Explanations - static-content.springer.com10.1007... · Web view11. (beta blocker$ OR BB OR acebutolol OR atenolol OR betaxolol OR bisoprolol OR . ... ti,ab,kw (Word variations

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


>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


>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


>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


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


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



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



e-Figure 3. Network map showing connection of treatments for change in E/A ratio

ENA

EPN

PCB

SPN

VEP

ENA: Enalapril

EPN: Eplerenone


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



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



e-Figure 5. Network map showing connection of treatments for change in LVEF

ENA

PCB

SPN

VEP

ENA: Enalapril


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



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



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



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



e-Figure 9. Network map showing connection of treatments for change in BNP levels

CVD

PCB

SPN

CVD: Carvedilol

PCB: Placebo

SPN: Spironolactone


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



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



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


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



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



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



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




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



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




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




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




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



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




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



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)





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)


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)


IMPORTANT

E-wave deceleration time (follow up: mean 6.75 months; assessed with: Echocardiograph)

8 randomized trials



IMPORTANT

Isovolumic relaxation time (follow up: mean 9 months; assessed with: Echocardiograph)

5 randomized trials



IMPORTANT





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)


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)


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

REFERENCES

1. Aronow WS, Kronzon I: Effect of enalapril on congestive heart failure treated with diuretics in elderly patients with prior myocardial infarction and normal left ventricular ejection fraction. Am J Cardiol 1993, 71(7):602-604.

2. Grandi AM, Imperiale D, Santillo R, Barlocco E, Bertolini A, Guasti L, Venco A: Aldosterone antagonist improves diastolic function in essential hypertension. Hypertension (Dallas, Tex : 1979) 2002, 40(5):647-652.

3. Hung MJ, Cherng WJ, Kuo LT, Wang CH: Effect of verapamil in elderly patients with left ventricular diastolic dysfunction as a cause of congestive heart failure. International journal of clinical practice 2002, 56(1):57-62.

4. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J: Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet (London, England) 2003, 362(9386):777-781.

5. Zi M, Carmichael N, Lye M: The effect of quinapril on functional status of elderly patients with diastolic heart failure. Cardiovascular drugs and therapy 2003, 17(2):133-139.

6. Bergstrom A, Andersson B, Edner M, Nylander E, Persson H, Dahlstrom U: Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). European journal of heart failure 2004, 6(4):453-461.

7. Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH: Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure. Circulation 2004, 110(5):558-565.

8. Takeda Y, Fukutomi T, Suzuki S, Yamamoto K, Ogata M, Kondo H, Sugiura M, Shigeyama J, Itoh M: Effects of carvedilol on plasma B-type natriuretic peptide concentration and symptoms in patients with heart failure and preserved ejection fraction. Am J Cardiol 2004, 94(4):448-453.

9. Di Pasquale P, Cannizzaro S, Scalzo S, Parrinello G, Fasullo S, Giambanco F, Fatta A, Paterna S: Effects of canrenoate plus angiotensin-converting enzyme inhibitors versus angiotensin-converting enzyme inhibitors alone on systolic and diastolic function in patients with acute anterior myocardial infarction. American heart journal 2005, 150(5):919.

10. Kasama S, Toyama T, Kumakura H, Takayama Y, Ichikawa S, Suzuki T, Kurabayashi M: Effects of candesartan on cardiac sympathetic nerve activity in patients with congestive heart failure and preserved left ventricular ejection fraction. Journal of the American College of Cardiology 2005, 45(5):661-667.

11. Roongsritong C, Sutthiwan P, Bradley J, Simoni J, Power S, Meyerrose GE: Spironolactone improves diastolic function in the elderly. Clinical cardiology 2005, 28(10):484-487.

12. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J: The perindopril in elderly people with chronic heart failure (PEP-CHF) study. European heart journal 2006, 27(19):2338-2345.

13. Liu Gang JZ, Liu Kun Shen.: Spironolactone in the treatment of elderly patients with hypertension and diastolic heart failure. Chinese Journal of New Drugs and Clinical Remedies 2006, 25(8):567-570.

14. Little WC, Zile MR, Klein A, Appleton CP, Kitzman DW, Wesley-Farrington DJ: Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol 2006, 98(3):383-385.

15. Orea-Tejeda A, Colin-Ramirez E, Castillo-Martinez L, Asensio-Lafuente E, Corzo-Leon D, Gonzalez-Toledo R, Rebollar-Gonzalez V, Narvaez-David R, Dorantes-Garcia J: Aldosterone

receptor antagonists induce favorable cardiac remodeling in diastolic heart failure patients. Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion 2007, 59(2):103-107.

16. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C et al: Irbesartan in patients with heart failure and preserved ejection fraction. The New England journal of medicine 2008, 359(23):2456-2467.

17. Yip GW, Wang M, Wang T, Chan S, Fung JW, Yeung L, Yip T, Lau ST, Lau CP, Tang MO et al: The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart (British Cardiac Society) 2008, 94(5):573-580.

18. Mak GJ, Ledwidge MT, Watson CJ, Phelan DM, Dawkins IR, Murphy NF, Patle AK, Baugh JA, McDonald KM: Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone. Journal of the American College of Cardiology 2009, 54(18):1674-1682.

19. van Veldhuisen DJ, Cohen-Solal A, Bohm M, Anker SD, Babalis D, Roughton M, Coats AJ, Poole-Wilson PA, Flather MD: Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). Journal of the American College of Cardiology 2009, 53(23):2150-2158.

20. Kampourides N, Tziakas D, Chalikias G, Papazoglou D, Maltezos E, Symeonides D, Konstantinides S: Usefulness of matrix metalloproteinase-9 plasma levels to identify patients with preserved left ventricular systolic function after acute myocardial infarction who could benefit from eplerenone. Am J Cardiol 2012, 110(8):1085-1091.

21. Kayrak M, Bacaksiz A, Vatankulu MA, Ayhan SS, Ari H, Kaya Z, Ozdemir K: The effects of spironolactone on atrial remodeling in patients with preserved left ventricular function after an acute myocardial infarction: a randomized follow-up study. Coronary artery disease 2010, 21(8):477-485.

22. Kitzman DW, Hundley WG, Brubaker PH, Morgan TM, Moore JB, Stewart KP, Little WC: A randomized double-blind trial of enalapril in older patients with heart failure and preserved ejection fraction: effects on exercise tolerance and arterial distensibility. Circulation Heart failure 2010, 3(4):477-485.

23. Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, Zamorano J, Vardas PE, Bohm M, Dei Cas L: Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study. European journal of heart failure 2012, 14(2):219-225.

24. Deswal A, Richardson P, Bozkurt B, Mann DL: Results of the Randomized Aldosterone Antagonism in Heart Failure with Preserved Ejection Fraction trial (RAAM-PEF). J Card Fail 2011, 17(8):634-642.

25. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W, Duvinage A, Stahrenberg R, Durstewitz K, Loffler M et al: Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial. Jama 2013, 309(8):781-791.

26. Yamamoto K, Origasa H, Hori M: Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). European journal of heart failure 2013, 15(1):110-118.

27. Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL et al: Effect of phosphodiesterase-5 inhibition on exercise capacity and

clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. Jama 2013, 309(12):1268-1277.

28. Vatankulu MA, Bacaksiz A, Sonmez O, Alihanoglu Y, Koc F, Demir K, Gul EE, Turfan M, Tasal A, Kayrak M et al: Does Spironolactone Have a Dose-Dependent Effect on Left Ventricular Remodeling in Patients with Preserved Left Ventricular Function After an Acute Myocardial Infarction? Cardiovascular Therapeutics 2013, 31(4):224-229.

29. Kurrelmeyer KM, Ashton Y, Xu J, Nagueh SF, Torre-Amione G, Deswal A: Effects of spironolactone treatment in elderly women with heart failure and preserved left ventricular ejection fraction. J Card Fail 2014, 20(8):560-568.

30. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL et al: Spironolactone for heart failure with preserved ejection fraction. The New England journal of medicine 2014, 370(15):1383-1392.

31. Montalescot G, Pitt B, Lopez de Sa E, Hamm CW, Flather M, Verheugt F, Shi H, Turgonyi E, Orri M, Vincent J et al: Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the Randomized Double-Blind Reminder Study. European heart journal 2014, 35(34):2295-2302.

32. Zile MR, Bourge RC, Redfield MM, Zhou D, Baicu CF, Little WC: Randomized, double-blind, placebo-controlled study of sitaxsentan to improve impaired exercise tolerance in patients with heart failure and a preserved ejection fraction. JACC Heart failure 2014, 2(2):123-130.

33. Kosmala W, Rojek A, Przewlocka-Kosmala M, Wright L, Mysiak A, Marwick TH: Effect of Aldosterone Antagonism on Exercise Tolerance in Heart Failure With Preserved Ejection Fraction. Journal of the American College of Cardiology 2016, 68(17):1823-1834.

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