Thessaloniki, 16 Feb 2012

Heart failure and cancer:Heart failure and cancer:

common pathophysiology & therapycommon pathophysiology & therapy

Stefan D. Anker, MD PhD

Applied Cachexia Research, Center for Cardiovascular Research,Applied Cachexia Research, Center for Cardiovascular Research,

Charite Medical School, Berlin, Germany

Conflicts: I am not an oncologistConflicts: I am not an oncologist

I am President Elect of the European HF Association

I work with many cardiology companies

USA

1970–2000

USA

1970–20001970–20001970–2000

Lenfant C.

NEJM 2003.

Causes of death in cancer

• Neoplasm

• Cachexia• Cachexia

• Cardiovascular incl. sudden death• Cardiovascular incl. sudden death

• Thromboembolic

• Infection

• Unknown• Unknown

Beta�blockers for cancer make headlines

• 466 patients with breast

cancer in UK & Germany

• 92 pats. received anti�

hypertensive therapy (47%

BBs)

• BBs related to: • BBs related to:

� better total survival

� 71% less cancer specific

mortality

� fewer metastais, both local

& distant

� 1,413 breast cancer patients (1995–2007), subgroup with triple�negative breast cancer (n = 377)

� patients who used BBs (n = 102), patients (n = 1,311) who did not use BBs

Melhem�Bertrand A et al., J Clin Oncol 2011

� overall: BB associated with better RFS (HR 0.52; 95%CI, 0.31–0.88) but not survival (P = .09)

� TNBC: BB assoc.w. better RFS (HR 0.30; 0.10–0.87; P=.027) , survial (HR 0.35 [ 0.12–1.00]; P=.05)

Norepinephrine drives metastasis development of

PC�3 cells in BALB/c nude micePC�3 cells in BALB/c nude mice

Primary tumor Metastasis

Palm et al. Int J Cancer. 2006

Norepinephrine (N) stimulates the growth of metastasis.

Propranolol (P) blocks this effect.

Propranolol increases survival in a

pancreatic cancer hamster model

NNK: nitrosamine 4�(methylnitrosamino)�1�(3�pyridyl)�1�butanone

Al-Wadei et al. Anticancer Drugs. 2009

NNK: nitrosamine 4�(methylnitrosamino)�1�(3�pyridyl)�1�butanone

Carvedilol against

anthracycline�induced cardiomyopathyanthracycline�induced cardiomyopathy

• 25 patients per group in

Kayseri, TurkeyKayseri, Turkey

• Single�blind placebo

controlled, 6 months

• Mostly pats with breast�• Mostly pats with breast�

Ca & lymphoma (85%

were women)

• CARV dose: 12.5mg od• CARV dose: 12.5mg od

Kalay N et al.

JACC 2006;48:2258�62.

Enalapril against high dose CT�induced

cardiomyopathycardiomyopathy

Control Enalapril

114 of 473 patients (24%) with raised were included when TnI raised >0.07 ng/mL

63% of patients were female

Randomised, open: Enalapril 20mg/d vs no treatment Randomised, open: Enalapril 20mg/d vs no treatment

Treatment start: 1 month after HD�chemo

1.EP: LVEF decrease >10% (43% vs 0%, p<0.001)Cardinale et al.

Circulation 2006;114:2474�81.

Managing patient cardiac events with adjuvant HerceptinThe Cardiac Guidelines Consensus Committee

LVEF decline of >15% or LVEF decline of >10% and below LLN (LLN=50%)LVEF decline of >15% or LVEF decline of >10% and below LLN (LLN=50%)

LVEF 40�50% LVEF <40%

Continue Herceptina Hold Herceptin and seek cardiologist input b

Monitor LVEF every month Monitor LVEF in 3 months

LVEF >40% LVEF <40% LVEF >40% LVEF <40%

Reconsider Herceptin only

when / if appropriate and

consider cardiac support at

LVEF >40% LVEF <40% LVEF >40% LVEF <40%

Continue Herceptin, monitor LVEF every 3 months

and consider cardiac support at discretion of cardiologistconsider cardiac support at

discretion of cardiologist

Amiodarone for Prevention of Atrial Fibrillation After

Lung Resection (NSCLC 78% & lung metastasis)

! 130 pats in Indianapolis / USA, randomised 1:1, open

! mean age 62 yrs, 50% female

! post!op therapy: BB 35%, statin 22%, ACEi 20%, CCB 2%

84 hrs

32%

84 hrs

14%

32%46 hrs

Tisdale et al. The Annals of Thoracis Surgery 2009

Symptoms of Patients with Cancer

•• impaired exercise capacity

• fatigue• fatigue

• shortness of breath

• general malaise

•• depression

• pain• pain

Symptoms of Patients with Cancer

•• impaired exercise capacity

• fatigue• fatigue

• shortness of breath

• general malaise

•• depression

• pain

very similar to

symptoms of • pain symptoms of

CHF patients

Appetite in CHF & COPD cachexia

CHFCHF

”appetite” (1 10)

7.5±1 7.5±1 P<0.058

VAS ”appetite”

66±10

4

6

7.5±1 7.5±1

6.5±1

P<0.058

40

60 49±10

66±10

P=0.02

4

2

40

0

2021±11

0Control No Yes

Cachexia

0Control No Yes

Cachexia

Garcia et al., JCEM 2005Cachexia

Garcia et al., JCEM 2005

“muscle hypothesis“ of SoB in cancer

Reduced peripheral

Blood flowTNF, insulin resistance,

muscle wasting

Vasoconstriction Catabolic

muscle wastingorgan / body

dysfunctionVasoconstriction

Endothelial dysfunctionCatabolic

metabolism

Increased sympathetic

activation Skeletal myopathie

IncreasedIncreased

Metabo&ergoreflex

Dyspnoe, FatigueIncreased Ventilationmodified from Coats et al.,

Br. Heart J 1994;72(Suppl 2):S36&9.

Muscle wasting (“sarcopenia”) in cancer &

chemotherapy toxicitychemotherapy toxicity

55 women women with metastatic breast cancer resistant to anthracycline

and/or taxane treatment – 25% of pats. showed muscle wasting

Chemotherapy induced

toxicity (1 cycle)Time to tumor

progression

and/or taxane treatment – 25% of pats. showed muscle wasting

60

toxicity (1 cycle)

50%

P=0.03

150

progression

P=0.05173 days

(126–220)200

40

20

60 50%

20%

100

50

150101 days

(60–143)

0

20

No Yes

20%

0

50

No YesNo Yes

Muscle wasting

Prado CM, Baracos VM et al. Clin Cancer Res 2009

No Yes

Muscle wasting

Muscle wasting (“sarcopenia”) in patients

with solid tumors vs survival

• Screened: 2115 respiratory & GI cancers

• Obese with BMI>30: 325 pats (15%)

• 250 pats with CT scan• 250 pats with CT scan

HR 4.2(95%CI 2.4–7.2)(95%CI 2.4–7.2)

P<0.0001

Prado CM et al & Baracos VE. Lancet Oncol 2008

Changes in body composition

in cachectic patients with non�small cell lung cancer

compared to healthy controlscompared to healthy controls

70 Body weight (kg)The proportional changes seen

17.3

50

60Fat

The proportional changes seen

for muscle & fat tissue are similar

2.8

0.7

8.3

8.1

3.1

40

50

FatNon�Muscle

Protein

Muscle�Protein

Muscle�Protein

Non�Muscle

Protein

�82%

�75%

19.1 12.9

0.7

20

30 Intra�cellular

WaterIntra�cellular

Water

Muscle�Protein �75%

15.1 17.510

20

Extra�cellular

Water

Extra�cellular

Water

Minerals Minerals3 2.60

Cancer

Minerals Minerals

Fearon, Preston 2000

Controls

Fat is a key to survival Fat is a key to survival

Energy storage

Isolation

Protection Protection

MUSCLE = Fitness / QoL

BUTBUT

FAT + Muscle = SurvivalFAT + Muscle = Survival

Similar results are available for patients with

CHF, CKD, cancer and ageing.CHF, CKD, cancer and ageing.

Definition of Cachexia

(resulting from consensus conference, Dec. 2006)(resulting from consensus conference, Dec. 2006)

Weight loss of at least 5% (edema�free) in 12 months or

less in the presence of underlying illness, PLUS THREEless in the presence of underlying illness, PLUS THREE

of the following criteria:

� decreased muscle strength (lowest tertile)� decreased muscle strength (lowest tertile)

� fatigue

� anorexia

� low fat�free mass index� low fat�free mass index

� abnormal biochemistrya) increased inflammatory markers (e.g. sialic acid, CRP, IL�6)

b) Anemia (< 12 g/dl)b) Anemia (< 12 g/dl)

c) Low serum albumin (< 3.2 g/dl)

The following needs to be excluded:The following needs to be excluded:

starvation, malabsorption, primary depression,

hyperthyroidism and age�related muscle loss

Evans WJ, Clin. Nutr. 2008

Definition of Cachexia

(resulting from consensus conference, Dec. 2006)(resulting from consensus conference, Dec. 2006)

Weight loss of at least 5% (edema�free) in 12 months or

less in the presence of underlying illness, PLUS THREEless in the presence of underlying illness, PLUS THREE

of the following criteria:

When weight loss cannot be assessed a BMI<20 kg/m2When weight loss cannot be assessed a BMI<20 kg/m2

may be sufficient.

Some proposed other cut�offs, like 18.5 or 22.0 kg/m2.

Evans WJ, Clin. Nutr. 2008

CACHEXIA: prevalence, pts at risk & mortality

prevalence pts at preval. Europe: 1�year

in populat. risk in pts pts with mortality

at risk cachexiaat risk cachexia

COPD 3.5 15 50 1,200,000 15�25(moderare severity)

CHF 2.0 80 10 720,000 20�40(NYHA II�IV)

Cancer 0.5 90 30 540,000 20�60Cancer 0.5 90 30 540,000 20�60(all types)

RA 0.8 20 10 100,000 5(severe RA) (cachexia)(severe RA) (cachexia)

55 400,000 2(muscle wasting)

CRF 0.14 50 50 120,000 20CRF 0.14 50 50 120,000 20

Population assumptions: Europe – 450 Mill, US – 300 Mill, Japan – 100 Mill

Frequency of „malnutrition“

in patients with malignant cancer *in patients with malignant cancer *

Tumor Patients (%)

Pancreas up to 85

Head & Neck up to 67Head & Neck up to 67

Stomach up to 65

Esophagus up to 57Esophagus up to 57

Lung up to 46

Colorectal up to 33Colorectal up to 33

Ovary / Cervix up to 15

Urologic up to 9

Breast up to 5 * ambulatory &

hospitlized

Pathophysiology of CHF & Cancer

Immune Activation / Inflammation

Neuroendocrine Activation

Hormone Resistance

Lack of Anabolism

Genetic Factors

Cachexia and plasma angiotensin II

pg/mL

similar results for norepinephrine

and aldosterone200 pg/mL and aldosterone200

150

100

normal valuenormal

range

20 � 40 pg/mL

50

normal value< 40 pg/mL

20 � 40 pg/mL

Controls nc�CHF c�AIDS c�CHF c�Liverfailure

Starvation c�C���� ancer ideopathic

0

Starvation c�C���� ancer ideopathic

Anker & Coats, unpublished

ACE inhibitors for cancer cachexia

A PHASE III TRIAL USING IMIDAPRIL (Vitor®)

IN CANCER CACHEXIA REPORTED

PROMISING RESULTS

1. weight: +1.2 kg1. weight: +1.2 kg

2. hand grip strength: higher

FDA APPROVAL FOR 2nd PHASE III TRIAL IN FDA APPROVAL FOR 2nd PHASE III TRIAL IN

NSCLC CACHEXIA ++ currently on hold

(ARK Therapeutics)

Causes of death in cancer

• Neoplasm

• Cachexia• Cachexia

• Cardiovascular incl. sudden death• Cardiovascular incl. sudden death

• Thromboembolic

• Infection

• Unknown• Unknown

Severe arrythmias in 24�hour ECG’s:

VT or >10,000 VESVT or >10,000 VES

p<0.05

6

86 of 44 (14.4%)

4

6

0

20 of 24 (0%)

0Controls Patients with

pancreatic cancer

MR�proANP and severe arrythmias in

24�hour ECG’s of pats with pancreatic cancer24�hour ECG’s of pats with pancreatic cancer

300

Mean levels of MR�pro ANP (pmol/L)

ANOVA p�value: p=0.0125

200

300 ANOVA p�value: p=0.0125

100

0

none VES VT

median MR�proANP in 325 healthy volunteers:median MR�proANP in 325 healthy volunteers:

45.0 pmol/L (95% CI 43.0 – 49.1 pmol/L)

New Cachexia Phenotyping Equipment

(Applied Cachexia Research ) CCR

ECGenie(non�invasive ECG)

EchoMRI�700(in�vivo body composition)

(Applied Cachexia Research )

for rats

TSE GS�meterrat front limb

Supermex(locomotor activity)

rat front limb

muscle strength

(locomotor activity)

= rat “QoL“

assessment oflean mass & fat mass:non�invasive, CV <2%

Design �� Cachexia Prevention

Sacrifice:

plasmaTumor inoculation

male Wistar rats

approx. 200 g

108 AH 130 cellsorgan weight

tissue storage

ActivityBody composition (NMR)

Tumor inoculation10 AH 130 cells

Echocardiography

Activity

Food intake

Body composition (NMR)

day

�2/�1 �1 160 10/11 111�2/�1 �1 160 10/11 111

many compounds or placeboe.g. bisoprolol, nebivolol, carvedilol,

Activity

Food intakee.g. bisoprolol, nebivolol, carvedilol,

bucindolol, MT�102 etc etc

Food intake

Advanced Cancer: echocardiography

ejection fraction

100

fractional shortening

60

40

60

80

100

%

40

60

%

0

20

40

0

20

p=0.0001

p=0.31 p=0.0025

p=0.0001

p=0.21 p=0.0025

p=0.0001 p=0.0001

Advanced Cancer: haemodynamics

dP/dt max

12000

dP/dt min

0

6000

8000

10000

12000

mm

Hg

/s

�6000

�4000

�2000

0

mm

Hg

/s

0

2000

4000mm

Hg

/s

�10000

�8000

�6000

mm

Hg

/s

p=0.014

p=0.81 p=0.0454

p=0.0093

p=0.68 p=0.0121

p=0.014 p=0.0093

Change in body weight

0

n= 49 13 14 23 20 11 12 6 16 16

�20

�10

0

�40

�30

�20

g ***

** **

*****

**

�60

�50

** ***

**

�70

0.5 2 5 50 2 5 50

bisoprolol oxypurinol spironolactoneplacebo

4 40

*

bisoprolol oxypurinol spironolactoneplacebo

sham: +59.8 ± 2.1g

Change in lean mass during treatment

0

�20

�10

0

�30

�20

g***

*** *

*** ***

**

�50

�40

*�60

0.5 2 5 50 2 5 50

bisoprolol oxypurinol spironolactoneplacebo

4 40

*

bisoprolol oxypurinol spironolactoneplacebo

sham: +41.7 ± 2g

Survival proportions

100

all doses in mg/kg/d

80

3mg MT�102 vs plac:

HR: 0.30 (95%CI: 0.15�0.62)

p=0.001ACT�ONE trial (phase II)ACT�ONE trial (phase II)

60

biso 5 mg

biso 50 mg

s�pindo 3 mg

Perc

en

t su

rviv

al

MT�102

ACT�ONE trial (phase II)

Coats et al. JCSM‘2011

ACT�ONE trial (phase II)

Coats et al. JCSM‘2011

40 biso 2 mgterta 0.5 mg

s�pindo 0.3 mg

Perc

en

t su

rviv

al

MT�102

20

40

biso 0.5 mg

nebi 1 mg

terta 0.5 mg

imida 0.4 mg

Perc

en

t su

rviv

al

0

20

terta 5 mg

imida 0.4 mg

imida 1 mgimida 10 mg

placebo

0 2 4 6 8 10 12 14 160

nebi 10 mgTime

Aldosterone is elevated in tumor�bearing rats and lead to

cardiac fibrosis

aldosterone [pg/mL]

800

cardiac fibrosis

Day 7 Day 11

200

400

600

800sham

placebo

sham

0

200

Springer et al. unpublished

LV mass & survival in cancer

Human cancer (cachexia) causes cardiac fibrosis

Control (n=5) Cancer (n=6) cancer cachexia (n=6)

Pathophysiology of CHF & Cancer

Immune Activation / Inflammation

Neuroendocrine Activation

Hormone Resistance

Lack of Anabolism

Genetic Factors

Total gain in life expectancy: 10 yrsTotal gain in life expectancy: 10 yrs

- Cardiology has added 7.2 yrs

- Oncology 2.1 months

Cancer as causes of death in heart failurefrom OPTIMAAL, age 67, mean follow�up 2.7 yrs, based on SAE reports

Event Rate

(per 100 at Cancer DeathsNew CancersPatients

Entering Each

Cleland et al. HFA 2005 (abstract)

84

(8.9%)

241

(4.4%)

All Events

(per 100 at risk/month*)

(and % of all deaths)

(and % of patients at risk)

Entering Each

Time Period

0.0

(8.9%)(4.4%)

None11

(0.2%)

54770"30 days

16 44 5040 180"365 days

7

(3.5%)

41

(0.8%)

524230"180 days 0.02

0.05

61 145 4892365"1200

16

(10.8%)

44

(0.9%)

5040 180"365 days 0.05

0.04

(16.9%)(4.7%)

4892days

* these data are censored for death – cancer deaths per 100 living�patient months

cardiologist & oncologists need to talk !!