Transcript Efficacy Slide Drafts - Dartmouth

Pulmonary Arterial Hypertension:
A Few Steps on the Long March to
Effective Treatment
Edward Catherwood, MD, MS
Cardiology Update, 2004
Schematic Progression of PAH
Pre-symptomatic/
Compensated
Symptomatic/
Decompensating
Declining/
Decompensated
CO
Symptom Threshold
PAP
PVR
CO=
Right Heart
Dysfunction
PAP
PVR
Time
Humbert M, et al. NEJM. 2004.
Humbert M, et al. JACC. 2004
WHO World Symposium, Venice 2003
PAH 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
100
PAH Survival
Survival (%)
80
60
68%
40
48%
34%
20
0
0
0.5
1
1.5
2
2.5
3
Years of Followup
Adapted from: D’Alonzo et al. Ann Internal Med. 1991
3.5
4
4.5
5
Survival Estimates in Scleroderma By
Organ Involvement
100
Percent Survival
90
80
70
None
60
50
Lung Involvement (without PH)
40
30
20
PAH
10
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Years from Diagnosis of Pulmonary Hypertension
Koh et al. Brit J Rheumatol 1996
13
WHO Functional Assessment
of PAH
Class I
Symptoms do not limit physical activity: Ordinary
physical activity does not cause undue discomfort.
Class II
Slight limitation of physical activity: Patient is
comfortable at rest, yet experiences symptoms
with ordinary physical activity.
Class III
Marked limitation of physical activity: Patient
is comfortable at rest, yet experiences symptoms
with minimal physical activity.
Class IV
Inability 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 may include:
Dyspnea
Syncope
Dizziness
Fatigue
Edema
Chest Pain
Non-specific nature of complaint:
Misdiagnosis
Delayed diagnosis
Gaine et al. The Lancet, 1998.
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
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
Increased sPAP or TR
jet
Right atrial &
ventricular
hypertrophy
Flattening of septum
Small LV dimension
Dilated PA
IVS
RV
LV
RA
LA
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
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
CO/CI
RAP
mPAP, SVO2
PAOP
PVR
Prognostic (RAP, CI, mPAP)
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
Survival (%)
100
Long distance group
80
p < 0.001
60
(Logrank test)
40
Short distance group
20
0
0
10
20
30
Months
Miyamoto et al Am J Respir Crit Care Med 2000.
40
50
60
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
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
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
ECG
CXR
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%
Right Heart Cath
Baseline
Adenosine
PA (mean)
72/49 (57)
68/45 (53)
PAOP
5-7
5-7
SVO2 (PA Sat)
59
76
CO (TD)
2.6
4.9
Arterial Sat
99
99
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
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
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
162 patients with iPAH
Eposprostenol
compared to expected
survival
62% vs 35% at 3 yrs.
Keys to survival:
Functional class
CI, mean PA
pressure
McLaughlin VV, et al. Circulation. 2002.
Epo Rx
Historical
Historical
Controls
Controls
McLaughlin VV, et al. Circulation. 2002.
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
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
Rubin, et al. NEJM 2002
PAH due to
iPAH
scleroderma
other connective tissue
diseases
iPAH
scleroderma
other connective tissue
diseases
WHO functional class III
WHO functional class III
or IV
Baseline 6-min walk test
 150 m and  450 m
Baseline hemodynamics
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
Mean PAP > 25 mmHg
PVR > 240 dyn•sec•cm-5
PCWP < 15 mmHg
Channick R et al. Lancet 2001. Rubin L, et al. NEJM 2002.
Baseline Hemodynamics
Channick, et al.
Lancet 2001
Mean PAP (mmHg)
Rubin, et al.
NEJM 2002
Pbo
(n = 11)
Bos
(n = 21)
Pbo
(n = 69)
Bos
(n = 144)
56  11
54  13
53  17
55  16
PVR (dyn·sec/cm5) 942  430 896  425
880  540 1014  678
CI (L/min/m2)
2.5  1.0
2.4  0.7
2.4  0.7
2.4  0.8
PCWP (mmHg)
8.3  3.3
9.3  2.4
9.2  4.1
9.2  3.9
Mean RAP (mmHg)
9.9  4.1
9.7  5.6
8.9  5.1
9.8  5.9
Mean  SD
Channick R et al. Lancet 2001. Rubin L, et al. NEJM 2002.
Bosentan Prevented Significant
Hemodynamic Decline
• Bosentan therapy significantly improved hemodynamics over 12 weeks
• Conventional therapy led to worsening hemodynamics over 12 weeks
Conventional Therapy
40%
30%
20%
10%
+5.1
mm Hg
Bosentan
+191
dyn-sec-cm-5
+0.5
L/min/m2
‡
‡
0%
-10%
-1.6
mm Hg
-20%
-30%
‡
‡
-223
dyn-sec-cm-5
-0.52
L/min/m2
-40%
mPAP
6.7 mm Hg
PVR
Treatment Effect:
- 415 dyn-sec cm-5
Adapted from Channick, et al. Lancet 2001.
CI
1.02 L/min/m2
‡ significant change vs baseline
Known Drug Interactions
Concomitant
Agent
Interaction
Cyclosporine A
Bosentan Steady State Concentration (3-4
times)
Cyclosporine A Concentration (50%)
Tacrolimus
Glyburide
Bosentan levels in animals (markedly)
Unknown in humans
Risk of elevated aminotransferases
Plasma concentrations of Bosentan and
Glyburide by 30-40%
TRACLEER [package insert], 2003
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
Block cGMP
breakdown by
PDE type 5
Enhance NOdependent
vasodilatation
Sildenafil
studied in
limited series
Mikhail GW, et al. Eur Heart J. 2004.
Pulmonary Hypertension, Class III-IV
Begin Conventional Rx
Right Heart Cath
Vasodilator Challenge
-
+
Ca++ Channel Rx
Sustained Response
Yes
No
Maintain Ca++
Channel Rx.
Class III
Class IV
Endothelin Antagonist
Prostacyclin
Prostacyclins
Endothelin Antagonist
Sildenafil, Atrial septostomy, lung
transplantation
Future Directions
Combination therapy
BREATHE-2: Prostacyclin with bosentan
Other novel treatments:
Vasoactive intestinal peptide
Serotonin blockers
NO supplementation
Studies on earlier intervention