Dr. Luke Garske's Presentation

Pulmonary arterial hypertension and Scleroderma - Summary

Luke Garske's Presentation Pulmonary arterial hypertensionWhere are we now and
where might we be in the future?


What is it?
* Pathophysiology
*Endothelial dysfunction
* Vasoconstriction
* Remodelling
* Thrombosis
* Progressively worse obstruction in small pulmonary arteries
* Right Ventricle struggles to squeeze blood

Why only some patients get this?
15% of patients

Older age at time of diagnosis of scleroderma ... Limited scleroderma ... Duration of scleroderma (often symptoms >10 yrs)
Severe Raynaud’s ... Genetic variation (“endoglin” variation)

What they experience before diagnosis?
*Gradually worse on exertion  * Breathlessness  * Fatigue  * Chest pain  * Palpitations  * “Black-out”- collapse

WHO “functional class”Intern Med J 2007: 485
I: no limitation of physical activity
II: slight limitation of physical activity
III: marked limitation of physical activity
IV: symptoms may be present with any activity or even at rest (sometimes swelling of liver and legs)

How can a pulmonary hypertension unit help?
Oxygen if needed, blood thinning tablets (warfarin)
Diuretic eg frusemide
Calcium channel blocker:  Sitbon Circulation 2005 111: 3105-11 
Daily Nifedipine  or Diltiazem
38/557 with idiopathic PAH (7%): marked improvement in symptoms and narrowing of arteries, with near 100% 7 yr survival
very few patients with scleroderma benefit

Historical Content
3 randomised trials pre 1990
>20 randomised trials since 2000

TGA approved: Bosentan*   Iloprost (nebulised)* Epoprostanol (*not for scleroderma)  Sildenafil * Treprostinil * PBS

Epoprostanol for scleroderma Barst RJ NEJM 1996: 334: 296-301

Antiplatelet, vasodilator, anti-inflammatory
12 week randomized open trial iv epoprostanol
111 patients scleroderma moderate and severe PAH predominantly WHO III
Narrowing small arteries improved 40%
Distance walked in 6 mins increased 108 m (CI 55-180)  with markedly improved breathlessness
No difference in mortality (statistical reasons)
Adverse events: intravenous line infection, nausea, diarrhea but trend to improved raynaud’s

Bosentan BREATHE  Rubin NEJM 2002; 346: 896-903
Dual endothelin receptor antagonist
213 patients predominantly WHO III
Idiopathic or connective tissue
16  week randomised trial
6MWT increased 44 m (21-67)
“Clinical worsening” week 28:      20% placebo v 6% bosentan
3% increased liver function blood tests
Pilot: hemodynamic benefit similar to epoprostanol

Nebulised iloprost AIR Olschewski NEJM 2002; 347: 322-9
Selective pulmonary circulation; Lasts 90 mins
NEB 6-9/day 12 weeks
203 patients WHO III+IV, idiopathic PAH, chronic thromboembolic, collagen vascular
6 minute walk increased 36 m, 59 m in idiopathic PAH
Stabilised narrowing of arteries  pre-iloprost
30% improvement narrowing post-iloprost

Sildenafil SUPER GalieNEJM 2005; 353: 2148-57
278 patients idiopathic, connective tissue, repaired congenital shunts
Placebo/Sildenafil 20mg 40mg 80 mg three times per day for 12 wks
One year extension 80 mg dose
6 minute walk increased 47 m at 12 weeks (no dose response)   51 m at 12 months
Hospitalization 12 wks 10% placebo 3% sildenafil
Placebo increased 42 m during extension

Combination: inhaled iloprost + sildenafil Ghofrani JACC 2003, 42: 158-64
14/73 PAH patients
Clinical deterioration on inhaled iloprost
25 mg- 50mg tds sildenafil

Combination: bosentan + iloprost
Randomised trial of 67 patients with idiopathic and other causes PAH, mostly WHO III, on bosentan for average 18 months prior
Randomised to NEB iloprost OR placebo for 12 weeks
6 minute walk improved 26 m
Narrowing of small arteries improved 25%

What do they experience with a pulmonary hypertension unit?

Assess cause of pulmonary hypertension: other causes (eg emphysema, heart disease, pulmonary embolus, sleep apnea): not always easy!
Echocardiography not always accurate
If possibility that may benefit from therapy - multiple tests including Right heart catheter
Apply to government for approval scripts q6/12

Future treatments
Combinations of drugs ?from outset in moderate-severe disease
Recognising earlier disease and preventing severe disease (? Same drugs; more likely different molecular approach)
Other drugs some promise: imatinib, serotonin re-uptake inhibitors
Cell based therapy (endothelial progenitor cells might allow gene therapy to vessels)

Conclusions: Scleroderma PAH
Pulmonary hypertension common in scleroderma
Often slow reduction in exercise capacity (easily ignored!) and may cause death once very severe
Echocardiogram with:  any symptoms; other risks for disease; if RVSP >40, or unexplained dyspnea ? designated centre
Maintaining activity/exercise very likely to  help
Rags to riches over 4 years in Australia (single drug)
Bosentan: convenient; most often used; more long term experience than iloprost or sildenafil
All single agents only partially effective
Many patients progress in longer term
Additive effect from combinations * worth the expense * best combination * when
Mild disease: no evidence able to prevent progression
Search for cure continues!!


Keith McNeil
John Armstrong
Harry Gibbs
Tom Marwick and echocardiography lab
Respiratory ward and clinic nurses
Respiratory pharmacists
Respiratory laboratory scientists


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Please note: The new phone number for the Scleroderma Association of Queensland is 07 32773460. Our postal has changed too; it is PO Box 316, SALISBURY Qld. 4107. The new physical address of our office is 124A Evans Road Salisbury. If you would like to come and browse through some books in our library or have a chat or help, please visit on Wednesday between 9:30 and 12 midday.