3 9QP
747	Research Site	Livingston		United Kingdom	EH54 6PP
748	Research Site	London		United Kingdom	SE1 7EH
749	Research Site	Manchester		United Kingdom	M8 5RB
750	Research Site	Romford		United Kingdom	RM7 0AG
751	Research Site	Stockport		United Kingdom	SK2 7JE
752	Research Site	Worcester		United Kingdom	WR5 1DD
753	Research Site	Worthing		United Kingdom	BN11 2DH
754	Research Site	York		United Kingdom	YO31 8HE

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• McMurray JJ, Anand IS, Diaz R, Maggioni AP, O'Connor C, Pfeffer MA, Polu KR, Solomon SD, Sun Y, Swedberg K, Tendera M, van Veldhuisen DJ, Wasserman SM, Young JB; RED-HF Committees and Investigators. Design of the Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF): a Phase III, anaemia correction, morbidity-mortality trial. Eur J Heart Fail. 2009 Aug;11(8):795-801. doi: 10.1093/eurjhf/hfp098. Erratum in: Eur J Heart Fail. 2010 Jul;12(7):765. Pouler, A C [corrected to Pouleur, A C].
• Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O'Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ; RED-HF Committees; RED-HF Investigators. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013 Mar 28;368(13):1210-9. doi: 10.1056/NEJMoa1214865. Epub 2013 Mar 10.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00358215
• Other Study ID Numbers: 20050222; RED-HF™ Trial
• First Posted: Jul 31, 2006
• Last Update Posted: Nov 2, 2021
• Last Verified: Oct 1, 2021

• Keywords provided by Amgen: Survival study; morbidity and mortality; heart failure hospitalization; all-cause death; patient-reported outcomes; Kansas City Cardiomyopathy questionnaire; anemia treatment
• Additional relevant MeSH terms: Heart Failure; Cardiovascular Diseases; Ventricular Dysfunction; Anemia; Darbepoetin alfa

Study Results

Participant Flow

Recruitment Details	First patient enrolled 13 June 2006; Last patient enrolled 4 May 2012

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received dose and administration schedule (every 2 weeks or once a month) changes that simulated the changes for participants receiving darbepoetin alfa.	Starting dose of 0.75 µg/kg subcutaneously every 2 weeks until hemoglobin concentrations reach 13.0 g/dL on 2 consecutive visits, then monthly dosing, titrated to achieve hemoglobin target of 13.0 g/dL, not to exceed 14.5 g/dL.
Period Title: Overall Study
STARTED	1142	1136
Received Investigational Product	1140	1133
COMPLETED	463	484
NOT COMPLETED	679	652

Baseline Characteristics

Arm/Group Title	Placebo	Darbepoetin Alfa	Total
Arm/Group Description	Participants received dose and administration schedule (every 2 weeks or once a month) changes that simulated the changes for participants receiving darbepoetin alfa.	Starting dose of 0.75 µg/kg subcutaneously every 2 weeks until hemoglobin concentrations reach 13.0 g/dL on 2 consecutive visits, then monthly dosing, titrated to achieve hemoglobin target of 13.0 g/dL, not to exceed 14.5 g/dL.	Total of all reporting groups
Overall Participants	1142	1136	2278
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.6 (11.3)	70.0 (11.6)	69.8 (11.4)
Sex: Female, Male (Count of Participants)
Female	486 42.6%	458 40.3%	944 41.4%
Male	656 57.4%	678 59.7%	1334 58.6%
Race/Ethnicity, Customized (participants) [Number]
White or Caucasian	768 67.3%	781 68.8%	1549 68%
Black or African American	113 9.9%	89 7.8%	202 8.9%
Hispanic or Latino	84 7.4%	98 8.6%	182 8%
Asian	162 14.2%	162 14.3%	324 14.2%
Japanese	0 0%	1 0.1%	1 0%
American Indian or Alaska Native	2 0.2%	2 0.2%	4 0.2%
Native Hawaiian or Other Pacific Islander	1 0.1%	0 0%	1 0%
Other	12 1.1%	3 0.3%	15 0.7%
Region (participants) [Number]
North America	323 28.3%	321 28.3%	644 28.3%
Latin America and Asia	286 25%	285 25.1%	571 25.1%
Western Europe, Israel, South Africa, Australia	306 26.8%	303 26.7%	609 26.7%
Eastern Europe and Russia	227 19.9%	227 20%	454 19.9%
Device Usage (participants) [Number]
CRT with or without ICD	143 12.5%	143 12.6%	286 12.6%
ICD without CRT	124 10.9%	122 10.7%	246 10.8%
None	875 76.6%	871 76.7%	1746 76.6%
Kansas City Cardiomyopathy Questionnaire: Overall Summary Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	56.5 (22.5)	55.8 (22.6)	56.2 (22.5)
Study Specific Characteristic [Kansas City Cardiomyopathy Questionnaire: Symptom Frequency Scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	63.3 (25.2)	63.1 (25.6)	63.2 (25.4)

Outcome Measures

1. Primary Outcome

Title	Time to All Cause Death or First Hospitalization for Worsening Heart Failure
Description	Time to death from any cause or first hospital admission for worsening heart failure (adjudicated by the Clinical Endpoint Committee), whichever occurred first, estimated by Kaplan-Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first.
Time Frame	From randomization to the end of study; maximum time on study was 73 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) analysis set, defined as all randomized participants

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received dose and administration schedule (every 2 weeks or once a month) changes that simulated the changes for participants receiving darbepoetin alfa.	Starting dose of 0.75 µg/kg subcutaneously every 2 weeks until hemoglobin concentrations reach 13.0 g/dL on 2 consecutive visits, then monthly dosing, titrated to achieve hemoglobin target of 13.0 g/dL, not to exceed 14.5 g/dL.
Measure Participants	1142	1136
Median (Inter-Quartile Range) [days]	1260.0	1184.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.871
	Comments	Stratification factors are: region and type of device (cardiac resynchronization therapy (CRT) with or without implantable cardioverter defibrillator (ICD), ICD without CRT, or none)
	Method	Stratified Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.90 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio and 95% confidence intervals are from the Cox proportional hazards model adjusted by the stratification factors.

2. Secondary Outcome

Title	Time to Death From Any Cause
Description	Time from randomization to death due to any cause, estimated by the Kaplan-Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first.
Time Frame	From randomization to the end of study; maximum time on study was 73 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received dose and administration schedule (every 2 weeks or once a month) changes that simulated the changes for participants receiving darbepoetin alfa.	Starting dose of 0.75 µg/kg subcutaneously every 2 weeks until hemoglobin concentrations reach 13.0 g/dL on 2 consecutive visits, then monthly dosing, titrated to achieve hemoglobin target of 13.0 g/dL, not to exceed 14.5 g/dL.
Measure Participants	1142	1136
Median (Inter-Quartile Range) [days]	1637.0	1629.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.512
	Comments	Stratification factors are: region and type of device (cardiac resynchronization therapy (CRT) with or without implantable cardioverter defibrillator (ICD), ICD without CRT, or none).
	Method	Stratified Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio and 95% confidence intervals are from the Cox proportional hazards model adjusted by the stratification factors.

3. Secondary Outcome

Title	Time to Cardiovascular Death or First Hospital Admission for Worsening Heart Failure
Description	Time to cardiovascular death or first hospital admission for worsening heart failure, whichever occured first, estimated using the Kaplan Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first.
Time Frame	From randomization to the end of study; maximum time on study was 73 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received dose and administration schedule (every 2 weeks or once a month) changes that simulated the changes for participants receiving darbepoetin alfa.	Starting dose of 0.75 µg/kg subcutaneously every 2 weeks until hemoglobin concentrations reach 13.0 g/dL on 2 consecutive visits, then monthly dosing, titrated to achieve hemoglobin target of 13.0 g/dL, not to exceed 14.5 g/dL.
Measure Participants	1142	1136
Median (Inter-Quartile Range) [days]	1414.0	1395.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.922
	Comments	Stratification factors are: region and type of device (cardiac resynchronization therapy (CRT) with or without implantable cardioverter defibrillator (ICD), ICD without CRT, or none).
	Method	Stratified Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio and 95% confidence intervals are from the Cox proportional hazards model adjusted by the stratification factors.

4. Secondary Outcome

Title	Change From Baseline to Month 6 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score
Description	The KCCQ is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Least squares means were calculated from a mixed effects model estimating treatment effect adjusted for region, type of device, and Baseline KCCQ score.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Intent-to-treat participants with non-missing change from Baseline to Month 6 in KCCQ score.

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received dose and administration schedule (every 2 weeks or once a month) changes that simulated the changes for participants receiving darbepoetin alfa.	Starting dose of 0.75 µg/kg subcutaneously every 2 weeks until hemoglobin concentrations reach 13.0 g/dL on 2 consecutive visits, then monthly dosing, titrated to achieve hemoglobin target of 13.0 g/dL, not to exceed 14.5 g/dL.
Measure Participants	929	928
Least Squares Mean (Standard Error) [units on a scale]	4.48 (0.68)	6.68 (0.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model estimating treatment effect adjusted for region, type of device, and Baseline KCCQ score.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.20
	Confidence Interval	(2-Sided) 95%; 0.65 to 3.75
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.79
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline to Month 6 in KCCQ Symptom Frequency Score
Description	The KCCQ is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Least squares means were calculated from a mixed effects model estimating treatment effect adjusted for region, type of device, and Baseline KCCQ score.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Intent-to-treat participants with non-missing change from Baseline to Month 6 in KCCQ score.

Arm/Group Title	Placebo	Darbepoetin Alfa
Arm/Group Description	Participants received dose and administration schedule (every 2 weeks or once a month) changes that simulated the changes for participants receiving darbepoetin alfa.	Starting dose of 0.75 µg/kg subcutaneously every 2 weeks until hemoglobin concentrations reach 13.0 g/dL on 2 consecutive visits, then monthly dosing, titrated to achieve hemoglobin target of 13.0 g/dL, not to exceed 14.5 g/dL.
Measure Participants	927	925
Least Squares Mean (Standard Error) [units on a scale]	3.91 (0.76)	6.20 (0.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects model estimating treatment effect adjusted for region, type of device, and Baseline KCCQ score.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.29
	Confidence Interval	(2-Sided) 95%; 0.53 to 4.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.90
	Estimation Comments

Adverse Events

Time Frame	Informed consent to 30 days post treatment. Max time 72 months
Adverse Event Reporting Description	The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
Arm/Group Title	Placebo		Darbepoetin Alfa
Arm/Group Description	Participants received dose and administration schedule (every 2 weeks or once a month) changes that simulated the changes for participants receiving darbepoetin alfa.		Starting dose of 0.75 µg/kg subcutaneously every 2 weeks until hemoglobin concentrations reach 13.0 g/dL on 2 consecutive visits, then monthly dosing, titrated to achieve hemoglobin target of 13.0 g/dL, not to exceed 14.5 g/dL.
All Cause Mortality
	Placebo		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	741/1140 (65%)		781/1133 (68.9%)
Blood and lymphatic system disorders
Anaemia	49/1140 (4.3%)		23/1133 (2%)
Anaemia of chronic disease	0/1140 (0%)		1/1133 (0.1%)
Coagulopathy	1/1140 (0.1%)		2/1133 (0.2%)
Haemolytic anaemia	2/1140 (0.2%)		0/1133 (0%)
Haemorrhagic anaemia	2/1140 (0.2%)		0/1133 (0%)
Heparin-induced thrombocytopenia	0/1140 (0%)		1/1133 (0.1%)
Iron deficiency anaemia	2/1140 (0.2%)		0/1133 (0%)
Leukocytosis	1/1140 (0.1%)		0/1133 (0%)
Lymphadenopathy	1/1140 (0.1%)		0/1133 (0%)
Pancytopenia	2/1140 (0.2%)		0/1133 (0%)
Sideroblastic anaemia	0/1140 (0%)		1/1133 (0.1%)
Splenic infarction	0/1140 (0%)		2/1133 (0.2%)
Thrombocytopenia	1/1140 (0.1%)		2/1133 (0.2%)
Cardiac disorders
Acute coronary syndrome	13/1140 (1.1%)		7/1133 (0.6%)
Acute left ventricular failure	5/1140 (0.4%)		5/1133 (0.4%)
Acute myocardial infarction	21/1140 (1.8%)		21/1133 (1.9%)
Adams-Stokes syndrome	0/1140 (0%)		1/1133 (0.1%)
Angina pectoris	27/1140 (2.4%)		26/1133 (2.3%)
Angina unstable	26/1140 (2.3%)		24/1133 (2.1%)
Aortic valve incompetence	1/1140 (0.1%)		0/1133 (0%)
Aortic valve stenosis	1/1140 (0.1%)		1/1133 (0.1%)
Arrhythmia	10/1140 (0.9%)		5/1133 (0.4%)
Arrhythmia supraventricular	2/1140 (0.2%)		0/1133 (0%)
Arteriosclerosis coronary artery	2/1140 (0.2%)		1/1133 (0.1%)
Atrial fibrillation	30/1140 (2.6%)		32/1133 (2.8%)
Atrial flutter	7/1140 (0.6%)		3/1133 (0.3%)
Atrial tachycardia	2/1140 (0.2%)		2/1133 (0.2%)
Atrioventricular block	3/1140 (0.3%)		2/1133 (0.2%)
Atrioventricular block complete	2/1140 (0.2%)		2/1133 (0.2%)
Bradyarrhythmia	1/1140 (0.1%)		1/1133 (0.1%)
Bradycardia	4/1140 (0.4%)		7/1133 (0.6%)
Bundle branch block left	0/1140 (0%)		1/1133 (0.1%)
Cardiac arrest	22/1140 (1.9%)		31/1133 (2.7%)
Cardiac asthma	3/1140 (0.3%)		2/1133 (0.2%)
Cardiac discomfort	0/1140 (0%)		2/1133 (0.2%)
Cardiac disorder	0/1140 (0%)		1/1133 (0.1%)
Cardiac failure	273/1140 (23.9%)		264/1133 (23.3%)
Cardiac failure acute	16/1140 (1.4%)		21/1133 (1.9%)
Cardiac failure chronic	8/1140 (0.7%)		9/1133 (0.8%)
Cardiac failure congestive	145/1140 (12.7%)		126/1133 (11.1%)
Cardiac valve disease	1/1140 (0.1%)		0/1133 (0%)
Cardio-respiratory arrest	10/1140 (0.9%)		14/1133 (1.2%)
Cardiogenic shock	11/1140 (1%)		17/1133 (1.5%)
Cardiomyopathy	4/1140 (0.4%)		2/1133 (0.2%)
Cardiopulmonary failure	0/1140 (0%)		5/1133 (0.4%)
Cardiorenal syndrome	1/1140 (0.1%)		2/1133 (0.2%)
Cardiovascular insufficiency	0/1140 (0%)		1/1133 (0.1%)
Congestive cardiomyopathy	2/1140 (0.2%)		1/1133 (0.1%)
Coronary artery disease	10/1140 (0.9%)		4/1133 (0.4%)
Coronary artery occlusion	0/1140 (0%)		1/1133 (0.1%)
Coronary artery stenosis	4/1140 (0.4%)		0/1133 (0%)
Coronary artery thrombosis	0/1140 (0%)		2/1133 (0.2%)
Hypertensive heart disease	1/1140 (0.1%)		0/1133 (0%)
Intracardiac thrombus	0/1140 (0%)		2/1133 (0.2%)
Ischaemic cardiomyopathy	5/1140 (0.4%)		6/1133 (0.5%)
Left ventricular dysfunction	1/1140 (0.1%)		3/1133 (0.3%)
Left ventricular failure	3/1140 (0.3%)		3/1133 (0.3%)
Mitral valve disease	1/1140 (0.1%)		0/1133 (0%)
Mitral valve incompetence	4/1140 (0.4%)		2/1133 (0.2%)
Mitral valve stenosis	0/1140 (0%)		1/1133 (0.1%)
Myocardial fibrosis	0/1140 (0%)		1/1133 (0.1%)
Myocardial infarction	35/1140 (3.1%)		36/1133 (3.2%)
Myocardial ischaemia	5/1140 (0.4%)		1/1133 (0.1%)
Palpitations	0/1140 (0%)		1/1133 (0.1%)
Pericardial effusion	1/1140 (0.1%)		2/1133 (0.2%)
Pericarditis	1/1140 (0.1%)		1/1133 (0.1%)
Pulseless electrical activity	1/1140 (0.1%)		2/1133 (0.2%)
Right ventricular failure	0/1140 (0%)		1/1133 (0.1%)
Sick sinus syndrome	3/1140 (0.3%)		1/1133 (0.1%)
Sinoatrial block	0/1140 (0%)		1/1133 (0.1%)
Sinus arrhythmia	0/1140 (0%)		1/1133 (0.1%)
Sinus bradycardia	0/1140 (0%)		2/1133 (0.2%)
Supraventricular tachycardia	2/1140 (0.2%)		2/1133 (0.2%)
Tachyarrhythmia	0/1140 (0%)		2/1133 (0.2%)
Tachycardia	2/1140 (0.2%)		1/1133 (0.1%)
Tachycardia paroxysmal	0/1140 (0%)		1/1133 (0.1%)
Tricuspid valve incompetence	1/1140 (0.1%)		0/1133 (0%)
Ventricular arrhythmia	3/1140 (0.3%)		6/1133 (0.5%)
Ventricular extrasystoles	0/1140 (0%)		1/1133 (0.1%)
Ventricular fibrillation	10/1140 (0.9%)		10/1133 (0.9%)
Ventricular tachyarrhythmia	0/1140 (0%)		1/1133 (0.1%)
Ventricular tachycardia	24/1140 (2.1%)		22/1133 (1.9%)
Congenital, familial and genetic disorders
Arteriovenous malformation	0/1140 (0%)		1/1133 (0.1%)
Gastrointestinal arteriovenous malformation	2/1140 (0.2%)		1/1133 (0.1%)
Ichthyosis	1/1140 (0.1%)		0/1133 (0%)
Ear and labyrinth disorders
Vertigo	2/1140 (0.2%)		1/1133 (0.1%)
Endocrine disorders
Adrenal insufficiency	0/1140 (0%)		1/1133 (0.1%)
Hyperparathyroidism	0/1140 (0%)		1/1133 (0.1%)
Hyperthyroidism	0/1140 (0%)		1/1133 (0.1%)
Hypothyroidism	1/1140 (0.1%)		0/1133 (0%)
Inappropriate antidiuretic hormone secretion	0/1140 (0%)		1/1133 (0.1%)
Eye disorders
Cataract	1/1140 (0.1%)		3/1133 (0.3%)
Cataract diabetic	1/1140 (0.1%)		0/1133 (0%)
Diabetic retinopathy	1/1140 (0.1%)		0/1133 (0%)
Macular fibrosis	1/1140 (0.1%)		0/1133 (0%)
Optic ischaemic neuropathy	0/1140 (0%)		1/1133 (0.1%)
Retinal artery occlusion	0/1140 (0%)		1/1133 (0.1%)
Retinal detachment	0/1140 (0%)		2/1133 (0.2%)
Retinal vein occlusion	1/1140 (0.1%)		0/1133 (0%)
Retinopathy	0/1140 (0%)		1/1133 (0.1%)
Scleral haemorrhage	1/1140 (0.1%)		0/1133 (0%)
Vision blurred	1/1140 (0.1%)		1/1133 (0.1%)
Visual acuity reduced	1/1140 (0.1%)		0/1133 (0%)
Vitreous haemorrhage	1/1140 (0.1%)		0/1133 (0%)
Gastrointestinal disorders
Abdominal adhesions	1/1140 (0.1%)		0/1133 (0%)
Abdominal discomfort	0/1140 (0%)		1/1133 (0.1%)
Abdominal distension	2/1140 (0.2%)		2/1133 (0.2%)
Abdominal hernia	2/1140 (0.2%)		1/1133 (0.1%)
Abdominal pain	6/1140 (0.5%)		13/1133 (1.1%)
Abdominal pain lower	0/1140 (0%)		1/1133 (0.1%)
Abdominal pain upper	3/1140 (0.3%)		5/1133 (0.4%)
Abdominal wall haematoma	0/1140 (0%)		1/1133 (0.1%)
Abdominal wall haemorrhage	0/1140 (0%)		1/1133 (0.1%)
Anal polyp	0/1140 (0%)		1/1133 (0.1%)
Ascites	3/1140 (0.3%)		1/1133 (0.1%)
Coeliac disease	0/1140 (0%)		1/1133 (0.1%)
Colitis	2/1140 (0.2%)		3/1133 (0.3%)
Colitis ischaemic	2/1140 (0.2%)		1/1133 (0.1%)
Colonic polyp	1/1140 (0.1%)		0/1133 (0%)
Colonic stenosis	1/1140 (0.1%)		0/1133 (0%)
Constipation	8/1140 (0.7%)		9/1133 (0.8%)
Crohn's disease	1/1140 (0.1%)		0/1133 (0%)
Diabetic gastroparesis	1/1140 (0.1%)		0/1133 (0%)
Diaphragmatic hernia	1/1140 (0.1%)		0/1133 (0%)
Diarrhoea	12/1140 (1.1%)		12/1133 (1.1%)
Diverticular perforation	0/1140 (0%)		1/1133 (0.1%)
Diverticulum	2/1140 (0.2%)		3/1133 (0.3%)
Diverticulum intestinal haemorrhagic	1/1140 (0.1%)		0/1133 (0%)
Duodenal ulcer	2/1140 (0.2%)		3/1133 (0.3%)
Duodenal ulcer haemorrhage	0/1140 (0%)		2/1133 (0.2%)
Duodenitis	0/1140 (0%)		1/1133 (0.1%)
Dyspepsia	1/1140 (0.1%)		1/1133 (0.1%)
Dysphagia	0/1140 (0%)		4/1133 (0.4%)
Enterocolitis	0/1140 (0%)		1/1133 (0.1%)
Epigastric discomfort	1/1140 (0.1%)		1/1133 (0.1%)
Erosive oesophagitis	1/1140 (0.1%)		0/1133 (0%)
Faecaloma	2/1140 (0.2%)		1/1133 (0.1%)
Functional gastrointestinal disorder	0/1140 (0%)		1/1133 (0.1%)
Gastric haemorrhage	2/1140 (0.2%)		3/1133 (0.3%)
Gastric ulcer	4/1140 (0.4%)		2/1133 (0.2%)
Gastric ulcer haemorrhage	1/1140 (0.1%)		2/1133 (0.2%)
Gastric ulcer perforation	2/1140 (0.2%)		0/1133 (0%)
Gastritis	4/1140 (0.4%)		4/1133 (0.4%)
Gastritis atrophic	1/1140 (0.1%)		0/1133 (0%)
Gastritis erosive	1/1140 (0.1%)		1/1133 (0.1%)
Gastritis haemorrhagic	1/1140 (0.1%)		0/1133 (0%)
Gastrointestinal angiodysplasia	0/1140 (0%)		1/1133 (0.1%)
Gastrointestinal haemorrhage	23/1140 (2%)		18/1133 (1.6%)
Gastrointestinal inflammation	1/1140 (0.1%)		0/1133 (0%)
Gastrointestinal obstruction	0/1140 (0%)		1/1133 (0.1%)
Gastrooesophageal reflux disease	2/1140 (0.2%)		2/1133 (0.2%)
Gingival bleeding	0/1140 (0%)		2/1133 (0.2%)
Haematemesis	0/1140 (0%)		1/1133 (0.1%)
Haemorrhoidal haemorrhage	0/1140 (0%)		1/1133 (0.1%)
Haemorrhoids	0/1140 (0%)		1/1133 (0.1%)
Hiatus hernia	1/1140 (0.1%)		2/1133 (0.2%)
Ileus	0/1140 (0%)		3/1133 (0.3%)
Impaired gastric emptying	0/1140 (0%)		1/1133 (0.1%)
Inflammatory bowel disease	1/1140 (0.1%)		0/1133 (0%)
Inguinal hernia	5/1140 (0.4%)		6/1133 (0.5%)
Inguinal hernia, obstructive	0/1140 (0%)		1/1133 (0.1%)
Intestinal haemorrhage	2/1140 (0.2%)		1/1133 (0.1%)
Intestinal infarction	1/1140 (0.1%)		1/1133 (0.1%)
Intestinal ischaemia	1/1140 (0.1%)		1/1133 (0.1%)
Intestinal mass	0/1140 (0%)		1/1133 (0.1%)
Intestinal obstruction	1/1140 (0.1%)		1/1133 (0.1%)
Intestinal polyp	1/1140 (0.1%)		0/1133 (0%)
Irritable bowel syndrome	1/1140 (0.1%)		0/1133 (0%)
Large intestinal ulcer	2/1140 (0.2%)		0/1133 (0%)
Lower gastrointestinal haemorrhage	1/1140 (0.1%)		3/1133 (0.3%)
Mallory-Weiss syndrome	1/1140 (0.1%)		0/1133 (0%)
Melaena	3/1140 (0.3%)		1/1133 (0.1%)
Nausea	5/1140 (0.4%)		6/1133 (0.5%)
Oesophageal achalasia	0/1140 (0%)		2/1133 (0.2%)
Oesophageal food impaction	1/1140 (0.1%)		0/1133 (0%)
Oesophageal motility disorder	1/1140 (0.1%)		0/1133 (0%)
Oesophagitis	1/1140 (0.1%)		3/1133 (0.3%)
Pancreatitis	2/1140 (0.2%)		3/1133 (0.3%)
Pancreatitis acute	3/1140 (0.3%)		1/1133 (0.1%)
Pancreatitis chronic	0/1140 (0%)		2/1133 (0.2%)
Peptic ulcer	0/1140 (0%)		2/1133 (0.2%)
Peptic ulcer haemorrhage	1/1140 (0.1%)		1/1133 (0.1%)
Poor dental condition	1/1140 (0.1%)		0/1133 (0%)
Proctalgia	1/1140 (0.1%)		0/1133 (0%)
Rectal haemorrhage	4/1140 (0.4%)		5/1133 (0.4%)
Rectal polyp	0/1140 (0%)		1/1133 (0.1%)
Small intestinal obstruction	2/1140 (0.2%)		2/1133 (0.2%)
Subileus	1/1140 (0.1%)		0/1133 (0%)
Thrombosis mesenteric vessel	0/1140 (0%)		3/1133 (0.3%)
Toothache	0/1140 (0%)		1/1133 (0.1%)
Umbilical hernia	0/1140 (0%)		1/1133 (0.1%)
Umbilical hernia, obstructive	0/1140 (0%)		1/1133 (0.1%)
Upper gastrointestinal haemorrhage	2/1140 (0.2%)		5/1133 (0.4%)
Varices oesophageal	0/1140 (0%)		1/1133 (0.1%)
Volvulus	0/1140 (0%)		1/1133 (0.1%)
Vomiting	9/1140 (0.8%)		9/1133 (0.8%)
General disorders
Adverse drug reaction	1/1140 (0.1%)		0/1133 (0%)
Asthenia	10/1140 (0.9%)		8/1133 (0.7%)
Cardiac death	29/1140 (2.5%)		34/1133 (3%)
Catheter site haemorrhage	0/1140 (0%)		1/1133 (0.1%)
Chest discomfort	1/1140 (0.1%)		0/1133 (0%)
Chest pain	3/1140 (0.3%)		2/1133 (0.2%)
Death	24/1140 (2.1%)		18/1133 (1.6%)
Device breakage	0/1140 (0%)		1/1133 (0.1%)
Device dislocation	1/1140 (0.1%)		1/1133 (0.1%)
Device lead damage	0/1140 (0%)		1/1133 (0.1%)
Device malfunction	8/1140 (0.7%)		10/1133 (0.9%)
Device misuse	0/1140 (0%)		1/1133 (0.1%)
Device stimulation issue	0/1140 (0%)		1/1133 (0.1%)
Drowning	1/1140 (0.1%)		0/1133 (0%)
Fatigue	2/1140 (0.2%)		2/1133 (0.2%)
General physical health deterioration	3/1140 (0.3%)		5/1133 (0.4%)
Generalised oedema	1/1140 (0.1%)		3/1133 (0.3%)
Hernia	1/1140 (0.1%)		0/1133 (0%)
Hyperpyrexia	0/1140 (0%)		1/1133 (0.1%)
Hypothermia	0/1140 (0%)		1/1133 (0.1%)
Impaired healing	1/1140 (0.1%)		2/1133 (0.2%)
Implant site haematoma	1/1140 (0.1%)		2/1133 (0.2%)
Implant site pain	1/1140 (0.1%)		0/1133 (0%)
Implant site ulcer	1/1140 (0.1%)		0/1133 (0%)
Inflammation	0/1140 (0%)		1/1133 (0.1%)
Malaise	2/1140 (0.2%)		1/1133 (0.1%)
Medical device complication	0/1140 (0%)		4/1133 (0.4%)
Medical device pain	0/1140 (0%)		1/1133 (0.1%)
Medical device site reaction	1/1140 (0.1%)		0/1133 (0%)
Multi-organ disorder	0/1140 (0%)		1/1133 (0.1%)
Multi-organ failure	13/1140 (1.1%)		5/1133 (0.4%)
Necrobiosis	1/1140 (0.1%)		0/1133 (0%)
Non-cardiac chest pain	27/1140 (2.4%)		22/1133 (1.9%)
Oedema	0/1140 (0%)		1/1133 (0.1%)
Oedema peripheral	2/1140 (0.2%)		4/1133 (0.4%)
Pain	1/1140 (0.1%)		0/1133 (0%)
Polyp	0/1140 (0%)		1/1133 (0.1%)
Pyrexia	8/1140 (0.7%)		8/1133 (0.7%)
Sudden cardiac death	8/1140 (0.7%)		21/1133 (1.9%)
Sudden death	19/1140 (1.7%)		11/1133 (1%)
Systemic inflammatory response syndrome	1/1140 (0.1%)		0/1133 (0%)
Thrombosis in device	0/1140 (0%)		1/1133 (0.1%)
Hepatobiliary disorders
Bile duct stone	0/1140 (0%)		1/1133 (0.1%)
Biliary colic	0/1140 (0%)		1/1133 (0.1%)
Cardiac cirrhosis	1/1140 (0.1%)		0/1133 (0%)
Cholangitis	2/1140 (0.2%)		0/1133 (0%)
Cholecystitis	3/1140 (0.3%)		5/1133 (0.4%)
Cholecystitis acute	3/1140 (0.3%)		4/1133 (0.4%)
Cholecystitis chronic	1/1140 (0.1%)		0/1133 (0%)
Cholelithiasis	2/1140 (0.2%)		9/1133 (0.8%)
Gallbladder non-functioning	0/1140 (0%)		1/1133 (0.1%)
Hepatic cirrhosis	0/1140 (0%)		1/1133 (0.1%)
Hepatic congestion	0/1140 (0%)		1/1133 (0.1%)
Hepatic failure	0/1140 (0%)		1/1133 (0.1%)
Hepatic lesion	1/1140 (0.1%)		0/1133 (0%)
Hepatitis	0/1140 (0%)		1/1133 (0.1%)
Hepatomegaly	1/1140 (0.1%)		0/1133 (0%)
Hepatorenal failure	0/1140 (0%)		1/1133 (0.1%)
Liver disorder	1/1140 (0.1%)		0/1133 (0%)
Immune system disorders
Heart transplant rejection	0/1140 (0%)		1/1133 (0.1%)
Hypogammaglobulinaemia	0/1140 (0%)		1/1133 (0.1%)
Sarcoidosis	0/1140 (0%)		1/1133 (0.1%)
Infections and infestations
Abdominal abscess	0/1140 (0%)		1/1133 (0.1%)
Abdominal infection	1/1140 (0.1%)		0/1133 (0%)
Abscess limb	0/1140 (0%)		3/1133 (0.3%)
Abscess neck	0/1140 (0%)		1/1133 (0.1%)
Appendicitis	1/1140 (0.1%)		1/1133 (0.1%)
Arthritis bacterial	2/1140 (0.2%)		0/1133 (0%)
Arthritis infective	0/1140 (0%)		1/1133 (0.1%)
Bacteraemia	5/1140 (0.4%)		1/1133 (0.1%)
Bacterial infection	0/1140 (0%)		1/1133 (0.1%)
Bacterial sepsis	0/1140 (0%)		1/1133 (0.1%)
Bone tuberculosis	0/1140 (0%)		1/1133 (0.1%)
Bronchitis	22/1140 (1.9%)		12/1133 (1.1%)
Bronchitis bacterial	0/1140 (0%)		1/1133 (0.1%)
Bronchopneumonia	4/1140 (0.4%)		5/1133 (0.4%)
Campylobacter infection	0/1140 (0%)		2/1133 (0.2%)
Catheter site infection	1/1140 (0.1%)		1/1133 (0.1%)
Cellulitis	16/1140 (1.4%)		18/1133 (1.6%)
Clostridial infection	1/1140 (0.1%)		3/1133 (0.3%)
Clostridium difficile colitis	2/1140 (0.2%)		3/1133 (0.3%)
Clostridium difficile sepsis	1/1140 (0.1%)		0/1133 (0%)
Cystitis	0/1140 (0%)		2/1133 (0.2%)
Device related infection	2/1140 (0.2%)		0/1133 (0%)
Diabetic foot infection	1/1140 (0.1%)		0/1133 (0%)
Diabetic gangrene	1/1140 (0.1%)		0/1133 (0%)
Diarrhoea infectious	0/1140 (0%)		1/1133 (0.1%)
Diverticulitis	1/1140 (0.1%)		4/1133 (0.4%)
Endocarditis	1/1140 (0.1%)		1/1133 (0.1%)
Enterococcal sepsis	1/1140 (0.1%)		1/1133 (0.1%)
Erysipelas	3/1140 (0.3%)		5/1133 (0.4%)
Escherichia bacteraemia	1/1140 (0.1%)		1/1133 (0.1%)
Escherichia urinary tract infection	0/1140 (0%)		1/1133 (0.1%)
External ear cellulitis	1/1140 (0.1%)		0/1133 (0%)
Fungaemia	1/1140 (0.1%)		0/1133 (0%)
Gangrene	4/1140 (0.4%)		1/1133 (0.1%)
Gastroenteritis	7/1140 (0.6%)		15/1133 (1.3%)
Gastroenteritis clostridial	0/1140 (0%)		1/1133 (0.1%)
Gastroenteritis viral	3/1140 (0.3%)		2/1133 (0.2%)
H1N1 influenza	1/1140 (0.1%)		0/1133 (0%)
Helicobacter gastritis	0/1140 (0%)		1/1133 (0.1%)
Herpes zoster	2/1140 (0.2%)		0/1133 (0%)
Implant site infection	1/1140 (0.1%)		1/1133 (0.1%)
Incision site infection	1/1140 (0.1%)		0/1133 (0%)
Infected skin ulcer	0/1140 (0%)		2/1133 (0.2%)
Infection	1/1140 (0.1%)		3/1133 (0.3%)
Infective exacerbation of chronic obstructive airways disease	1/1140 (0.1%)		1/1133 (0.1%)
Influenza	0/1140 (0%)		3/1133 (0.3%)
Lobar pneumonia	8/1140 (0.7%)		8/1133 (0.7%)
Localised infection	7/1140 (0.6%)		5/1133 (0.4%)
Lower respiratory tract infection	6/1140 (0.5%)		7/1133 (0.6%)
Lung infection	1/1140 (0.1%)		1/1133 (0.1%)
Lung infection pseudomonal	1/1140 (0.1%)		0/1133 (0%)
Malaria	1/1140 (0.1%)		0/1133 (0%)
Neutropenic sepsis	0/1140 (0%)		1/1133 (0.1%)
Nosocomial infection	1/1140 (0.1%)		0/1133 (0%)
Oropharyngitis fungal	1/1140 (0.1%)		0/1133 (0%)
Osteomyelitis	5/1140 (0.4%)		5/1133 (0.4%)
Osteomyelitis chronic	1/1140 (0.1%)		0/1133 (0%)
Otitis externa	0/1140 (0%)		1/1133 (0.1%)
Pelvic abscess	0/1140 (0%)		1/1133 (0.1%)
Peritonitis	0/1140 (0%)		1/1133 (0.1%)
Pneumococcal bacteraemia	1/1140 (0.1%)		1/1133 (0.1%)
Pneumonia	71/1140 (6.2%)		86/1133 (7.6%)
Pneumonia bacterial	0/1140 (0%)		1/1133 (0.1%)
Pneumonia escherichia	0/1140 (0%)		1/1133 (0.1%)
Pneumonia influenzal	1/1140 (0.1%)		0/1133 (0%)
Pneumonia klebsiella	1/1140 (0.1%)		0/1133 (0%)
Pneumonia staphylococcal	1/1140 (0.1%)		0/1133 (0%)
Post procedural infection	1/1140 (0.1%)		0/1133 (0%)
Postoperative wound infection	1/1140 (0.1%)		0/1133 (0%)
Pseudomonal sepsis	0/1140 (0%)		1/1133 (0.1%)
Pulmonary sepsis	2/1140 (0.2%)		0/1133 (0%)
Pyelonephritis	1/1140 (0.1%)		3/1133 (0.3%)
Pyelonephritis chronic	2/1140 (0.2%)		0/1133 (0%)
Rectal abscess	0/1140 (0%)		1/1133 (0.1%)
Respiratory tract infection	4/1140 (0.4%)		10/1133 (0.9%)
Respiratory tract infection viral	0/1140 (0%)		1/1133 (0.1%)
Sepsis	22/1140 (1.9%)		19/1133 (1.7%)
Septic shock	7/1140 (0.6%)		21/1133 (1.9%)
Sinusitis	1/1140 (0.1%)		0/1133 (0%)
Soft tissue infection	0/1140 (0%)		1/1133 (0.1%)
Staphylococcal infection	1/1140 (0.1%)		3/1133 (0.3%)
Staphylococcal osteomyelitis	0/1140 (0%)		1/1133 (0.1%)
Staphylococcal sepsis	3/1140 (0.3%)		0/1133 (0%)
Streptococcal infection	0/1140 (0%)		1/1133 (0.1%)
Subcutaneous abscess	1/1140 (0.1%)		0/1133 (0%)
Superinfection	0/1140 (0%)		1/1133 (0.1%)
Tracheobronchitis	0/1140 (0%)		1/1133 (0.1%)
Tuberculous pleurisy	0/1140 (0%)		1/1133 (0.1%)
Upper respiratory tract infection	3/1140 (0.3%)		4/1133 (0.4%)
Urinary tract infection	20/1140 (1.8%)		29/1133 (2.6%)
Urosepsis	9/1140 (0.8%)		8/1133 (0.7%)
Viral infection	1/1140 (0.1%)		1/1133 (0.1%)
Wound infection	1/1140 (0.1%)		0/1133 (0%)
Wound sepsis	1/1140 (0.1%)		1/1133 (0.1%)
Injury, poisoning and procedural complications
Accidental overdose	2/1140 (0.2%)		1/1133 (0.1%)
Acetabulum fracture	1/1140 (0.1%)		1/1133 (0.1%)
Alcohol poisoning	1/1140 (0.1%)		0/1133 (0%)
Ankle fracture	2/1140 (0.2%)		1/1133 (0.1%)
Burns third degree	0/1140 (0%)		1/1133 (0.1%)
Cervical vertebral fracture	0/1140 (0%)		2/1133 (0.2%)
Chest injury	0/1140 (0%)		1/1133 (0.1%)
Concussion	1/1140 (0.1%)		1/1133 (0.1%)
Confusion postoperative	0/1140 (0%)		1/1133 (0.1%)
Contusion	1/1140 (0.1%)		0/1133 (0%)
Craniocerebral injury	0/1140 (0%)		1/1133 (0.1%)
Cystitis radiation	0/1140 (0%)		1/1133 (0.1%)
Drug administered at inappropriate site	0/1140 (0%)		1/1133 (0.1%)
Eschar	0/1140 (0%)		1/1133 (0.1%)
Fall	8/1140 (0.7%)		16/1133 (1.4%)
Femoral neck fracture	5/1140 (0.4%)		7/1133 (0.6%)
Femur fracture	8/1140 (0.7%)		8/1133 (0.7%)
Fibula fracture	1/1140 (0.1%)		0/1133 (0%)
Foot fracture	1/1140 (0.1%)		0/1133 (0%)
Gun shot wound	0/1140 (0%)		1/1133 (0.1%)
Head injury	1/1140 (0.1%)		1/1133 (0.1%)
Hip fracture	18/1140 (1.6%)		14/1133 (1.2%)
Humerus fracture	3/1140 (0.3%)		3/1133 (0.3%)
Incisional hernia	1/1140 (0.1%)		0/1133 (0%)
Injury	0/1140 (0%)		1/1133 (0.1%)
Intentional overdose	1/1140 (0.1%)		0/1133 (0%)
Joint dislocation	0/1140 (0%)		1/1133 (0.1%)
Laceration	0/1140 (0%)		1/1133 (0.1%)
Ligament sprain	0/1140 (0%)		1/1133 (0.1%)
Lower limb fracture	0/1140 (0%)		1/1133 (0.1%)
Lumbar vertebral fracture	0/1140 (0%)		1/1133 (0.1%)
Multiple fractures	1/1140 (0.1%)		0/1133 (0%)
Multiple injuries	1/1140 (0.1%)		0/1133 (0%)
Overdose	4/1140 (0.4%)		3/1133 (0.3%)
Pelvic fracture	1/1140 (0.1%)		0/1133 (0%)
Poisoning	1/1140 (0.1%)		0/1133 (0%)
Post procedural complication	1/1140 (0.1%)		0/1133 (0%)
Post procedural haematoma	0/1140 (0%)		1/1133 (0.1%)
Post procedural haemorrhage	0/1140 (0%)		1/1133 (0.1%)
Procedural haemorrhage	0/1140 (0%)		1/1133 (0.1%)
Pubis fracture	0/1140 (0%)		1/1133 (0.1%)
Radius fracture	1/1140 (0.1%)		2/1133 (0.2%)
Rib fracture	1/1140 (0.1%)		3/1133 (0.3%)
Road traffic accident	1/1140 (0.1%)		0/1133 (0%)
Shunt occlusion	0/1140 (0%)		1/1133 (0.1%)
Soft tissue injury	1/1140 (0.1%)		0/1133 (0%)
Spinal compression fracture	1/1140 (0.1%)		0/1133 (0%)
Spinal fracture	2/1140 (0.2%)		1/1133 (0.1%)
Subdural haematoma	7/1140 (0.6%)		2/1133 (0.2%)
Subdural haemorrhage	1/1140 (0.1%)		1/1133 (0.1%)
Tendon rupture	1/1140 (0.1%)		0/1133 (0%)
Tibia fracture	0/1140 (0%)		1/1133 (0.1%)
Toxicity to various agents	7/1140 (0.6%)		5/1133 (0.4%)
Tracheal obstruction	0/1140 (0%)		1/1133 (0.1%)
Transfusion reaction	0/1140 (0%)		1/1133 (0.1%)
Traumatic haematoma	0/1140 (0%)		1/1133 (0.1%)
Ulna fracture	1/1140 (0.1%)		0/1133 (0%)
Upper limb fracture	3/1140 (0.3%)		6/1133 (0.5%)
Wound	1/1140 (0.1%)		2/1133 (0.2%)
Wound necrosis	1/1140 (0.1%)		0/1133 (0%)
Wrist fracture	2/1140 (0.2%)		1/1133 (0.1%)
Investigations
Arteriogram coronary	1/1140 (0.1%)		0/1133 (0%)
Blood glucose decreased	1/1140 (0.1%)		0/1133 (0%)
Blood glucose increased	0/1140 (0%)		1/1133 (0.1%)
Blood potassium increased	0/1140 (0%)		1/1133 (0.1%)
Blood uric acid increased	1/1140 (0.1%)		0/1133 (0%)
C-reactive protein abnormal	0/1140 (0%)		1/1133 (0.1%)
C-reactive protein increased	0/1140 (0%)		2/1133 (0.2%)
Cardiac output decreased	0/1140 (0%)		1/1133 (0.1%)
Coagulation time prolonged	1/1140 (0.1%)		0/1133 (0%)
Drug level increased	1/1140 (0.1%)		0/1133 (0%)
Ejection fraction decreased	0/1140 (0%)		2/1133 (0.2%)
Glycosylated haemoglobin increased	0/1140 (0%)		1/1133 (0.1%)
Haemodynamic test abnormal	0/1140 (0%)		1/1133 (0.1%)
Haemoglobin decreased	3/1140 (0.3%)		1/1133 (0.1%)
International normalised ratio abnormal	1/1140 (0.1%)		0/1133 (0%)
International normalised ratio increased	4/1140 (0.4%)		5/1133 (0.4%)
Liver function test abnormal	1/1140 (0.1%)		0/1133 (0%)
Occult blood	1/1140 (0.1%)		0/1133 (0%)
Occult blood positive	1/1140 (0.1%)		1/1133 (0.1%)
Platelet count decreased	0/1140 (0%)		1/1133 (0.1%)
Renal function test abnormal	0/1140 (0%)		1/1133 (0.1%)
Transaminases increased	1/1140 (0.1%)		1/1133 (0.1%)
Transferrin saturation decreased	0/1140 (0%)		1/1133 (0.1%)
Waist circumference increased	1/1140 (0.1%)		0/1133 (0%)
Weight decreased	1/1140 (0.1%)		2/1133 (0.2%)
Weight increased	0/1140 (0%)		1/1133 (0.1%)
Metabolism and nutrition disorders
Cachexia	0/1140 (0%)		1/1133 (0.1%)
Calciphylaxis	1/1140 (0.1%)		0/1133 (0%)
Decreased appetite	5/1140 (0.4%)		1/1133 (0.1%)
Dehydration	22/1140 (1.9%)		19/1133 (1.7%)
Diabetes mellitus	9/1140 (0.8%)		14/1133 (1.2%)
Diabetes mellitus inadequate control	5/1140 (0.4%)		6/1133 (0.5%)
Diabetic complication	1/1140 (0.1%)		0/1133 (0%)
Electrolyte imbalance	0/1140 (0%)		1/1133 (0.1%)
Failure to thrive	1/1140 (0.1%)		0/1133 (0%)
Fluid overload	2/1140 (0.2%)		2/1133 (0.2%)
Gout	10/1140 (0.9%)		5/1133 (0.4%)
Hypercalcaemia	2/1140 (0.2%)		1/1133 (0.1%)
Hyperglycaemia	13/1140 (1.1%)		7/1133 (0.6%)
Hyperkalaemia	15/1140 (1.3%)		13/1133 (1.1%)
Hyperlipidaemia	0/1140 (0%)		1/1133 (0.1%)
Hypocalcaemia	0/1140 (0%)		1/1133 (0.1%)
Hypoglycaemia	18/1140 (1.6%)		16/1133 (1.4%)
Hypokalaemia	6/1140 (0.5%)		9/1133 (0.8%)
Hyponatraemia	11/1140 (1%)		7/1133 (0.6%)
Hypovolaemia	5/1140 (0.4%)		6/1133 (0.5%)
Lactic acidosis	1/1140 (0.1%)		1/1133 (0.1%)
Type 1 diabetes mellitus	1/1140 (0.1%)		0/1133 (0%)
Type 2 diabetes mellitus	3/1140 (0.3%)		0/1133 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/1140 (0.3%)		4/1133 (0.4%)
Arthritis	3/1140 (0.3%)		0/1133 (0%)
Arthritis reactive	1/1140 (0.1%)		0/1133 (0%)
Back pain	7/1140 (0.6%)		4/1133 (0.4%)
Bone infarction	0/1140 (0%)		1/1133 (0.1%)
Costochondritis	0/1140 (0%)		1/1133 (0.1%)
Exostosis	1/1140 (0.1%)		0/1133 (0%)
Foot deformity	1/1140 (0.1%)		1/1133 (0.1%)
Fracture pain	1/1140 (0.1%)		0/1133 (0%)
Gouty arthritis	1/1140 (0.1%)		1/1133 (0.1%)
Haemarthrosis	0/1140 (0%)		1/1133 (0.1%)
Intervertebral disc disorder	1/1140 (0.1%)		0/1133 (0%)
Joint effusion	2/1140 (0.2%)		0/1133 (0%)
Lordosis	1/1140 (0.1%)		0/1133 (0%)
Lumbar spinal stenosis	1/1140 (0.1%)		1/1133 (0.1%)
Muscle haemorrhage	1/1140 (0.1%)		1/1133 (0.1%)
Muscular weakness	0/1140 (0%)		2/1133 (0.2%)
Musculoskeletal chest pain	2/1140 (0.2%)		2/1133 (0.2%)
Musculoskeletal pain	2/1140 (0.2%)		0/1133 (0%)
Neck pain	1/1140 (0.1%)		1/1133 (0.1%)
Neuropathic arthropathy	0/1140 (0%)		1/1133 (0.1%)
Osteoarthritis	7/1140 (0.6%)		7/1133 (0.6%)
Osteochondrosis	1/1140 (0.1%)		0/1133 (0%)
Osteonecrosis	0/1140 (0%)		1/1133 (0.1%)
Pain in extremity	6/1140 (0.5%)		3/1133 (0.3%)
Polymyalgia rheumatica	1/1140 (0.1%)		1/1133 (0.1%)
Rheumatoid arthritis	1/1140 (0.1%)		0/1133 (0%)
Spinal column stenosis	1/1140 (0.1%)		1/1133 (0.1%)
Spinal deformity	0/1140 (0%)		1/1133 (0.1%)
Spinal osteoarthritis	0/1140 (0%)		3/1133 (0.3%)
Tenosynovitis	1/1140 (0.1%)		0/1133 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	0/1140 (0%)		1/1133 (0.1%)
Acute myelomonocytic leukaemia	1/1140 (0.1%)		0/1133 (0%)
B-cell lymphoma	1/1140 (0.1%)		0/1133 (0%)
Bile duct cancer	0/1140 (0%)		1/1133 (0.1%)
Bladder cancer	1/1140 (0.1%)		1/1133 (0.1%)
Bladder transitional cell carcinoma stage II	1/1140 (0.1%)		0/1133 (0%)
Bone cancer metastatic	1/1140 (0.1%)		0/1133 (0%)
Breast cancer	3/1140 (0.3%)		0/1133 (0%)
Breast cancer metastatic	1/1140 (0.1%)		0/1133 (0%)
Bronchial carcinoma	1/1140 (0.1%)		0/1133 (0%)
Carcinoid tumour pulmonary	0/1140 (0%)		1/1133 (0.1%)
Colon adenoma	0/1140 (0%)		1/1133 (0.1%)
Colon cancer	5/1140 (0.4%)		2/1133 (0.2%)
Colon cancer metastatic	0/1140 (0%)		1/1133 (0.1%)
Colon cancer stage III	1/1140 (0.1%)		0/1133 (0%)
Endometrial cancer	0/1140 (0%)		1/1133 (0.1%)
Endometrial sarcoma	0/1140 (0%)		1/1133 (0.1%)
Gastric cancer	1/1140 (0.1%)		1/1133 (0.1%)
Hepatic neoplasm malignant	1/1140 (0.1%)		2/1133 (0.2%)
Hypopharyngeal cancer	1/1140 (0.1%)		0/1133 (0%)
Laryngeal cancer	0/1140 (0%)		1/1133 (0.1%)
Lipoma	0/1140 (0%)		1/1133 (0.1%)
Lung adenocarcinoma	1/1140 (0.1%)		0/1133 (0%)
Lung neoplasm	0/1140 (0%)		1/1133 (0.1%)
Lung neoplasm malignant	1/1140 (0.1%)		5/1133 (0.4%)
Lymphocytic leukaemia	0/1140 (0%)		1/1133 (0.1%)
Lymphoma	0/1140 (0%)		1/1133 (0.1%)
Malignant anorectal neoplasm	0/1140 (0%)		1/1133 (0.1%)
Malignant neoplasm of ampulla of Vater	1/1140 (0.1%)		0/1133 (0%)
Mantle cell lymphoma	1/1140 (0.1%)		0/1133 (0%)
Meningioma	1/1140 (0.1%)		3/1133 (0.3%)
Mesothelioma malignant	0/1140 (0%)		1/1133 (0.1%)
Metastases to bone	1/1140 (0.1%)		0/1133 (0%)
Metastases to central nervous system	1/1140 (0.1%)		0/1133 (0%)
Metastases to liver	6/1140 (0.5%)		2/1133 (0.2%)
Metastases to peritoneum	0/1140 (0%)		1/1133 (0.1%)
Metastases to spine	1/1140 (0.1%)		0/1133 (0%)
Metastasis	1/1140 (0.1%)		0/1133 (0%)
Metastatic bronchial carcinoma	1/1140 (0.1%)		0/1133 (0%)
Metastatic gastric cancer	0/1140 (0%)		1/1133 (0.1%)
Metastatic squamous cell carcinoma	1/1140 (0.1%)		0/1133 (0%)
Multiple myeloma	1/1140 (0.1%)		0/1133 (0%)
Myelodysplastic syndrome	1/1140 (0.1%)		0/1133 (0%)
Neoplasm	0/1140 (0%)		1/1133 (0.1%)
Neoplasm malignant	1/1140 (0.1%)		0/1133 (0%)
Neoplasm prostate	0/1140 (0%)		1/1133 (0.1%)
Non-Hodgkin's lymphoma	0/1140 (0%)		1/1133 (0.1%)
Non-small cell lung cancer metastatic	1/1140 (0.1%)		0/1133 (0%)
Oesophageal adenocarcinoma	1/1140 (0.1%)		0/1133 (0%)
Oesophageal carcinoma	1/1140 (0.1%)		1/1133 (0.1%)
Ovarian cancer	0/1140 (0%)		1/1133 (0.1%)
Pancreatic carcinoma	2/1140 (0.2%)		0/1133 (0%)
Pituitary tumour benign	1/1140 (0.1%)		0/1133 (0%)
Plasmacytoma	0/1140 (0%)		1/1133 (0.1%)
Prostate cancer	8/1140 (0.7%)		3/1133 (0.3%)
Prostate cancer metastatic	1/1140 (0.1%)		0/1133 (0%)
Rectal cancer	2/1140 (0.2%)		2/1133 (0.2%)
Renal cell carcinoma	1/1140 (0.1%)		1/1133 (0.1%)
Renal neoplasm	0/1140 (0%)		1/1133 (0.1%)
Salivary gland neoplasm	1/1140 (0.1%)		0/1133 (0%)
Skin papilloma	1/1140 (0.1%)		0/1133 (0%)
Small cell lung cancer stage unspecified	1/1140 (0.1%)		0/1133 (0%)
Small intestine carcinoma	0/1140 (0%)		1/1133 (0.1%)
Squamous cell carcinoma	0/1140 (0%)		3/1133 (0.3%)
Tonsillar neoplasm	0/1140 (0%)		1/1133 (0.1%)
Vulval cancer	0/1140 (0%)		1/1133 (0.1%)
Nervous system disorders
Altered state of consciousness	0/1140 (0%)		1/1133 (0.1%)
Balance disorder	1/1140 (0.1%)		1/1133 (0.1%)
Brain compression	0/1140 (0%)		1/1133 (0.1%)
Brain oedema	0/1140 (0%)		1/1133 (0.1%)
Carotid artery occlusion	0/1140 (0%)		1/1133 (0.1%)
Carotid artery stenosis	0/1140 (0%)		3/1133 (0.3%)
Cerebral haematoma	2/1140 (0.2%)		0/1133 (0%)
Cerebral haemorrhage	0/1140 (0%)		1/1133 (0.1%)
Cerebral infarction	1/1140 (0.1%)		0/1133 (0%)
Cerebral ischaemia	0/1140 (0%)		1/1133 (0.1%)
Cerebrovascular accident	14/1140 (1.2%)		27/1133 (2.4%)
Cerebrovascular insufficiency	0/1140 (0%)		1/1133 (0.1%)
Cervicobrachial syndrome	1/1140 (0.1%)		0/1133 (0%)
Convulsion	3/1140 (0.3%)		3/1133 (0.3%)
Dementia	0/1140 (0%)		2/1133 (0.2%)
Dementia Alzheimer's type	0/1140 (0%)		1/1133 (0.1%)
Diabetic hyperosmolar coma	1/1140 (0.1%)		0/1133 (0%)
Diabetic neuropathy	1/1140 (0.1%)		1/1133 (0.1%)
Dizziness	13/1140 (1.1%)		10/1133 (0.9%)
Dysarthria	1/1140 (0.1%)		1/1133 (0.1%)
Encephalopathy	1/1140 (0.1%)		0/1133 (0%)
Epilepsy	1/1140 (0.1%)		1/1133 (0.1%)
Extrapyramidal disorder	0/1140 (0%)		1/1133 (0.1%)
Haemorrhage intracranial	1/1140 (0.1%)		2/1133 (0.2%)
Haemorrhagic stroke	3/1140 (0.3%)		2/1133 (0.2%)
Headache	3/1140 (0.3%)		2/1133 (0.2%)
Hemiparesis	2/1140 (0.2%)		0/1133 (0%)
Hemiplegia	1/1140 (0.1%)		1/1133 (0.1%)
Hepatic encephalopathy	1/1140 (0.1%)		3/1133 (0.3%)
Hypoglycaemic coma	1/1140 (0.1%)		1/1133 (0.1%)
Hypoglycaemic unconsciousness	0/1140 (0%)		1/1133 (0.1%)
Hypoxic-ischaemic encephalopathy	0/1140 (0%)		1/1133 (0.1%)
Intercostal neuralgia	1/1140 (0.1%)		0/1133 (0%)
Ischaemic stroke	7/1140 (0.6%)		8/1133 (0.7%)
Lethargy	0/1140 (0%)		2/1133 (0.2%)
Loss of consciousness	3/1140 (0.3%)		6/1133 (0.5%)
Lumbar radiculopathy	1/1140 (0.1%)		0/1133 (0%)
Mental impairment	0/1140 (0%)		1/1133 (0.1%)
Metabolic encephalopathy	3/1140 (0.3%)		1/1133 (0.1%)
Nerve compression	1/1140 (0.1%)		0/1133 (0%)
Neuropathy peripheral	2/1140 (0.2%)		1/1133 (0.1%)
Paraesthesia	1/1140 (0.1%)		0/1133 (0%)
Presyncope	9/1140 (0.8%)		8/1133 (0.7%)
Radiculopathy	0/1140 (0%)		1/1133 (0.1%)
Somnolence	0/1140 (0%)		3/1133 (0.3%)
Spinal cord compression	0/1140 (0%)		1/1133 (0.1%)
Subarachnoid haemorrhage	2/1140 (0.2%)		2/1133 (0.2%)
Syncope	29/1140 (2.5%)		19/1133 (1.7%)
Toxic encephalopathy	0/1140 (0%)		1/1133 (0.1%)
Transient ischaemic attack	4/1140 (0.4%)		7/1133 (0.6%)
VIIth nerve paralysis	2/1140 (0.2%)		0/1133 (0%)
Vocal cord paralysis	0/1140 (0%)		1/1133 (0.1%)
Psychiatric disorders
Anxiety	0/1140 (0%)		2/1133 (0.2%)
Confusional state	5/1140 (0.4%)		6/1133 (0.5%)
Delirium	1/1140 (0.1%)		0/1133 (0%)
Depression	0/1140 (0%)		3/1133 (0.3%)
Disorientation	1/1140 (0.1%)		1/1133 (0.1%)
Insomnia	2/1140 (0.2%)		0/1133 (0%)
Major depression	2/1140 (0.2%)		0/1133 (0%)
Mental status changes	3/1140 (0.3%)		8/1133 (0.7%)
Psychiatric symptom	1/1140 (0.1%)		0/1133 (0%)
Restlessness	1/1140 (0.1%)		0/1133 (0%)
Sopor	1/1140 (0.1%)		0/1133 (0%)
Suicidal ideation	1/1140 (0.1%)		0/1133 (0%)
Suicide attempt	1/1140 (0.1%)		0/1133 (0%)
Renal and urinary disorders
Acute prerenal failure	3/1140 (0.3%)		1/1133 (0.1%)
Anuria	0/1140 (0%)		1/1133 (0.1%)
Azotaemia	5/1140 (0.4%)		1/1133 (0.1%)
Cystitis haemorrhagic	0/1140 (0%)		1/1133 (0.1%)
Dysuria	1/1140 (0.1%)		2/1133 (0.2%)
Haematuria	3/1140 (0.3%)		4/1133 (0.4%)
Hydronephrosis	1/1140 (0.1%)		0/1133 (0%)
Ischaemic nephropathy	1/1140 (0.1%)		0/1133 (0%)
Oliguria	0/1140 (0%)		1/1133 (0.1%)
Pollakiuria	0/1140 (0%)		1/1133 (0.1%)
Polyuria	0/1140 (0%)		1/1133 (0.1%)
Renal artery stenosis	1/1140 (0.1%)		3/1133 (0.3%)
Renal failure	37/1140 (3.2%)		41/1133 (3.6%)
Renal failure acute	62/1140 (5.4%)		58/1133 (5.1%)
Renal failure chronic	20/1140 (1.8%)		11/1133 (1%)
Renal impairment	4/1140 (0.4%)		9/1133 (0.8%)
Renal injury	1/1140 (0.1%)		2/1133 (0.2%)
Renal mass	1/1140 (0.1%)		0/1133 (0%)
Renal tubular necrosis	0/1140 (0%)		1/1133 (0.1%)
Urethral disorder	0/1140 (0%)		1/1133 (0.1%)
Urethral stenosis	2/1140 (0.2%)		0/1133 (0%)
Urinary bladder haemorrhage	0/1140 (0%)		1/1133 (0.1%)
Urinary retention	7/1140 (0.6%)		9/1133 (0.8%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	2/1140 (0.2%)		2/1133 (0.2%)
Breast haematoma	1/1140 (0.1%)		0/1133 (0%)
Epididymitis	1/1140 (0.1%)		0/1133 (0%)
Menorrhagia	1/1140 (0.1%)		0/1133 (0%)
Pelvic floor muscle weakness	1/1140 (0.1%)		0/1133 (0%)
Prostatic disorder	1/1140 (0.1%)		0/1133 (0%)
Prostatitis	1/1140 (0.1%)		0/1133 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	8/1140 (0.7%)		5/1133 (0.4%)
Acute respiratory distress syndrome	1/1140 (0.1%)		0/1133 (0%)
Acute respiratory failure	8/1140 (0.7%)		6/1133 (0.5%)
Asthma	4/1140 (0.4%)		1/1133 (0.1%)
Atelectasis	2/1140 (0.2%)		0/1133 (0%)
Bronchiectasis	2/1140 (0.2%)		1/1133 (0.1%)
Bronchitis chronic	1/1140 (0.1%)		0/1133 (0%)
Bronchospasm	2/1140 (0.2%)		0/1133 (0%)
Choking sensation	0/1140 (0%)		1/1133 (0.1%)
Chronic obstructive pulmonary disease	42/1140 (3.7%)		22/1133 (1.9%)
Chronic respiratory failure	1/1140 (0.1%)		1/1133 (0.1%)
Cough	2/1140 (0.2%)		2/1133 (0.2%)
Dyspnoea	29/1140 (2.5%)		27/1133 (2.4%)
Dyspnoea exertional	1/1140 (0.1%)		0/1133 (0%)
Dyspnoea paroxysmal nocturnal	1/1140 (0.1%)		0/1133 (0%)
Epistaxis	4/1140 (0.4%)		3/1133 (0.3%)
Haemoptysis	2/1140 (0.2%)		2/1133 (0.2%)
Haemothorax	1/1140 (0.1%)		1/1133 (0.1%)
Hypercapnia	1/1140 (0.1%)		0/1133 (0%)
Hypoxia	2/1140 (0.2%)		2/1133 (0.2%)
Lung consolidation	1/1140 (0.1%)		0/1133 (0%)
Pleural effusion	9/1140 (0.8%)		11/1133 (1%)
Pleural fibrosis	1/1140 (0.1%)		0/1133 (0%)
Pleurisy	0/1140 (0%)		1/1133 (0.1%)
Pneumonia aspiration	2/1140 (0.2%)		4/1133 (0.4%)
Pneumonitis	2/1140 (0.2%)		3/1133 (0.3%)
Pneumothorax	0/1140 (0%)		1/1133 (0.1%)
Productive cough	1/1140 (0.1%)		0/1133 (0%)
Pulmonary congestion	1/1140 (0.1%)		1/1133 (0.1%)
Pulmonary embolism	6/1140 (0.5%)		10/1133 (0.9%)
Pulmonary hypertension	2/1140 (0.2%)		3/1133 (0.3%)
Pulmonary oedema	9/1140 (0.8%)		11/1133 (1%)
Respiratory acidosis	1/1140 (0.1%)		1/1133 (0.1%)
Respiratory alkalosis	1/1140 (0.1%)		0/1133 (0%)
Respiratory arrest	2/1140 (0.2%)		1/1133 (0.1%)
Respiratory distress	4/1140 (0.4%)		1/1133 (0.1%)
Respiratory failure	19/1140 (1.7%)		13/1133 (1.1%)
Respiratory tract inflammation	0/1140 (0%)		1/1133 (0.1%)
Sleep apnoea syndrome	0/1140 (0%)		1/1133 (0.1%)
Upper-airway cough syndrome	1/1140 (0.1%)		0/1133 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/1140 (0.1%)		0/1133 (0%)
Blister	1/1140 (0.1%)		1/1133 (0.1%)
Decubitus ulcer	0/1140 (0%)		3/1133 (0.3%)
Diabetic foot	3/1140 (0.3%)		3/1133 (0.3%)
Dry gangrene	1/1140 (0.1%)		0/1133 (0%)
Ecchymosis	1/1140 (0.1%)		0/1133 (0%)
Eczema	0/1140 (0%)		1/1133 (0.1%)
Petechiae	0/1140 (0%)		1/1133 (0.1%)
Pruritus	1/1140 (0.1%)		1/1133 (0.1%)
Psoriasis	0/1140 (0%)		1/1133 (0.1%)
Rash	1/1140 (0.1%)		2/1133 (0.2%)
Skin disorder	1/1140 (0.1%)		0/1133 (0%)
Skin lesion	0/1140 (0%)		1/1133 (0.1%)
Skin maceration	0/1140 (0%)		1/1133 (0.1%)
Skin necrosis	2/1140 (0.2%)		0/1133 (0%)
Skin ulcer	12/1140 (1.1%)		5/1133 (0.4%)
Stasis dermatitis	0/1140 (0%)		1/1133 (0.1%)
Stevens-Johnson syndrome	1/1140 (0.1%)		1/1133 (0.1%)
Urticaria	1/1140 (0.1%)		0/1133 (0%)
Surgical and medical procedures
Cardiac pacemaker insertion	2/1140 (0.2%)		0/1133 (0%)
Cardiac resynchronisation therapy	0/1140 (0%)		2/1133 (0.2%)
Cardioversion	3/1140 (0.3%)		2/1133 (0.2%)
Coronary arterial stent insertion	1/1140 (0.1%)		0/1133 (0%)
Gastrostomy	0/1140 (0%)		1/1133 (0.1%)
Haemodialysis	1/1140 (0.1%)		1/1133 (0.1%)
Implantable defibrillator insertion	4/1140 (0.4%)		1/1133 (0.1%)
Percutaneous coronary intervention	0/1140 (0%)		1/1133 (0.1%)
Resuscitation	0/1140 (0%)		2/1133 (0.2%)
Therapy regimen changed	0/1140 (0%)		1/1133 (0.1%)
Vascular disorders
Accelerated hypertension	2/1140 (0.2%)		1/1133 (0.1%)
Aortic aneurysm rupture	0/1140 (0%)		1/1133 (0.1%)
Aortic arteriosclerosis	0/1140 (0%)		1/1133 (0.1%)
Arterial insufficiency	0/1140 (0%)		1/1133 (0.1%)
Arteriosclerosis	1/1140 (0.1%)		1/1133 (0.1%)
Artery dissection	1/1140 (0.1%)		0/1133 (0%)
Circulatory collapse	1/1140 (0.1%)		2/1133 (0.2%)
Deep vein thrombosis	5/1140 (0.4%)		8/1133 (0.7%)
Embolism	1/1140 (0.1%)		0/1133 (0%)
Essential hypertension	1/1140 (0.1%)		0/1133 (0%)
Extremity necrosis	1/1140 (0.1%)		1/1133 (0.1%)
Femoral artery aneurysm	1/1140 (0.1%)		0/1133 (0%)
Haematoma	6/1140 (0.5%)		4/1133 (0.4%)
Hypertension	6/1140 (0.5%)		8/1133 (0.7%)
Hypertensive crisis	4/1140 (0.4%)		1/1133 (0.1%)
Hypertensive emergency	0/1140 (0%)		1/1133 (0.1%)
Hypotension	24/1140 (2.1%)		22/1133 (1.9%)
Hypovolaemic shock	0/1140 (0%)		2/1133 (0.2%)
Intermittent claudication	1/1140 (0.1%)		3/1133 (0.3%)
Intra-abdominal haematoma	0/1140 (0%)		1/1133 (0.1%)
Ischaemia	1/1140 (0.1%)		1/1133 (0.1%)
Lymphoedema	0/1140 (0%)		1/1133 (0.1%)
Orthostatic hypotension	4/1140 (0.4%)		5/1133 (0.4%)
Peripheral arterial occlusive disease	4/1140 (0.4%)		7/1133 (0.6%)
Peripheral artery aneurysm	1/1140 (0.1%)		0/1133 (0%)
Peripheral artery stenosis	1/1140 (0.1%)		1/1133 (0.1%)
Peripheral artery thrombosis	1/1140 (0.1%)		0/1133 (0%)
Peripheral embolism	0/1140 (0%)		1/1133 (0.1%)
Peripheral ischaemia	5/1140 (0.4%)		5/1133 (0.4%)
Peripheral vascular disorder	4/1140 (0.4%)		2/1133 (0.2%)
Phlebitis	1/1140 (0.1%)		0/1133 (0%)
Phlebitis superficial	0/1140 (0%)		1/1133 (0.1%)
Poor peripheral circulation	0/1140 (0%)		1/1133 (0.1%)
Poor venous access	0/1140 (0%)		1/1133 (0.1%)
Shock	0/1140 (0%)		1/1133 (0.1%)
Shock haemorrhagic	0/1140 (0%)		1/1133 (0.1%)
Steal syndrome	0/1140 (0%)		1/1133 (0.1%)
Thrombophlebitis	0/1140 (0%)		2/1133 (0.2%)
Varicose vein	1/1140 (0.1%)		0/1133 (0%)
Venous insufficiency	0/1140 (0%)		2/1133 (0.2%)
Venous thrombosis limb	1/1140 (0.1%)		0/1133 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	741/1140 (65%)		710/1133 (62.7%)
Cardiac disorders
Angina pectoris	60/1140 (5.3%)		52/1133 (4.6%)
Cardiac failure	92/1140 (8.1%)		69/1133 (6.1%)
Gastrointestinal disorders
Constipation	68/1140 (6%)		81/1133 (7.1%)
Diarrhoea	135/1140 (11.8%)		148/1133 (13.1%)
Nausea	75/1140 (6.6%)		71/1133 (6.3%)
General disorders
Asthenia	112/1140 (9.8%)		88/1133 (7.8%)
Fatigue	84/1140 (7.4%)		86/1133 (7.6%)
Oedema peripheral	118/1140 (10.4%)		115/1133 (10.2%)
Infections and infestations
Bronchitis	88/1140 (7.7%)		99/1133 (8.7%)
Influenza	71/1140 (6.2%)		61/1133 (5.4%)
Nasopharyngitis	111/1140 (9.7%)		117/1133 (10.3%)
Upper respiratory tract infection	73/1140 (6.4%)		95/1133 (8.4%)
Urinary tract infection	71/1140 (6.2%)		82/1133 (7.2%)
Injury, poisoning and procedural complications
Fall	68/1140 (6%)		80/1133 (7.1%)
Metabolism and nutrition disorders
Gout	75/1140 (6.6%)		71/1133 (6.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	78/1140 (6.8%)		101/1133 (8.9%)
Back pain	87/1140 (7.6%)		93/1133 (8.2%)
Pain in extremity	93/1140 (8.2%)		94/1133 (8.3%)
Nervous system disorders
Dizziness	143/1140 (12.5%)		138/1133 (12.2%)
Headache	69/1140 (6.1%)		67/1133 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	132/1140 (11.6%)		126/1133 (11.1%)
Dyspnoea	174/1140 (15.3%)		157/1133 (13.9%)
Vascular disorders
Hypotension	83/1140 (7.3%)		73/1133 (6.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results aftercompletion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.