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, and should be promptly evaluated at an expert pulmonary hypertension center to determine the appropriate treatment pathway based on their specific PH group. 1, 2, 3

Critical First Step: Diagnosis and Classification

• Right heart catheterization is mandatory—never start PAH-specific drugs empirically without confirming diagnosis, as this can cause harm, particularly in Group 2 PH (left heart disease) where these medications may worsen outcomes 2, 3
• Pulmonary hypertension is defined as mean pulmonary arterial pressure ≥25 mmHg at rest with specific hemodynamic criteria distinguishing five clinical groups 1, 4
• Vasoreactivity testing must be performed during right heart catheterization in patients with idiopathic, heritable, or drug-induced PAH to identify calcium channel blocker responders 2, 3

Treatment Algorithm by PH Classification

Group 1: Pulmonary Arterial Hypertension (PAH)

For vasoreactive patients (positive acute vasoreactivity test):

• High-dose calcium channel blockers are first-line therapy and should be initiated immediately 1, 2, 3

For non-vasoreactive patients, treatment is risk-stratified:

Low-risk patients (WHO FC I-II, 6MWD >440m, no RV dysfunction, estimated 1-year mortality <5%):

• Initial oral combination therapy with ambrisentan plus tadalafil is recommended as superior to monotherapy in delaying clinical failure 2, 3

Intermediate-risk patients (WHO FC III, moderately impaired exercise capacity, signs of RV dysfunction but not failure, estimated 1-year mortality 5-10%):

• Initial oral combination therapy targeting multiple pathways is recommended 1, 3

High-risk patients (WHO FC III-IV, progressive disease, severe RV dysfunction or failure, estimated 1-year mortality >10%):

• Initial combination therapy including intravenous prostacyclin analogs (epoprostenol) should be prioritized, as this improves survival 2, 3, 5
• Epoprostenol is FDA-approved for PAH (WHO Group 1) to improve exercise capacity in predominantly NYHA FC III-IV patients 5

Sequential therapy for inadequate responders:

• Add additional PAH-specific medications targeting different pathways if initial therapy fails to achieve low-risk status 1, 3

Group 2: PH Due to Left Heart Disease

• PAH-specific therapies are not recommended and may be harmful 2, 6
• Treatment must focus on optimizing the underlying cardiac condition 6, 4

Group 3: PH Due to Lung Disease

• Long-term oxygen therapy to maintain saturations >90% is recommended and has been shown to partially reduce PH progression 2, 6
• PAH-specific drugs are not recommended as they lack proven benefit and may worsen gas exchange 6
• Conventional vasodilators like calcium channel blockers should be avoided as they can worsen ventilation-perfusion matching 6

Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

• Surgical pulmonary endarterectomy in deep hypothermia with circulatory arrest is the treatment of choice for operable patients 1, 2, 3
• Operability assessment must be performed by a multidisciplinary CTEPH team at an expert center 1
• Lifelong anticoagulation is mandatory for all CTEPH patients, even after successful surgery 1, 3
• For inoperable CTEPH or persistent/recurrent PH after surgery, riociguat is the only approved targeted therapy, demonstrating a mean increase of 39m in 6-minute walk distance 1, 4
• Balloon pulmonary angioplasty may be considered in expert centers for technically non-operable patients or those with unacceptable surgical risk 1

Essential Supportive Care Measures (All Groups)

Diuretics:

• Recommended for all PAH patients with signs of right ventricular failure and fluid retention, with careful monitoring of electrolytes and renal function 2, 3

Oxygen therapy:

• Continuous long-term oxygen is recommended when arterial oxygen pressure is consistently <60 mmHg or to maintain saturations >90% 2, 3
• In-flight oxygen should be considered for WHO FC III-IV patients 1

Anticoagulation:

• Should be considered in idiopathic PAH, heritable PAH, and anorexigen-induced PAH, targeting INR 1.5-2.5 2
• For CTEPH, target INR 2-3 2

Exercise and rehabilitation:

• Supervised exercise training should be considered in physically deconditioned PAH patients under medical therapy 1, 3
• Excessive physical activity leading to distressing symptoms is not recommended 1

Pregnancy and contraception:

• Pregnancy must be avoided in PAH patients due to substantial mortality risk (historically 30-50%, though recent data suggest improvement in well-controlled patients) 1, 3
• Effective contraception is mandatory; progesterone-only preparations or levonorgestrel-releasing intrauterine devices are preferred 1
• Note that bosentan may reduce oral contraceptive efficacy 1

Psychosocial support:

• Psychosocial support is recommended, with referral to patient support groups to improve coping and outlook 1
• Proactive advanced care planning with specialist palliative care services should be implemented when appropriate 1

Immunizations:

• Influenza and pneumococcal vaccination are recommended 1

Monitoring and Treatment Goals

Follow-up schedule:

• Regular assessments every 3-6 months in stable patients are mandatory 1, 3
• Assessments should include WHO functional class, 6-minute walk test, BNP/NT-proBNP, echocardiography, and consideration of right heart catheterization 1

Primary treatment goal:

• Achieving and maintaining low-risk status is the target: WHO FC I-II, 6-minute walk distance >440m, no signs of clinically relevant RV dysfunction, estimated 1-year mortality <5% 1, 2
• The 6MWD threshold of >440m is based on the largest cohort studied, though lower values may be acceptable in elderly patients or those with significant comorbidities 1
• Intermediate-risk status (estimated 1-year mortality 5-10%) should be considered inadequate response for most patients, prompting treatment escalation 1

Advanced Therapies and Rescue Options

Lung transplantation:

• Consider eligibility after inadequate response to initial monotherapy or combination therapy 2, 3
• Refer for transplantation evaluation soon after inadequate response is confirmed on maximal combination therapy 2

Balloon atrial septostomy:

• May be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy 2

Critical Care Management

ICU admission criteria:

• Hospitalization is recommended for PH patients with high heart rate (>110 bpm), systolic blood pressure <90 mmHg, low urine output, or rising lactate 2
• Inotropic support is recommended for hypotensive patients rather than aggressive fluid boluses, as volume overload worsens RV ischemia 2, 7

Intubation considerations:

• Should be avoided if possible, as positive pressure ventilation can worsen RV function 7
• However, hypoxemia and hypercapnia also worsen right-sided heart function and must be corrected 7

Vasopressor selection:

• Vasopressors and inotropes are preferred over fluid boluses in shock to augment cardiac output and reduce risk of RV ischemia 7

Critical Pitfalls to Avoid

• Never initiate PAH-specific drugs without right heart catheterization confirmation, as empiric treatment can delay appropriate therapy and cause harm, especially in Group 2 PH 2
• Do not use ACE inhibitors, ARBs, or beta-blockers in PAH unless specifically required for comorbidities, as they lack proven benefit 2
• Avoid aggressive fluid resuscitation in right ventricular failure, as volume overload exacerbates RV dysfunction 2, 7
• Do not use calcium channel blockers in non-vasoreactive patients or those with lung disease, as they can worsen outcomes 6
• Recognize that patients on chronic pulmonary vasodilators may rapidly deteriorate if these medications are interrupted, potentially leading to RV failure and death 7
• Epidural anesthesia should be preferred over general anesthesia in elective surgery whenever possible 1