Pulmonary Hypertension Versus Pulmonary Arterial

6/27/2019

VERSUS

PULMONARY ARTERIAL HYPERTENSION

WHAT’S THE DIFFERENCE?

Angela Hatch, PA-C

DISCLOSURES

• Consultant for Actelion Pharmaceuticals, providing consultation on patient perspective and barriers to disease recognition.

1 6/27/2019

PULMONARY HYPERTENSION

A disease of hemodynamics.

• Increased blood pressure in the pulmonary circulation • PH is defined as mean pulmonary artery pressure > 20 mmHg • Normal mean arterial pressure at rest is 14.0+3.3 mmHg • New definition as of March 2018 (published January 2019).

HISTORY OF THE WORLD SYMPOSIA ON PULMONARY HYPERTENSION (WSPH)

1st WSPH (1973) • Organized by WHO because of an epidemic of PAH cases due to aminorex (an anorexigen drug)

• Achievements • Classification system of PH was created: Primary and Secondary Pulmonary Hypertension • Hemodynamic definition of the disease as a mean arterial pressure of > 25 mmHg was set

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WSPH (CONTINUED)

2nd WSPH (1998) • A decision was made to start an ongoing series of symposia, fueled by the development of 2 effective treatments: • Flolan (epoprostenol) • High dose CCBs in patients who respond to acute vasoreactivity testing

• 5 group classification system was created “Primary and Secondary Pulmonary Hypertension” were abandoned

WSPH (CONTINUED)

3rd WSPH (2003) • Specific treatment algorithms were proposed because additional medications were available: • ERAs • Prostacyclins and prostanoids • PDE5 inhibitors • Soluble guanylate cyclase stimulators • Gene mutations had begun to be identified for familial PAH (BMPR2 mutation and others). • 5 classifications remained.

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WSPH (CONTINUED)

4th WSPH (2008) • Randomized control trial parameters were discussed and defined. • New management strategies again discussed, now including recommendations for treatment of mildly symptomatic patients.

5th WSPH (2013) • Findings and recommendations of 12 Worldwide Task Forces were presented

WSPH (CONTINUED)

6th WSPH (2018) – Findings published January 2019 • New definition of pulmonary hypertension was established lowering threshold for diagnosis from a mPAP > 25 mmHg to > 20 mmHg

• Following patients should undergo more aggressive assessment and screening: • Congential heart disease (CHD) • Connective tissue disease (CTD) • HIV • Portopulmonary hypertension (POPH)

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WSPH (CONTINUED)

6th WSPH (continued) • Genetic counseling was recommended for all idiopathic, anorexiant and familial PAH patients and first generation asymptomatic family members.

• Post-operative congenital heart disease patients throughout long-term cardiology follow up.

• A definition of exercise-induced pulmonary hypertension was still not established.

13 TASK FORCES

1) Pathology and Pathobiology 8) New trial designs and potential 2) Genetics and genomics therapies for PAH 3) Pathophysiology 9) Chronic Thromboembolic Pulmonary Hypertension 4) Definitions and Diagnosis 10 & 11) PH due to left heart and lung 5) Epidemiology and registries diseases 6) Standard of care 12)Pediatric PH 7) Treatment Goals 13)Patients’ Perspectives • Defined success of therapy based on symptoms, exercise capacity, and RV function

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MODIFIED CLASSIFICATION OF PH

1. Pulmonary arterial hypertension (PAH) 3. PH due to lung disease and/or hypoxia 1.1 Idiopathic PAH (IPAH) 3.1 COPD 1.2 Heritable PAH (FPAH) 3.2 Interstitial lung disease 1.2.1 BMPR2 3.3 Other pulmonary diseases with mixed restrictive and 1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3 obstructive pattern 1.2.3 Unknown 3.4 Sleep-disordered breathing 1.3 Drug- and toxin-induced 3.5 Alveolar hypoventilation disorders 1.4 Associated with 3.6 Chronic exposure to high altitude 1.4.1 Connective tissue diseases 3.7 Developmental lung diseases 1.4.2 HIV infection 4. CTEPH 1.4.3 Portal hypertension 5. PH with unclear multifactorial mechanisms 1.4.4 Congenital heart disease 5.1 Hematological disorders: chronic hemolytic anemia, 1.4.5 Schistosomiasis myeloproliferative disorders, splenectomy Group 1’. Pulmonary veno-occlusive disease and/or pulmonary 5.2 Systemic disorders: sarcoidosis, pulmonary capillary hemangiomatosis Langerhans cell histiocytosis, lymphangioleiomyomatosis, Group 1”. Persistent pulmonary hypertension of the newborn neurofibromatosis, vasculitis PAH long-term responders to calcium channel blockers (2018) 5.3 Metabolic disorders: glycogen storage disease, 2. PH due to left heart disease Gaucher disease, thyroid disorders 2.1 LV systolic dysfunction 5.4 Others: tumoral obstruction, fibrosing mediastinitis, 2.2 LV diastolic dysfunction chronic renal failure, segmental PH 2.3 Valvular disease 2.4 Congenital / acquired left heart inflow / outflow obstruction

SO, WHERE’S THE PH REALLY AT?

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WHY IS PAH SO MUCH WORSE THAN PH?

• It’s progressive and there is no reversing damage once it has occurred. The goal of treatment is directed at slowing it down.

• There is not a cure and it’s considered terminal – the patient will either die from complete RV failure or require a lung transplant.

• Average time from diagnosis to death based on registry findings: • 2.8 years without therapy. • 7 years on therapy. • Average time from lung transplant to death is 5.5 years. • Double lung transplant is required (possible heart and lung).

PAH VASCULAR DYSFUNCTION AND REMODELING

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PAH VASCULAR DYSFUNCTION AND REMODELING

Plexiform Lesions

https://www.youtube.com/watch?v=VCvBh41OyZs

The majority of cases are mixed class disease.

(i.e., LV dysfunction and OSA)

Over time, PH can cause PAH!

8 6/27/2019

PATHOGENESIS OF PAH: LESSONS FROM CANCER

HOW DOES PAH PRESENT CLINICALLY? • First symptom is dyspnea on exertion • Breathlessness without overt signs of heart and lung disease is concerning. • Are they always the one who is slower than everyone else? • Fatigue, often chronic and tends to worsen over time • Angina • Edema • Weakness • Lightheadedness and syncope

• Tips: • PAH is nearly 4 times as prevalent in females than males, even in FPAH. • Look for hypoxia with exertion • 6MWT is part of the formal diagnostic protocol. • Shape-HF submaximal cardiopulmonary exercise testing provides more information.

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DIAGNOSIS OF PH

• It starts with you….. • Incidental findings on EKG, Chest Xray, Echocardiogram

• EKG: RVH, RAE, or right axis deviation. Normal EKG doesn’t exclude PH. • CXR, CT: Cardiomegaly with RV enlargement, enlarged pulmonary arteries, pulmonary venous congestion. • Echo: Elevated RVSP and RA pressures, RA and/or RV enlargement, tricuspid regurgitation.

10 6/27/2019

DEGREE OF PH BASED ON ECHO

Jet of TR (RVSP = 4V2) RA pressure is calculated based on IVC diameter and inspiratory collapse. PASP = RVSP + RAP

Tip: If you see a patient’s echo has normal LV systolic and diastolic function, but elevated RVSP you should start to be concerned about possible PAH or CTEPH. 21

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PAH IS A DISEASE OF RESISTANCE Progression of PVR on Catheterization

A dilated RV with low pressures on echo is cause for concern.

PH TREATMENT

• Early identification and treatment of pulmonary hypertension is advised because advanced disease is less responsive to therapy. • “Primary therapies” are directed at the underlying etiologies. • “Advanced therapies” are directed at the PH itself, rather than the underlying disease. • Only used in Group 1 PAH and Group 4 (CTEPH) • All patients with SpO2 of less than 90% should have oxygen therapy  This is critical! • Other medications effective in all groups include the following when indicated: • Diuretics, digoxin, and exercise • Anticoagulation guidelines are unclear. It’s theorized that AC should be used in the following patient groups: • IPAH • FPAH • PAH due to anorexigens • CTEPH

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PH TREATMENT • Group 1 PAH • There are no effective primary therapies for Group 1 PAH • Oxygen therapy is indicated. Keep SpO2 >90% • CCB (less than 10% of patient’s are responders on RHC) and advanced therapies • Group 2 PH (left heart disease)  treat the underlying disease • Group 3 (lung diseases) • Oxygen therapy is the only modality with a proven mortality benefit in this group • Again, treat the underlying disease • Group 4 PH (CTEPH) • Very specific recommendations from Task Force on CTEPH • Anticoagulation • Pulmonary endarterectomy (PEA) is the treatment of choice – don’t wait on this • Medical therapy for patients who aren’t surgical candidates or with residual PH s/p surgery • Group 5 PH • The occurrence of PH in this category is rare and treatment should be directed at the underlying disease

ADVANCED THERAPIES • Medication categories: • Calcium channel blockers (if patient shows acceptable vasoreactivity on testing) • Amlodipine, nifedipine, diltiazem • Phosphodiesterase 5 inhibitors • Sildenafil, tadalfil, and vardenafil • Endothelin receptor antagonists • Ambrisentan, macitentan, and bosentan • Prostacyclins/prostanoids • Soluble guanylate cyclase stimulants • Adempas (riociguat) • Increase the sensitivity of sGC to NO and directly stimulate the receptor to mimic the action of NO

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PROSTANOID DETAILS • Prostanoids – The big guns in PH. • Dilate the blood vessels in the lungs • Slow scarring and cell growth in pulmonary vasculature

• Flolan (epoprostenol), Ventavis (iloprost), Remodulin (treprostinil) • Various forms of administration: SubQ and IV most common. • IV therapy is continuous infusion through a central line. • Inhaled variants require 4 times a day dosing. • Oral treprostinil (Orenitram) was approved in 2013 after having been declined by the FDA for approval on two previous occasion. • Uptravi (selexipag) • Granted orphan drug status for PAH in December 2015 • Decreases PVR and increases stroke volume

• Combination therapy versus step up therapy becomes an issue with insurance providers due to cost.

• Combo therapy is preferred, but often not approved initially.

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ONGOING TESTS AND COSTS

• Monthly pregnancy tests once advanced therapies are started • Frequent labs (monitor liver function, kidney function, anemia, etc.) • PFTs and 6MWT vs. SHAPE every 6 months • At least yearly echocardiograms and chest x-rays • Possible yearly right heart catheterization once you hit the transplant team • Visits to pulmonologist, cardiologist, rheumatologist, and anyone else that matters.

• Which leads us to...

Should a patient get a lung transplant?

15 6/27/2019

LUNGS VS. HEART & LUNGS

• Another reason to not miss this… • You can get by with just lungs if PAH is caught in time. • If not, you could require heart and lungs. • This happens to patients on the wait lists that don’t get a lung match in time. • Heart is also indicated in patients with structural heart disease.

CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (CTEPH)

The other bad PH  -- It’s also progressive.

• Cannot be excluded with CT angio! • Normal V/Q scan is the only way to rule out CTEPH • Only cure is pulmonary endarterectomy (PEA) • Adempas (riociguat) is only FDA approved medication at this time. • Indicated if not a surgical candidate or if residual PH is present. • Interesting finding on SHAPE testing –> These patient’s tend to have the

greatest decrease in ETCO2.

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PULMONARY ENDARTERECTOMY

TIPS ON FINDING PH, PAH, AND CTEPH 1) Detailed HPI: • Any symptoms consistent with PH (DOE, SOB, angina, etc.) • Onset and speed of progression of symptoms • Instigating activities • Listen for murmurs (TR, AS, MS, MR) 2) Detailed PMH, including a full medication history. • Take note of any pertinent disorders: • Rheumatoid arthritis, lupus, interstitial lung disease, sarcoidosis, scleroderma, etc. • Pay attention to past surgeries  congenital shunts? • Any history of blood clots? • Be aware of confounding factors such as liver disease, smoking, obesity, asthma, etc. • Don’t exclude the possibility of PAH or CTEPH because one of these is present. • Most patient’s are “muddy” PHers – Unicorns are rare. 3) Family history – Remember, there are genetic variants. 4) Pay attention to the “hits”

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Screen for these in ANY patient complaining of dyspnea, cardiovascular symptoms, or with a heart murmur.

Offending anorexigens were removed from the US market in 1999 for causing PAH and valvular heart disease.

LET A TEAM HELP YOU GET IT RIGHT • Patient’s with PAH have symptoms for an average of 2 years before being properly diagnosed. • Inappropriate, incomplete, and delayed diagnosis of PAH is common and reported in up to 85% of at-risk patients. • You can also harm the patient by misdiagnosing and treating the wrong class of PH. • Don’t start sildenafil if you don’t specialize in treating this disease. • Group 2 patient may develop pulmonary edema and respiratory failure if given a pulmonary vasodilator. • Group 3 patient can develop increased V/Q mismatch and worsening hypoxia on pulmonary vasodilators. • CTEPH patient won’t be accepted for PEA if their pulmonary pressures are too high because of increased risk of mortality from surgery. They will lose their window for a cure.

If there’s any chance  Refer the patient to pulmonology and cardiology.

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CASE STUDY - HPI • 53 YOM admitted with 2 months hx of recurrent syncope with exertion, acutely worsened over the prior 4 days. Able to walk approximately 30- 40 feet before experiencing syncope. 5-6 episodes of syncope the 4 days prior with the last episode resulting in traumatic head injury.

• Was at his baseline until 1 year prior. Additional symptoms worsening since that time: • Dyspnea on exertion • Decreased energy and endurance • Increased fatigue • Dizziness and lightheadedness • “I used to work as a firefighter and now it seems like I’m just sitting in a chair.”

CASE STUDY – HISTORY (CONTINUED) • Past medical history • Hepatitis C – underwent full treatment course. • Cirrhosis 2/2 hepatitis C; known esophageal varices. • Pancreatitis. • Thrombocytopenia 2/2 cirrhosis. • Polycythemia. • COPD • Chronic neck and back pain. Allergies: NKDA • Allergies • NKDA • Social history • 40-pack year smoker who was still an active smoker. • Rarely drinks alcohol • Small amount of cocaine and marijuana use 30 years prior. No IV drug use. • Family history • No family history of CAD, CVA, DVTs or PEs.

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CASE STUDY – PHYSICAL EXAM

• Prominent S2, mild RV heave, harsh systolic murmur at LLSB. • JVD to mandible of the jaw. • 3+ pitting edema in BLE with edema up to 4 cm below umbilicus. • No telengiectasias. • No joint deformities.

CASE STUDY – RESULTS

• Labs: H&H 17.7/50.4, platelets 71, ALT 28, AST 44, ANA negative • CT angio chest: Negative for PE but hepatic cirrhosis, portal hypertension, and emphysematous changes • ONOX on RA: Nadir SpO2 of 85% with DEI of 24.2. • PFTs: Mild asthma and COPD. • V/Q scan: Low probability for pulmonary embolism. • 6MWT: Could not complete on admission. Walked 30-40 feet before becoming presyncopal and tachycardic. SpO2 maintained above 90%.

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CASE STUDY – CARDIAC STUDIES • Echocardiogram • EF 67%, mild LVH, moderately enlarged RV, RV septal wall flattening, TAPSE 20 mm, moderate RA enlargement, severe TR, estimated PA systolic pressure of 76 mmHg.

• Cardiac catheterization • Mild, non-hemodynamically significant coronary artery disease in the LAD. • Pulmary artery pressure 75/34 with a mean of 50. • Mean PCWP of 6. • Estimated Fick cardiac output of 3.43 L/min and cardiac output by thermodilution of 2.63 L/min. • PVR of 16.7 Wood units by Fick and 12.8 WU by thermodilution. • Met all 3 critera for diagnosis of pulmonary arterial hypertension (severe)

CASE STUDY – ADVANCED THERAPIES Entire screening and testing regimen was completed as an inpatient. • Treatment plan: • Started on epoprostenol IV while we obtained approval for treprostinil SQ. • You can only titrate as fast as they can tolerate because it’s painful and nauseating . • Once at full dose treprostinil IV as an outpatient  added sildenafil  then added ambrisentan • Triple-combination therapy = prostaglandin + PDE5 + ERA • Transition plan: • Subcutaneous therapy is very uncomfortable and the majority of patients eventually end up off it. • Patient was doing so well on triple therapy we admitted him for transition from treprostinil to oral selexipag.

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CASE STUDY - FOLLOW UP TESTS

• 6MWT • July 2018 – Aborted after approximately 10 meters. • 8 days later (on low dose epoprostenol IV) – 112 meters. • 10 days later (Dual titration from epoprostenol to treprostinil) – 253 meters. • December 2018 – 510 meters. • Echocardiogram • July 2018 – PASP 76 mmHg, TAPSE 20 mm • November 2018 – RVSP 52 mmHg (IVC not visualized) • February 2019 – PASP 58-62 mmHg • May 2019 – PASP 65 mmHg, TAPSE 25 mm

CASE STUDY - FOLLOW UP TESTS

• Right Heart Catheterization (6 months after initiation of advanced therapy while on maximum triple-combination therapy)

• Mean PA pressure decreased from 50 to 33 • PVR decreased from 16.7 to 3.2 • Cardiac output increased from 3.2 L/min to 7.2 L/min

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REFERENCES • Barst, Robyn. Pulmonary Hypertension Association (2017). PAH Evidenced-based Treatment Algorithm. [image] Available at: http://www.phaonlineuniv.org/Journal/Article.cfm?ItemNumber=757 [Accessed 20 Aug. 2017]. • Batton, Kyle A., et al. “Sex Differences in Pulmonary Arterial Hypertension: Role of Infection and Autoimmunity in the Pathogenesis of Disease.” Biology of Sex Differences, BioMed Central, 18 Apr. 2018, bsd.biomedcentral.com/articles/10.1186/s13293-018-0176-8. • Borlaug, Barry A., and Nowell M. Fine. “Use of the Echocardiogram to Define the Presence, Extent, and Etiology of Cardiac Dysfunction.”The Cardiology Advisor, 12 Dec. 2017, www.thecardiologyadvisor.com/cardiology/use-of-the- echocardiogram-to-define-the-presence-extent-and-etiology-of-cardiac-dysfunction/article/584293/. • “Chapter 30. Pulmonary Hypertension.” AccessMedicine, McGraw Hill Education, accessmedicine.mhmedical.com/content.aspx?bookid=715§ionid=48214564. • “CURRENT Diagnosis & Treatment Cardiology, 4e.” AccessMedicine, accessmedicine.mhmedical.com/book.aspx?bookid=715. • D'Alonzo GE, e. (1991). Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. - PubMed - NCBI. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/pubmed/1863023 [Accessed 20 May 2018]. • Dickinson, Michael G., et al. “Animal Models for PAH and Increased Pulmonary Blood Flow.”Pediatric and Congenital Cardiology, Cardiac Surgery and Intensive Care, 2013, pp. 2103–2121., doi:10.1007/978-1-4471-4619-3_203. • Farber, H., Miller, D., Poms, A., Badesch, D., Frost, A., Rouzic, E., Romero, A., Benton, W., Elliott, C., McGoon, M. and Benza, R. (2015). Five-Year Outcomes of Patients Enrolled in the REVEAL Registry. Chest, 148(4), pp.1043-1054.

REFERENCES (CONTINUED)

• Feldman, MD, Dr. Jeremy. (2018). Prostanoid Treatment of Pulmonary Arterial Hypertension. [online] Pulmonaryhypertensionrn.com. Available at: http://pulmonaryhypertensionrn.com/prostanoids-for-treatment-of- pulmonary-arterial-hypertension-pah/ [Accessed 20 Jun 2018]. • “Formation of Plexiform Lesions in Experimental Severe Pulmonary Arterial Hypertension.” Circulation, www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.109.927681. • Galiè, Nazzareno, and Gerald Simonneau. “The Fifth World Symposium on Pulmonary Hypertension.” Journal of the American College of Cardiology, vol. 62, no. 25, 2013, doi:10.1016/j.jacc.2013.10.030. • Galiè, Nazzareno, et al. “An Overview of the 6th World Symposium on Pulmonary Hypertension.” European Respiratory Society, European Respiratory Society, 1 Jan. 2018, erj.ersjournals.com/content/early/2018/12/05/13993003.02148-2018. • Gordeuk, V. R., et al. “Pathophysiology and Treatment of Pulmonary Hypertension in Sickle Cell Disease.”Blood, vol. 127, no. 7, 2016, pp. 820–828., doi:10.1182/blood-2015-08-618561. • Guignabert, Christophe, et al. “Pathogenesis of Pulmonary Arterial Hypertension: Lessons from Cancer.” European Respiratory Society, European Respiratory Society, 1 Dec. 2013, err.ersjournals.com/content/22/130/543. • Hopkins, MD, Dr. William and Rubin, MD, Dr. Lewis J. (2018). UpToDate. [online] Uptodate.com. Available at: https://www.uptodate.com/contents/treatment-of-pulmonary-hypertension-in-adults [Accessed 20 May. 2018]. • Malotte, Kasey L., et al. “Treatment and Palliation of Symptoms in Patients With Advanced Pulmonary Arterial Hypertension.” Advances in Pulmonary Hypertension, vol. 17, no. 1, 2018, pp. 20–24., doi:10.21693/1933-088x- 17.1.20.

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REFERENCES (CONTINUED) • Maron, Bradley A., and Nazzareno Galiè. “Diagnosis, Treatment, and Clinical Management of Pulmonary Arterial Hypertension in the Contemporary Era.”JAMA Cardiology, vol. 1, no. 9, 2016, p. 1056., doi:10.1001/jamacardio.2016.4471. • Mclaughlin, Vallerie V., et al. “ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension.” Journal of the American College of Cardiology, vol. 53, no. 17, 2009, pp. 1573–1619., doi:10.1016/j.jacc.2009.01.004. • PHA. (2018). Prostaglandins - PHA. [online] Available at: http://www.phauk.org/treatment-for-pulmonary- hypertension/prostaglandins/ [Accessed 20 Jun. 2018]. • Preston IR, Roberts KE, Miller DP, et al. Effect of Warfarin Treatment on Survival of Patients with Pulmonary Arterial Hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Circulation 2015; 132;2403. • Simonneau, Gerald, et al. “Updated Clinical Classification of Pulmonary Hypertension.” Journal of the American College of Cardiology, vol. 62, no. 25, 2013, doi:10.1016/j.jacc.2013.10.029. • Singh, MD, Dr. Surya (2018). New Horizons for PAH Treatments | CVS Health Payor Solutions. [online] CVS Health Payor Solutions. Available at: https://payorsolutions.cvshealth.com/insights/new-horizons-for-pah-treatments [Accessed 15 May 2018]. • Viknevich, Y. (2018). Risk Factors: Drug Induced. [image] Available at: https://www.slideshare.net/YuryViknevich/pulmonary-arterial-hypertension-pah-presentation [Accessed 27 Aug. 2017].

THE END