Pulmonary Hypertension For CardiologistsEric Adler MD

Case…• 71 year old female with h/o morbid obesity, pulmonary

hypertension on home O2, HFpEF, hypothyroidism, mild aortic stenosis and Afib.

• Admitted for Volume Overload..• Pulmonary Hypertension

– Unclear Etiology– Treated Previously With Sildenefil/Bosentan at OSH

• Seen in Pulm Clinc B/C fet not to have primary pulmHtn, felt to have HFPEF (WHO 2)

Case Continued• Pt reports worsened SOB for the last 2yrs or so. At

present her activity level is limited to about 50ft, walks from bed to bathroom and that's about it. Limited by SOB. Of late, her home O2 requirements have increased from 2L to 3L

Pulmonary Hypertension

GeneralDefinitionRestingSystolicPAP >35mmHg

RestingDiastolicPAP >15mmHg

RestingMeanPAP >25mmHg

PulmonaryArterialHypertensionPCWP,LAP,LVEDP <15mmHg

PulmonaryArteriolarResistance >3WoodUnits(>240dyn·s/cm5)

Pulmonary Hypertension

PulmonaryArterialHypertensionPre-capillaryHighPVR,HighTPG

PulmonaryVenousHypertensionPost-capillaryNormalTPG

HyperdynamicPulmonaryHypertensionPre-capillaryNormaltranspulmonary resistance

ClassificationGroup1 PulmonaryArterialHypertension

Group2 Left-SidedHeartDisease

Group3 Lungdiseaseand/orHypoxemia

Group4 Chronicthromboticand/orembolicdisease

Group5 Miscellaneous:Sarcoidosis, compressionofpulmonary vessels(adenopathy, tumor, fibrosingmediastinitis)

At-Risk Populations for PAH

Populations PrevalenceIPAH1 6cases/million

ConnectiveTissueDisease2 27%(13%newlyidentified)

CongenitalHeartDisease3 Upto50%ofpatientswithlargeVSDsdevelopEisenmengersyndrome,oftenassociatedwithPAH

HIVinfection4 0.5%

SickleCellDisease5 20%to40%

Drugs/Toxins6Directrelationshipwithanorexigens(amphetamines, cocaine);L-tryptophanmayalsobeassociatedwithPAH

1HumbertMetal. AmJRespirCritCareMed. 2006;173:1023-1020.2WigleyFMetal. ArthritisRheum. 2005;52:2125-2132.3SimonneauGetal. JAmCollCardiol. 2004;43:5S-12S.4Limsukon Aetal.MountSinaiJMed. 2006;73:1037-1044.5LinEEetal. CurrHematolRep. 2005;4:117-125.6RichSetal. Chest. 2000;117:870-874.

Dana Point Clinical Classification of PH (2008)Group 1: PAH1. Pulmonary arterial hypertension (PAH)

1.1 Idiopathic PAH (“primary pulmonary hypertension”)1.2 Heritable

1.2.1 BMPR21.2.2 ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia)1.2.3 Unknown

1.3 Drug- and toxin-induced1.4 Associated with

1.4.1 Connective tissue diseases1.4.2 HIV infection1.4.3 Portal hypertension

1.4.4 Congenital heart disease1.4.5 Schistosomiasis1.4.6 Chronic hemolytic anemia

1.5 Persistent pulmonary hypertension of the newborn

1'. Pulmonary veno-occlusive (PVOD) and /or pulmonary capillary hemangiomatosis (PCH)

Pulmonary Hypertension

Chest. 2004;126:78S–92S.

Mean survival based on etiology of pulmonary hypertension

Pulmonary Vascular Dysfunction

Risk Factors: Shear stress (HD, CHD), HIV, CTD, toxins

Genetic Predisposition: BMPR2, ALK-1, 5-HTT

Endothelial Cell Dysfunction: NO, PGI2, ET-1

Smooth Muscle Cell Dysfunction: Kv1.5

Pulmonary Vascular Remodeling and Disease

Progression

Inflammation and Remodeling: IL-1, IL-6,

PDGF, Chemokines

Pulmonary Hypertension

NormalPA

SMCproliferation

Fibrosis

Plexiform lesionformation

AdaptedfromCoolCDetal.Chest.2005;128:565S-571S.

Evaluation• History

• Physical Examination• CXR

• ECG• PFTs

• Echo• Overnight Oximetry

• VQ Scan vs. CT Scan

• Blood Tests• Right Heart Catheterization

ANA

RF / Anti-CCP

LFTs/HCV

HIV

Anticentromere

SCL-70

Anti-Jo, Anti U1 RNP, ANCA

BNP (pBNP), RDW, CRP

APLA, LAC

EvaluationECHO:• Mild PH defined by a tricuspid

valve velocity of 2.8-3.0m/sec, which corresponds to a tricuspid insufficiency pressure gradient (TIPG) of 31mmHg or higher

• (Modified Bernoulli equation pressure = 4v2)

• More stringent criteria would be a TIPG of 45mmHg to reduce the number of falls positives.

TAPSE(Tricuspid annularplanesystolicexcursion, <1.8cm)

Other ECHO measures of RV dysfunction

Evaluation

D. Mukerjee, D. St. George, C. Knight, J. Davar, et al. Rheumatology; 43 (4): 461

ECHO:• The greater the degree of pulmonary hypertension by catheterization, the

worse the correlation between echocardiogram measurement of RVSP and catheterization measured values.

PATIENT CONTINUED• Right atrial mean pressure: 12 mmHg • Right ventricular pressure: 104/12 mmHg • Pulmonary artery pressure: 104/32, mean 63 mmHg • Pulmonary capillary wedge pressure, mean: 27 mmHg • Non invasive blood pressure, 115/57 mean 79 mmHg • Fick cardiac output: 5.69 L per minute • Fick cardiac index: 2.68 L per minute/ m2 • Pulmonary vascular resistance (Fick): 6.3 Woods units • Pulmonary artery saturation: 70% • Systemic arterial saturation: 93%

Evaluation: Hemodynamics• Vasoreactivity Testing:

• Fall in mean pulmonary artery pressure of >10mmHg, to a value <40mmHg (older criteria: 20% decrease in mPAP)

• Increased or unchanged CO• No significant decrease in BP

• Agents used for testing:• Epoprostenol: 1-2 ng/kg/min and increased by 2ng/kg/min every

5-10 minutes until significant fall in BP, increase in heart rate or symptoms

• Adenosine: 50 µg/kg/min, increase every 2 minutes until dose of 200-250 µg/kg/min

• iNO: 20ppm for 10 minutes followed by 40ppm for 10 minutes

vasoreactive fixed

Hemodynamics with 1.0 mcg/kg/min Nipride

• Pulmonary artery pressure: 89/26, mean 51 mmHg • Pulmonary capillary wedge pressure, mean: 18 mmHg • Fick cardiac output: 7.05 L per minute • Fick cardiac index: 3.32 L per minute/ m2• Pulmonary artery saturation: 72 % •

IMPRESSION:• 1) Elevated right and left filling pressures• 2) Normal cardiac output / index• 3) Positive response to nipride. PCWP 27 --> 18 mmHg

Right Ventricular Adaptations

• After PAH-targeted therapy, RV function can deteriorate despite a reduction in PVR.

• Loss of RV function is associated with a poor outcome, irrespective of any changes in PVR.

J Am Coll Cardiol 2011;58:2511–9

EvaluationV/Q SCAN:

• Sensitivity 90-100%, Specificity 94-100% for distinction between IPAH and CTEPH

• A Normal V/Q will rule out CTEPH but mismatched perfusion defects can be seen in veno-occlusive disease, pulmonary arterial sarcoma, large-vessel pulmonary arteritis, or extrinsic vascular compression.

PAH Determinants of Risk

LowerRisk DeterminantsofRisk HigherRisk

No ClinicalevidenceofRVfailure Yes

Gradual Progression Rapid

II,III WHOclass IV

Longer(>400m) 6MWdistance Shorter (<300m)

Minimallyelevated BNP Veryelevated

MinimalRVdysfunction Echocardiographicfindings Pericardialeffusion,significantRVdysfunction

Normal/nearnormalRAPandCI Hemodynamics HighRAP,lowCI

McLaughlin VV, McGoon MD. Circulation. 2006; 114:1417-1431.

6MWD Predicts Survival at Initial Screening

Miyamoto et al Am J Respir Crit Care Med 2000;161:487-492

Short distance group(<332 meters)

Long distance group(332 meters)

Months

0

20

40

60

80

100

0 10 30 4020 50 60

p < 0.001(Logrank test)

Surv

ival

(%

)

MedicalTreatmentofPulmonaryHypertension

N Engl J Med 2004;351:1425-36.

Vasoactive Mediators Involved In PAH

1.HumbertM, Morrell NW, Archer SL, etal. Cellular and molecular pathobiology of pulmonary arterial hypertension. JAmCollCardiol. 2004;43(supplS):13S-24S. 2.GalièN, TorbickiA, BarstR, etal. Guidelines on diagnosis and treatment of pulmonary arterial hypertension: the Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. EurHeartJ.2004;25:2243-2278. 3.HumbertM, SitbonO, Simonneau G.Treatment of pulmonary arterial hypertension. Nengl J Med. 2004;351:1425-1436.

Nitric Oxidedeficiency

EndothelinOverexpression

Prostacyclindeficiency

ETRA’sBlock the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-12

PDE-5 inhibitors/sGCBlock the activity of PDE-5, restoring vasodilationthrough an increase in cGMP1

ProstacyclinSupplement the deficiency in PGI2, resulting in vasodilation, anti proliferation and inhibition of platelet aggregation4

THERAPIES

ABNORMALITIES

pahdiseasestate_v.124

SitbonOetal.Circulation. 2005;111:3105-3111.

Long-termCCBresponders represent<10%ofiPAHpatients

CCB Therapy is Effective in Only a Small Percent of PAH Patients

A retrospective study of 557 patients who were tested for acute vasoreactivity:

§ 70 (12.6%) patients responded and were put on CCB therapy

§ Of those 70 patients, only 38 improved

§ Therefore only 6.8% of the total number of patients benefited from long-term CCB therapy

§ For the 32 patients who responded positively to acute vasoreactivity testing but who failed to respond to CCB therapy, the 5-year survival rate was 48%

Treatment: Adjunctive Therapy

• Anticoagulants (oral)– Used in ~70% of patients in recent RCTs– Recommended to be used if no

contraindications exist– Caution with potential drug-drug interactions

(DDIs)– There is no difference in efficacy based on FC

severity

• Diuretics:– Usedin~50−70%ofpatientsinrecentRCTs– Notstudiedincontrolledtrials(andwon’tbe)– Recommendedtobeusedincasesoffluidretention– SpirinolactonemaybehelpfulindecreasingRVfibrosis

• Digoxin:– Usedin~25−50%ofpatientsinrecentRCTs– Noevidenceforitsefficacy

• Supplementaloxygen

Why do we decompensate?

Treatment: PDE5 Inhibitors

PDE5Inhibitor Dose Sideeffects

Sildenafil(Revatio) 20mgTIDto40mgTID • Minimalsideeffects• Shorter1/2life

Tadalafil(Adcirca) 40mgdaily • Lesscostly• Longer1/2life• Headaches

SideEffects:headaches,lowerbloodpressure,sinuscongestion,diarrhea,visionchanges,myalgias,flushing

Date of download: 12/4/2014 Copyright © 2014 American Medical Association. All rights reserved.

From: Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial

JAMA. 2013;309(12):1268-1277. doi:10.1001/jama.2013.2024

proBNP, with or without atrial fibril-lation or treated or not with renin-angiotensin system antagonists,!-blockers, or statins.

Secondary End Pointsand Safety DataThere were no significant differences inthe clinical rank score, change in 6-min-ute walk distance at 24 weeks, orchange in peak oxygen consumption or6-minute walk distance at 12 weeks be-tween treatment groups (Table 3).There were no significant differences inthe components of the clinical rankscore at 24 weeks or in the overall in-cidence of adverse, or serious adverse,events in the treatment groups.

Adverse events occurred in 78 pa-tients (76%) who received placebo and90 patients (80%) who receivedsildenafil. Serious adverse events oc-curred in 16 patients (16%) who re-ceived placebo and 25 patients (22%)who received sildenafil. Adverse eventsoccurring in 5% or more of either studygroup are listed in eTable 4 (available athttp://www.jama.com). Patients treatedwith sildenafil had a higher incidence ofvascular adverse events, which in-cluded (but were not limited to) head-ache, flushing, and hypotension, al-though the change in mean arterialpressure from baseline to 24 weeks wasnot significantly different in patients

treated with sildenafil ("1 [95% CI, "8to 6]) and patients treated with placebo("2 [95% CI, "10 to 7]), (P=.45). Allserious adverse events exclusive of deathor cardiovascular or cardiorenal hospi-talization (Table 3) are listed in eTable5. There were no other notable differ-ences in the incidence of specific seri-ousadverseeventsbetweenstudygroups.

Study Drug and Cyclic GuanosineMonophosphate LevelsMedian sildenafil concentrations mea-sured approximately 2 hours after the lastdose were 78 (IQR, 35-130 ng/mL) at 12weeks and 200 (IQR, 92-330 ng/mL) at24 weeks. At week 24, there was a weakcorrelation between sildenafil dose andsildenafil level (r=0.29, P=.008). Inpaired analysis, plasma cyclic guano-sine monophosphate levels increased sig-nificantly from baseline to 24 weeks inpatients randomized to receive sildena-fil (mean increase, 8.72 pmol/mL, [95%CI, 2.56-14.87], P=.006), but not in pa-tients randomized to placebo (mean in-crease, 1.28 pmol/mL, [95% CI, "6.27to 8.83], P=.74), although the change incyclic guanosine monophosphate wasnot significantlydifferentbetweengroups(P=.11).

Additional End PointsAt CMRI, there was no difference inchange in left ventricular mass or left

ventricular end-diastolic volume indexbetween treatment groups (TABLE 4).There was also no difference in changein Doppler-assessed left ventricular dia-stolic function parameters or pulmo-nary artery systolic pressure betweentreatment groups. By CMRI, arterial elas-tance decreased more and systemic vas-cular resistance tended to decrease morein patients treated with sildenafil(P=.09). However, the change in meanarterial pressure in the entire studypopulation was not significantly differ-ent between groups, as noted above.More patients had missing data for aor-tic distensibility at 24 weeks than at base-line, but there was no difference inchange in distensibility between groups.Patients treated with sildenafil had agreater increase in creatinine, cystatin C,NT-proBNP, uric acid, and endothe-lin-1 than patients treated with pla-cebo, whereas changes in aldosteroneand NT-procollagen III were not signifi-cantly different between groups.

COMMENTTo our knowledge, the RELAX trial isthe first multicenter study to investi-gate the effect of PDE-5 inhibition inHFPEF. Contrary to our hypothesis,long-term PDE-5 inhibition in HFPEFhad no effect on maximal or submaxi-mal exercise capacity, clinical status,quality of life, left ventricular remod-

Table 3. Primary, Secondary, and Safety End PointsPlacebo Sildenafil

PValue

No. ofPatients Variable

No. ofPatients Variable

Primary end pointChange in peak oxygen consumption at 24 wk, median (IQR), mL/kg/min 94 "0.20 ("0.70 to 1.00) 91 "0.2 ("1.70 to 1.11) .90

Secondary end pointsClinical rank score, meana 94 95.8 95 94.2 .85Change in 6-minute walk distance at 24 wk, median (IQR), m 95 15.0 ("26.0 to 45.0) 90 5.0 ("37.0 to 55.0) .92Change in peak oxygen consumption at 12 wk, median (IQR), mL/kg/min 96 0.03 ("1.10 to 0.67) 97 0.01 ("1.35 to 1.25) .98Change in 6-minute walk distance at 12 wk, median (IQR), m 96 18.0 ("14.5 to 48.0) 99 10.0 ("25.0 to 36.0) .13

Components of clinical rank score at 24 wkDeath, No. (%)b 103 0 113 3 (3) .25Hospitalization for cardiovascular or renal cause, No. (%) 103 13 (13) 113 15 (13) .89Change in MLHFQ, median (IQR) 91 "8 ("21 to 5) 91 "8 ("19 to 0) .44

Safety end points, No. (%)Adverse events 103 78 (76) 113 90 (80) .49Serious adverse events 103 16 (16) 113 25 (22) .22

Abbreviations: IQR, interquartile range; MLHFQ, Minnesota Living with Heart Failure Questionnaire.aA mean value of 95 in each group is expected under the null hypothesis of no treatment effect.bSite investigator identified causes of death were sudden death (n=1), progressive cardiorenal failure (n=1), and noncardiovascular (n=1).

PHOSPHODIESTERASE-5 INHIBITION IN HEART FAILURE

©2013 American Medical Association. All rights reserved. JAMA, March 27, 2013—Vol 309, No. 12 1273

Downloaded From: http://jama.jamanetwork.com/ on 12/04/2014

Sildenefil in Secondary Pulmonary Hypertension due to Systolic Dysfunction may have benefit

Lewis G D et al. Circulation. 2007;116:1555-1562

Copyright © American Heart Association, Inc. All rights reserved.

Soluble Guanylate Cyclase (sGC) Inhibitors• Cinaciguat and Riociguat• Next Class of Agents that work distally to PDE5 inhibitors.

– Antiproliferative, Antiplatelet, and Vasoldilatory• Multiple Clinical Trials support Benefit in 6 minute walk

time, NYHA Class.• Benefit In CTEPH (Riociguat)• Cannot be combined with PDE5 inhibitors

*Dataaremean± SEM.Walkdistancewassomewhatgreater with250mgBID,butthepotentialforincreasedliverinjurycausesthisdosenotto berecommended[125mgBID(n=74)changeinwalkdistance(m):27±75,250mgBID(n=70)changeinwalkdistance(m):46±62].RubinLJetalNEnglJMed. 2002;346:896-903.

Treatment: Endothelin Antagonists

Placebo (n=69)

Bosentan 125/250 mg bid(n=144)

0 4 8 16Weeks

62.5 mg bid 125 or 250 mg bid

Treatment Effect: 44 m (P<0.001)

Δin

6M

WD

(m)

12

0

20

30

40

10

-10

Treatment: ProstacyclinProstanoid RoutesofAdministration Half-life

Epoprostenol(Flolan) Intravenous 6min

Treprostinil(Remodulin) SubcutaneousIntravenousInhaledOral

240min

Iloprost(Ventavis) InhaledIntravenous

20-30min

Beraprost Oral 60min

SideEffects:jawpain,diarrhea,legpain,flushing,plateletinhibition

Treatment: Epoprostenol

N Engl J Med 1996; 334:296-304• 12-week prospective, randomized, multicenter open trial

comparing epoprostenol to conventional therapy • 81 patients with severe primary pulmonary hypertension

(New York Heart Association functional class III or IV).• Exercise capacity improved (Net 6MWT difference:

113m)• PAPmean decrease of 8%, PVR decrease by 21%.• Eight deaths, all in conventional arm (p = 0.003).

How Effective is Monotherapy?

In Clinical Trials:

• 1/2 to 3/4 of patients did not improve > 1 functional class• 1/3 to 1/2 of patients did not achieve a 6MWD > 380

meters

Long Term Response in PH:

• Is incomplete• Is not universal

ACCF/AHA Consensus PAH Treatment Algorithm

Interventional and Surgical Therapy

Lung Transplantation• ISHLT 2006 registry survival: 78% at 1 yr, 49% at 5 yr and

25% at 10 yr.

• IPAH: 1990 accounted for 10% of all transplants, 2004 accounted for 3.9% of all lung transplants.

• Options include: single lung, double lung and heart-lung.

• ISHLT registry suggests no survival benefit of double lung over single lung.

• Heart Lung reserved for congenital heart disease / Eisenmenger

Surgical Therapy for PH: Pulmonary Thromboemblectomy

• Cumulative incidence after PE is up to 3.8%.1• PH therapy may have minimal effect on hemodynamics although

may allow for some symptomatic improval.2• UCSD Remains Highest Volume PTE Referral Center Worldwide,

Performing Roughy 150-200 PTE yearly.

1 NEnglJMed350:22572Circulation.2009;120(13):1248-54

• Pulmonary thromboendarterectomy is the only definitive treatment.

• Operative mortality with surgery can be 4.4% at experienced centers and up to 24%. (Refer to UCSD)

• Persistent pulmonary hypertension (PVR > 6 WU) after surgery is marker for poor outcomes.

Patient Follow Up…• Discharged on:

Hydralazine 100mg tid, – Carvedilol 6.25mg bid.

She was then restarted Sildenafil 20mg tid

• Now only 2L NC. • Ambulating farther, still

using her walker.• She is able to sleep

better and her husband feels she is a new woman.

CardioMEMS™ HF System

40

PA Sensor is permanently implanted in the distal pulmonary

artery via a right-heart catheterization procedure.

Patient-initiated sensor readings are wirelessly

transmitted to anexternal electronics unit

Directly monitoring PA pressure not only enables early detection ofworsening heart failure, but also allows the titration of medications for

proactive and personalized patient management.

The CardioMEMS™ HF System provides ambulatory pulmonary artery (PA) pressure monitoring

Data stored in a secure website for cliniciansto access and review.

Findings:1. HemodynamicsRA 6 mean mm HgRV 100/11 mm HgPA 100/38 mean 61 mm HgPAW Mean 21 mm HgTD CO/CI 6.87 L/min / 3.2 L/min/m2 FICK CO/CI 9.5 L/min / 4.56 L/min/m2 SVO2 74 % , SPO2 94%PVR (Wood units): 5.96

Conclusions• Pulmonary Hypertension can be divided into 5 categories.

Patients with Group I PH (PAH) are potential candidates for PH-specific treatments.

• Catheterization is mandatory to work-up PH. Vasodilator testing should be performed during catheterization.

• Non-invasive testing can provide additional information.

• Specific treatment for PAH includes ERAs (bosentan, ambrisentan), PDE5 inhibitors (sildenafil, tadalafil) and prostacyclins (epoprostenol, treprostinil, iloprost)

• Patients who do not respond to therapy should be referred for lung transplantation/heart lung.