Supplementary Material
Title: Pharmacological Treatments for Heart Failure with Preserved Ejection Fraction – A Systematic Review and Indirect Comparison
Authors: Kwadwo Osei Bonsu, Poukwan Arunmanakul, Nathorn Chaiyakunapruk
A. Search strategy
Databases: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid
MEDLINE(R))
Date of search: August 18, 2017
1. exp Heart Failure/
2. Cardiomyopathy, Dilated/
3. (heart failure or cardiac failure or cardiac insufficiency or cardiomyopath$).tw.
4. ((cardi$ or myocard$) adj2 (failure$ or insufficien$)).tw.
5. (Heart failure, preserved ejection fraction).tw.
6. OR/1-5
7. exp digitalis/
8. exp Angiotensin-Converting Enzyme Inhibitors/
9. (angiotensin converting enzyme inhibitor OR ACEI OR ACEI OR antagonist$ OR
inhibitor$ benazepril OR captopril OR enalapril OR fosinopril OR imidapril OR lisinopril
OR moexipril OR perindopril OR quinapril OR ramipril OR trandolapril OR zofenopril
OR alacepril OR cilazapril OR spirapril OR delapril).mp.
10. exp beta adrenergic receptor blocking agent/ OR exp Adrenergic beta-Antagonists/
11. (beta blocker$ OR BB OR acebutolol OR atenolol OR betaxolol OR bisoprolol OR
carvedilol OR labetalol OR metoprolol OR nadolol OR nebivolol OR penbutolol OR
pindolol OR propranolol OR sotalol OR timolol).mp.
12. exp aldosterone antagonist/
13. (aldosterone antagonist$ OR mineralocorticoid-receptor antagonist OR MRA OR eplerenone OR spironolactone OR Aldactone OR canrenoate potassium OR canrenoate OR canrenone OR canrenoic acid OR eplerenone OR Inspra,).mp.
14. exp angiotensin receptor antagonist/
15. (angiotensin receptor blocker$ OR angiotensin receptor antagonist$ OR ARB OR azilsartan OR candesartan OR eprosartan OR irbesartan OR losartan OR olmesartan OR telmisartan OR valsartan).mp.
16. OR/6-14
17. "randomized controlled trial".pt.
18. (random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.
19. (retraction of publication or retracted publication).pt.
20. OR/18-20
21. (animals not humans).sh.
22. ((comment or editorial or meta-analysis or practice-guideline or review or letter or journal
correspondence) not "randomized controlled trial").pt.
23. (random sampl$ or random digit$ or random effect$ or random survey or random
regression).ti,ab. not "randomized controlled trial".pt.
24. 20 OR 21 OR 22
25. 19 NOT 23
26. (random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.
27. RETRACTED ARTICLE/
28. OR/25-26
29. (animal$ not human$).sh, hw.
30. (book or conference paper or editorial or letter or review).pt. not exp randomized controlled
trial/
31. (random sampl$ or random digit$ or random effect$ or random survey or random
regression).ti,ab. not exp randomized controlled trial/
32. OR/28-30
33. 27 NOT 31
34. 24 OR 32
35. 6 AND 19 AND 33
36. limit 34 to "all adult (19 plus years)"
37. limit 36 to human
38. limit 37 to yr="1940 – August 2017"
Database: Cochrane Library of Clinical Trials
Date of search: August 18, 2017
#1 MeSH descriptor: [Heart Failure] explode all trees
#2 MeSH descriptor: [Cardiomyopathy, Dilated] explode all trees
#3 (heart failure or cardiac failure or cardiac insufficiency or cardiomyopath$):ti,ab,kw
(Word variations have been searched)
#4 #1 or #2 or #3
#5 (LCZ696 or LCZ 696 or LCZ-696) :ti,ab,kw
#6 MeSH descriptor: [Angiotensin-Converting Enzyme Inhibitors] explode all trees
#7 (angiotensin converting enzyme inhibitor or ACEI or ACEI or antagonist$ or inhibitor$
benazepril or captopril or enalapril or fosinopril or imidapril or lisinopril or moexipril or
perindopril or quinapril or ramipril or trandolapril or zofenopril or alacepril or cilazapril
or spirapril or delapril):ti,ab,kw (Word variations have been searched)
#8 MeSH descriptor: [Adrenergic beta-Antagonists] explode all trees
#9 (beta blocker$ or BB or acebutolol or atenolol or betaxolol or bisoprolol or carvedilol or
labetalol or metoprolol or nadolol or nebivolol or penbutolol or pindolol or propranolol or
sotalol or timolol):ti,ab,kw (Word variations have been searched)
#10 MeSH descriptor: [Mineralocorticoid Receptor Antagonists] explode all trees
#11 (aldosterone antagonist$ or mineralocorticoid-receptor antagonist or MRA or eplerenone
or spironolactone):ti,ab,kw (Word variations have been searched)
#12 MeSH descriptor: [Angiotensin Receptor Antagonists] explode all trees
#13 (angiotensin receptor blocker$ or angiotensin receptor antagonist$ or ARB or azilsartan
or candesartan or eprosartan or irbesartan or losartan or olmesartan or telmisartan or
valsartan):ti,ab,kw (Word variations have been searched)
#14 #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13
#15 #4 and #14
#16 human not animal
#17 #15 and #16
#18 #17 in trials
#17 #18
B. Selection and Characteristics of Studies
e-Table 1. Shows criteria for inclusion of Randomized Controlled Trials (RCTs)
NoAuthor/Study Year Treatment Control Cut off
EF (%)mean EF Inclusion criteria
Domain 1 Domain 2 Domain 3Symptoms of HF
EF ≥50% Elevated Natriuretic
peptide levels
Evidence of Structural
heart disease
Evidence of
Diastolic dysfunctio
n1 Aronow [1] 1993 Enalapril Standard
therapy>50 _ Yes Yes No Yes Yes
2 Grandi [2] 2002 Canrenone ACEI normal − Yes No No Yes Yes3 Hung [3] 2002 Verapamil Placebo >50 _ Yes Yes No Yes Yes4 Yusuf
(CHARM)[4] 2003 Candesartan Placebo >40 54 Yes No No Yes Yes
5 Zi[5] 2003 Quinapril Placebo ≥40 − Yes No No Yes Yes6 Bergstrom [6] 2004 Carvedilol Placebo >45 - Yes No Yes No Yes7 Mottram [7] 2004 Spironolactone Placebo >50 − Yes Yes Yes Yes Yes8 Takeda [8] 2004 Carvedilol Standard
therapy≥ 45 56.7
(53.6–59.6)
Yes Yes Yes Yes Yes
9 Di Pasquale [9] 2005 Canrenone Placebo >40 44.5 Yes No No Yes No10 Kasama [10] 2005 Candesartan Placebo >40 - Yes No Yes No No11 Roongsriton[11] 2005 Spironolactone Placebo ≥ 45 65 Yes No Yes Yes Yes 12 Cleland [12] 2006 Perindopril Placebo ≥40 65 (56-66) Yes Yes Yes Yes Yes13 Lui [13] 2006 Spironolactone Standard
therapy>50 _ Yes Yes Yes Yes Yes
14 Little [14] 2006 Losartan HCTZ >50 - Yes Yes No No Yes15 Orea-Tejada [15] 2007 Spironolactone Placebo − − Yes No No Yes Yes16 Massie [16] 2008 Irbesartan Placebo ≥45 59.5 Yes No No Yes No17 Yip [17] 2008 Irbesartan +
diuretic andDiuretic >45 67.4 Yes No No Yes Yes
Ramipril + Diuretic
18 Mak GJ[18] 2009 Eplerenone Placebo >45 63+/-9 Yes No Yes Yes Yes19 SENIORS[19] 2009 Nebivolol Placebo >35 49.2 Yes No No Yes Yes20 Kampouride
s[20]2012 Eplerenone Standard
therapy>40 57 (53-60) Yes Yes Yes Yes Yes
21 Kayrak[21] 2010 Spironolactone Placebo >40 50 Yes No No Yes No22 Kitzman
DW[22]2010 Enalapril Placebo >50 − Yes Yes No Yes Yes
23 Conraads[23] 2011 Nebivolol Placebo >45 - Yes No Yes No Yes24 Deswel[24] 2011 Eplerenone Placebo >50 − Yes Yes No Yes Yes 25 Edelmann F [25] 2013 Spironolactone Placebo >50 − Yes Yes Yes Yes Yes26 J-DHF [26] 2013 Carvedilol Placebo >40 63 Yes No Yes Yes No 27 Redfield [27] 2013 Sildenafil Placebo ≥50 60 (56-65) Yes Yes Yes No Yes28 Vatankulu [28] 2013 Spironolactone Placebo >40 51.1
(41-53)Yes No No Yes No
29 Kurrelmeyer[29] 2014 Spironolactone Placebo >50 − Yes Yes Yes Yes Yes30 Pitt B[30] 2014 Spironolactone Placebo >45 56 (51-62) Yes Yes Yes Yes Yes31 REMINDER[31] 2014 Eplerenone Placebo >40 − Yes No Yes Yes No32 Zile[32] 2014 Sitaxsentan Placebo ≥ 50 - Yes Yes No No Yes33 Kosmala[33] 2016 Spironolactone Placebo >50 - Yes Yes Yes Yes Yes
Abbreviations: ACEI; Angiotensin converting enzyme inhibitors; HCTZ; Hydrochlorthiazide;
e-Table 2. Study design and baseline patient characteristics of included RCTs
Author Year
Study design
Study Duration (months)
N Interventions EF Cut off (%)
Mean EF(%)
Male(%)
Mean age
NYHA class 1 (%)
NYHA class 2 (%)
NYHA class 3 (%)
NYHA class 4 (%)
Duration of HF(months)
Hypertension (%)
AF (%)
Aronow1993
OL, SC
3 1011
EnalaprilStandard therapy
>50 64 14 80 0 0 100 0 NR NR NR
Hung2002
DB, SC, PC
3 78
VerapamilPlacebo
>50 70 60 64 NR NR NR NR NR 47 0
Mottram 2004
DB, SC, PC
6 1515
SpironolactonePlacebo
>50 67 36 62 0 100 0 0 NR 100 NR
Takeda2004
OL 12 1921
CarvedilolStandard therapy
≥ 45 57 52 71 0 68 32 0 NR 60 30
Cleland2006
DB,SC,PC
26.2 424426
PerindoprilPlacebo
≥40 64 45 75 27 48 18 7 10 78 20
Lui2006
OL 6 4038
SpironolactoneStandard therapy
>50 NR 20 63 0 35 65 0 ≥ 2 100 NR
Little2006
DB,SC
6 1921
LosartanHydrochlorthiazide
>50 NR 67 61 NR NR NR NR NR 60 NR
Kampourides 2010
OL,SC
24 206121
EplerenoneStandard therapy
> 40 57 76 58 NR NR NR NR NR 58 3
Kitzman 2010
DB, SC, PC
12 3536
EnalaprilPlacebo
>50 65 16 69 0 78 22 0 NR 73 NR
Deswel 2011
DB, SC, PC
6 2123
EplerenonePlacebo
>50 62 93 70 0 59 41 0 ≥ 2 100 13
Edelmann 2013
SB,SC,PC
12 213209
SpironolactonePlacebo
>50 67 48 67 0 86 14 0 NR 92 22
Redfield2013
DB,MC,PC
6 113103
SildenafilPlacebo
≥ 50 60 52 69 0 47 53 0 NR 85 51
Kumelmeyer DB, 6 24 Spironolactone > 50 62 0 70 0 37 63 0 NR 83 25
2014 SC, PC
24 Placebo
Pitt B2014
DB, MC, PC
39.6 17221723
SpironolactonePlacebo
>45 56 48 67 3 63 32 0.4 35 91 NR
Zile2014
DB,MC,PC
6 12864
SitaxsentanPlacebo
≥ 50 NR 37 65 0 56 44 0 NR NR NR
Kosmala2016
DB,SC,PC
6 7575
SpironolactonePlacebo
>50 71 27 67 0 78 22 0 < 12 NR NR
DB; Double-blind, SC; Single-blind, OL; Open-label, SC; Single-center, MC; Multi-center, PC; Placebo-controlled
e-Table 3. Baseline characteristics and concomitant treatment for Heart Failure with Preserved Ejection Fraction (HFpEF)
Author Year
Intervention class
Main intervention ACEI (%)
ARB (%)
CCB (%)
BB (%) Digoxin (%)
Diuretic(%) [loop or thiazide]
Nitrates (%)
MRA (%)
Oral Anticoagulants (%)
Aspirin (%)
Statins * (%)
Aronow1993
ACEI Enalapril Not allowed
Not allowed
Not allowed
Not allowed
Not allowed
100 NR NR NR NR NR
PCB Standard therapy Not allowed
Not allowed
Not allowed
Not allowed
Not allowed
100 NR NR NR NR NR
Hung2002
CCB Verapamil NR NR Not allowed
NR NR NR NR NR NR NR NR
PCB Placebo NR NR Not allowed
NR NR NR NR NR NR NR NR
Mottram 2004
MRA Spironolactone Not allowed
Not allowed
53 40 NR 40 NR Not allowed
NR NR NR
PCB Placebo Not allowed
Not allowed
60 20 NR 26 NR Not allowed
NR NR NR
Takeda 2004
BB Carvedilol 79 79 NR Not allowed
0 NR NR NR NR NR NR
PCB Standard therapy 86 86 NR Not allowed
19 NR NR NR NR NR NR
Cleland2006
ACEI Perindopril Not allowed
Not allowed
32 55 11 50.5 53 9 17 67 36
PCB Placebo Not allowed
Not allowed
33 54 13 49.5 49 11 15 66 31
Lui2006
MRA Spironolactone NR NR NR NR NR NR NR Not allowed
NR NR NR
PCB Standard therapy NR NR NR NR NR NR NR Not allowed
NR NR NR
Kampourides 2010
MRA Eplerenone 23 59 10 84 NR 9 8 Not allowed
1 96 95
PCB Standard therapy 23 59 10 84 NR 9 8 Not allowed
1 96 95
Kitzman2010
ACEI Enalapril Not allowed
Not allowed
31 29 0 49 0 NR NR NR NR
PCB Placebo Not allowed
Not allowed
22 39 0 58 6 NR NR NR NR
Deswel 2011
MRA Eplerenone 95.2 95.2 52.4 76.2 NR 95.2 NR Not allowed
NR NR NR
PCB Placebo 100 100 47.8 82.6 NR 100 NR Not allowed
NR NR NR
Edelmann 2013
MRA Spironolactone 78 78 22 69 NR 55 NR Not allowed
NR NR 53
PCB Placebo 76 76 28 75 NR 52 NR Not allowed
NR NR 56
Redfield2013
PDE5I Sildenafil 65 65 27 77 NR 83 NR 12 NR NR 63
PCB Placebo 76 76 34 75 NR 88 NR 9 NR NR 65
Kurrelmeyer 2014
MRA Spironolactone 70.8 29.2 25.0 62.5 12.5 83.3 54.2 Not allowed
20.8 25.0 54.2
PCB Placebo 66.7 37.5 29.2 62.5 8.3 75.0 33.3 Not allowed
20.8 33.3 58.3
Pitt B2014
MRA Spironolactone 84.3 84.2 36.3 78.2 NR 81.4 15.2 Not allowed
23.4 65.2 52.8
PCB Placebo 84.2 84.2 38.9 77.3 NR 82.3 14.7 Not 22.3 65.6 52.0
allowedZile2014
ERA Sitaxsentan 53 53 NR 42 NR 51 NR NR 49 NR 47
PCB Placebo 27 27 NR 22 NR 26 NR NR 24 NR 23
Kosmala2016
MRA Spironolactone 97 97 36 78 NR 67 NR Not allowed
NR NR NR
PCB Placebo 95 95 49 72 NR 64 NR Not allowed
NR NR NR
ACEI; Angiotensin converting enzyme inhibitor, CCB; Calcium Channel Blockers, MRA; Mineralocorticoid receptor antagonists, PDE5I; phosphodiesterase type 5 inhibitor and ERA; endothelin receptor antagonist (ERA).
C. Results of primary analyses of Clinical Outcomes1. Mortality
Number of RCTs = 8
Number of patients = 5360
Number of treatments = 5
e-Figure 1. Network map showing connection of treatments for mortality outcomes
EPN
PCB
PDN
SLD
SPN
EPN: Eplerenone
PCB: Placebo (reference)
PDN: Perindopril
SLD: Sildenafil
SPN: Spironolactone
Test for Global Consistency (Risk Ratio)
RR 95% CI P-valueEplerenone 1.01 0.28 3.67 0.98Perindopril 1.06 0.75 1.51 0.74Sildenafil 6.39 0.33 122.16 0.22Spironolactone
0.92 0.79 1.08 0.32
Placebo
Net League
placebo 0.92 (0.79,1.08) 6.39 (0.33,122.16) 1.06 (0.75,1.51) 1.01 (0.28,3.67)
1.08 (0.93,1.27) spironolactone 6.92 (0.36,132.89) 1.15 (0.78,1.69) 1.10 (0.30,4.02)
0.16 (0.01,3.00) 0.14 (0.01,2.78) sildenafil 0.17 (0.01,3.25) 0.16 (0.01,3.97)
0.94 (0.66,1.34) 0.87 (0.59,1.28) 6.02 (0.31,117.49) perindopril 0.95 (0.25,3.63)
0.99 (0.27,3.58) 0.91 (0.25,3.33) 6.30 (0.25,157.73) 1.05 (0.28,3.98) eplerenone
Net rank
ID andRank
Treatment
Placebo Eplerenone Perindopril
Sildenafil Spironolactone
1Best 4.7 39.5 12.5 8.2 35.12nd 31.6 7.9 16.6 2.2 41.73rd 43.5 7.3 30.1 1.2 18.04th 18.6 36.0 35.6 5.0 4.9Worst 1.7 9.3 5.3 83.4 0.3
SUCRA
Treatment SUCRA Pr Best Mean RankPlacebo 54.8 4.7 2.8Eplerenone 58.1 39.5 2.7Perindopril 48.9 12.5 3.0Sildenafil 11.7 8.2 4.5Spironolactone 76.6 35.1 1.9
2. Hospitalization
Number of RCTs = 8
Number of patients = 5238
Number of treatments = 8
e-Figure 2. Network map showing connection of treatments for hospitalization
CVD
ENA
EPN
PCB
PED
SLD
SPN
STX
CVD: Carvedilol
ENA: Enalapril
EPN: Eplerenone
PCB: Placebo (Reference)
PED: Perindopril
SLD: Sildenafil
SPN: Spironolactone
STX: Sitaxsentan
Test for Global consistency (Risk Ratio)
RR 95% CI P-valueCarvedilol 0.55 0.05 5.80 0.62Enalapril 0.88 0.31 2.54 0.82Eplerenone 0.50 0.05 5.30 0.57Perindopril 0.88 0.54 1.44 0.62Sildenafil 1.05 0.48 2.33 0.90Spironolactone 0.97 0.69 1.35 0.84Sitaxsentan 1.85 0.53 6.47 0.34Placebo Reference
Net league
placebo 1.85 (0.53,6.47
)
0.97 (0.69,1.35)
1.05 (0.48,2.33
)
0.88 (0.54,1.44
)
0.50 (0.05,5.30
)
0.88 (0.31,2.54
)
0.55 (0.05,5.80
)0.54
(0.15,1.90)
sitaxsentan
0.52 (0.14,1.92)
0.57 (0.13,2.51
)
0.48 (0.12,1.84
)
0.27 (0.02,3.93
)
0.48 (0.09,2.47
)
0.30 (0.02,4.30
)1.03
(0.74,1.44)
1.91 (0.52,6.99
)
spironolactone
1.09 (0.46,2.57
)
0.91 (0.50,1.65
)
0.52 (0.05,5.62
)
0.91 (0.30,2.77
)
0.57 (0.05,6.14
)0.95
(0.43,2.10)
1.76 (0.40,7.74
)
0.92 (0.39,2.18)
sildenafil 0.84 (0.33,2.13
)
0.48 (0.04,5.74
)
0.84 (0.22,3.15
)
0.53 (0.04,6.28
)1.14
(0.69,1.86)
2.10 (0.54,8.07
)
1.10 (0.60,1.99)
1.19 (0.47,3.04
)
perindopril
0.57 (0.05,6.34
)
1.00 (0.31,3.22
)
0.63 (0.06,6.93
)2.00
(0.19,21.22)
3.69 (0.25,53.5
3)
1.93 (0.18,21.01)
2.10 (0.17,25.4
1)
1.76 (0.16,19.6
7)
eplerenone
1.76 (0.13,23.4
7)
1.11 (0.04,30.9
5)1.13
(0.39,3.27)
2.09 (0.41,10.8
1)
1.10 (0.36,3.33)
1.19 (0.32,4.48
)
1.00 (0.31,3.22
)
0.57 (0.04,7.55
)
enalapril 0.63 (0.05,8.26
)1.81
(0.17,18.99)
3.34 (0.23,47.9
7)
1.75 (0.16,18.80)
1.90 (0.16,22.7
6)
1.59 (0.14,17.6
1)
0.90 (0.03,25.3
4)
1.60 (0.12,21.0
3)
carvedilol
Net rank
ID andRank
Treatment
Placebo Carvedilol
Enalapril Eplerenone Perindopril Sildenafil
Spironolactone
Sixtasentan
3Best 0.2 37.7 9.6 41.3 4.4 3.8 1.4 1.62nd 2.2 20.6 19.6 19.4 15.2 10.9 7.6 4.5
3rd 10.1 6.4 17.2 6.1 24.0 14.3 17.0 5.0
4th 24.0 3.9 10.4 3.3 20.1 12.3 21.7 4.35th 32.2 3.4 8.5 3.3 14.6 11.8 21.9 4.36th 22.3 5.5 11.7 5.1 11.9 17.1 18.3 8.07th 7.9 9.5 15.0 9.3 7.7 20.2 10.0 20.4Worst 1.0 13.2 8.0 12.1 2.0 9.7 2.1 51.9
SUCRA
Treatment SUCRA PrBest Mean Rank Placebo 44.3 0.2 4.9 Carvedilol 66.4 37.7 3.3 Enalapril 53.7 9.6 4.2 Eplerenone 68.5 41.3 3.2 Perindopril 56.9 4.4 4.0 Sildenafil 43.1 3.8 5.0 Spironolactone 48.5 1.4 4.6 Sixtasenten 18.5 1.6 6.7
D. Results of primary analyses of surrogate outcomes
1. Change in E/A ratio Number of RCTs = 9
Number of patients = 861
Number of treatments = 5
e-Figure 3. Network map showing connection of treatments for change in E/A ratio
ENA
EPN
PCB
SPN
VEP
ENA: Enalapril
EPN: Eplerenone
PCB: Placebo (reference)
SPN: Spironolactone
VEP: Verapamil
Test for global consistency (Mean Difference)
MD 95% CI P-value
Enalapril 0.97 0.56 1.70 0.93Eplerenone 1.13 0.58 2.20 0.73Spironolactone 1.03 0.79 1.32 0.85Verapamil 0.98 0.54 1.78 0.95Placebo reference
Net league
Placebo -0.02 (-0.62,0.58) 0.03 (-0.23,0.28) 0.12 (-0.55,0.79) -0.03 (-0.58,0.53)
0.02 (-0.58,0.62) Verapamil 0.05 (-0.60,0.69) 0.14 (-0.76,1.04) -0.01 (-0.82,0.81)
-0.03 (-0.28,0.23) -0.05 (-0.69,0.60) Spironolactone 0.09 (-0.62,0.81) -0.05 (-0.66,0.56)
-0.12 (-0.79,0.55) -0.14 (-1.04,0.76) -0.09 (-0.81,0.62) Eplerenone -0.15 (-1.02,0.73)
0.03 (-0.53,0.58) 0.01 (-0.81,0.82) 0.05 (-0.56,0.66) 0.15 (-0.73,1.02) Enalapril
2. Change in E/e’ ratio
Number of RCTs = 6
Number of patients = 729
Number of treatments = 5
e-Figure 4. Network map showing connection of treatments for change in E/e’ ratio
ENA
EPN
PCB
SPN
STX
ENA: Enalapril
EPN: Eplerenone
PCB: Placebo
SPN: Spironolactone
STX: Sitaxsentan
Test of global consistency (Mean Difference)
MD 95% CI P-valueEnalapril 0.407 0.009 16.99 0.64Eplerenone 0.029 0.0003 2.72 0.13
Spironolactone 1.255 0.168 9.37 0.83Sitaxsentan 0.449 0.010 19.98 0.68Placebo reference
Net League
Placebo -0.80 (-4.59,2.99) 0.23 (-1.78,2.24) -3.55 (-8.10,1.00) -0.90 (-4.63,2.83)
0.80 (-2.99,4.59) Sitaxsentan 1.03 (-3.27,5.32) -2.75 (-8.67,3.17) -0.10 (-5.42,5.22)
-0.23 (-2.24,1.78) -1.03 (-5.32,3.27) Spironolactone -3.78 (-8.75,1.20) -1.13 (-5.36,3.11)
3.55 (-1.00,8.10) 2.75 (-3.17,8.67) 3.78 (-1.20,8.75) Eplerenone 2.65 (-3.23,8.53)
0.90 (-2.83,4.63) 0.10 (-5.22,5.42) 1.13 (-3.11,5.36) -2.65 (-8.53,3.23) Enalapril
3. Change in Left Ventricular Ejection Fraction (LVEF)
Number of RCTs = 5
Number of patients = 660
Number of treatments = 4
e-Figure 5. Network map showing connection of treatments for change in LVEF
ENA
PCB
SPN
VEP
ENA: Enalapril
PCB: Placebo (reference)
SPN: Spironolactone
VEP: Verapamil
Test for Global consistency (Mean Difference)
MD 95% CI P-value
Enalapril 1.69 0.06 46.55 0.76Spironolactone 2.26 0.85 5.97 0.10Verapamil 0.37 0.0001 1376.79 0.81Placebo Reference
Net League
Placebo -1.00 (-9.23,7.23) 0.81 (-0.16,1.79) 0.53 (-2.79,3.84)
1.00 (-7.23,9.23) Verapamil 1.81 (-6.47,10.10) 1.53 (-7.34,10.40)
-0.81 (-1.79,0.16) -1.81 (-10.10,6.47) Spironolactone -0.29 (-3.74,3.17)
-0.53 (-3.84,2.79) -1.53 (-10.40,7.34) 0.29 (-3.17,3.74) Enalapril
4. Change in E-wave deceleration time
Number of RCTs = 8
Number of patients = 840
Number of treatments = 5
e-Figure 6. Network map showing connection of treatments for change in E-wave deceleration time
ENA
EPN
PCB
SPN
VEP
ENA: Enalapril
EPN: Eplerenone
PCB: Placebo
SPN: Spironolactone
VEP: Verapamil
Test for Global consistency (Standardized Mean difference)
SMD 95% CI P-value
Enalapril 0.57 0.020 16.16 0.74Eplerenone 0.91 0.032 26.17 0.96Spironolactone 0.53 0.119 2.38 0.41Verapamil 0.96 0.030 30.56 0.98Placebo
Net league
Placebo -0.04 (-3.50,3.42) -0.63 (-2.13,0.87) -0.10 (-3.46,3.26) -0.56 (-3.90,2.78)
0.04 (-3.42,3.50) Verapamil -0.59 (-4.36,3.18) -0.06 (-4.88,4.77) -0.52 (-5.33,4.29)
0.63 (-0.87,2.13) 0.59 (-3.18,4.36) Spironolactone 0.54 (-3.15,4.22) 0.07 (-3.59,3.74)
0.10 (-3.26,3.46) 0.06 (-4.77,4.88) -0.54 (-4.22,3.15) Eplerenone -0.46 (-5.20,4.28)
0.56 (-2.78,3.90) 0.52 (-4.29,5.33) -0.07 (-3.74,3.59) 0.46 (-4.28,5.20) Enalapril
5. Change in Isovolumic relaxation time (IVRT)
Number of RCTs = 5
Number of patients = 635
Number of treatments = 4
e-Figure 7. Network map showing connection of treatments for change in IVRTI
ENA
PCB
SPN
VEP
Test for global consistency model (Standardized Mean Difference)
SMD 95% CI P-valueEnalapril 0.72 0.006 84.09 0.89Spironolactone 0.48 0.031 7.53 0.60Verapamil 0.34 0.003 43.96 0.66Placebo
Net league
Placebo 0.34 (0.00,43.96) 0.48 (0.03,7.53) 0.72 (0.01,84.10)
2.94 (0.02,380.91) Verapamil 1.41 (0.01,377.84) 2.12 (0.00,1914.04)
2.08 (0.13,32.63) 0.71 (0.00,188.88) Spironolactone 1.50 (0.01,366.36)
1.39 (0.01,161.47) 0.47 (0.00,424.16) 0.67 (0.00,162.40) Enalapril
6. Change in Left ventricular mass index
Number of RCTs = 6
Number of patients = 746
Number of treatments = 4
e-Figure 8. Network map showing connection of treatments for Left ventricular mass index
EPN
PCB
SPN
STX
EPN: Eplerenone
PCB: Placebo
SPN: Spironolactone
STX: Sitaxsentan
Test for Global Consistency (Standardized Mean Difference)
SMD 95% CI p-value
Eplerenone 0.673 0.0008 534.28 0.91Spironolactone 0.345 0.012 9.75 0.53Sitaxsentan 1.257 0.003 989.72 0.95Placebo reference
Net league
Placebo 0.23 (-6.44,6.90) -1.06 (-4.40,2.28) -0.40 (-7.07,6.28)-0.23 (-6.90,6.44) Sitaxsentan -1.29 (-8.75,6.17) -0.63 (-10.06,8.81)1.06 (-2.28,4.40) 1.29 (-6.17,8.75) Spironolactone 0.67 (-6.80,8.13)0.40 (-6.28,7.07) 0.63 (-8.81,10.06) -0.67 (-8.13,6.80) Eplerenone
7. Change in Brain Natriuretic Peptide (BNP) levels
Number of RCTs = 4
Number of patients = 589
Number of treatments = 3
e-Figure 9. Network map showing connection of treatments for change in BNP levels
CVD
PCB
SPN
CVD: Carvedilol
PCB: Placebo
SPN: Spironolactone
Test for Global Consistency (Standardized Mean Difference)
SMD 95% CI P-value
Carvedilol 0.136 0.0008 21.709 0.440
Spironolactone 0.379 0.0204 7.021 0.514
Placebo reference
Net League
Placebo -0.97 (-3.89,1.95) -2.00 (-7.07,3.08)
0.97 (-1.95,3.89) Spironolactone -1.03 (-6.88,4.83)
2.00 (-3.08,7.07) 1.03 (-4.83,6.88) Carvedilol
8. Change in N-Terminal Propeptide of Type III Collagen (PIIINP) levels
Number of RCTs = 3
Number of patients = 171
Number of treatments = 3
e-Figure 10. Network map showing connection of treatments for change in PIIINP levels
EPN
PCB
SPN
EPN: Eplerenone
PCB: Placebo
SPN: Spironolactone
Test for global consistency
MD 95% CI P-valueEplerenone 0.90 0.02 39.41 0.959Spironolactone 0.86 0.06 12.07 0.908Placebo reference
Net League
Spironolactone -0.16 (-2.80,2.49) -0.10 (-3.87,3.67)0.16 (-2.49,2.80) Eplerenone 0.06 -4.55,4.66)
9. Quality of Life (QoL)
Number of RCTs = 6
Number of patients = 909
Number of treatments = 6
e-Figure 11. Network map showing connection of treatments for Quality of Life (QoL)
ENA
EPNPCB
SLD
SPN STX
ENA: Enalapril
EPN: Eplerenone
PCB: Placebo
SLD: Sildenafil
SPN: Spironolactone
STX: Sitaxsentan
Test for Global Consistency (Standardized Mean Difference)
SMD 95% CI P-valueEnalapril 0.673 0.023 19.668 0.818Eplerenone 1.867 0.063 55.753 0.719Sildenafil 0.851 0.029 24.349 0.925Spironolactone 0.303 0.028 3.329 0.329Sitaxsentan 0.912 0.032 26.247 0.957
Placebo
Net league
Placebo -0.09 (-3.45,3.27) -1.19 (-3.59,1.20) -0.16 (-3.52,3.19) 0.62 (-2.77,4.02) -0.40 (-3.77,2.98)
0.09 (-3.27,3.45) Sitaxsentan -1.10 (-5.23,3.02) -0.07 (-4.82,4.68) 0.72 (-4.06,5.49) -0.30 (-5.07,4.46)
1.19 (-1.20,3.59) 1.10 (-3.02,5.23) Spironolactone 1.03 (-3.09,5.15) 1.82 (-2.34,5.97) 0.80 (-3.34,4.94)
0.16 (-3.19,3.52) 0.07 (-4.68,4.82) -1.03 (-5.15,3.09) Sildenafil 0.79 (-3.99,5.56) -0.23 (-4.99,4.52)
-0.62 (-4.02,2.77) -0.72 (-5.49,4.06) -1.82 (-5.97,2.34) -0.79 (-5.56,3.99) Eplerenone -1.02 (-5.81,3.77)
0.40 (-2.98,3.77) 0.30 (-4.46,5.07) -0.80 (-4.94,3.34) 0.23 (-4.52,4.99) 1.02 (-3.77,5.81) Enalapril
10. Six-minute walk distance (6MWD)
Number of RCTs = 6
Number of patients = 849
Number of treatments = 5
e-Figure 12. Network map showing connection of treatments for Six-minute distance walk test
ENA
EPN
PCB
SLD
SPN
ENA: Enalapril
EPN: Eplerenone
PCB: Placebo
SLD: Sildenafil
SPN: Spironolactone
Test for Global Consistency (SMD)
SMD 95% CI P-value
Enalapril 0.904 0.0017 487.403 0.975Eplerenone 1.357 0.0025 739.109 0.924Sildenafil 0.731 0.0012 389.911 0.922Spironolactone 0.655 0.0173 24.787 0.820Placebo Reference
Net League
Placebo -0.42 (-4.06,3.21) -0.31 (-6.59,5.97) 0.31 (-6.00,6.61) -0.10 (-6.39,6.19)
0.42 (-3.21,4.06) Spironolactone 0.11 (-7.14,7.36) 0.73 (-6.55,8.00) 0.32 (-6.94,7.59)
0.31 (-5.97,6.59) -0.11 (-7.36,7.14) Sildenafil 0.62 (-8.28,9.51) 0.21 (-8.67,9.10)
-0.31 (-6.61,6.00) -0.73 (-8.00,6.55) -0.62 (-9.51,8.28) Eplerenone -0.41 (-9.31,8.50)
0.10 (-6.19,6.39) -0.32 (-7.59,6.94) -0.21 (-9.10,8.67) 0.41 (-8.50,9.31) Enalapril
E. Results of Subgroup Analyses
1. Study duration < 6 monthsComparative analysis not practicable due to insufficient data from few RCTs with study duration less than 6 months.
2. Study duration ≥ 6 months
1. Change in E/A ratio
Number of RCTs = 7
Number of patients = 825
Number of treatments = 5
Test for Global Consistency (Mean Difference)
Mean Difference (MD)
95% CI P-value
Enalapril 1.11 0.58 2.12 0.76Eplerenone 1.13 0.54 2.35 0.75Spironolactone 1.04 0.76 1.44 0.79Verapamil 0.98 0.50 1.91 0.95Placebo Reference
Net league
Placebo -0.02 (-0.69,0.65) 0.04 (-0.28,0.37) 0.12 (-0.61,0.85) 0.10 (-0.55,0.75)
0.02 (-0.65,0.69) Verapamil 0.06 (-0.68,0.80) 0.14 (-0.85,1.13) 0.12 (-0.81,1.05)
-0.04 (-0.37,0.28) -0.06 (-0.80,0.68) Spironolactone 0.08 (-0.72,0.88) 0.06 (-0.67,0.78)
-0.12 (-0.85,0.61) -0.14 (-1.13,0.85) -0.08 (-0.88,0.72) Eplerenone -0.02 (-1.00,0.96)
-0.10 (-0.75,0.55) -0.12 (-1.05,0.81) -0.06 (-0.78,0.67) 0.02 (-0.96,1.00) Enalapril
2. Change in E/e’
Number of RCTs = 6
Number of patients = 729
Number of treatments = 5
Test of global consistency (Mean Difference)
MD 95% CI P-valueEnalapril 0.407 0.009 16.99 0.64Eplerenone 0.029 0.0003 2.72 0.13Spironolactone 1.255 0.168 9.37 0.83Sitaxsentan 0.449 0.010 19.98 0.68Placebo reference
Net League
Placebo -0.80 (-4.59,2.99) 0.23 (-1.78,2.24) -3.55 (-8.10,1.00) -0.90 (-4.63,2.83)
0.80 (-2.99,4.59) Sitaxsentan 1.03 (-3.27,5.32) -2.75 (-8.67,3.17) -0.10 (-5.42,5.22)
-0.23 (-2.24,1.78) -1.03 (-5.32,3.27) Spironolactone -3.78 (-8.75,1.20) -1.13 (-5.36,3.11)
3.55 (-1.00,8.10) 2.75 (-3.17,8.67) 3.78 (-1.20,8.75) Eplerenone 2.65 (-3.23,8.53)
0.90 (-2.83,4.63) 0.10 (-5.22,5.42) 1.13 (-3.11,5.36) -2.65 (-8.53,3.23) Enalapril
3. Change in Left Ventricular Ejection Fraction (LVEF)
Number of RCTs = 3
Number of patients = 624
Number of treatments = 3
Test for Global Consistency (Mean Difference)
MD 95% CI P-value
Enalapril 1.00 0.03 35.03 1.00
Spironolactone 2.25 0.86 6.01 0.10
Placebo reference
Net league
Spironolactone 0.81 (-0.17,1.79) 0.00 (-3.56,3.56)-0.81 (-1.79,0.17) _Enalapril -0.81 (-4.50,2.88)
4. Change in E-wave deceleration time
Number of RCTs = 6
Number of patients = 746
Number of treatments = 4
A: ENA
B: EPN
C (reference): PCB
D: SPN
MD 95% CI P-valueEnalapril 1.71e-15 6.72e-29 0.0437382 0.031Eplerenone 0.003 1.75e-19 5.04e+13 0.760Spironolactone
0.589 0.0003 1029.568 0.890
Placebo Reference
placebo -0.53 (-7.99,6.94) -5.82 (-43.19,31.55) -34.00 (-64.87, -3.13)0.53 (-6.94,7.99) spironolactone -5.29 (-43.40,32.82) -33.47 (-65.23, -1.71)5.82 (-31.55,43.19) 5.29 (-32.82,43.40) eplerenone -28.18 (-76.65, 20.29)34.00 (3.13,64.87) 33.47 (1.71,65.23) 28.18 (-20.29,76.65) enalapril
5. Change in Isovolumic relaxation time (IVRT)
Number of RCTs = 3
Number of patients = 541
Number of treatments = 3
Test for Global Consistency (Mean Difference)
MD 95% CI P-valueEnalapril 0.007 3.94e-08 1153.302 0.416Spironolactone 4.552 0.004 4787.062 0.669
Placebo reference
Net league
Spironolactone 1.52 (-5.44,8.47) -5.00 (-17.05,7.05)
-1.52 (-8.47,5.44) Enalapril -6.52 (-20.43,7.40)
6. Change in Left Ventricular mass index
Number of RCTs = 6
Number of patients = 746
Number of treatments = 4
Test for Global Consistency (Standardized Mean Difference)
SMD 95% CI p-value
Eplerenone 0.673 0.0008 534.28 0.91Spironolactone 0.345 0.012 9.75 0.53Sitaxsentan 1.257 0.003 989.72 0.95Placebo Reference
Net league
Placebo 0.23 (-6.44,6.90) -1.06 (-4.40,2.28) -0.40 (-7.07,6.28)-0.23 (-6.90,6.44) Sitaxsentan -1.29 (-8.75,6.17) -0.63 (-10.06,8.81)1.06 (-2.28,4.40) 1.29 (-6.17,8.75) Spironolactone 0.67 (-6.80,8.13)0.40 (-6.28,7.07) 0.63 (-8.81,10.06) -0.67 (-8.13,6.80) Eplerenone
7. Change in Brain Natriuretic Peptide (BNP) levels
Number of RCTs = 4
Number of patients = 589
Number of treatments = 3
Test for Global Consistency (Standardized Mean Difference)
SMD 95% CI P-value
Carvedilol 0.136 0.0008 21.709 0.440
Spironolactone 0.379 0.0204 7.021 0.514
Placebo Reference
Net League
Placebo -0.97 (-3.89,1.95) -2.00 (-7.07,3.08)
0.97 (-1.95,3.89) Spironolactone -1.03 (-6.88,4.83)
2.00 (-3.08,7.07) 1.03 (-4.83,6.88) Carvedilol
8. Change in N-Terminal Propeptide of Type III Collagen (PIIINP) levels
Number of RCTs = 3
Number of patients = 171
Number of treatments = 3
Test for global consistency
MD 95% CI P-valueEplerenone 0.90 0.02 39.41 0.959Spironolactone 0.86 0.06 12.07 0.908Placebo reference
Net League
Spironolactone -0.16 (-2.80,2.49) -0.10 (-3.87,3.67)0.16 (-2.49,2.80) Eplerenone 0.07 -4.55,4.66)
9. Quality of Life
Number of RCTs = 6
Number of patients = 909
Number of treatments = 6
Test for Global Consistency (Standardized Mean Difference)
SMD 95% CI P-valueEnalapril 0.673 0.023 19.668 0.818Eplerenone 1.867 0.063 55.753 0.719Sildenafil 0.851 0.029 24.349 0.925Spironolactone 0.303 0.028 3.329 0.329Sitaxsentan 0.912 0.032 26.247 0.957
Placebo Reference
Net league
Placebo -0.09 (-3.45,3.27) -1.19 (-3.59,1.20) -0.16 (-3.52,3.19) 0.62 (-2.77,4.02) -0.40 (-3.77,2.98)
0.09 (-3.27,3.45) Sitaxsentan -1.10 (-5.23,3.02) -0.07 (-4.82,4.68) 0.72 (-4.06,5.49) -0.30 (-5.07,4.46)
1.19 (-1.20,3.59) 1.10 (-3.02,5.23) Spironolactone 1.03 (-3.09,5.15) 1.82 (-2.34,5.97) 0.80 (-3.34,4.94)
0.16 (-3.19,3.52) 0.07 (-4.68,4.82) -1.03 (-5.15,3.09) Sildenafil 0.79 (-3.99,5.56) -0.23 (-4.99,4.52)
-0.62 (-4.02,2.77) -0.72 (-5.49,4.06) -1.82 (-5.97,2.34) -0.79 (-5.56,3.99) Eplerenone -1.02 (-5.81,3.77)
0.40 (-2.98,3.77) 0.30 (-4.46,5.07) -0.80 (-4.94,3.34) 0.23 (-4.52,4.99) 1.02 (-3.77,5.81) Enalapril
10. Six-minute walk distance (6MWD)
Number of RCTs = 6
Number of patients = 849
Number of treatments = 5
Test for Global Consistency (SMD)
SMD 95% CI P-value
Enalapril 0.904 0.0017 487.403 0.975Eplerenone 1.357 0.0025 739.109 0.924Sildenafil 0.731 0.0012 389.911 0.922Spironolactone 0.655 0.0173 24.787 0.820Placebo Reference
Net League
Placebo -0.42 (-4.06,3.21) -0.31 (-6.59,5.97) 0.31 (-6.00,6.61) -0.10 (-6.39,6.19)
0.42 (-3.21,4.06) Spironolactone 0.11 (-7.14,7.36) 0.73 (-6.55,8.00) 0.32 (-6.94,7.59)
0.31 (-5.97,6.59) -0.11 (-7.36,7.14) Sildenafil 0.62 (-8.28,9.51) 0.21 (-8.67,9.10)
-0.31 (-6.61,6.00) -0.73 (-8.00,6.55) -0.62 (-9.51,8.28) Eplerenone -0.41 (-9.31,8.50)
0.10 (-6.19,6.39) -0.32 (-7.59,6.94) -0.21 (-9.10,8.67) 0.41 (-8.50,9.31) Enalapril
F. Strength of Evidence of estimates assessment using GRADE
Author(s):
Date: 5/10/2017
Question: Pharmacological treatment compared to placebo for patients with heart failure and preserved ejection fraction
Setting: randomized controlled trials
Bibliography:
Certainty assessment № of patients Effect
Certainty Importance№ of
studiesStudy design Risk of bias Inconsistency Indirectness Imprecision Other considerations Pharmacological
treatment Placebo Relative(95% CI)
Absolute(95% CI)
All-cause mortality (follow up: mean 15.73 months)
5 randomized trials
not serious not serious not serious not serious none 318/2735 (11.6%) 330/2625 (12.6%) RR 0.9244(0.8005 to 1.0686)
10 fewer per 1,000
(from 9 more to 25 fewer)
⨁⨁⨁⨁HIGH
CRITICAL
Hospitalization (follow up: mean 14.64 months)
8 randomized trials
not serious not serious not serious not serious none 358/2601 (13.8%) 397/2637 (15.1%) RR 0.9142(0.8010 to 1.0434)
13 fewer per 1,000
(from 7 more to 30 fewer)
⨁⨁⨁⨁HIGH
CRITICAL
Quality of Life (follow up: mean 8 months)
6 randomized trials
not serious not serious not serious not serious none 475 434 - SMD 0.1239 SD lower(0.2542 lower to 0.0063 higher)
⨁⨁⨁⨁HIGH
IMPORTANT
Six-minute walk test (follow up: mean 8 months)
6 randomized trials
serious a not serious not serious not serious none 428 421 - SMD 0.0034 SD lower
(0.138 lower to 0.1311 higher)
⨁⨁⨁◯MODERATE
IMPORTANT
Ratio of peak velocity of early (E) to late (A) mitral inflow (E/A) (follow up: mean 6.67 months; assessed with: Echocardiograph)
Certainty assessment № of patients Effect
Certainty Importance№ of
studiesStudy design Risk of bias Inconsistency Indirectness Imprecision Other considerations Pharmacological
treatment Placebo Relative(95% CI)
Absolute(95% CI)
9 randomized trials
serious a not serious not serious not serious none 429 432 - SMD 0.027 SD lower(0.1606 lower to 0.1066 higher)
⨁⨁⨁◯MODERATE
IMPORTANT
Ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (E') (E/E') (follow up: mean 8 months; assessed with: Echocardiograph)
6 randomized trials
not serious not serious not serious not serious none 374 355 - SMD 0.3185 SD lower(0.4646 lower to 0.1723 lower)
⨁⨁⨁⨁HIGH
IMPORTANT
Left Ventricular Ejection Fraction (follow up: mean 7.2 months; assessed with: Echocardiograph)
5 randomized trials
serious a not serious not serious not serious none 329 331 - SMD 0.2484 SD higher
(0.0953 higher to 0.4016 higher)
⨁⨁⨁◯MODERATE
IMPORTANT
E-wave deceleration time (follow up: mean 6.75 months; assessed with: Echocardiograph)
8 randomized trials
serious a not serious not serious not serious none 419 421 - SMD 0.0596 SD lower(0.1949 lower to 0.0756 higher)
⨁⨁⨁◯MODERATE
IMPORTANT
Isovolumic relaxation time (follow up: mean 9 months; assessed with: Echocardiograph)
5 randomized trials
serious a not serious not serious not serious none 319 316 - SMD 0.0937 SD lower(0.2493 lower to 0.0619 higher)
⨁⨁⨁◯MODERATE
IMPORTANT
Certainty assessment № of patients Effect
Certainty Importance№ of
studiesStudy design Risk of bias Inconsistency Indirectness Imprecision Other considerations Pharmacological
treatment Placebo Relative(95% CI)
Absolute(95% CI)
Left Ventricular Mass Index (follow up: mean 7 months; assessed with: Echocardiograph)
6 randomized trials
not serious not serious not serious not serious none 383 363 - SMD 0.1809 SD lower(0.3247 lower to
0.037 lower)
⨁⨁⨁⨁HIGH
IMPORTANT
B-type Natriuretic Peptide (follow up: mean 9 months)
4 randomized trials
serious a not serious not serious not serious none 296 293 - SMD 0.2053 SD lower(0.3672 lower to 0.0433 lower)
⨁⨁⨁◯MODERATE
IMPORTANT
Amino-terminal Peptide of Procollagen Type-III (follow up: mean 6 months)
3 randomized trials
serious b not serious not serious not serious none 85 86 - SMD 0.0111 SD higher
(0.2887 lower to 0.3109 higher)
⨁⨁⨁◯MODERATE
IMPORTANT
CI: Confidence interval; RR: Risk ratio; SMD: Standardized mean difference
Explanations
a. The inclusion of few low quality randomized trials raises some concerns about risk of bias regarding this outcome
b. The inclusion of one low quality randomized trial raises some concern about risk of bias regarding this outcome
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