What are the treatment options for a patient diagnosed with pulmonary hypertension?

Treatment of Pulmonary Hypertension

All patients with suspected pulmonary hypertension must undergo right heart catheterization to confirm diagnosis and establish hemodynamic classification before initiating any therapy, as treatment differs fundamentally based on PH group classification. 1, 2, 3

Initial Diagnostic and Risk Stratification Requirements

Before treatment initiation:

• Right heart catheterization is mandatory to confirm PH (mean PAP ≥25 mmHg) and distinguish pre-capillary from post-capillary disease 1, 2
• Vasoreactivity testing must be performed during catheterization in patients with idiopathic, heritable, or drug-induced PAH to identify calcium channel blocker responders 1, 2, 3
• All patients should be evaluated at an expert PH center before starting therapy, ideally prior to first treatment 1, 2
• Risk stratification using multiple parameters (WHO functional class, 6-minute walk distance, BNP/NT-proBNP, echocardiographic findings, hemodynamics) determines treatment intensity 1, 2

Risk Categories Guide Treatment Aggressiveness

• Low risk (estimated 1-year mortality <5%): WHO FC I-II, 6MWD >440m, no significant RV dysfunction 1
• Intermediate risk (5-10% mortality): WHO FC III, moderately impaired exercise capacity, RV dysfunction without failure 1
• High risk (>10% mortality): WHO FC III-IV, progressive disease, severe RV dysfunction or failure 1

Treatment Algorithm for Pulmonary Arterial Hypertension (Group 1)

Vasoreactive Patients (Positive Acute Vasodilator Response)

High-dose calcium channel blockers are first-line therapy for the small subset (~10%) of patients demonstrating acute vasoreactivity during right heart catheterization 1, 2, 3

• This applies only to idiopathic, heritable, or drug-induced PAH patients with documented acute vasodilator response 2, 3
• Requires close monitoring with repeat assessment at 3-6 months to confirm sustained response 1

Non-Vasoreactive Patients: Treatment Based on Risk

Low or intermediate-risk patients: Initial oral combination therapy with ambrisentan plus tadalafil is recommended as it has proven superior to monotherapy in delaying clinical failure 2

• This represents a paradigm shift from sequential monotherapy to upfront combination therapy 1, 2
• Alternative initial combinations targeting multiple pathways (endothelin, nitric oxide, prostacyclin) are also recommended 3

High-risk patients: Initial combination therapy including intravenous prostacyclin analogues (epoprostenol) is mandatory as this improves survival in severe disease 2, 3, 4

• Epoprostenol is FDA-approved for PAH (WHO Group 1) to improve exercise capacity, with studies predominantly in NYHA FC III-IV patients 4
• Intravenous prostacyclin should be prioritized for high-risk patients from treatment initiation 2

Inadequate Response to Initial Therapy

Sequential combination therapy targeting additional pathways is recommended for patients not achieving low-risk status on initial treatment 1, 3

• Reassess at 3-6 months using the comprehensive risk panel 1, 2
• Add medications from different drug classes (phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostacyclin analogues) 3, 5

Treatment for Other PH Groups

Group 2: PH Due to Left Heart Disease

PAH-specific therapies are NOT recommended and may be harmful in patients with left heart disease 1, 2, 6

• Treatment must focus on optimizing the underlying cardiac condition 6
• This is a critical pitfall: starting PAH drugs empirically without proper classification can delay appropriate treatment and cause harm 2

Group 3: PH Due to Lung Disease

Long-term oxygen therapy to maintain saturations >90% is the primary treatment and has been shown to partially reduce PH progression 2, 6

• PAH-specific therapies are not recommended for lung disease-associated PH 6
• Conventional vasodilators like calcium channel blockers should be avoided as they can worsen gas exchange 6

Group 4: Chronic Thromboembolic PH (CTEPH)

Surgical pulmonary endarterectomy in deep hypothermia with circulatory arrest is the treatment of choice for operable patients 1, 2, 6, 3

• Operability assessment must be performed by a multidisciplinary CTEPH team at an expert center 1, 6
• Lifelong anticoagulation is mandatory for all CTEPH patients, even after successful surgery 1, 3
• Target INR 2-3 for CTEPH (higher than the 1.5-2.5 used in idiopathic PAH) 2

For inoperable CTEPH or persistent/recurrent PH after surgery: Riociguat is the only approved targeted therapy 1, 5

• Riociguat demonstrated significant improvement in 6MWD (39m increase) and PVR reduction in this population 1
• Balloon pulmonary angioplasty may be considered at expert centers for selected inoperable patients 1

Essential Supportive Care Measures (All PAH Patients)

Diuretics are recommended for all patients with signs of right ventricular failure and fluid retention 2, 6

• Monitor electrolytes and renal function carefully during diuretic therapy 6, 3
• Avoid volume overload as it worsens RV function 6

**Continuous long-term oxygen is recommended when arterial oxygen pressure is consistently <60 mmHg** or to maintain saturations >90% 2, 6

Anticoagulation should be considered in idiopathic PAH, heritable PAH, and anorexigen-induced PAH, targeting INR 1.5-2.5 2

Pregnancy must be avoided due to 12-30% mortality risk even with modern therapy 1, 3

• Effective contraception is mandatory; progesterone-only preparations or levonorgestrel IUD are preferred 1
• Note that bosentan reduces oral contraceptive efficacy, requiring dual contraceptive methods 1

Supervised exercise training should be considered for physically deconditioned PAH patients already on medical therapy 1, 3

Psychosocial support is recommended given the significant psychological impact of this life-threatening disease 1

Monitoring and Treatment Goals

Regular assessments every 3-6 months in stable patients are mandatory 1, 2, 3

Assessment should include:

• WHO functional class 1, 2
• 6-minute walk test with Borg dyspnea score 1, 2
• BNP or NT-proBNP levels 1, 2
• Echocardiography 1, 2
• Right heart catheterization should be considered at intervals, particularly 3-6 months after treatment changes 1

The primary treatment goal is achieving and maintaining low-risk status (WHO FC I-II, 6MWD >440m, preserved RV function) 1, 2, 3

• Target 6MWD >440m for most patients, though lower values may be acceptable in elderly patients or those with significant comorbidities 1, 2
• Achievement/maintenance of intermediate-risk profile should be considered inadequate response requiring treatment escalation 1

Advanced Therapies and Rescue Options

Consider lung transplantation eligibility after inadequate response to initial therapy 2, 3

• Refer for transplantation evaluation soon after inadequate response is confirmed on maximal combination therapy 2
• Patients may require interventions including pulmonary artery catheter, inhaled pulmonary vasodilators, or mechanical support with RV assist device or ECMO 7

Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy 1

Critical Pitfalls to Avoid

Never start PAH-specific drugs without right heart catheterization confirmation of diagnosis and classification 2

• This is the most dangerous error: PAH drugs can harm Group 2 PH patients and delay appropriate treatment 2

Do not use ACE inhibitors, ARBs, or beta-blockers in PAH unless specifically required for comorbidities, as they lack proven benefit 2

Avoid intubation if possible in acute decompensation, as positive pressure ventilation worsens RV function; however, severe hypoxemia and hypercapnia also worsen RV function 7

Patients on chronic prostacyclin therapy may rapidly develop RV failure and death if therapy is interrupted 7

• Emergency physicians must recognize this and ensure continuity of pulmonary vasodilator therapy 7

Acute/Critical Care Situations

ICU hospitalization is recommended for PH patients with high heart rate (>110 bpm), systolic blood pressure <90 mmHg, low urine output, or rising lactate 2

In hypotensive shock: Use vasopressors and inotropes rather than fluid boluses to augment cardiac output and avoid exacerbating RV ischemia 7

• Volume overload worsens RV function in the setting of pressure overload 7
• Early consultation with PH specialist and transfer to tertiary center with mechanical support capabilities is advised 7