10/11/2016

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Essentials of Cardiovascular Care

for Older Adults (ECCOA) Launch

Illinois Chapter

Wisconsin Chapter

PULMONARY HYPERTENSION IN THE ELDERLY

* Who Should We Evaluate?

* Where to Refer / When?

* What Treatments?

Dianne L. Zwicke, MD, FACCClinical Adjunct Professor of Medicine

University of Wisconsin School of Medicine and Public Health-MCC, Milwaukee, WI

Medical Director, Pulmonary Hypertension Clinic

Aurora St. Luke’s Medical Center

Pulmonary

Hypertension

Clinic

Advanced

Heart

Failure

LVAD

RVAD

TAH

Heart

Transplant

4th Floor Galleria Building

St. Luke’s Medical Center

STAFF

PHTN: Dianne L. Zwicke, MD

Sara Paulus, PA-C

Eric Roberts, MD

Ramagopal Tumuluri, MD

RN Coordinators (24/7)

Medical Assistants

Clinical Trials RN’s

Administrative Assistant

SPECIALITY PHYSICIANS

Nephrology

Pulmonary

Hepatology

GI

CV Surgeon

CV Anesthesiology

Infectious Disease

SHARED SERVICES

Pharmacist

Social Worker

Palliative Care

Psychologists

Financial Counselling

INPATIENT SERVICE

• Average of 30 patients

• Dedicated HF and PHTN Telemetry Units

• 4 NP’s

• 1 Attending

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DEPARTMENT CONTACTS

PHTN Clinic: 414-646-2438 (select MD)

HF/MAD/Tx Clinic: 414-646-0549

Answering Service: St. Luke’s Medical Center

(414) 649-6000 (switchboard)

Tertiary Access: (414) 385-2500

Nursing Supervisor: (414) 649-6000 (switchboard)

Pulmonary Hypertension Association Care Centers

CCC

Comprehensive

Care Center

RCP

Regional Care

Center

PHAssocation.org

CRITERIA NEEDED FOR A CCC

APPLICATION

� Uniform evaluation of patients

� Appropriate use of Therapies

� Access to PAH specific therapy

� Experience in treating all forms of PAH

� Participation in Clinical Research

� All patients must be in National Database

AT THE TIME OF APPLICATION–APPLICANTS MUST BRIEFLY SUMMARIZE:

History Multidisciplinary PAH care team

Leadership Teaching

IP & OP Facilities Quality Improvement

Strengths PAH related research

Challenges Patients / families

Major changes

CCC CRITERIA

• All forms of oral, inhaled and parenteral

therapies

• 25 patient on IV Therapy

ACCREDITATION

Cost = $13,000.00 for 3 years

Standard of Patient Care

Cum

ulat

ive

surv

ival

All Participants (N=1413)Overall log rank p<0.001

1.00

0.95

0 2 6 84Time (yr)

PASP quintile1: 15-23 mm Hg2: 24-25 mm Hg3: 26-29 mm Hg4: 30-32 mm Hg*5: 34-66 mm Hg*

Cum

ulat

ive

surv

ival

No Cardiopulmonary Disease (N=778)Overall log rank p=0.002

6 84Time (yr)

0 2

PASP tertile1: 15-24 mm Hg2: 24-28 mm Hg3: 28-43 mm Hg*

1.000

0.975

0.900.950

0.85

0.925

0.900

Implications of PH in Community

*Bonferroni-adjusted p<0.05 in pairwise comparison with lowest tertile.Lam CSP et al. Circulation. 2009;119:2663-2670. (Olmstead County, MN data from the Rochester Epidemiology Project)

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Pathologic correlates of PAP (Mitral Stenosis)

Med

ialt

hick

ness

of a

rter

yex

pres

sed

as %

of d

iam

eter

20 6030 40 50

Pulmonary artery pressure (mm Hg)

40.0

30.0

10.0

0.0

20.0

Tandon H, Kasturi J. Br Heart J. 1975;37:26-36.

P<0.01

Medial Hypertrophy

Rich S et al. Pulm Circ 2013:3; 203-205

Disease Specific PA- pressure

HFrEF HFpEF

http://www.pah-info.com/Diagnosing-PAH

PULMONARY HYPERTENSIONDiagnostics - Basics

• History & Physical

• Labs- CBC, CMP, TSH with Reflex, ANA with Reflex, CRP, ESR, HIV, ANTICARDIOLIPIN AB

• EKG, CXR

• Full PFT’S

• Lung scan

• Echo with contrast / TEE

PULMONARY HYPERTENSION Diagnostics - Advanced

• HR Chest CT

• Pulmonary Angiography

• Sleep study / screen

• 6 minute walk

• Cardiac Cath with pharmacologic

challenge -- LAST STUDY!

5th World (NICE) Symposium on PH

1. Pulmonary arterial hypertension (PAH)

1. Idiopathic PAH2. Heritable PAH

1. BMPR22. ALK1, ENG, SMAD9, CAV1, KCNK33. Unknown

3. Drug- and toxin-induced4. Associated with

1. Connective tissue disease2. HIV infection3. Portal hypertension4. Congenital heart diseases (update)5. Schistosomiasis

1’. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis

1’’. PPHN

2. PH due to LHD

1. LV systolic dysfunction2. LV diastolic dysfunction3. Valvular disease4. Congenital/acquired left heart inflow/outflow

tract obstruction and congenital cardiomyopathies

3. PH due to lung diseases and/or hypoxia

1. COPD2. Interstitial lung disease3. Other pulmonary diseases with mixed restrictive

and obstructive pattern4. Sleep-disordered breathing5. Alveolar hypoventilation disorders6. Chronic exposure to high altitude7. Developmental lung diseases (update)

4. CTEPH

5. PH with unclear multifactorial mechanisms

1. Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

2. Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis

3. Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

4. Others: tumor obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

Simonneau G et al. JACC. 2013;62:D34-D41.

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1. Pulmonary Arterial Hypertension 2. Left Heart Disease

3. Chronic Hypoxemia

4. Thromboembolic5. Miscellaneous

-Sarcoid, fibrosing mediastinitis

WHO Classification of Pulmonary Hypertension Clinical Classification: Where Is the Lesion?

ALK-1, activates receptor-like kinase 1; Ao, aorta; BMPR2, bone morphogenetic receptor type 2; HHT, hereditary hemorrhagic telangiectasia;

HIV, human immunodeficiency virus; LA, left atrium; LV, left ventricle; PA, pulmonary artery; PC, pulmonary capillary bed; PV, pulmonary vein;

RA, right atrium; RV, right ventricle; VC, vena cava.

Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S54.

VC RA RV PA PC PV LA LV Ao

Graphic adapted from http://cme.medscape.com/viewarticle/530730.

PULMONARY ARTERIAL HYPERTENSION (PAH)Hemodynamic Diagnostic Criteria

• Mean PA pressure > 24 mmHg

• PCWP < 15mmHg

• PVR > 2.5

Epidemiology of PAH (WHO Group 1)1

• Prevalence of PAH in associated conditions:

– CTDa: 8%-12%2,3

– CHD: 15%-30%4

– PoPH: 2%-6%5,6

– HIV: 0.5%7

CHD, congenital heart disease; CTD, connective tissue disease; FPAH, familial pulmonary arterial hypertension; HIV, human immunodeficiency virus; IPAH, idiopathic pulmonary arterial hypertension; PoPH, portopulmonary hypertension.1. Simonneau et al. J Am Coll Cardiol. 2009;54(1 suppl S):S43-S54. 2. Hachulla et al. Arthritis Rheum. 2009;60:1831-1839. 3. Mukerjee et al. Ann Rheum Dis. 2003;62:1088-1093. 4.Landzberg. Clin Chest Med. 2007;28:243-253. 5. Hadengue et al. Gastroenterology. 1991;100:520-528. 6. Krowka et al. Hepatology. 2006;44:1502-1510. 7. Sitbon et al. Am J Respir Crit Care Med. 2008;177:108-113. 8. Humbert et al. Am J Respir Crit Care Med. 2006;173:1023-1030.

IPAH

>1 Risk factorAppetite suppressant

HIV

FPAHCTD

CHD

PoPH

Distribution of PAH in French Registry 8

a Systemic sclerosis.

N=483 of 4579 patients with echo PASP >40 mm Hg.Gabby E. Am J Respir Crit Care Med. 2007;175:A713.

How Common is Pulmonary Hypertension

• Single echo lab / Australian community of 160,000

• ~10% of patients had estimated sPAP>40 mm Hg

– Only 2.3% with PAH after full evaluation

Left heart disease, 78.7%

PAH, 2.3%

Congenital heart disease, 1.9%

Lung disease/Sleep-related hypoventilation,

9.7%

CTEPH, 0.6%

Unknown, 6.8%

Nitric oxidedeficiency

Endothelinoverexpression

Prostacyclindeficiency

ERAsBlock the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-13

PDE-5 inhibitorsBlock the activity of PDE-5, restoring vasodilation through an increase incGMP1

ProstacyclinSupplement the deficiency in PGI2, resulting in vasodilation and inhibition of platelet aggregation2

THERAPIES

ABNORMALITIES

Vasoactive Mediators Involved In PAH

cGMP, cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; ET-1, endothelin; PDE-5, phosphodiesterase type 5; PGI2, prostacyclin.1. Humbert et al. J Am Coll Cardiol. 2004;43(suppl S):13S-24S. 2. Humbert et al.N Engl J Med. 2004;351:1425-1436.

3. Galiè et al. EurHeart J. 2004;25:2243-2278.

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Nitric Oxide Deficiency

o Nitric Oxide – inhaled

o Sildenafil (Viagra®, Revatio®)

o Tadalafil (Adcirca®)

o NO GCS DRUGS

Prostacylcin Deficiency

o Epoprostenol (Flolan®, Veletri®) – IV

o Treprostinil (Remodulin®) - SQ, IV

o Iloprost (Ventavis®) – inhaled

o Epoprostenol (Flolan®, Veletri®) – inhaled

o Treprostinil (Tyvaso®) – inhaled

o Treprostinil (Orenitram®) - oral

Endothelin Overexpression

o Bosentan (Tracleer®)

o Abrisentan (Letairis®)

o Macitentan (Opsumit®)

Guanylate Cyclate Stimulator

o Riociguat (Adempas®)

Epoprostenol Inhaled

Epoprostenol

Delivery Device Connector

Humidifier

Epoprostenol

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HPAH, hereditary pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; NS, not significant; PGI2, prostacyclin; Tx, treatment.

Sitbon et al. Slides presented at European Respiratory Society; September 16-18, 2007; Stockholm, Sweden.

Has Survival Meaningfully Improved With Modern Therapies?

0 12 24 36 48 60

n=269

n=260

n=118

Before 1992 (no specific Tx)

1992-1999 (only IV PGI2)

After 2000 (current therapies)

NS

P<0.05, log-rank test

Months0

25

50

75

100IPAH, HPAH, and anorexigen-associated PAH

Overall PAH Therapy Use in Enrolled Population1,2

ERA, endothelin receptor antagonist; PDE-5I, phosphodiesterase type 5 inhibitor; QuERI, Quality Enhancement Research Initiative.

1. McLaughlin et al. Am J Respir Crit Care Med. 2009;179:A1043. 2. Mathier et al. Am J Respir Crit Care Med. 2009;179:A2658.

Pat

ient

s(%

)

N=782

1-Year Mortality Remains High in FC IV Patients1,2

FC, functional class; QuERI, Quality Enhancement Research Initiative; WHO, World Health

Organization.

1. McLaughlin et al. Am J Respir Crit Care Med. 2009;179:A1043. 2. Mathier et al. Am J Respir Crit Care Med. 2009;179:A2658.

WHO FC

1-Y

ear

mor

talit

y (%

)

N=782

<30% onprostanoid

Why is Differentiating PH

Due to Left Heart Disease Important

Prognosis is dependent on diagnosis

o Left Heart disease with PH is associated with worse

prognosis

Therapies are dramatically different

o PAH treatments costly

o PAH therapy can have serious side effects

Incorrect treatment can worsen clinical outcomes

0

100

200

300

400

500

600

700

800

900

1000

1980 1985 1990 1995 2000 2005 2010

8.17.2

3.44.4

55.7

1980 1985 1990 1995 2000 2005 2010

% Hospital Mortality Prevelance/ 10X6

Hospitalization/ 105

Mortality X 103

Incidence X 103

US Trends in Heart Failure Over the Last 30 Years

-5

5

15

25

35

45

55

65

55-64 65-74 75-84 85-94

men

women

Age years

Inci

de

nce

pe

r 1

00

0 p

ers

on

ye

ars

0 2 4 6 8 10 12

20-39

40-59

60-79

80+

Percent

US Age Distribution for Incident Heart Failure

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Normal

HFPEF HFREF

REMODELINGREMODELING

SYMPTOMSSYMPTOMSSYMPTOMSSYMPTOMS

Prognosis

? Systole

AO

LV

LA

RF

Compliance

Contraction Relaxation

Suction

Diastasis AC

Pre

ssu

re

Time

IVRT

Relaxation Compliance

Preload

DIASTOLIC DYSFUNCTION

DIASTOLIC DYSFUNCTION

Diastology and Heart Failure

Pressure(mmHg)

0

90

75

60

45

30

15

30 Ugly

18 Bad

8 Good

Hemodynamic Implications of Heart Failure

PressureRelaxation Compliance

Preload

DIASTOLIC DYSFUNCTION

DIASTOLIC DYSFUNCTION

Diastolic parameters can

be accurately assessed by

several ECHO Doppler

techniques

LVEDP

Higher

LA pressure

High LV

pressure

Hemodynamic Consequence of Heart Failure

� Left Atrial Pressure = impaired hemodynamics

� Death

�Pulmonary Congestion = pulmonary HTN

�Shortness of breath = worse NYHA classification

�Hospitalizations = Frailty, disability

�End Organ Failure = Renal, Lung, Liver, Muscle

Distinguishing Features

*Includes hypertension, DM, obesity, and CAD..

Characteristics HFrEF PAH HFpEFAge Older Younger Much Older

Comorbidities* Frequent Rare More frequent

ECHO

RAE Frequent Most frequent Rare

LAE Frequent Absent Frequent

LV / RV function Low / Normal Normal / Low Normal / Normal

Diastolic E/e’>12 E/e’<8 E/e’> 12

Hemodynamics

mRAP Normal Normal-High Normal-High

mPAP Mild Elevated Very elevated Mild elevated

CO Low Normal/ Low Normal

PVRNormal or mild elevated

Markedly elevatedNormal or mild

elevated

Can PAH exist with left heart disease?

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Implications of WHO Group 2 PH

J Cardiac Fail 2014; 20: 98-104

The presence of elevated PASP irrespective of LVEF is an

independent prognostic marker for higher risk

(morbidity and mortality)

Clinical Spectrum of HFpEF

Relative

numbers

affected

Guazzi Circ 2014;7: 367-77

“Multi-hit” causes of PH in HFpEF

ElevatedPA pressure

in HFpEF

Systemic HTN

Aortic and mitral valve disease

Obesity, metabolic syndrome

↑LA pressure,diastolic dysfunction

Chronic kidneydisease

Obstructive sleep apnea

Aging

Lung disease

Pulmonary Hypertension HFpEF

• n= 548 pts with HFpEF over 5

years

• PH Echo Doppler data

– RVSP> 47 mmHg

– RV dysfunction (TAPSE)

Mohammed Circ. 2014; 2310-20

The combination of RV dysfunction and PASP> 47mm Hg were strong independent risk

factors of mortality

Pulmonary Hypertension and HFrEF

• HFrEF (n=463 RHC)

JACC HF 2013;1:290-9

HFrEF patients with elevated PAP and PVR

(mixed) are at the highest risk

PH with Valvular Heart Disease

Magne et al JACC Imaging 2015:8;83-99

PH in patients with severe heart valve disease is an

independent risk for morbidity and mortality

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ARE THERE TREATMENTS???

Vachiery et al JACC 2013; 62: D100-8

Traditional PAH therapies have resulted in no benefit or harm

U Mn (05’-09’)

n=50 BTT

Duration of support 135+60

Hemodynamic assessments:•Pre- HMII

•3 mos post HMII

•1 mos post TP

Severe PHTN was defined as:•TPG>15 or PVR>4

ConclusionsNearly all patients with

AHF have PH

30% severe PH

<10% severe refractory PH

Survival/ Transplant to

6mos

89.1% total group

88.8 % Severe PH

93.3% Non severe PH

32 patients have

undergone transplant (11

severe PH)

CF LVAD is a viable strategy

to reduce PH in BTT

patients

Sildenafil in PH-HFpEF

• PDE-5A inhibitor, ↑cGMP, ↑NO downstream activity

• Selective pulmonary arterial vasodilator

• But may also improve coronary and systemic endothelial

function

• Murine models:

– ↓ LV hypertrophy in response to pressureoverload, and decreased fibrosis in this setting

– ↑ lusitropy independent of BP (↑enhances LVrelaxation)

Waxman AB. Circulation. 2011;124:133-135.

Guazzi M et al. Circulation. 2011;124:164-174. Redfield M et al. JAMA. 2013;309:1268-1277.

Guazzi et al RELAX

Evidence of PH required Evidence of PH not required

N=44 N=216

PASP 53 mm Hg PASP 41 mm Hg

Mean PADP-PCWP: 9 mm Hg Hemodynamic testing not done

12 month follow-up 6 month follow-up

Primary outcome: hemodynamics,RV performance, QOL

Primary outcome: peak VO2

Positive trial Negative trial

RCT of Sildenafil and HFpEF Use of PAH-specific therapies with LHD

Treatment Acute Response Long-term Outcome

Prostacyclin 1 �PVR, �SVR, �PAWP, �CO � Mortality

Sildenafil 2-8 �PVR, �PAWP, �MPAP, �COLower PAP, improved endothelial function and exercise tolerance

Bosentan 9-11 �PVR�Transaminases,�Fluid retention

Darusentan 12,13 �SVR No benefits

Tezosentan 14 �PVR, �SVR, �PAWP, �CI No benefits

No therapies that are approved for WHO Group 1 PAH are FDA-approved for PH resulting from left heart failure.

1. Califf RM et al. Am Heart J. 1997;134:44-54. 2. Galie N et al. N Engl J Med. 2005;353:2148-2157. 3. Alaeddini J et al. Am J Cardiol. 2004;94:1475-1477. 4. Lepore JJ et al. Chest. 2005;127:1647-1653. 5. Lewis GD et al. Circulation. 2007;115:59-66. 6. Guazzi M et al. Circ Heart Fail. 2011;4:8-17. 7. Guazzi M et al. Eur J Heart Fail. 2012;14:82-90.8. Guazzi M et al. Circulation. 2011;124:164-174. 9. Cowburn PJ, Cleland JGF. Eur Heart J. 2001;22:1772-1784. 10. Kelland NF, Webb DJ. Heart. 2007;93:2-4. 11. Sutsch G et al. Circulation. 1998;98:2262-2268. 12. Luscher TF et al. Circulation. 2002;106:2666-2672. 13. Anand PI et al. Lancet. 2004;364:347-354. 14. Kaluski E et al. JACC. 2003;41:204-210.

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Conclusions RELAX trial

• Long-term PDE-5 inhibition in HFpEF had no effect on:

– maximal or submaximal exercise capacity, clinical status, quality of life, LV remodeling, or diastolic function parameters

– PA systolic pressure (ECHO)

• Renal function worsened more

• NT-proBNP, endothelin-1, and uric acid levels increased more in patients treated with sildenafil

Findings from RELAX do not suggest that sildenafil provides clinical benefit in an HFpEF population.

Redfield MM et al. JAMA. 2013:309:1268-1277

Trials on the Horizon

Vachiery et al JACC 2013; 62: D100-8

Some promising results but awaiting publications of large scale

trials

Cardiopulmonary Symptoms

Isolated

DPG< 7 PVR<3

RV dysfunction

HF reduce EF HF preserved EF Valvular Heart Disease

WHO-2 Group (PCWP> 15 and Mean PAP> 25)

Combined

DPG> 7 PVR>3

Valve InterventionHigh risk surgery

TAVR program

Co-morbiditiesOSA, HTN, AFIB, CKD,

COPD

OMTMedical/ CRT

Eval for AHF options

Pulmonary Vascular Remodeling

Referral to AHFT program for managementClinical trials, LVAD, BiVAD, Palliative

Summary

• WHO group 2 comprises 70-80% of all patients with PH

• PH among patient with left heart disease (HFpEF, HFrEF, VHDz) is

under-recognized and carries the highest risk of morbidity and

mortality

• Therapies designed for the treatment of PAH are ineffective in

WHO group 2 PH and some have serious adverse effects

• Diagnostic approaches require multi-modality cardiovascular

testing (Echo/Doppler, RHC/ vasodilator and possibly exercise

testing) to understand cardiac and pulmonary vascular physiology

• Clinical trials using traditional PAH therapy are underway to

address “combined” (DPG>7 and PVR>3)

Vague Symptoms

Major presenting symptoms are syncope, shortness of breath and fatigue

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Syncope is prodrome to death

Treatment options are

frequently available if not

seen at end stage

Correct diagnosis must

be established

Empiric vasodilator

therapy is not

recommended