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Effective Strategies and Clinical Updates in Pulmonary Arterial

Hypertension

Hap Farber Director, Pulmonary Hypertension Center

Boston University School of Medicine

Disclosures

1) Honoria: Actelion, Gilead, Bayer 2) Consultant: Actelion, Gilead, United Therapeutics, Bayer, Bellerephon3) Research Grants: United Therapeutics, Gilead, Actelion

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Discussion today

1) Identify the latest recommendations and clinical guidelines for the management of patients with PAH 2) Explore the advances in the diagnostic algorithm for PH3) Evaluate the latest data on oral prostanoids and how they can be incorporated into appropriate treatment plans4) Discuss effective therapeutic strategies to modify treatment for patients with worsening PAH despite existing therapy5) Analyze the differences between conventional and emerging PAH therapies based on current evidence for their efficacy, safety, and utility

Discussion today

Choice of treatment for PAH: what we do and why do we do it this way?

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Treatment Issues in PAH

1) One, two, or three drugs?

Monotherapy

Dual combination therapy

Triple combination therapy

2) When?

Upfront

Add-on (stable vs. failing)

3) Which drugs and in what order?

1. Pulmonary arterial hypertension

1.1 Idiopathic PAH1.2 Heritable PAH1.2.1 BMPR21.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK31.2.3 Unknown1.3 Drug and toxin induced1.4 Associated with:1.4.1 Connective tissue disease1.4.2 HIV infection1.4.3 Portal hypertension1.4.4 Congenital heart diseases1.4.5 Schistosomiasis

1′ Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis1′′ Persistent pulmonary hypertension of the newborn (PPHN)

Classification of Pulmonary Hypertension (Nice, 2013)

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Classification of Pulmonary Hypertension (Nice, 2013)

2. Pulmonary hypertension due to left heart disease

2.1 Left ventricular systolic dysfunction2.2 Left ventricular diastolic dysfunction2.3 Valvular disease2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

3. Pulmonary hypertension owing to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing3.5 Alveolar hypoventilation disorders3.6 Chronic exposure to high altitude3.7 Developmental lung disorders

Classification of Pulmonary Hypertension (Nice, 2013)

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with unclear multifactorial mechanisms

5.1 Hematological disorders: chronic hemolytic anemias, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary Langerhan’s cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis

5.3 Metabolic disorders: glycogen storage disease, Gaucher’s disease, thyroid disease

5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental PH

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Definition of PAH (Nice, 2013)

1) Mean PAP ≥25mm Hg at rest; PCWP or LVEDP ≤15mm Hg; PVR 3 WU (240 dynes).

2) ?Exercise PAH

3) Volume loading?

4) What about mPAP 21-24?

Echocardiographic Estimation of PH in Clinical Practice

1) ACC/ AHA expert consensus recommends further evaluation of patients with dyspnea and an estimated RVsp >40 mm Hg

2) ECHO-estimated measurements of PH are NOT diagnostic (for anything) and should NEVER be the basis for the prescription of PAH specific agents

3) Estimates >60 and/or right ventricular enlargement/dysfunction are cause for significant concern and expedited evaluation by an expert team

Rudski LG, et al. J Am Soc Echocardiogr. 2010;23:685-713.McLaughlin VV, et al. Circulation. 2009:119:2250-2294.

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PAH: Echocardiography

ECHO compared to right heart catheterization:

False negative rate: <1%False positive rate: 30-40%

Treatment Issues in PAH

1) One, two, or three drugs?

Monotherapy

Dual combination therapy

Triple combination therapy

2) When?

Upfront

Add-on (stable vs. failing)

3) Which drugs and in what order?

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Calcium Channel Blockers1) Small subset (<<10%) of patients with IPAH have favorable long-term

response to high-dose CCB2) Potential patients identified by reduction in mPAP ≥10 with absolute

mPAP <40 and increased or unchanged CO3) Vasoreactivity testing only performed with short-acting pulmonary

vasodilators (iNO currently agent of choice)

4) Slow up-titration with CCB required with high level maintenance doses(Diltiazem, 240–720mg; nifedipine, 120–240mg)

5) Patients without sustained hemodynamic response to NYHA FC I or II require other PAH therapy

Humbert M, et al. Circulation 2014; 130:2189-2208Sitbon O, et al. Circulation 2005; 111:3105–11

REVEAL: Monotherapy and Combination Therapy in Patients with PAH

Badesch DB, et al. Chest 2010; 137;376-87.

N = 2438. Treatment reported at time of enrollment in REVEAL

18.50% 17.10%11.10%

0.90%

21.10% 24.40%16.10%

5.80%7.40% 7.50% 4.80% 3.00%

0%

20%

40%

60%

80%

100%

ERA PDE51 IV/SCProstacyclin

InhaledProstacyclin

Per

cent

(%

)

Monotherapy Dual Combination Triple Combination

48% of patients were receiving monotherapy at the time of study enrollment.

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Use of Parenteral Prostanoids at Time of Death in the REVEAL Registry

Farber H, et al. J Heart Lung Transpl 2013; 32:1114-22.

N=909. All-cause mortality.

16%

Total IV/SC prostanoid therapy use = 43.0%

12%

8%

4%

0%

7.6%8.4%

14.4%11.2%

1.1%

5.6%3.0%

12.4%

15.1%

4.6%

11.2%

5.3%

REVEAL: Under-use of Parental Prostanoids in FC IV PAH

5.8%

43.2%51.0%

IV Prostacyclin Use 1 Day Prior to

Designation as FC IVPGI MonotherapyPGI Combination TherapyNo PGI

52.0%48.0%

IV/SC Prostacyclin Use 90 Days After

Designation as FC IV

PGI Therapy No PGI

Farber H, et al. J Heart Lung Transpl 2013; 32:1114-22.

N=294 patients worsening to FC IV.

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PAH Long-term Monotherapy Trials: Caveats

1) Most long-term data come from open-label extensions of placebo-controlled trials (no comparator arm)

2) These trials allowed add-on therapy after initial blinded treatment phase; thus, some or all of the efficacy seen in open-label phase could be due to add-on therapy, not “primary” study medication

3) Some trials defined add-on therapy as a clinical endpoint; others did not

4) Results cannot be compared across studies because each trial was unique, with fundamental protocol differences (study size, FC, outcomes definitions, use of additional medications without reaching trial endpoint, etc.)

PAH Long-term Combination Therapy Trials: Caveats

1) Only AMBITION prospectively studied the question of monotherapy versus de novo combination therapy

2) All other currently reported trials featured “add-on” protocols

3) Relative contribution of individual agents to treatment success difficult to assess

4) Combination therapy trials often have only a short-term component, with no long-term follow-up

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AMBITION: Ambrisentan-Tadalafil Combination Therapy. Primary Study Endpoint: Time To Clinical Worsening

Primary Endpoint: Time to First Clinical Failure Event

0

25

50

75

100

Eve

nt-

Fre

e (%

)

Time (weeks)0 24 48 72 96 120 144 168 192

1 year 88.9%

1 year 75.5%

Combination therapyPooled monotherapy

2 year 79.7%

2 year 63.2%3 year 56.1%

3 year 67.6%

Combination: 253 229 186 145 106 71 36 4

Pooled monotherapy: 247 209 155 108 77 49 25 5

Number at risk:

Nazzareno G, et al. ERS 2014

Galiè N et al. N Engl J Med 2015;373:834-844.

Kaplan–Meier Curves for the Probability of a First Adjudicated Primary End-Point Event.

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AMBITION: Subgroup Analysis

Rubin L, et al. Chest 2014; 146:339A.

0

3

7

10

13Favors Combination Favors Monotherapy

0.125 0.25 0.5 1 2 4Hazard Ratio (95% CI)

Combination Therapy Pooled Monotherapy

Subgroup n Events n Events Hazard Ratio (95% CI)

IPAH/HPAH 134 25 (19%) 145 46 (32%) 0.535 (0.329-0.871)

APAH 119 21 (18%) 102 31 (30%) 0.453 (0.259-0.790)

WHO FC II 76 4 (5%) 79 17 (22%) 0.211 (0.071-0.629)

WHO FC III 177 42 (24%) 168 60 (36%) 0.576 (0.388-0.855)

Age <57 years 124 13 (10%) 120 31 (26%) 0.367 (0.192-0.701)

Age ≥57 years 129 33 (26%) 127 46 (36%) 0.581 (0.371-0.910)

BL 6MWD <363.7 m 129 35 (27%) 121 51 (42%) 0.537 (0.349-0.827)

BL 6MWD ≥363.7 m 124 11 (9%) 126 26 (21%) 0.380 (0.187-0.769)

North America 116 22 (19%) 112 34 (30%) 0.505 (0.295-0.866)

Rest of world 137 24 (18%) 135 43 (32%) 0.506 (0.307-0.834)

Female 188 32 (17%) 200 61 (31%) 0.473 (0.308-0.726)

Male 65 14 (22%) 47 16 (34%) 0.581 (0.283-1.194)

AMBITION: Comparison of Initial Combination Therapy in WHO FC II and WHO FC III Patients

5%

22%24%

36%

0%

10%

20%

30%

40%

FC II Combination FC II Pooled Monotherapy FC III Combination FC III Pooled Monotherapy

Primary Endpoint – Clinical Failure Events

Frost A, et al. Am J Respir Crit Care Med 2015; 191:A4781.

*

†

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Pulido T et al. N Engl J Med 2013;369:809-818.

SERAPHIN: Effect of Macitentan on Composite Primary End Point of a First Event Related to PAH or Death from Any Cause

Pulido T et al. N Engl J Med 2013;369:809-818.

SERAPHIN: Effect of Macitentan on Composite Secondary End Point of Death Due to PAH or Hospitalization for PAH as First Event

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Sitbon O et al. N Engl J Med 2015;373:2522-2533.

GRIPHON: Primary Composite End Point.

0

25

50

75

100

McLaughlin VV, et al. Chest 2014; 146:860A.

COMPASS-2: No Benefit of Bosentan Added to Stable Sildenafil

Primary Endpoint: Time to First Morbidity or Mortality Event

N=334. Randomized placebo-controlled event-driven trial of bosentan added to stable sildenafil.

Pat

ien

ts W

ith

ou

t an

Eve

nt

(%)

Placebo 175 154 140 123 118 107 90 76 68 61 55 48 43 36 32 26

Bosentan 159 144 128 114 103 97 88 82 69 57 50 42 32 24 21 15

Time From Randomization (months)

Bosentan: Risk reduction = 17%;HR = 0.831; log-rank P = 0.2508

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60

Patients at risk:

PlaceboBosentan

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Upfront triple combination therapy in PAH: a pilot study

Sitbon O, et al. Eur Resp J 2014; 43:1691-7.

28Galiè N et al. Eur Heart J 2015:doi:10.1093/eurheart/ehv317.

ESC/ERS 2015 treatment algorithm for PAH

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ESC/ERS 2015 recommendations for monotherapy in PAH

Galiè N et al. Eur Heart J 2015:doi:10.1093/eurheart/ehv317.

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ESC/ERS 2015 recommendations for upfront and sequential combination therapy in PAH

Galiè N et al. Eur Heart J 2015:doi:10.1093/eurheart/ehv317.

Upfront Sequential

Consideration: Dose adjustments and potential side effects may be simpler to manage with sequential administration of combination partners

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Treatment Issues in PAH

1) One, two, or three drugs?

Monotherapy

Dual combination therapy

Triple combination therapy

2) When?

Upfront

Add-on (stable vs. failing)

3) Which drugs and in what order?

Anticoagulation

1) Anticoagulation recommended in PAH with vitamin K antagonist1 (INR of 1.5-2.5, unless contraindicated). No evidence for NAC.

2) Small observational studies support survival benefit of anticoagulation in IPAH2-4

3) Survival benefit recently suggested by COMPERA trial in EU5

4) Improvement in survival not observed in other forms of APAH (such as SSc)

5) Anticoagulation warranted to minimize catheter-related thrombosis in those receiving continuous intravenous prostanoid therapy

1. Humbert M, et al. Circulation 2014;130: 2189-22082. Rich S, et al. NEMJ 1992; 327:76–813. Frank H, et al. Chest 1997; 112:714–21 4. Fuster V, et al. Circulation 1984; 70:580–75. Olsson KM, et al. Circulation 2014; 129:57–65

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Anticoagulation: Kaplan-Meier estimates of survival at 36 months for IPAH patients.

IPreston et al. Circulation 2015; 132:2403-11

Anticoagulation: Kaplan-Meier estimates of survival at 36 months for SSc-PAH patients.

Preston et al. Circulation 2015; 132:2403-11

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Summary: Long-term Management of Patients With PAH

1) Availability of oral, inhaled, and parenteral PAH therapies provides multiple treatment strategies for patients with PAH; trend toward multi-drug therapy

2) Long-term data on choice of initial medical therapy, de novo combination therapy, or therapy sequencing are still incomplete

3) Considerations for initial therapy selection and for combining therapies should take into account consensus recommendation/guidelines, long-term efficacy and safety data, second-line choices, and patient characteristics, with an individualized approach for each patient

4) In patients with severe disease or in those failing medical therapy, early referral to PAH centers for advanced therapy important

5) Anticoagulation: not sure for IPAH; definite no for scleroderma/CTD