1 Supplementary Online Content

3 Kozhuharov N, Goudev A, Flores D, et al; GALACTIC Investigators. Effect of a strategy of

4 comprehensive vasodilation vs usual care on mortality and heart failure rehospitalization
5 among patients with acute heart failure: the GALACTIC randomized clinical trial. JAMA.
6 doi:10.1001/jama.2019.18598

8 eAppendix. Supplemental Methods and Results

9 eTable 1. Detailed Eligibility Criteria
10 eTable 2. Protocol-Defined De-escalation Schema
11 eTable 3. Prespecified Secondary Endpoints of the Study
12 eTable 4. Post Hoc Analysis of the Mixed Effect Model With Site as a Random Effect and an
13 Unadjusted Analysis for the Primary Endpoint
14 eTable 5. Post Hoc Analysis of Medication, Weight Reduction, and Prespecified Exploratory
15 Analysis of Blood Pressure over Time (Median and Interquartile Range) Among Patients
16 Treated with Early Intensive and Sustained Vasodilation vs Usual Care
17 eTable 6. Dyspnea at Baseline, Day 2 and Day 6 in Patients with Available Assessment
18 eTable 7. Course of Serum Creatinine, Estimated Glomerular Filtration Rate, and NT-
19 proBNP Concentrations during Hospitalization among Patients in the Early Intensive and
20 Sustained Vasodilation Group versus the Usual Care Group
21 eTable 8. Medication at Baseline and 180-Days Follow-up
22 eTable 9. Medication at Baseline and 180-Days Follow-Up Stratified by Recruitment Period
23 eTable 10. Angiotensin-Converting-Enzyme Inhibitor, Angiotensin Receptor Blocker and
24 Angiotensin Receptor-Neprilysin Inhibitor Medication at Baseline, Discharge, and 180-Days
25 Follow-up
26 eTable 11. Prescribed Percentage of the ACE-I, ARB, and ARNi Target Dose at
27 Presentation, Discharge and 180-Days Follow-up
28 eFigure 1. Treatment Algorithm for the Intensive and Sustained Vasodilation Group
29 eFigure 2. Dyspnea Evaluation at Baseline, Day 2 and Day 6 Among Patients in the Early
30 Intensive and Sustained Vasodilation Group Versus the Usual Care Group
31 eReferences

32

33 This supplementary material has been provided by the authors to give readers additional
34 information about their work.
35

© 2019 American Medical Association. All rights reserved.

36 eAppendix. Supplemental Methods and Results

37 Adjudication of the final diagnosis of AHF: The final diagnosis of the AHF phenotypes,

38 predisposing conditions, and precipitating factors was adjudicated by an independent

39 cardiologist, who had access to all patients' medical records (clinical history, physical

40 examination, 12-lead ECG, laboratory findings including natriuretic peptide

41 measurements, estimated glomerular filtration rate, chest X-ray, non-invasive and

42 invasive cardiac imaging studies including echocardiography, cardiac magnetic

43 resonance imaging, coronary angiography, myocardial per-fusion scanning, lung

44 function testing, chest computed tomography, the response to therapy, and follow-up,

45 according to current guidelines).1,2 In situations of uncertainty about the diagnosis,

46 cases were reviewed and adjudicated in conjunction with a second cardiologist.

47 Randomization: Specifically, in the utilized static stratified block randomization schema

48 the range of block sizes complied with the allocation ratio of randomization numbers. 3

49 As of June 2016, the allocation ratio (= block size) was 50 for each stratum (BNP/NT-

50 proBNP and center). For high-recruiting centers (“University Hospital Basel”, “Fifth

51 Multifunctional Hospital for Active Treatment, Sofia” and “University Hospital Queen

52 Ioanna, Sofia”), the allocation ratio was set to 150 (as of May 2017). For each

53 allocation, there were exactly 50% “standard” and 50% “intervention” groups.

54 Subgroup analysis: Pre-specified subgroups were as follows: patients younger versus

55 older than 75 years of age, men versus women, HF with reduced LVEF (LVEF< 40%)

56 versus HF with mid-range LVEF (LVEF 40-49%) versus HF with preserved LVEF

57 (LVEF≥50%), systolic blood pressure at randomization lower versus ≥120 mmHg,

58 coronary artery disease present or not, BNP concentration at randomization lower or

59 ≥1000 ng/L, patients with versus without known chronic heart failure, and estimated

60 glomerular filtration rate <60ml/min/1.73 m2 versus ≥60ml/min/1.73 m2.

© 2019 American Medical Association. All rights reserved.

61 The cut-points used to define the subgroups based on LVEF were modified following

62 the recommendation for the new classification by the European Society of Cardiology.2

63 Statistical methods: Baseline characteristics as well as percent target dose, drug dose,

64 time to discharge, blood pressure, quantitative assessment of dyspnea, NT-proBNP

65 concentrations, and creatinine concentrations were compared using Fisher's exact test

66 in case of categorical variables and Mann–Whitney U test or student t test as

67 appropriate for continuous variables. Comparisons were made separately at each day.

68 Results

69 From December 10th 2007 to February 19th 2018, patients were enrolled in 5 countries

70 on 2 continents (4 sites in Switzerland [n=637], 2 in Bulgaria [n=58], 1 in Germany

71 [n=50], 1 in Brazil [n=39], and 2 in Spain [n=4]) with minor shifts of recruitment rates

72 among the sites over the recruitment period.

73 Orthopnea and peripheral edema were present in 71% and 73% and rales in 90% of

74 patients.

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 75 eTable 1. Detailed Eligibility Criteria

76 Inclusion Criteria
77 • AHF a expressed by acute dyspnea New York Heart Association class III or IV, and BNP or NT-
78 proBNP plasma concentration ≥ 500 ng/L or ≥ 2000 ng/L b, respectively.
79 • Age at least 18 years.
80 • Informed consent.
81 • Negative pregnancy test (only in female patients younger than 60 years).
82
83 Exclusion Criteria
84 • Cardiopulmonary resuscitation less than 7 days ago.
85 • Cardiogenic shock, ST-elevation myocardial infarction, or other clinical conditions that require
86 immediate ICU admission or urgent PTCA.
87 • Systolic blood pressure lower than 100 mmHg at presentation.
88 • Primary rhythmogenic cause of acute decompensation (ventricular tachycardia, re-entry
89 tachycardia, atrial fibrillation or atrial flutter with a ventricular rate exceeding 140 beats per
90 minute).
91 • NSTEMI as primary diagnosis.
92 • Severe aortic or mitral stenosis.
93 • Adult congenital heart disease as primary cause of AHF.
94 • Hypertrophic obstructive cardiomyopathy.
95 • Isolated right ventricular failure due to pulmonary hypertension.
96 • Chronic kidney disease with creatinine levels > 250 µmol/L.
97 • Bilateral renal artery stenosis.
98 • Severe sepsis or other causes of high output failure.
99 • Cirrhosis of the liver CHILD class C.
100 • Systemic Lupus erythematosus and related diseases.
101 • Acute aortic dissection.
102 • Porphyria.
103 • Previous adverse reactions to nitrates.
104 • Known hypersensitivity to hydralazine or dihydralazine.
105 • Patient in an emergency situation resulting in an inability to give informed
106 consent.
107 a The diagnosis of AHF is additionally based on typical symptoms and clinical findings, supported by
108 appropriate investigations such as ECG, chest X-ray, and Doppler-echocardiography as
109 recommended by current ESC guidelines on the diagnosis and treatment of AHF.

110 bDue to inverse association of natriuretic peptide levels and body mass index (BMI), for patients
111 presenting with BMI of ≥ 35 kg/m 2 both cut-off levels were adjusted to ≥ 350 ng/L and ≥ 1400 ng/L for
112 BNP and NT-proBNP, respectively.4 Only NT-proBNP, but not BNP, were used for the inclusion of
113 patients treated with ARNi.5,6

114 AHF=Acute heart failure, ARNi=angiotensin receptor-neprilysin inhibitor, BNP=B-type natriuretic

115 peptide, ICU=intensive care unit, NSTEMI=non-ST elevation myocardial infarction, NT-proBNP=N-
116 terminal pro-B-type natriuretic peptide, PTCA=percutaneous transluminal coronary angioplasty.

117

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118 eTable 2. Protocol-Defined De-escalation Schema

119 Symptomatic Arterial Hypotension

120 If systolic blood pressure should fall below the target of 90 mm Hg to 110 mm Hg and signs or symptoms of arterial hypotension occur, an adjustment of medical
121 therapy following a predefined schedule will be performed:

122 Day 1 and 2 (0 h till 48 h): Reduction of 50% of the transdermal applied nitrates by immediate removal of the patches and temporary withdrawal of hydralazine.
123 Additionally blood pressure monitoring will be performed every 30 minutes to 60 minutes until hemodynamic stability has been reestablished.

124 Day 3 till discharge: Reduction of 50% of the transdermal applied nitrates by immediate removal of the patches and temporary dosage reduction of the ACE-
125 inhibitor or ARB to the dosage of the last day when the patient was asymptomatic. Additionally blood pressure monitoring may be performed if deemed
126 necessary. At any time during the study: If these measures do not help to increase systolic arterial blood pressure, physical measures like the elevation of the
127 patient's legs and as an ultima ratio intravenous administration of crystalloid fluid can remove symptoms and hemodynamic impairment. After termination of the
128 symptomatic hypotensive episode, a stepwise augmentation of transdermal nitrates, hydralazine or ACE-inhibitor / ARB will be reinitiated. Importantly,
129 asymptomatic hypotension without evidence for critical organ dysfunction will not lead to any change in medical therapy, as maximal afterload reduction is an
130 integral part of the intervention.

131 Worsening Renal Function

132 Some rise in creatinine and blood urea nitrogen levels is commonly seen in patients with acute HF. Often it is not possible to identify a single cause, but
133 hypovolemia induced by diuretic treatment, low output as part of acute HF, renal venous congestion or initiation of ACE-inhibitors / ARB may play a role.
134 Regarding the up-titration of ACE-inhibitors / ARB current guidelines suggest that changes in creatinine or blood urea nitrogen levels should not be considered
135 clinically important unless they are rapid and substantial. Accordingly, a creatinine rise less than 50% from baseline values will be carefully monitored without
136 adjustment of treatment schedule. In case of a rise of more than 50% of the baseline value, the treatment with ACE-inhibitors / ARB will be continued without
137 augmentation and creatinine levels will be monitored every 24 hours to 48 hours. As soon as creatinine levels begin to decline, dosage of ACE-inhibitor / ARB will
138 be up-titrated according to the treatment schedule (Supplement 1, Figures 4a / 4b). In case of acute renal injury, defined as a doubling in serum creatinine levels
139 compared to baseline levels, the following procedural schedule will be applied: A 50% reduction of the last ACE-inhibitor / ARB dosage will be performed and
140 creatinine levels will be measured 24 hours to 48 hours later. When creatinine levels continue to rise despite this measure, a further stepwise decrease of 50% of
141 the ACE-inhibitor / ARB is scheduled and will be repeated every 48 hours until creatinine levels begin to decline. When creatinine levels remain unchanged or
142 decrease less than 30% of peak level, the current dosage of ACE-inhibitor / ARB will remain unchanged. As soon as creatinine levels decrease at least 30% to
143 peak value, the initial study therapy schedule will be continued (Supplement 1, Figures 4a / 4b). As the dose of diuretics is an important contributor to renal injury,
144 diuretic dose will also be reduced by at least 50% in patients with renal injury.

145 If systolic blood pressure still persists over 140 mm Hg despite the treatment schedule described above during day 3 to 6, higher doses of ACE-inhibitors or
146 ARBs are recommended. The addition of a calcium-channel blocker (preferably amlodipine) can be considered alternatively. The use of beta-blockers and
147 spironolactone will be identical to that described in the control group.

148

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149 eTable 3. Prespecified Secondary Endpoints of the Study

150
151 • All-cause mortality at 180 days.

152 • HF re-hospitalization at 180 days.

153 • Death or re-hospitalization from all causes at 180 days.

154 • Need for ICU admission during initial hospitalization.

155 • Acute coronary syndrome during initial hospitalization.

156 • Symptomatic hypotension during initial hospitalization.

157 • BNP and creatinine level at 48 h and at discharge.

158 • Changes in circumferences of both legs and central venous pressure during hospitalization.

159 • Change in patient-assessed dyspnea at 48 h and prior to discharge.

160 • Blood pressure course over the first 6 days.

161 • Time to disappearance of a third heart sound (if present initially).

162 • Time to discharge.

163 • In-hospital days for HF at 180 days and 360 days.

164 • Total treatment cost at 180 days and 360 days.

165 • Functional status at 180 days and 360 days.

166 • Quality of life assessed by using the EQ-5D-3L questionnaire at 180 days and 360 days.

167 • Fractures due to falls within 180 days and 360 days.

168 • Death or HF re-hospitalization at 360 days.

169
170 BNP=B-type natriuretic peptide, HF=Heart failure, ICU=Intensive care unit.

© 2019 American Medical Association. All rights reserved.

171 eTable 4. Post Hoc Analysis of the Mixed Effect Model With Site as a Random Effect and an Unadjusted Analysis for the Primary Endpoint

172
Model Parameter Parameter Hazard 95% CI P value P value
estimate ratio
Fixed model (original) Assigned group (Control vs 0.07121 1.074 0.828-1.393 .59 .84
Intervention)
Mixed effect model with site as a Assigned group (Control vs 0.06734 1.070 0.825-1.388 .61
random effect (ad-hoc) Intervention)
Unadjusted model Assigned group (Control vs 0.10251 1.108 0.855-1.437 .44
Intervention)

173
174 CI=confidence interval.

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175 eTable 5. Post Hoc Analysis of Medication, Weight Reduction, and Prespecified Exploratory Analysis of Blood Pressure Over Time (Median and
176 Interquartile Range) Among Patients Treated With Early Intensive and Sustained Vasodilation vs Usual Care

Intervention Group Usual Care Group P Value

Nitroglycerin, median (IQR), mg
Day 1 42.4 (40.0-62.4) 0.0 (0.0-5.0) <.001
Day 2 60.0 (20.0-80.0) 0.0 (0.0-10.0) <.001
Day 3 30.0 (10.0-50.0) 0.0 (0.0-10.0) <.001
Day 4 15.0 (0.0-30.0) 0.0 (0.0-10.0) <.001
Day 5 0.0 (0.0-10.0) 0.0 (0.0-5.0) <.001
Day 6 0.0 (0.0-0.0) 0.0 (0.0-5.0) .04
Day 7 0.0 (0.0-0.0) 0.0 (0.0-5.0) .007
Hydralazine, median (IQR), mg
Day 1 50.0 (25.0-75.0) 0.0 (0.0-0.0) <.001
Day 2 100.0 (75.0-100.0) 0.0 (0.0-0.0) <.001
Day 3 25.0 (0.0-50.0) 0.0 (0.0-0.0) <.001
Day 4 0.0 (0.0-0.0) 0.0 (0.0-0.0) .28
Day 5 0.0 (0.0-0.0) 0.0 (0.0-0.0) .94
Day 6 0.0 (0.0-0.0) 0.0 (0.0-0.0) .86
Day 7 0.0 (0.0-0.0) 0.0 (0.0-0.0) .70
Furosemide equivalent dose, median (IQR), mg
Day 1 40.0 (0.0-80.0) 40.0 (20.0-80.0) .14
Day 2 60.0 (40.0-100.0) 60.0 (40.0-120.0) .25
Day 3 60.0 (40.0-100.0) 80.0 (40.0-120.0) .15
Day 4 60.0 (40.0-115.0) 80.0 (40.0-120.0) .06
Day 5 60.0 (40.0-115.0) 80.0 (40.0-120.0) .13
Day 6 60.0 (40.0-120.0) 80.0 (40.0-120.0) .60
Day 7 40.0 (20.0-120.0) 60.0 (20.0-120.0) .96
Day of discharge 40.0 (40.0-95.0) 60.0 (40.0-120.0) .50
180 days follow-up 40.0 (0.0-80.0) 40.0 (0.0-80.0) .25
ACEi/ARB/ARNi percent change in target dose, median (IQR), %
Day 2 0.0 (0.0-12.5) 0.0 (0.0-12.5) .99
Day 3 0.0 (0.0-25.0) 0.0 (0.0-12.5) .04

© 2019 American Medical Association. All rights reserved.

 Day 4 0.0 (0.0-25.0) 0.0 (0.0-25.0) .008
Day 5 12.5 (0.0-37.5) 0.0 (0.0-25.0) .001
Day 6 12.5 (0.0-50.0) 0.0 (0.0-25.0) <.001
Day 7 12.5 (0.0-50.0) 0.0 (-25.0-12.5) <.001
Day of discharge 12.5 (0.0-50.0) 0.0 (0.0-25.0) <.001
180 days follow-up 0.0 (-25.0-25.0) 0.0 (-25.0-6.2) .11
Systolic blood pressure, median (IQR), mmHg
Day 1 130.0 (117.2-145.0) 131.0 (118.0-150.0) .22
Day 2 115.0 (104.0-129.0) 125.0 (110.0-140.0) <.001
Day 3 119.0 (105.0-131.0) 123.0 (110.0-140.0) <.001
Day 4 120.0 (109.0-138.0) 121.0 (110.0-140.0) .33
Day 5 123.0 (110.0-140.0) 120.0 (109.0-140.0) .45
Day 6 121.0 (110.0-138.0) 121.0 (108.0-138.5) >.999
Day 7 122.0 (110.0-139.0) 122.5 (110.0-139.8) .77
Day of discharge 120.0 (110.0-138.0) 120.0 (110.0-140.0) .63
Diastolic blood pressure, median (IQR), mmHg
Day 1 75.0 (65.0-86.0) 75.0 (65.0-86.0) .86
Day 2 63.0 (55.0-71.0) 70.0 (60.0-80.0) <.001
Day 3 64.0 (56.0-72.0) 70.0 (60.0-79.5) <.001
Day 4 66.5 (60.0-75.0) 70.0 (60.0-79.0) .06
Day 5 68.0 (60.0-80.0) 67.0 (60.0-75.0) .30
Day 6 68.5 (60.0-79.0) 67.0 (60.0-77.0) .74
Day 7 69.0 (60.0-78.0) 68.0 (60.0-75.0) .57
Day of discharge 69.0 (60.0-77.0) 68.0 (60.0-79.5) .93
Weigh reduction, median (IQR), kg
Day 2 0.0 (-0.8-1.8) 0.2 (-1.0-2.1) .50
Day 3 0.6 (-1.1-2.1) 1.0 (-0.5-3.0) .01
Day 4 0.8 (-1.1-2.9) 1.4 (-0.3-3.5) .004
Day 5 1.1 (-0.8-3.4) 1.9 (0.0-4.0) .01
Day 6 1.5 (-0.6-3.7) 2.0 (0.2-4.6) .03
Day 7 1.8 (0.0-4.1) 2.2 (0.1-4.8) .07
Day of discharge 2.8 (0.7-5.4) 3.0 (1.0-5.6) .27
177 ACEi /ARB/ARNi=angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, IQR=interquartile range.

© 2019 American Medical Association. All rights reserved.

178 eTable 6. Dyspnea at Baseline, Day 2 and Day 6 in Patients With Available Assessment

Day 1 Day 2 Day 6

Intervention Usual Care P Value Interventio Usual Care P Value Interventio Usual Care P
Group Group n Group Group n Group Group Value

Dyspnea at 60
.90 .77 .37
Degrees

None, No. (%) 109 (31) 116 (31) 141 (46) 150 (45) 180 (71) 175 (66)

Mild, No. (%) 115 (33) 115 (31) 110 (36) 116 (35) 54 (21) 71 (27)

Intermediate, No. (%) 81 (23) 97 (26) 40 (13) 53 (16) 18 (7) 17 (6)

Severe, No. (%) 33 (9) 32 (9) 13 (4) 10 (3) 2 (1) 0 (0)

Very severe, No. (%) 10 (3) 12 (3) 2 (1) 3 (1) 1 (0) 1 (0)

2.0 (0.0- 1.0 (0.0-

VAS, median (IQR) 3.0 (1.0-5.0) 4.0 (1.0-5.0) .50 2.0 (0.0-4.0) .99 1.0 (0.0-3.0) .38
4.0) 3.0)

Dyspnea at 20
.69 .14 .37
degrees

None, No. (%) 70 (21) 67 (19) 109 (37) 109 (33) 157 (63) 140 (54)

Mild, No. (%) 71 (22) 66 (18) 93 (31) 94 (29) 50 (20) 68 (26)

Intermediate, No. (%) 92 (28) 109 (31) 69 (23) 74 (23) 32 (13) 34 (13)

Severe, No. (%) 63 (19) 77 (22) 19 (6) 41 (13) 10 (4) 13 (5)

Very severe, No. (%) 34 (10) 38 (11) 7 (2) 8 (2) 2 (1) 3 (1)

3.0 (1.0- 1.0 (0.0-

VAS, median (IQR) 5.0 (2.0-7.0) 5.0 (3.0-7.0) .26 3.0 (1.0-6.0) .40 2.0 (0.0-4.0) .18
5.0) 4.0)
179
180 VAS=visual analogue scale, IQR=interquartile range.

181

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182 eTable 7. Course of Serum Creatinine, Estimated Glomerular Filtration Rate, and NT-proBNP
183 Concentrations During Hospitalization Among Patients in the Early Intensive and Sustained
184 Vasodilation Group Versus the Usual Care Group

Intervention Group Usual Care Group P value

(N=382) (N=399)
Baseline
Serum creatinine, median 108 (85.0-136.8) 105.0 (83.5-139.5) .49
(IQR) [N=781], mol/L
eGFR, median (IQR) [N=781], 51.5 (37.8-68.8) 52.9 (36.6-72.2) .45
mL/min per 1.73 m2
NT-proBNP, median (IQR) 6256.5 (3680.2- 6131.5 (3729.8- .93
[N=752], ng/L 12005.5) 10900.0)
Day 2
Serum creatinine, median 113.0 (91.0-146.0) 112.0 (89.0-140.0) .38
(IQR) [N=710], mol/L
eGFR, median (IQR) [N=710], 47.3 (34.6-64.9) 49.9 (35.7-67.2) .27
mL/min per 1.73 m2
NT-proBNP, median (IQR) 4806.0 (2682.5- 9222.5) 5110.0 (2998.0-9846.2) .18
[N=698], ng/L
Day 3
Serum creatinine, median 119.0 (90.0-159.0) 107.5 (89.0-143.0) .04
(IQR) [N=691], mol/L
eGFR, median (IQR) [N=691], 46.6 (32.3-63.6) 50.0 (36.0-68.5) .04
mL/min per 1.73 m2
NT-proBNP, median (IQR) 3770.0 (1918.0-6986.0) 3751.0 (2053.0-7209.0) .87
[N=672], ng/L
Day 6
Serum creatinine, median 118.0 (97.0-158.0) 110.5 (92.8-151.2) .35
(IQR) [N=490], mol/L
eGFR, median (IQR) [N=490], 46.2 (33.2-62.5) 49.2 (32.1-66.4) .39
mL/min per 1.73 m2
NT-proBNP, median (IQR) 3571.0 (1835.5-7045.8) 2931.0 (1387.5-5257.5) .02
[N=507], ng/L
Discharge
Serum creatinine, median 115.8 (92.0-149.0) 114.0 (87.6-151.8) .89
(IQR) [N=621], mol/L
eGFR, median (IQR) [N=621], 47.9 (33.7-63.6) 47.8 (33.2-67.9) .67
mL/min per 1.73 m2
NT-proBNP, median (IQR) 3077.0 (1482.5-5959.0) 2584.0 (1415.5-5182.0) .12
[N=590], ng/L

185
186
187 NT-proBNP=N-terminal pro b-type natriuretic peptide, IQR=interquartile range.

188

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189 eTable 8. Medication at Baseline and 180-Days Follow-up

190
Medication at Baseline Medication at Discharge Medication at 180 Days FU

Intervention Usual Care P Value Intervention Usual Care P Value Intervention Usual Care P Value
Group Group Group Group Group Group
(N=382) (N=399) (N=382) (N=399) (N=382) (N=399)

Beta blockers, No. (%) 270 (71) 287 (72) .76 315 (82) 331 (83) .93 235 (62) 254 (64) .59
ACE inhibitor, No. (%) 171 (45) 194 (49) .31 239 (63) 249 (62) >.99 157 (41) 173 (43) .57
ARBs, No. (%) 94 (25) 94 (24) .80 110 (29) 86 (22) .02 83 (22) 72 (18) .23
Calcium channel blockers, No. (%) 82 (21) 90 (23) .78 72 (19) 88 (22) .31 57 (15) 60 (15) >.99
Diuretics, No. (%) 289 (76) 309 (77) .61 363 (95) 376 (94) .74 266 (70) 295 (74) .21
Mineralocorticoid receptor 67 (18) 86 (22) .19 174 (46) 188 (47) .71 122 (32) 153 (38) .07
antagonist, No. (%)
Statins, No. (%) 61 (16) 51 (13) .24 172 (45) 189 (47) .56 149 (39) 164 (41) .60
Digoxin, No. (%) 25 (7) 27 (7) >.99 36 (9) 39 (10) .96 26 (7) 32 (8) .61
Vasodilators, No. (%) 16 (4) 16 (4) >.99 80 (21) 97 (24) .30 19 (5) 25 (6) .53
Vitamin K antagonists, No. (%) 97 (25) 110 (28) .54 100 (26) 113 (28) .55 96 (25) 124 (31) .08
NOAC, No. (%) 45 (12) 36 (9) .25 65 (17) 42 (11) .01 54 (14) 46 (12) .33
ASA, No. (%) 90 (24) 115 (29) .11 99 (26) 126 (32) .10 113 (30) 110 (28) .59
P2Y12 platelet inhibitor, No. (%) 26 (7) 38 (10) .21 35 (9) 43 (11) .53 22 (6) 30 (8) .40
191
192 ACE inhibitor=angiotensin-converting-enzyme inhibitor, ARBs=angiotensin receptor blockers, ASA=acetylsalicylic acid, FU=follow-up, NOAC=non-vitamin K
193 antagonist oral anticoagulant.

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194 eTable 9. Medication at Baseline and 180-Days Follow-up Stratified by Recruitment Period

195
Medication at Baseline Medication at Discharge Medication at 180 Days FU

Recruited Recruited P Value Recruited Recruited P Value Recruited Recruited P Value

2007-2014 2014-2018 2007-2014 2014-2018 2007-2014 2014-2018
(N=391) (N=390) (N=391) (N=390) (N=391) (N=390)
Beta blockers, No. (%) 262 (67) 295 (76) .01 305 (78) 341 (87) .001 208 (53) 281 (72) <.001
ACE inhibitor, No. (%) 183 (47) 182 (47) >.99 260 (66) 228 (58) .03 159 (41) 171 (44) .41
ARBs, No. (%) 100 (26) 88 (23) .37 108 (28) 88 (23) .12 84 (21) 71 (18) .29
Calcium channel blockers, No. (%) 96 (25) 76 (19) .11 93 (24) 67 (17) .03 54 (14) 63 (16) .41
Diuretics, No. (%) 299 (76) 299 (77) >.99 364 (93) 375 (96) .08 255 (65) 306 (78) <.001
Mineralocorticoid receptor
antagonist, No. (%) 56 (14) 97 (25) <.001 139 (36) 223 (57) <.001 104 (27) 171 (44) <.001
Statins, No. (%) 5 (1) 107 (27) <.001 146 (37) 215 (55) <.001 138 (35) 175 (45) .008
Digoxin, No. (%) 32 (8) 20 (5) .12 45 (12) 30 (8) .09 33 (8) 25 (6) .35
Vasodilators, No. (%) 3 (1) 29 (7) <.001 133 (34) 44 (11) <.001 17 (4) 27 (7) .16
Vitamin K antagonists, No. (%) 109 (28) 98 (25) .43 99 (25) 114 (29) .25 126 (32) 94 (24) .02
NOAC, No. (%) 7 (2) 74 (19) <.001 12 (3) 95 (24) <.001 11 (3) 89 (23) <.001
ASA, No. (%) 100 (26) 105 (27) .73 99 (25) 126 (32) .04 113 (29) 110 (28) .89
P2Y12 platelet inhibitor, No. (%) 30 (8) 34 (9) .69 37 (9) 41 (11) .71 24 (6) 28 (7) .66

196
197 ACE inhibitor=angiotensin-converting-enzyme inhibitor, ARBs=Angiotensin II receptor blockers, ASA=acetylsalicylic acid, FU=Follow-up, NOAC=non-Vitamin K
198 antagonist oral anticoagulant.

199

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200 eTable 10. Angiotensin-Converting-Enzyme Inhibitor, Angiotensin Receptor Blocker and Angiotensin Receptor-Neprilysin Inhibitor Medication at Baseline,
201 Discharge, and 180-days Follow-up

Medication at Baseline Medication at Discharge Medication at 180 Days FU

Intervention Usual Care P Intervention Usual Care P Intervention Usual Care P Value
Group Group Value Group Group Value Group Group
(N=382) (N=399) (N=382) (N=399) (N=382) (N=399)
ACEi/ARB/ARNI, No. (%) 268 (70) 291 (73) .44 341 (89) 337 (84) .06 237 (62) 252 (63) .80
% target dose in treated patients (IQR) 50 (25-100) 50 (25-100) .77 67 (38-100) 50 (25-100) .006 50 (25-100) 50 (25-94) .05
ACEi, No. (%) 171 (45) 194 (49) .31 239 (63) 249 (62) >.99 157 (41) 173 (43) .57
% target dose in treated patients (IQR) 50 (25-100) 50 (25-100) .64 75 (50-100) 50 (25-100) .03 50 (25-100) 50 (25-100) .20
ARB, No. (%) 94 (25) 94 (24) .80 110 (29) 86 (22) .02 83 (22) 72 (18) .23
% target dose in treated patients (IQR) 50 (25-67) 50 (25-50) .90 50 (33-100) 50 (25-67) .11 50 (25-100) 50 (25-54) .22
ARNI, No. (%) 4 (1) 5 (1) >.99 6 (2) 9 (2) .66 11 (3) 11 (3) >.99
% target dose in treated patients (IQR) 50 (44-50) 25 (25-50) .32 41 (27-50) 25 (13-50) .50 50 (25-63) 50 (25-50) .44

202
203 ACEi=angiotensin-converting-enzyme inhibitor, ARBs=angiotensin receptor blockers, ARNI = Angiotensin Receptor-Neprilysin Inhibitor, FU= Follow-up.
204 IQR=interquartile range.

205
206
207

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208 eTable 11. Prescribed Percentage of the ACE-I, ARB, and ARNi Target Dose at Presentation, Discharge and 180-Days Follow-up
209
210
211
Overall Intervention Usual Care P Value
Group Group
Percentage of the target dose at 25 (0-67) 25 (0-67) 33 (0-67) .40
presentation, median (IQR), %
Percentage of the target dose at 50 (25-100) 50 (25-100) 50 (25-100) .001a
discharge, median (IQR), %
Percentage of the target dose at 25 (0-50) 25 (0-75) 25 (0-50) .49
180 days, median (IQR), %
212
213
214 a Mann-Whitney U test mean rank 364.65 for the standard of care group and 418.53 for the intervention group

215 ACE inhibitor=angiotensin-converting-enzyme inhibitor, ARBs=angiotensin II receptor blockers, ARNi=angiotensin receptor-neprilysin inhibitor, IQR=interquartile
216 range.

217

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218 eFigure 1. Treatment Algorithm for the Intensive and Sustained Vasodilation Group
1)
The lowest blood pressure value
Intervention group day 1 day 1 meassured at the emergency
department before study inclusion
at hospital admission 6 h after admission will be considered.
1) 1)
systolic blood pressure [mm Hg] < 130 > 130 90 - 110 111 - 130 > 130 2)
The first capsule should be admini-
stered at study inclusion, 10 and 20
minutes after the first capsule one
per oral Glyceryl trinitrate capsule 3 3 more capsule should be administered
(i e. Nitroglycerin Streuli®) 0.8 mg2) (total three capsules).
or or
or Spray 3)
Only one ACE-inhibitor should be
(i.e. Corangin Nitrospray®)0.4mg 6 applic. 6 applic. started.
4)
ARB will only be administered initally
transdermal Glyceryl trinitrate if patients already recive the maximal
40 - 60 60 - 80 +0 + 20 - 40 + 20 - 60 dosage of an ACE-inhibitor or if
(i.e. Nitroderm® TTS) [mg / 24 h]
ACE-inhibitor intolerance is known.
Hydralazine (i. e. Hydrapres®) 25 mg 1-1-1-1 1-1-1-1 1-1-1-1 1-1-1-1 1-1-1-1
5)
An additional treatment with ARB
3)
Ramipril (i. e. Triatec®) [mg/d] should be considered (according to
the ARB up-titration days 2 to 7).
Lisinopril (i. e. Zestril®) [mg/d]3)
Enalapril (i. e. Reniten®) [mg/d]3)
Captopril (i. e. Capoten®) [mg/d]3)
Candesartan (i. e. Atacand®) [mg/d]4)
Losartan (i. e. Cozaar®) [mg/d]4)
219
Intervention group day 2 day 3
continuation 24 h till 48 h after admission 48 h till 72 h after admission
systolic blood pressure [mm Hg] 90 - 110 111 - 130 131 - 150 > 150 90 - 110 111 - 130 131 - 150 > 150
transdermal Glyceryl trinitrate 50% of 50% of 75% of 100% of
+ 20 - 40 + 20 - 60 + 40 - 80 + 40 - 80
(i.e. Nitroderm® TTS) [mg / 12 h] day 2 day 2 day 2 day 2
Hydralazine (i. e. Hydrapres®) 25 mg 1-1-1-1 1-1-1-1 1-1-1-1 1-1-1-1
3)
Ramipril (i. e. Triatec®) [mg/d] 1.25 1.25 2.5 2.5 2.5 - 3.75 2.5 - 3.75 2.5 - 5 2.5 - 5

Lisinopril (i. e. Zestril®) [mg/d]3) 2.5 2.5 5 5 2.5 - 5 5 - 7.5 10- 15 10 - 20

Enalapril (i. e. Reniten®) [mg/d]3) 5 5 10 10 5 - 10 5 - 10 10 - 15 10 - 20

Captopril (i. e. Capoten®) [mg/d]3) 37.5 37.5 50 50 37.5 - 50 37.5 - 50 50 - 75 50 - 75

4)
Candesartan (i. e. Atacand®) [mg/d] 4 4 8 8 8 - 16 8 - 16 16 - 24 16 - 24

Losartan (i. e. Cozaar®) [mg/d]4) 25 25 50 50 25 - 50 25 - 50 50 - 75 50 - 75

220
221
Intervention group day 4 day 5
continuation 72 h till 96 h after admission 96 h till 120 h after admission
systolic blood pressure [mm Hg] 90 - 110 111 - 130 131 - 150 > 150 90 - 110 111 - 130 131 - 150 > 150
transdermal Glyceryl trinitrate 25% of 25% of 50% of 75% of 25% of 50% of
(i.e. Nitroderm® TTS) [mg / 12 h] day 2 day 2 day 2 day 2 day 2 day 2
Ramipril (i. e. Triatec®) [mg/d]3) 3.75 - 5 3.75 - 5 5 - 7.5 5 - 7.5 5 - 7.5 5 - 7.5 7.5 - 10 7.5 - 10
3)
Lisinopril (i. e. Zestril®) [mg/d] 5 - 10 10 - 15 15 - 20 15 - 25 10 - 15 15 - 20 20 - 30 20 - 30

Enalapril (i. e. Reniten®) [mg/d]3) 10 - 15 10 - 15 15 - 20 20 - 30 15 - 20 15 - 20 20 - 30 30 - 40

3)
Captopril (i. e. Capoten®) [mg/d] 50 - 75 50 - 75 75 - 100 75 - 100 75 - 100 75 - 100 100 - 150 100 - 150

Candesartan (i. e. Atacand®) [mg/d]4) 12 - 24 12 - 24 16 - 24 16 - 24 16 - 24 24 - 32 24 - 32 24 - 32

4)
Losartan (i. e. Cozaar®) [mg/d] 50 - 75 50 - 75 75 - 100 75 - 100 75 - 100 75 - 100 75 - 100 75 - 100
222

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223
Intervention group day 6 day 7
continuation 120 h till 144 h after admission 144 h till 168 h after admission
systolic blood pressure [mm Hg] 90 - 110 111 - 130 131 - 150 > 150 90 - 110 111 - 130 131 - 150 > 150
transdermal Glyceryl trinitrate
(i.e. Nitroderm® TTS) [mg / 12 h]
Ramipril (i. e. Triatec®) [mg/d]3) 7.5 - 10 7.5 - 10 10 105) 10 10 105) 105)

Lisinopril (i. e. Zestril®) [mg/d]3) 15 - 20 20 - 30 20 - 30 305) 20 - 30 20 - 30 305) 305)

3) 5) 5)
Enalapril (i. e. Reniten®) [mg/d] 20 - 30 20 - 30 30 - 40 40 30 - 40 30 - 40 40 405)

Captopril (i. e. Capoten®) [mg/d]3) 100 - 150 100 - 150 150 1505) 150 150 1505) 1505)

Candesartan (i. e. Atacand®) [mg/d]4) 24 - 32 24 - 32 32 32 24 - 32 24 - 32 32 32

4)
Losartan (i. e. Cozaar®) [mg/d] 75 - 100 75 - 100 100 100 75 - 100 100 100 100
224
225 Important Treatment Rules
226 1. ACE-inhibitor can be administered once or twice per day. ARB should be administered only once a day.
227 2. If Patient is already on ACE-inhibitor or ARB continue dosage unchanged during day 1 and perform up-titration following
228 day 2 till 7 schedule.
229 3. If the patient is already treated with another ACE-inhibitor / ARB than listed in the schedule, previously prescribed ACE-
230 inhibitor / ARB should be continued unchanged during day 1. A daily up-titration of approximate 50% (25% to 75%
231 depending on blood pressure response) starting from day 2 is recommended. The maximal dosage should be achieved at
232 day 5 to 7 of treatment if well tolerated.
233 4. If creatinine levels rise more than 50% from baseline continue ACE-inhibitor / ARB in unchanged dosage to creatinine
234 levels begin to decline. Then continue up-titration according to the treatment schedule.
235 5. If creatinine levels rise more than 100% from baseline reduce ACE-inhibitor / ARB treatment by 50% and continue therapy
236 with unchanged dosage until creatinine levels decline more than 30%.
237 6. Treatment with any diuretics or aldosterone-antagonsist at any time is at discretion of treating physician and not
238 determined by the study protocol.
239
240 ACE inhibitor=angiotensin-converting-enzyme inhibitor, ARBs=Angiotensin II receptor blockers.

241

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242 eFigure 2. Dyspnea Evaluation at Baseline, Day 2 and Day 6 Among Patients in the Early Intensive
243 and Sustained Vasodilation Group Versus the Usual Care Group

244
245
246 Putting patients with AHF from the sitting position (60°) into a lying position (20°) is an established
247 provocation test to evaluate orthopnea.

© 2019 American Medical Association. All rights reserved.

248
249 eReferences
250
251 1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the
252 Management of Heart Failure. Circulation. 2013;128(16):e240-327.
253 doi:10.1161/CIR.0b013e31829e8776
254 2. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the
255 diagnosis and treatment of acute and chronic heart failure. Eur Heart J.
256 2016;37(27):2129-2200. doi:10.1093/eurheartj/ehw128
257 3. Pocock SJ, Simon R. Sequential Treatment Assignment with Balancing for
258 Prognostic Factors in the Controlled Clinical Trial. Biometrics. 2006;31(1):103.
259 doi:10.2307/2529712
260 4. Mueller C, McDonald K, de Boer RA, et al. Heart Failure Association of the
261 European Society of Cardiology practical guidance on the use of natriuretic
262 peptide concentrations. Eur J Heart Fail. 2019;21(6):715-731.
263 doi:10.1002/ejhf.1494
264 5. Packer M, McMurray JJV V., Desai AS, et al. Angiotensin receptor neprilysin
265 inhibition compared with enalapril on the risk of clinical progression in surviving
266 patients with heart failure. Circulation. 2015;131(1):54-61.
267 doi:10.1161/CIRCULATIONAHA.114.013748
268 6. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–Neprilysin Inhibition
269 versus Enalapril in Heart Failure. N Engl J Med. 2014;371(11):993-1004.
270 doi:10.1056/NEJMoa1409077
271

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