Stefan D. Anker, MD PhD

Transcription

1 Thessaloniki, 16 Feb 2012 Heart failure and cancer: common pathophysiology & therapy Stefan D. Anker, MD PhD Applied Cachexia Research, Center for Cardiovascular Research, Charite Medical School, Berlin, Germany Conflicts: I am not an oncologist Conflicts: I am not an oncologist I am President Elect of the European HF Association I work with many cardiology companies

2 USA Lenfant C. NEJM 2003.

3 Causes of death in cancer Neoplasm Cachexia Cardiovascular incl. sudden death Thromboembolic Infection Unknown

4 Betablockers for cancer make headlines 466 patients with breast cancer in UK & Germany 92 pats. received anti hypertensive therapy (47% BBs) BBs related to: better total survival 71% less cancer specific mortality fewer metastais, both local & distant 1,413 breast cancer patients ( ), subgroup with triplenegative breast cancer (n = 377) patients who used BBs (n = 102), patients (n = 1,311) who did not use BBs overall: BB associated with better RFS (HR 0.52; 95%CI, ) but not survival (P =.09) TNBC: BB assoc.w. better RFS (HR 0.30; ; P=.027), survial (HR 0.35 [ ]; P=.05) MelhemBertrand A et al., J Clin Oncol 2011

5 Norepinephrine drives metastasis development of PC3 cells in BALB/c nude mice Primary tumor Metastasis Norepinephrine (N) stimulates the growth of metastasis. Propranolol (P) blocks this effect. Palm et al. Int J Cancer. 2006

6 Propranolol increases survival in a pancreatic cancer hamster model NNK: nitrosamine 4(methylnitrosamino)1(3pyridyl)1butanone Al-Wadei et al. Anticancer Drugs. 2009

7 Carvedilol against anthracyclineinduced cardiomyopathy 25 patients per group in Kayseri, Turkey Singleblind placebo controlled, 6 months Mostly pats with breast Ca & lymphoma (85% were women) CARV dose: 12.5mg od Kalay N et al. JACC 2006;48:

8 Enalapril against high dose CTinduced cardiomyopathy 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 Treatment start: 1 month after HDchemo 1.EP: LVEF decrease >10% (43% vs 0%, p<0.001) Cardinale et al. Circulation 2006;114:

9 Managing patient cardiac events with adjuvant Herceptin The Cardiac Guidelines Consensus Committee LVEF decline of >15% or LVEF decline of >10% and below LLN (LLN=50%) LVEF 4050% LVEF <40% Continue Herceptin a Hold Herceptin and seek cardiologist input b Monitor LVEF every month Monitor LVEF in 3 months LVEF >40% LVEF <40% LVEF >40% LVEF <40% Continue Herceptin, monitor LVEF every 3 months and consider cardiac support at discretion of cardiologist Reconsider Herceptin only when / if appropriate and consider cardiac support at discretion of cardiologist

10 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% 46 hrs 14% Tisdale et al. The Annals of Thoracis Surgery 2009

11 Symptoms of Patients with Cancer impaired exercise capacity fatigue shortness of breath general malaise depression pain

12 Symptoms of Patients with Cancer impaired exercise capacity fatigue shortness of breath general malaise depression pain very similar to symptoms of CHF patients

13 Appetite in CHF & COPD cachexia CHF appetite (110) VAS appetite ±1 7.5±1 P< ±1 Control No Yes Cachexia 66± ± P= ±11 0 Control No Yes Cachexia Garcia et al., JCEM 2005

14 muscle hypothesis of SoB in cancer Reduced peripheral Blood flow Vasoconstriction Endothelial dysfunction organ / body dysfunction TNF, insulin resistance, muscle wasting Catabolic metabolism Increased sympathetic activation Skeletal myopathie Increased Metabo&ergoreflex modified from Coats et al., Br. Heart J 1994;72(Suppl 2):S36&9. Increased Ventilation Dyspnoe, Fatigue

15 Muscle wasting ( sarcopenia ) in cancer & chemotherapy 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) 40 P= % % No Yes Muscle wasting Time to tumor progression days ( ) 101 days (60 143) No Yes Muscle wasting P=0.05 Prado CM, Baracos VM et al. Clin Cancer Res 2009

16 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 HR 4.2 (95%CI ) P< Prado CM et al & Baracos VE. Lancet Oncol 2008

17 Changes in body composition in cachectic patients with nonsmall cell lung cancer compared to healthy controls 70 Body weight (kg) 60 Fat 17.3 The proportional changes seen for muscle & fat tissue are similar NonMuscle Protein MuscleProtein 30 Intracellular Water Fat Intracellular 19.1 Water % 3.1 NonMuscle Protein 8.1 MuscleProtein % Extracellular Water Extracellular 15.1 Water Minerals 3 Minerals 2.6 Controls Cancer Fearon, Preston 2000

18 Fat is a key to survival Energy storage Isolation Protection

19 MUSCLE = Fitness / QoL BUT FAT+ Muscle= Survival Similar results are available for patients with CHF, CKD, cancer and ageing.

20 Definition of Cachexia (resulting from consensus conference, Dec. 2006) Weight loss of at least 5%(edemafree) in 12 months or less in the presence of underlying illness, PLUS THREE of the following criteria: decreased muscle strength (lowest tertile) fatigue anorexia low fatfree mass index abnormal biochemistry a) increased inflammatory markers (e.g. sialic acid, CRP, IL6) b) Anemia (< 12 g/dl) c) Low serum albumin (< 3.2 g/dl) The following needs to be excluded: starvation, malabsorption, primary depression, hyperthyroidism and agerelated muscle loss Evans WJ, Clin. Nutr. 2008

21 Definition of Cachexia (resulting from consensus conference, Dec. 2006) Weight loss of at least 5%(edemafree) in 12 months or less in the presence of underlying illness, PLUS THREE of the following criteria: When weight loss cannot be assessed a BMI<20 kg/m 2 may be sufficient. Some proposed other cutoffs, like 18.5 or 22.0 kg/m 2. Evans WJ, Clin. Nutr. 2008

22 CACHEXIA: prevalence, pts at risk & mortality prevalence pts at preval. Europe: 1year in populat. risk in pts pts with mortality at risk cachexia COPD ,200, (moderare severity) CHF , (NYHA IIIV) Cancer , (all types) RA ,000 5 (severe RA) (cachexia) ,000 2 (muscle wasting) CRF , Population assumptions: Europe 450 Mill, US 300 Mill, Japan 100 Mill

23 Frequency of malnutrition in patients with malignant cancer * Tumor Patients (%) Pancreas up to 85 Head & Neck up to 67 Stomach up to 65 Esophagus up to 57 Lung up to 46 Colorectal up to 33 Ovary / Cervix up to 15 Urologic up to 9 Breast up to 5 * ambulatory & hospitlized

24 Pathophysiology of CHF & Cancer Immune Activation / Inflammation Neuroendocrine Activation Hormone Resistance Lack of Anabolism Genetic Factors

25 Cachexia andplasmaangiotensin II 200 pg/ml similar results for norepinephrine and aldosterone normal value < 40 pg/ml normal range pg/ml Controls ncchf caids cchf cliverfailure Starvation cc ancer ideopathic Anker & Coats, unpublished

26 ACE inhibitors for cancer cachexia A PHASE III TRIAL USING IMIDAPRIL (Vitor ) IN CANCER CACHEXIA REPORTED PROMISING RESULTS 1. weight: +1.2 kg 2. hand grip strength: higher FDA APPROVAL FOR 2 nd PHASE III TRIAL IN NSCLC CACHEXIA ++ currently on hold (ARK Therapeutics)

27 Causes of death in cancer Neoplasm Cachexia Cardiovascular incl. sudden death Thromboembolic Infection Unknown

28 Severe arrythmias in 24hour ECG s: VT or >10,000 VES p< of 44 (14.4%) of 24 (0%) Controls Patients with pancreatic cancer

29 MRproANP and severe arrythmias in 24hour ECG s of pats with pancreatic cancer Mean levels of MRpro ANP (pmol/l) 300 ANOVA pvalue: p= none VES VT median MRproANP in 325 healthy volunteers: 45.0 pmol/l (95% CI pmol/l)

30 New Cachexia Phenotyping Equipment (Applied Cachexia Research ) CCR ECGenie (noninvasive ECG) EchoMRI700 (invivo body composition) for rats Supermex (locomotor activity) = rat QoL TSE GSmeter rat front limb muscle strength assessment of lean mass & fat mass: noninvasive, CV <2%

31 Design Cachexia Prevention Tumor inoculation Activity Food intake male Wistar rats approx. 200 g 10 8 AH 130 cells Body composition (NMR) Echocardiography Sacrifice: plasma organ weight tissue storage day 2/ / many compounds or placebo e.g. bisoprolol, nebivolol, carvedilol, bucindolol, MT102 etc etc Activity Food intake

32 Advanced Cancer: echocardiography ejection fraction fractional shortening % % p=0.31 p= p=0.21 p= p= p=0.0001

33 Advanced Cancer: haemodynamics dp/dt max dp/dt min mm mhg/s mm mhg/s p=0.81 p= p=0.68 p= p=0.014 p=0.0093

34 Change in body weight n= g *** 40 ** ** * 50 ** ** *** placebo * bisoprolol oxypurinol spironolactone sham: ±2.1g

35 Change in lean mass during treatment 0 10 g *** * ** * *** *** ** placebo * bisoprolol oxypurinol spironolactone sham: ±2g

36 100 Survival proportions all doses in mg/kg/d Percent survi vival mg MT102 vs plac: HR: 0.30 (95%CI: ) p=0.001 biso 5 mg spindo 3 mg MT102 biso 50 mg MT102 spindo 0.3 mg 40 biso 2 mg terta 0.5 mg nebi 1 mg ACTONE trial (phase II) Coats et al. JCSM Time biso 0.5 mg imida 0.4 mg imida 1 mg imida 10 mg terta 5 mg nebi 10 mg placebo

37 Aldosterone is elevated in tumorbearing ratsand lead to cardiac fibrosis aldosterone [pg/ml] sham placebo Day 7 Day sham Springer et al. unpublished

38 LV mass & survival in cancer

39 Human cancer (cachexia) causes cardiac fibrosis Control (n=5) Cancer (n=6) cancer cachexia (n=6)

40 Pathophysiology of CHF & Cancer Immune Activation / Inflammation Neuroendocrine Activation Hormone Resistance Lack of Anabolism Genetic Factors

41 Total gain in life expectancy: 10 yrs -Cardiology has added 7.2 yrs - Oncology 2.1 months

42 Cancer as causes of death in heart failure from OPTIMAAL, age 67, mean followup 2.7 yrs, based on SAE reports All Events 0"30 days Patients Entering Each Time Period 5477 New Cancers (and % of patients at risk) 241 (4.4%) 11 (0.2%) Cleland et al. HFA 2005 (abstract) Cancer Deaths (and % of all deaths) 84 (8.9%) None Event Rate (per 100 at risk/month*) 30"180 days "1200 days 4892 (0.8%) 145 (3.5%) 180"365 days (0.9%) (4.7%) (10.8%) 61 (16.9%) * these data are censored for death cancer deaths per 100 livingpatient months

43 cardiologist & oncologists need to talk!!