Challenges in Hypertension and Challenges in Hypertension and Challenges in Hypertension and Challenges in Hypertension and

Hyperlipidemia Hyperlipidemia Hyperlipidemia Hyperlipidemia TTTTreatment in Cancer:reatment in Cancer:reatment in Cancer:reatment in Cancer:What are the best drugs to use and why?

Daniel J Lenihan, MD

Professor, Division of Cardiovascular Medicine

Director, Cardio-Oncology Center of Excellence

Washington University in St Louis

Christopher Domenico, Pharm D

Cardiology and Anticoagulation Clinical Specialist

Hospital of the University of Pennsylvania

Presenter Disclosure InformationACC Cardio-Oncology 1.26.19

•I will not discuss off label use or investigational use in my presentation.

•I have financial relationships to disclose:

–Consultant (modest): Roche, Pfizer, Takeda, Prothena, BMS, Akcea

Chemotherapy Induced Hypertension

Abi Aad. Crit Rev Oncol Hematol. 2015;93:28-35.

Cardiovascular SAEs in RCTs

Phase 3 Carfilzomib Trials

• ASPIRE Trial

Total Cardiac AEs

Total Cardiac AEs

+ Dyspnoea

26.6%

46%

11.4%

14.2%

15.6%

30.5%

5.7%

7.5%

DVT/PE 10.2% 6.2%

Stewart, AK et al, NEJM 2015, p.142-152.

Case study

32 y/o M

• Diagnosed 6/19/2004 at 18y with Hodgkins Disease Stage IVB. Sites of

disease included neck, chest, abdomen, spleen

• Completed therapy 2/2/2005. Received radiation therapy to chest, para-

aortic and pelvis

• Chemotherapy included - Anthracyclines:240mg/m², Bleomycin:80mg/m²,

Cytoxan:4800mg/m², Procarbazine:2800mg/m²,Dacarbazine, Prednisone,

Vinblastine, and Vincristine. Can be considered cured.

• Asymptomatic

• BP 128/94, P 92 Weight 244. Exam only notable for an S4.

• Chol 171, trig 144, LDL 117, HDL 39, CRP .59 NTproBNP 50

• Current meds: Lisinopril 10mg daily

What to do now?

• MRI: LVEF 53%, RV EF 43%, enlarged main pulmonary

artery (3cm), LVEDV 250ml, septal and lateral wall

enhancement indicating fibrosis

• Would you change therapy in some way?

What is the best overall therapeutic choice now?Mild HTN, mild tachycardia, possible LV and RV dysfunction,

previous cardiotoxic therapy

1. Continue Lisinopril, increase exercise

2. Continue Lisinopril, add carvedilol, avoid Na+, increase

exercise

3. Check BP regularly, lose weight

4. Switch to candesartan

5. Switch to Entresto

Pharmacology of ACEICaptopril Enalapril Lisinopril Benazepril Quinapril Ramipril Trandolapril Moexipril Fosinopril

Zinc ligandZinc ligandZinc ligandZinc ligand Sulfhydryl Carboxyl Carboxy Carboxy Carboxy Carboxy Carboxy Carboxy Phosphinyl

ProdrugProdrugProdrugProdrug No Yes No Yes Yes Yes Yes Yes Yes

TTTTmaxmaxmaxmax, hours, hours, hours, hours 0.7-0.9 2-8 6-8 1-2 2 3 4-10 1.5 3

HalfHalfHalfHalf life, life, life, life,

hourshourshourshours

1.7 11 12 10-11 0.8-3 9-18 15-24 2-9 12

EliminationEliminationEliminationElimination Kidney Kidney Kidney Kidney Kidney Kidney Kidney,

Liver

Kidney Kidney,

Liver

Dose range, Dose range, Dose range, Dose range,

mgmgmgmg

6.25-300 2.5-40 5-40 5-80 5-80 1.25-20 1-8 7.5-30 10-80

F,F,F,F, %%%% 75-91 60 6-60 >37 >60 50-60 70 13 36

Pharmacology of ARBBioavailability Food Effect Active Metabolite Half-life, h Protein Binding,

%

Losartan 33 No Yes 2 (6-9) 99

Valsartan 25 Yes No 9 95

Irbesartan 70 No No 11-15 90

Candesartan 42 No Yes 3-11 99.5

Telmisartan 15 No No 24 >99

Olmesartan 26 No Yes 13 99

Beta Blockers DrugDrugDrugDrug αααα----1 1 1 1

BlockadeBlockadeBlockadeBlockade

ββββ----1 Selectivity1 Selectivity1 Selectivity1 Selectivity ISAISAISAISA MSAMSAMSAMSA LipophilicityLipophilicityLipophilicityLipophilicity HalfHalfHalfHalf----life, life, life, life,

hourshourshourshours

EEEElllliiiimmmmiiiinnnnaaaattttiiiioooonnnn,,,,

PrimaryPrimaryPrimaryPrimary

Atenolol No Yes No No Low 6-7 Renal

Bisoprolol No Yes No No Moderate 9-12 Hepatic

Carvedilol Yes No No Yes High 7-10 Hepatic

Esmolol No Yes No No Low 9 minutes Blood

esterases

Labetalol Yes No Yes Low Moderate 5-8 Hepatic

Metoprolol No Yes No Low Moderate 3-7 Hepatic

Nadolol No No No No Low 20-24 Renal

ACE Inhibition appears quite important in preventing heart failure

Cardinale D et al. Circulation. 2006;114:2474-2481

Carvedilol appears protective during adriamycin

based chemotherapy

Kalay et al. JACC. Dec 2006. 48:2258-62

Data expressed as mean values.

PRADA. Gulati, G et al.

European Heart Journal 2016

doi:10.1093/eurheartj/ehw022

Candesartan is

modestly protective,

but not metoprolol

The combination of ACE/BB can prevent cardiotoxicity

Bosch, X et al, JACC 2013, p 2355

Curigliano, G et al; CA Cancer Clin Journal 2016

Can LV dysfunction be Prevented?“An ounce of prevention is worth a pound of cure”

• ACE/ARB

• Carvedilol/nebivolol

• Enalapril/carvedilol

• Spironolactone

• Statins

All these medications have some evidence that they can

prevent cardiac dysfunction

Curigliano, G et al; CA Cancer Clin Journal 2016

Case 1:What I did……

• Started coreg 6.25 bid and increased in 2 weeks to 12.5

bid

• Aspirin 81mg daily

• Encouraged Increased exercise

• Avoid extreme weight lifting (he enjoys that activity)

Statin Therapy

Case 241 y/o F

• DIAGNOSES:

1. Stage III neuroblastoma 1980

2. Metastatic leiomyosarcoma 2017.

• Cancer THERAPY HISTORY:

1. MADDOC (nitrogen mustard, doxorubicin, cisplatin, dacarbazine, vincristine, and cyclophosphamide) and chest/abdominal radiation 1980

2. Adriamycin and olaratumab with dexrazoxane 2017-10/2018

3. Just starting anlotinib (novel TKI inhibiting VEGFR,FGF,PDGF, c-kit, Ret)

Case 2: Current Phys Exam/Labs

• No overt symptoms but is not active

• P 114, BP 124/85 (was 93/68 prior to new med), weight

154 lbs, BMI 30

• Mild systolic murmur at RUSB, soft S4, trace edema

• Labs: Chol 221, trig 164, HDL 73, LDL 115, trop neg,

NTproBNP 65, CRP 2.26

• Echo/ECG basically normal

• Current meds: no cardiac meds

Would anyone start a statin at this point?

1. Yes, I would go with pravastatin 20mg qhs

2. No, she needs to increase exercise and diet

3. No, I would start with fish oil and Zetia 10mg

4. Yes, I would start with rosuvastatin 10 mg qhs

5. Yes, I would start with lovastatin 20mg qhs.

Statins are helpful in renal cell cancer especially with anti-

VEGF directed therapy

R McKay et al European Journal of Cancer 52 (2016) 155-162

OS Anti-VEGF

Statins: yesStatins: yes

Statin therapy prior to and during chemotherapy prevented HF

JACC 2012, p 2384

Case 2:What I did……

• Started crestor 10 mg qhs

• Started coreg 6.25 bid and increased in 2 weeks to 12.5

bid

• Aspirin 81mg daily

• Encouraged Increased exercise

Beta Blocker Drug Interactions

ACEI/ARB Drug Interactions

Calcium Channel Blocker Drug Interactions

Calcium Channel Blocker Drug Interactions

Common Drug Interactions with Statins

Wiggins BS. Circulation. 2016;134:e468-495.

Treatment of HTN and Hyperlipidemia in patients with cancer

• More aggressive treatment is usually indicated since these are pateints at

high risk at least in part due to previous cancer therapy

• Diet, Exercise, Monitoring are still the fundamentals in management

• Target goals for the general population have not been tested in patients being

treated for cancer or long term survivors.

• We need to develop more data to support preferred treatments!