Treatment of pulmonary hypertension for md exam answer 10 marks from fishman and Murray only

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Treatment of Pulmonary Hypertension

10-Mark MD Exam Answer (Based on Fishman's Pulmonary Diseases and Disorders, 2-Volume Set & Murray & Nadel's Textbook of Respiratory Medicine)

1. Prerequisite: Accurate Diagnosis and Classification

Treatment must be driven by an appropriately established diagnosis. PAH (Group 1) is one form of pulmonary hypertension (PH) and is overall less common than PH due to parenchymal lung disease (Group 3) or left heart disease (Group 2). Misapplication of PAH-targeted therapies in non-PAH groups is not just ineffective but potentially lethal. For example: epoprostenol increased mortality in patients with left ventricular dysfunction; bosentan worsened hypoxemia and quality of life in COPD-related PH; riociguat caused excess deaths in idiopathic interstitial pneumonia (RISE-IIP trial, terminated early). (Fishman's, Ch. 72)

2. General (Non-Pharmacologic) Management

a. Exercise and Rehabilitation

Patients should maintain as active a lifestyle as possible. Bed rest leads only to deconditioning. Regular, steady aerobic exercise - ideally through a pulmonary/cardiac rehabilitation programme - is recommended. Randomized trials of exercise rehabilitation in PAH/CTEPH showed improvements in 6-minute walk distance (6MWD) exceeding those seen in most pharmacologic trials. (Fishman's)

b. Oxygen Supplementation

Supplemental oxygen is indicated for patients with resting hypoxemia (SaO2 <90%). Hypoxic pulmonary vasoconstriction worsens pulmonary pressures; correcting hypoxia reduces this stimulus.

c. Diuretics

Diuretics are used for right heart failure with fluid overload. They reduce preload and relieve oedema, ascites, and hepatic congestion. However, excessive diuresis may reduce right ventricular preload and worsen cardiac output.

d. Digoxin

Digoxin can improve right ventricular contractility and control heart rate in patients with atrial arrhythmias complicating PAH. Its role is adjunctive.

e. Anticoagulation

Oral anticoagulation with warfarin has historically been used in idiopathic PAH based on the rationale that in situ thrombosis contributes to vascular obstruction. However, evidence for survival benefit is limited, and practice varies across expert centres.

f. Avoid Precipitants

High altitude and unprotected air travel should be avoided if hypoxemia is present.
Vasoconstrictors, serotonergic drugs (e.g., for migraine), and drugs causing fluid retention should be used cautiously.
Pregnancy carries a very high mortality risk and should be avoided. Effective contraception is mandatory.
Surgical procedures carry considerable perioperative risk; anesthesia induction may provoke a vasovagal crisis.

3. Risk Stratification to Guide Therapy Intensity

Before initiating therapy, PAH patients are stratified into low, intermediate, and high risk using the 2015 ESC/ERS PAH Risk Assessment (Table 72-9 in Fishman's):

Parameter	Low Risk (<5% 1-yr mortality)	Intermediate Risk (5-10%)	High Risk (>10%)
Signs of RHF	Absent	Absent	Present
WHO Functional Class	I, II	III	IV
6MWD	>440 m	165-440 m	<165 m
BNP/NT-proBNP	Low	Intermediate	High
Echocardiography/CMR	Normal RV	Mild-mod RV dysfunction	Severe RV dysfunction

This risk assessment drives initial therapy choice (mono- vs. combination therapy) and guides subsequent reassessment.

4. PAH-Targeted Pharmacotherapy: Three Pathways

Three established pathways are targeted in PAH therapy - the prostacyclin pathway, the endothelin pathway, and the nitric oxide pathway. All three are deficient or dysregulated in PAH. (Fishman's)

Pathway 1: Prostacyclin Pathway

Prostacyclin (PGI2) is produced by vascular endothelium. It is a potent vasodilator, inhibitor of smooth muscle proliferation, and antiplatelet agent. Deficiency is noted in PAH patients. It acts via cAMP.

a. Epoprostenol (IV prostacyclin)

The first FDA-approved PAH therapy; the most potent available.
Administered by continuous intravenous infusion via a central venous catheter.
Has a very short half-life (2-3 minutes); any interruption risks rebound vasoconstriction and acute decompensation.
Demonstrated survival benefit in idiopathic PAH (RCT terminated early due to significant survival advantage).
Requires intensive patient/family education, hospitalization for initiation, and dedicated multidisciplinary team support.

b. Treprostinil

A longer-acting prostacyclin analogue; available in multiple formulations: IV, subcutaneous (SC), inhaled, and oral.
SC infusion is an alternative to IV but causes significant injection site pain.
Inhaled treprostinil allows targeted pulmonary delivery, reducing systemic side effects.

c. Iloprost (inhaled)

Synthetic prostacyclin analogue; inhaled 6-9 times daily.
Available IV in Europe; inhaled form only in the USA.

d. Selexipag (oral)

An oral, selective IP (prostacyclin) receptor agonist - not a prostacyclin analogue per se.
In the GRIPHON trial, it significantly reduced the composite primary endpoint of mortality or PAH-related complications, primarily by reducing disease progression and hospitalization.
(Fishman's, block 20)

Pathway 2: Endothelin Receptor Antagonists (ERAs)

Endothelin-1 (ET-1) is the major endothelium-derived vasoconstrictor and smooth muscle mitogen. ET-1 levels are elevated in PAH. ERAs block ET-A and/or ET-B receptors.

a. Bosentan (oral)

Dual ERA (blocks both ET-A and ET-B receptors).
Improves exercise capacity, WHO functional class, haemodynamics, and delays clinical worsening.
Requires monthly LFT monitoring due to hepatotoxicity risk (dose-dependent elevation of transaminases in ~10%).
Contraindicated in pregnancy.

b. Ambrisentan (oral)

Selective ET-A receptor antagonist.
Lower risk of liver toxicity compared with bosentan; monthly LFT monitoring is still recommended.

c. Macitentan (oral)

Newer dual ERA; FDA approved for Group 1 PAH.
In the SERAPHIN trial, significantly reduced PVR by 35%; favorable hepatic safety profile but did not significantly improve 6MWD in a phase 4 RCT.
Not recommended for Group 2 PH (MELODY-1 trial showed increased fluid retention and clinical worsening in HFpEF patients).

Pathway 3: Nitric Oxide Pathway

Nitric oxide (NO) activates soluble guanylate cyclase (sGC), generating cGMP, which causes vasodilation. cGMP is degraded by phosphodiesterase type 5 (PDE5). PAH is associated with reduced NO production.

a. PDE5 Inhibitors

Sildenafil (oral): Inhibits PDE5, preventing cGMP breakdown, thereby prolonging vasodilation. FDA-approved for PAH. Improves 6MWD, haemodynamics, and WHO functional class. Note: NOT recommended in Group 2 PH after corrected valvular heart disease (SIOVAC trial showed worse outcomes).
Tadalafil (oral): Once-daily PDE5 inhibitor, FDA-approved for PAH; longer half-life than sildenafil.

b. Soluble Guanylate Cyclase Stimulator

Riociguat (oral): Directly stimulates sGC independent of NO, and also sensitizes sGC to endogenous NO.
- Approved for both PAH and chronic thromboembolic pulmonary hypertension (CTEPH) - the only medical therapy approved for CTEPH.
- Improves 6MWD, PVR, NT-proBNP, functional class, and time to clinical worsening in PAH.
- Contraindicated in combination with PDE5 inhibitors (risk of severe hypotension) and in idiopathic interstitial pneumonias (RISE-IIP trial showed excess deaths).

5. Calcium Channel Blockers (CCBs)

CCBs are not approved for PAH but retain a role in the rare subset (~10%) with demonstrated acute pulmonary vasoreactivity.

Vasoreactivity testing uses inhaled NO, IV adenosine, or IV epoprostenol.
Positive response (Sitbon criteria): Decrease in mPAP by ≥10 mmHg to an absolute value ≤40 mmHg, with unchanged or increased cardiac output.
Of responders, only ~50% sustain a long-term response to CCBs.
5-year survival in sustained CCB responders: ~94% at 1, 3, and 5 years.
CCBs must NOT be used without documented vasoreactivity - they can cause systemic hypotension, reduced cardiac output (negative inotropy), arrhythmias, syncope, and death in non-responders. (Fishman's)

6. Combination Therapy

Modern PAH management favours initial combination therapy for most patients, particularly at intermediate or high risk.

The AMBITION trial demonstrated that upfront combination therapy with ambrisentan + tadalafil was superior to either agent alone, reducing the risk of the composite endpoint (death, hospitalization, unsatisfactory clinical response, or disease progression).
Sequential add-on therapy remains an option for stable low-risk patients initially.
Goals of therapy include reaching low-risk status (WHO FC I/II, 6MWD >440 m, normal BNP/NT-proBNP, absence of RHF signs).

7. Treatment of Non-PAH Groups (Murray & Nadel)

Group 2 PH (Left Heart Disease - LHD-PH)

Strong recommendation against PAH-specific drugs in LHD-PH.
No multicenter RCTs show benefit; several show harm:
- Epoprostenol: increased mortality in HFrEF (trial terminated early).
- Macitentan: MELODY-1 trial showed increased fluid retention and worsening in HFpEF-Cpc-PH subgroup.
- Sildenafil: worsened outcomes in PH after corrected valvular disease (SIOVAC).
Management = optimise the underlying left heart disease (diuretics, ACE inhibitors/ARBs, beta-blockers, revascularisation, valve correction). (Murray & Nadel, Ch. 83)

Group 3 PH (Chronic Lung Disease)

Treat the underlying lung disease maximally.
Supplemental oxygen is important (corrects hypoxic vasoconstriction).
PAH-specific drugs are not recommended for routine use.

Group 4 PH (CTEPH)

Surgical pulmonary endarterectomy (PEA) is the treatment of choice for operable CTEPH.
Riociguat is the only approved medical therapy for inoperable or persistent/recurrent CTEPH after PEA.
Balloon pulmonary angioplasty (BPA) is an emerging option for inoperable CTEPH.

8. Interventional and Surgical Options

Atrial Septostomy

Creation of a right-to-left interatrial shunt to decompress the right ventricle and improve left ventricular filling and systemic output.
Used as a bridge to transplantation or as palliative therapy in end-stage PAH refractory to medical therapy.
Carries significant procedural risk; best done in expert centres.

Lung Transplantation

Reserved for patients who continue to progress despite optimal medical therapy.
Both bilateral lung transplantation and heart-lung transplantation are options.
Remains the only potentially curative option.
The decision to list requires careful timing, as PAH patients may deteriorate rapidly while awaiting organs.

9. Follow-up and Monitoring

After initiation of therapy, PAH patients are reassessed using a combination of:

WHO functional class
6MWD
Echocardiography (RV function)
Serum biomarkers (NT-proBNP/BNP)
Right heart catheterization (in selected cases)

The frequency of reassessment depends on risk profile and clinical stability. The goal is to achieve and maintain low-risk status. (Fishman's)

Summary Table: Approved PAH-Targeted Therapies

Drug	Pathway	Route	Key Point
Epoprostenol	Prostacyclin	IV (continuous)	Most potent; survival benefit; requires permanent IV line
Treprostinil	Prostacyclin	IV / SC / Inhaled / Oral	Multiple routes; SC causes injection site pain
Iloprost	Prostacyclin	Inhaled (6-9x/day)	Short duration
Selexipag	Prostacyclin receptor	Oral	IP receptor agonist; GRIPHON trial
Bosentan	ERA (dual)	Oral	Monthly LFTs required
Ambrisentan	ERA (ET-A selective)	Oral	Lower hepatic risk
Macitentan	ERA (dual)	Oral	SERAPHIN/MELODY data
Sildenafil	PDE5 inhibitor	Oral	Avoid in Group 2 PH
Tadalafil	PDE5 inhibitor	Oral (once daily)
Riociguat	sGC stimulator	Oral	Also approved for CTEPH; never combine with PDE5i

Sources:

Fishman's Pulmonary Diseases and Disorders, 2-Volume Set (Ch. 72: Pulmonary Arterial Hypertension - Therapy section)
Murray & Nadel's Textbook of Respiratory Medicine, 2-Volume (Ch. 83: Pulmonary Hypertension - Treatment of Group 2 PH)

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