State of the Art of Drug Therapy in Heart Failure

-What is still missing?

M. Böhm
Innere Medizin III (Kardiologie / Angiologie / Internistische Intensivmedizin)
Universitätsklinikum des Saarlandes
Homburg/Saar

michael.boehm@uks.eu
EHJ (2012) 33, 1787-1847
 Beta-blocker dose and heart rate reduction
in chronic HF patients
23 trials in 19 209 HF patients with beta-blocker (mean EF=17%-36%)

Results of 13 univariable meta-regressions evaluating the effect of individual covariates on mortality benefits
of beta-blockers in heart failure

McAlister et al. Ann Intern Med. 2009;150:784-794.

Beta-Blocker: HR Reduction in Atrial Fibrillation and Sinus Rhythm

Rienstra et al, JACC Heart Failure 1 (2013): 21-28 AS-aj1-1213

Beta-Blocker: Mortality in Atrial Fibrillation and Sinus Rhythm

Rienstra et al, JACC Heart Failure 1 (2013): 21-28 AS-aj2-1213

 Survival

Katecha et al, Lancet (2014): 10.1016/S0140-6736(14)61373-8

 Survival

Katecha et al, Lancet (2014): 10.1016/S0140-6736(14)61373-8

 T1:38-61, T2:62-72, T3:73-124 T1:40-72, T2:73-85, T3:86-155
Böhm et al., Eur J Heart Fail, 2014
 Chronic Heart Failure
- What is missing?

- Prospective Study in AFib

- Most likely not applicable!
 DOCA E

DOCA+Fin F

Kolkhof et al, J Cardiovasc Pharmacol 64 (2014): 69-78 AS-ak6-0415

 Results of ARTS-HF:
finerenone versus eplerenone in patients with worsening chronic heart failure
and diabetes and/or chronic kidney disease
Gerasimos Filippatos, Stefan D Anker, Michael Böhm, Mihai Gheorghiade, Lars Køber, Henry Krum, Aldo P Maggioni, Piotr Ponikowsk
Adriaan A Voors, Faiez Zannad, So-Young Kim, Christina Nowack, Giovanni Palombo, Peter Kolkhof, Nina Kimmeskamp-Kirschbaum
Alexander Pieper and Bertram Pitt,
for the MinerAlocorticoid Receptor AnTagonist Study In Heart Failure (ARTS-HF) Committees and Investigators

Study period Follow-up

100
Probability of survival (%)

90

80

70
Eplerenone (n = 207) Finerenone 7.5–15 mg (n = 158)
60
Finerenone 2.5–5 mg (n = 162) Finerenone 10–20 mg (n = 160)
50
Finerenone 5–10 mg (n = 157) Finerenone 15–20 mg (n = 158)
0
0 10 20 30 40 50 60 70 80 90 100 110 120
Number at risk:
Time (days)
Eplerenone 207 192 176 161 152 139 134 130 126 121 2 0 0
Finerenone 2.5–5 mg 162 149 133 122 115 109 103 101 97 90 0 0 0
Finerenone 5–10 mg 157 147 137 130 122 117 113 111 109 105 1 0 0
Finerenone 7.5–15 mg 158 151 145 138 127 123 117 112 107 96 0 0 0
Finerenone 10–20 mg 160 154 143 139 134 132 126 123 120 107 2 0 0
Finerenone 15–20 mg 158 148 137 129 124 121 118 111 108 95 2 1 0

European Society of Cardiology Congress, 31 August 2015, London, UK AS-ag11-0815

AS-ag1-0815
Vardeny et al, Circ Heart Fail 7 (2014): 573-579
Time to First Recurrence of Hyperkalemia during the Randomized Withdrawal Phase

Weir et al, N Engl J Med 372 (2015): 211-221 AS-aw3-0415

Chronic Heart Failure
- What is missing?

Prospective Randomized Studies!

- GFR 15-45 ml/min below 30 ml/min!)

- Planned with Patiromir (SAPPHIRE; DIAMOND)

- Spiro plus Patiromir vs. Standard treatment

 Baseline heart rate is a predictor of
endpoints on placebo
Stable CHF, SR > 70 bpm
50
Patients with primary composite endpoint (%)
≥87 bpm
P<0.001
40

80 to <87 bpm
75 to <80 bpm
30
72 to <75 bpm
70 to <72 bpm
20

10

0
0 6 12 18 24 30
Months
Primary composite endpoint: risk increases by 2.9% per 1-bpm increase, and by 15.6% per 5-bpm increase

Böhm et al, Lancet 2010; 376: 886-894.

 Prediction of Outcome by Discharge Heart Rate
- One Year Mortality -

Patients at high HR at Discharge had 41%

Increase in Mortality

Logeart D et al. Eur J Heart Failure 2012

 Primary composite endpoint
NYHA II-IV, SR > 70 bpm

Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY)

Cumulative frequency (%) HR = 0.82 p<0.0001

40
Ivabradine
Placebo

30
- 18%

20

NNT=26 (annualized)
10

0
0 6 12 18 24 30
Months
Swedberg et al, Lancet 376 (2010): 875-885
 Pre-Discharge Management:
Targeting the Vulnerable Patient
 Estimated Treatment Effects of Ivabradine and
Associated Numbers Needed to Treat (NNT) for
SHIFT Outcomes

Rogers et al, (2015): submitted AS-al2-0715

 Estimated Treatment Effects of Ivabradine and
Associated Numbers Needed to Treat (NNT) for
SHIFT Outcomes

P-Value NNT

Primary Endpoint <0.0001 26

1st HF Hospitalization <0.0001 27

Recurrent HF Hospitalization <0.0001 14

1st All-cause Hospitalization 0.0036 37

Recurrent All-Cause Hospitalization <0.0001 10

0.6 0.7 0.8 0.9 1.0

HR (95% CI)

Rogers et al, (2015): submitted AS-al1-0715

Chronic Heart Failure
- What is missing?

- Once a day compound!

- EDIfY – Proof of concept in HFPEF

- Trial in Post Discharge Patients

LCZ 696
Regulation of Natriuretic Peptides, Bradykinin and Angiotensin II
Angiotensin I Angiotensin II
ACE
Bradykinin Inactive products

{ Natriuretic peptides
(ANP, BNP, CNP)
NEP
Inactive products

Cardioprotection Hypertrophy

Heart

Vasodilation Vasoconstriction

Blood vessels
Sodium
Sodium Retention
excretion
Kidney
 Concept of ARNIs : Pharmacologic Actions
Angiotensin I Angiotensin II
ACE Inhibition

{
Bradykinin Inactive products
Natriuretic peptides NEP Inhibition
(ANP, BNP, CNP) Inactive products

Cardioprotection Hypertrophy

Heart

Vasodilation Vasoconstriction

Blood vessels
Sodium
Sodium Retention
excretion
Kidney
 What is new? Molecular structure of LCZ696
Angiotensin Receptor Neprilysin Inhibitor (ARNI )

• The LCZ696 molecular structure comprises molecular moieties of the NEP

inhibitor pro-drug AHU377 and the AT-1 receptor blocker valsartan
• LCZ696 belongs to the novel ARNI class of compounds (Angiotensin
Receptor Neprilysin Inhibitors)
Similar valsartan exposures follow dosing of LCZ696
and corresponding doses of Diovan®
Geometric mean
Parameter
ratio (90% CI)
Cmax
0.98 (0.87–1.10)
(ng/mL)
Concentration time profiles for valsartan
AUC0–∞
0.90 (0.82–0.99)
Mean plasma concentration (ng/mL)

10000 (ng∙h/mL)
3000
1000
300
100
30
10
3 Valsartan 320 mg
1
LCZ696 400 mg
0.3

0 6 12 18 24 30 36 42 48 54 60 66 72
Time (h)

Gu et al. J Clin Pharm 2009

 PARADIGM-HF: Primary outcome
Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial

40
HR: 0.80 (0.73, 0.87)
p = 0.0000002
Cumulative Proportion of Patients
1117
Enalapril
with Primary End Point (%)

(n=4212)
30
914

LCZ696
20 (n=4187)

10

0
0 180 360 540 720 900 1080 1260
Days after Randomization
At risk
Enalapril: 4212 3883 3579 2922 2123 1488 853 236
LCZ696: 4187 3922 3663 3018 2257 1544 896 249
 PARADIGM-HF
Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial

Death from CV causes HF hospitalization

20% risk reduction 21% risk reduction

P = 0.00004 P = 0.00004

693
658

558
537

McMurray, Packer et al NEJM 2014

 PARADIGM-HF
Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial

Death from any cause

16% risk reduction
40
HR: 0.84 (0.76, 0.93)
Cumulative Proportion of Patients
Who Died from Any Cause (%)

p < 0.0001

30 835

Enalapril
(n=4212) 711
20
LCZ696
(n=4187)
10

0
0 180 360 540 720 900 1080 1260
Days after Randomization
 PARADIGM-HF: Safety
LCZ696 Enalapril p value
(n=4187) (n=4212)

Hypotension (%)
symptoms 14.0 9.2 < 0.001
symptoms and SBP < 90 mmHg 2.7 1.4 <0.001

Renal impairment (%)

Cr ≥ 2.5 mg/dl 3.3 4.5 0.007
Cr ≥ 3.0 mg/dl 1.5 2.0 0.10

Hyperkalaemia (%)
K+ > 5.5 mmol/l 16.2 17.4 0.15
K+ > 6.0 mmol/l 4.3 5.6 0.007

Cough (%) 11.3 14.3 < 0.001

Böhm et al (2015) AS-aq1-0515
McMurray et al (2015) AS-ap5-0515
Simpson et al., JACC 66: 2059-71, 2015
 What can the Guideline Committee Do?

Class I:
Evidence and/or general agreement that a given treatment is beneficial,
useful and effective.

Evidence A:
Data derived from multiple randomised clinical trials or meta-analyses.

Evidence B:
Data derived from a single randomised trial or multiple non-randomized
studies ("registry trials") or a single metaanalysis
 Levels of significance to obtain
regulatory approval/change clinical practice

Number of trials P value required PARADIGM-HF PARADIGM-HF

with P < 0.05 in a single trial to Effect on Effect on
showing efficacy provide same strength primary endpoint cardiovascular death
of evidence

1 0.05
2 0.00125 0.00008
3 0.00003125
4 0.00000078
0.0000004
5 0.0000000195

Based on formula (0.025)n x 2 (personal communication Stuart Pocock)

McMurray et al., EHFA 2015 AS-at1-0515
Chronic Heart Failure
- What is missing?

- PARAGON in HFPEF Patients!

- New indications like resistant hypertension, CKD

- Once daily drug

McMurray et al, Eur Heart J 33 (2012): 1787-1847 AS-ab2-0613
Risk of Diabetes Development in CHF

Tenenbaum et al, Am J Med 114 (2003): 271-275 AS-br-0608

Outcome:

Advanced
CHF

Smooke et al, Am Heart J 149 (2005): 168-174 AS-bp-0608

Glucose Filtration in Health and Disease

Normal
600 plasma
glucose
Glucose (mg/min)

400

200

0
0 70 110 200 400 600 800
Plasma glucose (mg/dL)
Silverman M, Turner RJ. In: Windhager EE, ed. Handbook of Physiology, Vol. II. New York, NY: Oxford University Press; 1992:2017-2038. AS-aj12-0512
Glucose Filtration in Health and Disease

Normal
600 plasma
glucose
Glucose (mg/min)

Tubular
400 reabsorption

200 TmG Transport Maximum

Threshold

0
0 70 110 200 400 600 800
Plasma glucose (mg/dL)
Silverman M, Turner RJ. In: Windhager EE, ed. Handbook of Physiology, Vol. II. New York, NY: Oxford University Press; 1992:2017-2038. AS-aj12-0512
Glucose Filtration in Health and Disease

Normal
600 plasma
glucose
Urine
Glucose
Glucose (mg/min)

Tubular
400 reabsorption

Glucose in
200 TmG
urine

Threshold

0
0 70 110 200 400 600 800
Plasma glucose (mg/dL)
Silverman M, Turner RJ. In: Windhager EE, ed. Handbook of Physiology, Vol. II. New York, NY: Oxford University Press; 1992:2017-2038. AS-aj12-0512
Glucose Filtration in Health and Disease

Normal Elevated Plasma glucose

600 plasma
glucose
Urine
Glucose
Glucose (mg/min)

negligible
glucose in Tubular
400 reabsorption
urine

Glucose in
200 TmG
urine

Threshold

0
0 70 110 200 400 600 800
Plasma glucose (mg/dL)
Silverman M, Turner RJ. In: Windhager EE, ed. Handbook of Physiology, Vol. II. New York, NY: Oxford University Press; 1992:2017-2038. AS-aj12-0512
Glucose- Reabsorption Takes Place in the
Proximal Tubule

Glomerular filtration
Glucose
Proximal tubular reabsorbtion

 S1 Segment of the proximal

tubule
 ~90% Glucose reabsorbed
 transport by SGLT2 Collecting
duct

 Distal S3 Segment of the

proximal tubule
 ~10% glucose reabsorbed
 transport by SGLT1

No Glucose
SGLT: sodium glucose transporter in Filtrate

Silverman M, Turner RJ. In: Windhager EE, ed. Handbook of Physiology, Vol. II. New York, NY: Oxford University Press; 1992:2017-2038.
Bakris GL, et al. Kidney Int. 2009;75:1272-1277.
Zinman et al., New Engl J Med (2015): [doi:10.1056/NEJMoa1504720] AS-aq3-0915
Zinman et al., New Engl J Med (2015): [doi:10.1056/NEJMoa1504720] AS-aq1-0915
Zinman et al, N Engl J Med (Suppl.) [doi: 10.1056/NEJMoa1504720] AS-ac4-1115
Zinman et al, N Engl J Med (Suppl.) [doi: 10.1056/NEJMoa1504720] AS-ac5-1115
Zinman et al, N Engl J Med (Suppl.) [doi: 10.1056/NEJMoa1504720] AS-ac7-1115
Chronic Heart Failure
- What is missing?

- Prospective Randomized Studies!

- Heart Failure
- in general
- obese, diabetic CHF patients
- HFPEF
??? !!!
Iron Deficiency

Diabetes
 Thank you!

M. Böhm
Klinik für Innere Medizin III
Universitätsklinikum des Saarlandes
Homburg/Saar, Germany
Tel. 06841-16-23372
Fax. 06841-16-23369
michael.boehm@uks.eu