Idiopathic Pulmonary Arterial Hypertension Treatment & Management

Treating IPAH requires significant education regarding, and exposure to, the available therapies for IPAH and their potential complications. Because IPAH is relatively rare, management is best left to expert personnel at centers with regular exposure to these patients. Failure to heed this advice can result in medicolegal pitfalls should patient outcome be less than optimal.

A national program designed to develop accredited PH Care Centers (PHCC) has begun, with the goal of raising the overall quality of care and outcomes in patients with PH. ^[21]

Note that there are no therapies approved for use as primary prevention of IPAH. All approved treatments are for use in patients that have already developed clinical manifestations of IPAH.

Until about 15 years ago, calcium channel blockers (CCBs) had been the most widely used class of drugs for IPAH. These drugs are thought to act on the vascular smooth muscle to dilate the pulmonary resistance vessels and lower the pulmonary artery pressure. Several studies report clinical and hemodynamic benefits from the use of long-term calcium channel blockade.

Only patients with an acute vasodilator response to an intravenous or inhaled pulmonary vasodilator challenge (eg, with inhaled nitric oxide at 10 to 20 parts per million, intravenous epoprostenol (2 to 12 ng/kg/min), intravenous adenosine (50 to 350 mg/min), or inhaled iloprost [5 mg]) derive any long-term benefit from CCBs. Such patients constitute less than 5% of patients with IPAH and probably less than 3% of patients with other forms of PAH. By consensus definition, a positive acute vasodilator response is defined by a decrease in mPAP 10 mm Hg or more to reach a mPAP less than 40 mm Hg. It should be noted that less than 50% of responders derive a long-term favorable response to CCBs, and thus close clinical monitoring of patients on CCBs for IPAH is required.

Long-term treatment improves the quality of life and survival rate in patients who are proven responders to such therapy. In general, CCBs are used at high doses in patients with IPAH.

The use of CCBs should be limited to patients without overt evidence of right-sided heart failure. In patients with IPAH (or any other form of PAH), a cardiac index of less than 2 L/min/m² or a right atrial pressure above 15 mm Hg is a contraindication to CCB therapy, as these agents may worsen right ventricular failure in such cases.

Stable patients who demonstrate vasoreactivity and are candidates for high-dose CCB therapy should undergo a CCB challenge to determine their vasodilator response.

Perform this challenge in a critical care unit with a balloon flotation catheter in the pulmonary artery. Administer oral nifedipine every hour (diltiazem can be used if resting tachycardia is present) until a 20% decrease in pulmonary artery pressure and pulmonary vascular resistance is observed or systemic hypotension or other adverse effects preclude further drug administration.

Calculate the daily dosage requirement at half the total initial effective dose and administer this every 6-8 hours. Typical doses of nifedipine and diltiazem can reach 240 mg/d and 900 mg/d, respectively. Use caution when withdrawing CCBs because rebound pulmonary hypertension upon cessation of PAH therapy has been reported.

Approved medications for PAH (including IPAH) currently available in the United States are as follows:

• Epoprostenol (Flolan or generic) - Intravenous, parenteral prostacyclin analogue, sometimes referred to as a "prostanoid" ^{[22, 23]}

• Treprostinil (Remodulin) - Intravenous or subcutaneous, parenteral prostacyclin analogue, sometimes referred to as a prostanoid ^{[24, 25]}

• Treprostinil inhaled (Tyvaso) - Nebulized inhalation; prostacyclin analogue

• Treprostinil extended-release tablet (Orenitram) - Twice-daily oral prostacyclin analogue

• Iloprost (Ventavis) - Nebulized inhalation; prostacyclin analogue, sometimes referred to as a prostanoid ^[26]

• Selexipag (Uptravi) - Oral prostacyclin agonist that is selective for the IP receptor over other prostanoid receptors ^[27]

• Bosentan (Tracleer) - Oral; endothelin receptor antagonist (ERA) ^{[28, 29]}

• Ambrisentan (Letairis) - Oral ERA ^{[30, 31]}

• Sildenafil (Revatio) - Oral phosphodiesterase type 5 (PDE-5) inhibitor ^[32]

• Tadalafil (Adcirca) - Oral PDE-5 inhibitor ^[33]

• Riociguat (Adempas) - Oral soluble guanylate cyclase (sGC) stimulator ^{[34, 35, 36, 37]} (currently approved only for adults)

• Macitentan (Opsumit) – Oral ERA ^{[38, 39]} (also currently approved for adults ^{[40, 41]} )

In the SERAPHIN trial (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), macitentan was shown to lower the risk of clinical events in patients with PAH. Administration of macitentan at 10 mg/day led to a 45% reduction in a clinical primary endpoint that included death, initiation of intravenous or subcutaneous prostanoids, or worsening of PAH. Benefit was driven primarily by reductions in PAH worsening. A dosage of 3 mg/day also improved clinical outcome but to a lesser degree. ^{[38, 39, 41, 40]}

Combination therapy of ambrisentan (an ERA) with tadalafil (a PDE-5 inhibitor) was approved as first-line treatment by the FDA in October 2015. The combination decreased disease progression and hospitalization, and more effectively improved exercise ability. Approval of the first-line ambrisentan/tadalafil combination for PAH is based on results of the ambrisentan and tadalafil in patients with pulmonary arterial hypertension (AMBITION) trial involving 605 patients with World Health Organization functional class II or III PAH. Patients were randomly assigned to receive once-daily ambrisentan plus tadalafil or to either drug alone. Doses were titrated from 5-10 mg/day for ambrisentan and from 20-40 mg/day for tadalafil. Treatment with the combination was associated with ~50% reduction in risk for clinical failure compared with either drug alone (P = 0.0002). ^[42]

For patients with IPAH in whom CCBs are contraindicated, ineffective, or poorly tolerated, ACCP guidelines recommend using the patient’s World Health Organization’s modified New York Heart Association (NYHA) functional class (WHO FC) to guide the choice of PAH-specific therapy. ^{[43, 44]} PAH-specific therapies by functional class from the ACCP are as follows: ^[45]

• WHO FC II – Monotherapy may be initiated with a currently approved endothelin receptor antagonist (ETA), phosphodiesterase-5 (PDE5) inhibitor, or the soluble guanylate cyclase stimulator riociguat.

• WHO FC III (treatment-naïve) - Monotherapy be initiated with a currently approved ERA, a PDE5 inhibitor, or the soluble guanylate cyclase stimulator riociguat.

• WHO FC III (treatment-naïve with rapid progression or other markers of poor prognosis) - Parenteral prostanoid.

• WHO FC III (non-treatment-naïve with rapid progression or other markers of poor prognosis) - Parenteral or inhaled prostanoid.

• WHO FC IV (treatment-naïve) - Parenteral prostanoid. If unable to manage parenteral prostanoid therapy, use inhaled prostanoid in combination with an ERA.

A newer concept of goal-oriented therapy has been developed after observations that patients with an inadequate clinical response to an initial therapy have a much worse prognosis. Thus:

• For WHO FC III or IV PAH patients with unacceptable clinical status despite established PAH-specific monotherapy, a 2^nd class of PAH therapy to improve exercise capacity is recommended in addition to referral to a center with expertise in the evaluation and treatment of complex patients with PAH.

Finally, for patients who do not fall into the above categories, reference to the ACCP Guideline for specific evidence-based scenarios and simultaneous referral to an expert PAH center is suggested. Failure of medical therapy dictates prompt consideration for lung transplantation.

It is important to perform vasoactivity testing in patients with IPAH before prescribing PAH-specific therapy. Intravenous epoprostenol or adenosine or inhaled nitric oxide are used most commonly for acute vasodilator testing. Oxygen, nitroprusside, and hydralazine should not be used as pulmonary vasodilator testing agents.

Note that while the above agents are often referred to as pulmonary vasodilator medications, their actions are likely pleiotropic, affecting endothelial function and intimal and smooth muscle proliferation. Their ability to dilate pulmonary arteries and thereby lower pulmonary arterial pressure is modest in most cases.

Patients who do not have an acute vasodilator response to a vasodilator challenge have a worse prognosis on long-term oral PAH-specific therapy compared with those who have an initial response. However, the absence of an acute response to intravenous or inhaled vasodilators does not preclude the use of intravenous prostanoid therapy. In fact, continuous intravenous prostanoid therapy is strongly suggested for these patients because CCBs are contraindicated.

Patients receiving epoprostenol or intravenous treprostinil therapy must have a central venous catheter placed surgically and receive their initial dose in an inpatient setting. This allows for monitoring of acute adverse effects and provides the opportunity for the patient and support personnel to master the drug preparation and administration technique before discharge.

Continuous intravenous prostanoid therapy is delivered via an ambulatory infusion pump.

Despite concerns regarding ocular toxicity with chronic PDE-5 inhibition, no detrimental effects were observed during a pivotal phase III randomized clinical trial of sildenafil versus placebo for patients with pulmonary arterial hypertension. ^[46]

A 52-week extension study demonstrated the long-term safety and efficacy of tadalafil in patients with pulmonary arterial hypertension. ^[47]

Patients with IPAH may benefit from therapy with anticoagulants, digoxin, diuretics, or supplemental oxygen.

Anticoagulation

Several studies, using both univariate and multivariate analyses, have shown that survival in IPAH, regardless of histopathologic subtype, is increased when patients are treated with anticoagulant therapy. However, these studies were retrospectively performed. No randomized, controlled clinical trials of anticoagulation in IPAH exist; thus, the data are mostly consensus-driven rather than based on prospective evidence-based medicine.

Warfarin should be used, provided the patient has no contraindications to anticoagulation. Maintain an international normalized ratio (INR) of 1.5 to 2.

Digoxin

Digoxin therapy can be used to improve right ventricular function in patients with right ventricular failure. However, no randomized controlled clinical study has been performed to validate this strategy for patients with IPAH or any other form of PAH.

Diuretics

Use diuretics to manage peripheral edema. The use of loop diuretics (eg, furosemide, bumetanide) requires potassium supplementation and close monitoring of serum potassium. Potassium-sparing diuretics may have a role in ameliorating the sometimes-intractable hypokalemia observed with daily diuretic use.

Oxygen therapy

Give supplemental oxygen in patients with resting or exercise-induced hypoxemia. Use caution if patients have a left-to-right shunt via a patent foramen ovale, because supplemental oxygen in these instances may provide little or no benefit.

Consider supplemental oxygen for PAH patients who are planning air travel, as mild hypobaric hypoxia can start at altitudes between 1500 and 2000 m, and commercial airliners are pressurized to the equivalent of an altitude between 1600 and 2500 m. ^[1] A prospective observational study of 34 air travelers with pulmonary hypertension found that 1 in 4 travelers experienced hypoxemia, which was associated with lower cabin pressure, ambulation during flight, and longer flight durations. Results suggest travelers with PH, who will be traveling on long flights or those with a history of oxygen use, should be considered for supplemental in-flight oxygen. ^[48]

No specific diet is recommended; however, a low-sodium and low-fluid diet is recommended in patients with significant volume overload due to right ventricular failure.

Patients taking warfarin must limit their intake of vitamin K–containing foods, such as green leafy and coliform vegetables.

L -arginine supplementation (a precursor to nitric oxide) has not been proven to improve outcome in IPAH or any other form of PAH.

Limited data are available on cardiopulmonary rehabilitation. The generally accepted recommendation is that patients with pulmonary hypertension and heart failure should perform mild symptom-limited aerobic activity and avoid complete bed rest. Isometric exercises (weight lifting) are contraindicated.

A European study involving an intensive inpatient and outpatient exercise training and conditioning program demonstrated the safety and efficacy of exercise as a treatment modality for patients with PAH. ^[49] While longer-term outcomes are needed, the PAH community considers exercise in moderation a safe and potentially effective adjunctive nonpharmacologic therapy.

A single- or double-lung transplant is indicated for patients who do not respond to medical therapy. Simultaneous cardiac transplantation may not be necessary even with severe right ventricular dysfunction; however, this depends on the transplant institution. Interestingly, IPAH is not thought to recur after transplant.

Go to Pediatric Lung Transplantation for more complete information on this topic.

Atrial septostomy is a palliative procedure that may afford some benefit to patients whose condition is deteriorating. This procedure works by allowing interatrial right-to-left shunting to occur, thus delivering more overall oxygen content to the respiring tissues, albeit with a lower overall saturation.

Currently, no precise dosage adjustment algorithm is available for patients with IPAH who are on PAH-specific therapy. Monitor the patient with frequent physical examinations and focus the history on heart failure symptoms and adverse effects of medications.

Echocardiography has been used in several studies to serially monitor changes in the right ventricular–right atrial pressure gradient and the right and left ventricular chamber sizes. Findings from other noninvasive modalities (eg, electron-beam CT measurements of cardiac chamber sizes) correlate with hemodynamic improvements in pulmonary physiology.

More recently, cardiopulmonary exercise testing, serial invasive hemodynamic testing, and 6-minute walk testing have been used to monitor the disease status of patients with IPAH.

Clinical trials are under way to determine the safety and efficacy of several new therapies for IPAH. These include oral and inhaled prostanoids, phosphodiesterase inhibitors, tyrosine kinase inhibitors, and other novel agents. ^[50] Efforts are currently focused on prostacyclin analogues, newer endothelin antagonists, and PDE-5 inhibitors.