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Pulmonary Arterial Hypertension: A Few Steps on the Long March to Effective Treatment. Edward Catherwood, MD, MS Cardiology Update, 2004. PAP. CO=. PVR. Schematic Progression of PAH. Pre-symptomatic/ Compensated. Symptomatic/ Decompensating. Declining/ Decompensated. CO.

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pulmonary arterial hypertension a few steps on the long march to effective treatment

Pulmonary Arterial Hypertension:A Few Steps on the Long March to Effective Treatment

Edward Catherwood, MD, MS

Cardiology Update, 2004

schematic progression of pah

PAP

CO=

PVR

Schematic Progression of PAH

Pre-symptomatic/ Compensated

Symptomatic/ Decompensating

Declining/ Decompensated

CO

Symptom Threshold

PAP

Right Heart Dysfunction

PVR

Time

who world symposium venice 2003 pah classification
WHO World Symposium, Venice 2003PAH Classification
  • Pulmonary arterial hypertension
    • Familial
    • Idiopathic
    • Related to:
      • Collagen vascular disease
      • Congenital heart disease
      • Portal hypertension
      • HIV infection
      • Drugs / toxins/other
  • PAH with significant venous and/or capillary involvement
  • PAH related to disorders of respiratory system
  • PAH due to thromboembolic disease
    • PE
    • Sickle cell
    • Non-thrombotic pulmonary embolism: tumor, parasites
  • Miscellaneous: Sarcoid, extrinsic compression

Humbert M, et al. NEJM. 2004.

pah a progressive disease of poor survival
PAH: A Progressive Disease of Poor Survival

68%

48%

34%

Adapted from: D’Alonzo et al. Ann Internal Med. 1991

survival estimates in scleroderma by organ involvement
Survival Estimates in Scleroderma By Organ Involvement

100

90

80

None

70

60

Percent Survival

50

Lung Involvement (without PH)

40

30

PAH

20

10

0

0

1

2

3

4

5

6

7

8

9

10

11

12

13

Years from Diagnosis of Pulmonary Hypertension

Koh et al. Brit J Rheumatol 1996

who functional assessment of pah
WHO Functional Assessmentof PAH

Class ISymptoms do not limit physical activity: Ordinary physical activity does not cause undue discomfort.

Class IISlight limitation of physical activity: Patient is comfortable at rest, yet experiences symptoms with ordinary physical activity.

Class IIIMarked limitation of physical activity: Patient is comfortable at rest, yet experiences symptoms with minimal physical activity.

Class IVInability to carry out any physical activity: Patient may experience symptoms even at rest. Discomfort is increased by any physical activity. These patients manifest signs of right heart failure.

Humbert M. NEJM. 2004

symptoms of pah
Symptoms of PAH
  • Symptoms may include:
    • Dyspnea Fatigue
    • Syncope Edema
    • Dizziness Chest Pain
  • Non-specific nature of complaint:
    • Misdiagnosis
    • Delayed diagnosis

Gaine et al. The Lancet, 1998.

physical examination
Physical Examination
  • Loud pulmonic valve closure (P2)
  • TR murmur
  • Right-sided fourth heart sound
  • Right ventricular heave
  • Jugular venous distention
  • Peripheral edema, ascites
findings on chest radiography
Findings on Chest Radiography
  • Cardiac enlargement
  • Prominent proximal PA
  • “Pruning” of distal PA
  • no evidence of pulmonary edema (sign of left-sided disease)
  • lungs look normal
signs indicative of ph on echo

IVS

RV

LV

RA

LA

Signs indicative of PH on ECHO
  • Increased sPAP or TR jet
  • Right atrial & ventricular hypertrophy
  • Flattening of septum
  • Small LV dimension
  • Dilated PA
normal range in pasp
Normal Range in PASP
  • 3800 TTE database with PASP measured
  • 28% with PASP est. over 30 mmHg
  • 5% men over 50 had PASP >40 mmHg
  • Increasing values correlate with:

Age, BMI, sex

McQuillan BM, et al. Circulation. 2001

auxillary studies
Auxillary Studies
  • Baseline labs: CBC, LFTs, ANA, coagulation battery, HIV serology
  • PFTs: screen for restrictive or obstructive disease, diffusing capacity
  • Pulmonary thromboemboli: Perfusion lung scan, CT scan, angio
  • OSA: sleep study
right heart catheterization diagnostic gold standard
Right Heart CatheterizationDiagnostic Gold Standard
  • CO/CI
  • RAP
  • mPAP, SVO2
  • PAOP
  • PVR
  • Prognostic (RAP, CI, mPAP)
6 mwt methods
6 MWT Methods
  • The 6 MWT is a non-encouraged test performed on room air
  • The corridor should be a minimum of 30 meters in length
  • Required equipment
    • Stop watch
    • 2 cones
    • Portable pulse oximeter
  • Patient instructions:
    • “The object of this test is to walk as far as possible for 6 minutes. You are permitted to slow down, to stop, and to rest as necessary. You may lean against the wall while resting, but resume walking as soon as you are able to.”
    • “You will be walking back and forth around the cones (or chairs). You should pivot briskly around the cones and continue back the other way without hesitation..”
6mw predicts survival at initial screening

100

Long distance group

80

p < 0.001(Logrank test)

60

Survival (%)

40

Short distance group

20

0

0

10

20

30

40

50

60

Months

6MW Predicts Survival at Initial Screening

Miyamoto et al Am J Respir Crit Care Med 2000.

history
History
  • 35yo woman, single mother, notes increasing DOE over two years duration.
  • Ultimately develops SOB at rest and marked swelling in her legs
  • Diuresis of 15 lbs at OSH with improvement.
  • ECHO demonstrates RA/RV dilatation, PASP 60 mmHg, normal LV
slide19
PMH:
  • Toxemia of pregnancy
  • Mild diastolic hypertension
  • No history of PE, COPD, OSA, diet drug use, coll-vasc disease, liver disease, toxic exposures
  • Single, 8yo child, works as a waitress. 15 ppd smoker. No alcohol excess
  • FH negative
  • ROS: Nonproductive cough, hoarse voice
physical exam
Physical Exam
  • WD, WN 35 yo woman, BP 100/70 P 90 R 12, Wt. 70kg
  • HEENT: No JVD
  • Lungs: Clear
  • Cardiac exam: Loud P2, RV lift.
  • ABD: unremarkable
  • Ext: Trace edema
  • Neuro: Normal
lab studies
Lab Studies
  • CBC: Hgb 17.8, Hct 52 WBC 7800 with unremarkable differential Plts 27K
  • Na+ 131 K+ 3.8 Cl 94 CO2 28 Creat 0.7
  • LFTs normal
  • ANA neg
  • CT chest negative for PE or interstitial lung abn.
  • Abdominal CT: spleen mildly enlarged
  • PFTs: Mild obstructive pattern, DLCO 77%
what do you think
What Do You Think??
  • What is the etiology of her PHTN?
  • What additional testing or examination would you order?
  • Would you treat her PHTN now? With what?
treatments for pah
Treatments for PAH
  • Treat modifiable contributors
    • Left heart disease, shunts
    • Pulmonary parenchymal or thrombotic processes, OSA
  • Pharmacotherapies
    • General measures: diuretics, warfarin, O2, ?Dig
    • Ca++ channel blockers
    • Prostanoids
    • Endothelin antagonists
    • Phosphodiesterase inhibitors
prostanoid therapy
Prostanoid Therapy
  • Physiologic impact
    • Induces vasodilatation of vascular smooth muscle cells (cAMP)
    • Inhibits growth of vascular SMCs
    • Potent inhibitor of platelet aggregation
  • Available agents
    • Epoprostenol (Flolan): central access, constant infusion
    • Treprostinil (Remodulin): sq constant infusion
    • Iloprost: inhaled
    • Beraprost: oral
longer term impact of epoprostenol on ipah
Longer Term Impact of Epoprostenol on iPAH
  • 162 patients with iPAH
  • Eposprostenol compared to expected survival
  • 62% vs 35% at 3 yrs.
  • Keys to survival:
    • Functional class
    • CI, mean PA pressure

Epo Rx

Historical Controls

Historical Controls

McLaughlin VV, et al. Circulation. 2002.

endothelin 1
Endothelin-1
  • Family of 21 amino acid peptides
  • Identified in 1988
  • Highest expression in lung, vascular endothelium, smooth muscle and airway epithelium
  • One of the most potent endogenous vasoconstrictors
    • 100 x more potent v/s NE
    • 10 x more potent v/s A-II

Adapted from Yanagisawa M, et al. Nature. 1988.

endothelin receptor antagonists
Endothelin Receptor Antagonists
  • Bosentan (Tracleer):
    • Blocks ETA and ETB

Agents in Phase III Trials

  • Sitaxentan:
    • ETA selective blockade
  • Ambrisentan:
    • ETA selective blockade
main inclusion criteria
Channick, et al. Lancet 2001

PAH due to

iPAH

scleroderma

other connective tissue diseases

WHO functional class III

Baseline 6-min walk test  150 m and  500 m

Baseline hemodynamics

Mean PAP > 25 mmHg

PVR > 240 dyn•sec•cm-5

PCWP < 15 mmHg

Rubin, et al. NEJM 2002

PAH due to

iPAH

scleroderma

other connective tissue diseases

WHO functional class III or IV

Baseline 6-min walk test  150 m and  450 m

Baseline hemodynamics

Mean PAP > 25 mmHg

PVR > 240 dyn•sec•cm-5

PCWP < 15 mmHg

Main Inclusion Criteria

Channick R et al. Lancet 2001. Rubin L, et al. NEJM 2002.

baseline hemodynamics
Baseline Hemodynamics

Rubin, et al. NEJM 2002

Channick, et al. Lancet 2001

Bos

(n = 144)

Pbo

(n = 69)

Bos

(n = 21)

Pbo

(n = 11)

Mean PAP (mmHg)

PVR (dyn·sec/cm5)

CI (L/min/m2)

PCWP (mmHg)

Mean RAP (mmHg)

56  11

942  430

2.5  1.0

8.3  3.3

9.9  4.1

54  13

896  425

2.4  0.7

9.3  2.4

9.7  5.6

53  17

880  540

2.4  0.7

9.2  4.1

8.9  5.1

55  16

1014  678

2.4  0.8

9.2  3.9

9.8  5.9

Mean  SD

Channick R et al. Lancet 2001. Rubin L, et al. NEJM 2002.

bosentan prevented significant hemodynamic decline
Bosentan Prevented Significant Hemodynamic Decline
  • Bosentan therapy significantly improved hemodynamics over 12 weeks
  • Conventional therapy led to worsening hemodynamics over 12 weeks

+191 dyn-sec-cm-5

+0.5L/min/m2

+5.1mm Hg

-1.6mm Hg

-223dyn-sec-cm-5

  • 0.52L/min/m2

Treatment Effect: 6.7 mm Hg

- 415 dyn-sec cm-5

1.02 L/min/m2

Adapted from Channick, et al. Lancet 2001.

‡ significant change vs baseline

known drug interactions
Known Drug Interactions

TRACLEER [package insert], 2003

bosentan safety
Bosentan Safety
  • Mild anemia may be induced
  • LFT surveillance
  • Teratogencity: may be an ERA class effect
    • Ensure negative Pregnancy test before Rx
    • Monthly thereafter
  • Headaches, peripheral edema

TRACLEER [package insert], 2003

phosphodiesterase inhibitors
Phosphodiesterase Inhibitors
  • Block cGMP breakdown by PDE type 5
  • Enhance NO-dependent vasodilatation
  • Sildenafil studied in limited series

Mikhail GW, et al. Eur Heart J. 2004.

slide38

Pulmonary Hypertension, Class III-IV

Begin Conventional Rx

Right Heart Cath

Vasodilator Challenge

-

+

Ca++ Channel Rx

Class III

Class IV

Sustained Response

Endothelin Antagonist

Prostacyclins

Prostacyclin

Endothelin Antagonist

Yes

No

Maintain Ca++ Channel Rx.

Sildenafil, Atrial septostomy, lung transplantation

future directions
Future Directions
  • Combination therapy
    • BREATHE-2: Prostacyclin with bosentan
  • Other novel treatments:
    • Vasoactive intestinal peptide
    • Serotonin blockers
    • NO supplementation
  • Studies on earlier intervention