Pulmonary Hypertension: An Update

US Pharm. 2008;33(8):HS-9-HS-16.

The pulmonary vasculature is normally a low-pressure system with approximately one-tenth the resistance to flow of the systemic vasculature.¹ Pulmonary hypertension (PH), a life-threatening condition with a poor prognosis if untreated, is characterized by elevated mean pulmonary arterial pressure (mPAP), which can lead to right ventricular failure.² By expert consensus, PH is defined as an mPAP greater than 25 mmHg at rest or 30 mmHg with exercise, as measured by right-heart catheterization.² Data from 194 patients with idiopathic pulmonary arterial hypertension (IPAH) in the National Institutes of Health registry from 1981 to 1985--before the advent of disease-modifying therapy--found one-, three-, and five-year survival rates to be 68%, 48%, and 34%, respectively; median survival was 2.8 years.³

Pulmonary hypertension is a rare disorder, and epidemiologic data come largely from patients with IPAH. In this subset of PH, the incidence rate is estimated to be two to five individuals per million per year in the general population. The female:male ratio is 1.7:1, and the third and fourth decades of life are the most common time IPAH is diagnosed.¹

Most patients with PH experience lethargy, fatigue, and exertional dyspnea. Measuring patients' exercise capacity determines their World Health Organization (WHO) or New York Heart Association (NYHA) functional status (TABLE 1).⁴ Eventually, right ventricular enlargement (cor pulmonale) and right-sided heart failure will develop due to the increased pressure the heart must pump against to send blood to the lungs, leading to symptoms such as angina, syncope, peripheral edema, and abdominal distention. In addition, PH and right-sided heart failure lead to characteristic changes in the heart sounds detectable by auscultation.

Classification
In recent years, the classification scheme of PH has changed. Many clinicians continue to use the terms IPAH (also known as primary PH) and secondary PH (inconclusive of all cases of PH with known causes). The Second World Symposium on Pulmonary Hypertension, held in 1998 in Evian, France, recommended a new classification system; this system is now known as the Evian classification and is used by the WHO. In 2003, this classification was revised at the Third World Symposium (TABLE 2).⁵ The five main PH categories are PAH, pulmonary venous hypertension, PH secondary to respiratory-system disorders or hypoxemia, PH secondary to thrombotic or embolic events, and a miscellaneous category consisting mainly of PH secondary to diseases affecting the pulmonary vasculature.

Pathogenesis

The pathogenesis of PH is complex, likely multifactorial, and imperfectly understood. However, agents now exist that counteract the action (or supplement the lack thereof) of three molecular pathways known to be implicated in PH--specifically, PAH. Prostacyclin synthase in endothelial cells makes prostacyclin (PGI2); in pulmonary-artery smooth muscle cells (SMCs), PGI2 stimulates adenylate cyclase to convert adenosine triphosphate to the second messenger cyclic adenosine monophosphate (cAMP), which is responsible for maintaining pulmonary-artery SMC relaxation and inhibiting proliferation. These same endothelial cells also make nitric oxide (NO), which induces guanylate cyclase to convert guanosine triphosphate to cyclic guanosine monophosphate (cGMP), a second messenger with a mechanism of action similar to that of cAMP. In PH, levels of cAMP and cGMP are diminished, so administration of exogenous prostanoids (which increase cAMP levels) and phosphodiesterase (PDE) inhibitors (which increase cGMP levels) are beneficial.

Endothelin (ET) A and B receptors (ET_A, ET_B) also are known to be involved in PAH, and the actions of ET-1 are mediated through them. Stimulation of ET_A receptors on pulmonary-artery SMCs results in sustained vasoconstriction and cellular proliferation. In contrast, ET_B receptors on endothelial cells are theorized to be involved in the clearance of ET-1 in the vascular beds. ET_B receptor activation by ET-1 also leads to the release of vasodilatory NO and PGI2, thereby offsetting the effects of the ET_A receptor. Selective and nonselective ET antagonists are available to counteract these actions.

Additional causes of PH include receptor and transporter genetic abnormalities; serotonergic mechanisms including upregulation of the 5-hydroxytryptamine_1B receptor; downregulation of inhibition of voltage-dependent potassium channels by hypoxia and agents such as fenfluramine; inflammation; procoagulant states; and endothelial-cell dysfunction.¹

Treatment
Treatment of PH with disease-modifying therapy has been shown to improve hemodynamic measures, WHO or NYHA functional class, and six-minute walking-test distance. Improved survival has been found in uncontrolled trials and in a meta-analysis not reaching statistical significance.^6-9,10 Generally, however, loop diuretics are considered for all patients with PH who have peripheral edema and hepatic congestion. Oxygen therapy is administered to all WHO Class III patients who have PH secondary to respiratory-system disorders. WHO Class I patients also commonly receive oxygen, as do those with other classes, if hypoxic. Warfarin is prescribed for all WHO Class IV (PH secondary to thromboembolic disease) and typically Class I patients with IPAH and familial PAH, given a recent review of seven observational trials (n = 488) showing a mortality benefit.¹¹ The goal international normalized ratio (INR) is 2.0 (range 1.5–2.5), except for WHO Class IV patients, whose goal INR is 2.5 (range 2.0–3.0). Exercise training also has been shown to improve the six-minute walking distance and WHO functional class in as few as four months.¹² Some experts prescribe digoxin in patients with PH and refractory right ventricular dysfunction. Some experts also advocate its use in patients with PH taking calcium channel blockers (CCBs) to decrease the negative inotropic effects of these agents.¹³ Data regarding the use of digoxin in patients with PH and right ventricular dysfunction are limited and conflicting.^14,15 Digoxin has not been shown to provide long-term benefit or improve survival in patients with PH and right ventricular dysfunction.

WHO Clinical Class I: For PAH or WHO Class I, treatment focuses on using chronic pulmonary vasodilator therapy (CCBs, prostanoids, ET receptor antagonists, and PDE type 5 [PDE5] inhibitors) to promote pulmonary SMC vasodilation and inhibit cellular proliferation. It is not uncommon for patients to take one or a combination of these therapies. The monthly cost for each drug therapy is given in TABLE 3.¹⁶

Prior to initiating therapy, all patients other than those with portopulmonary hypertension should undergo right-heart catheterization for an acute vasodilator challenge to determine whether they are candidates for CCB therapy. Vasodilatory agents used include intravenous (IV) epoprostenol, IV adenosine, and inhaled NO. The test is deemed positive if mPAP decreases by at least 10 mmHg and to less than 40 mmHg. Roughly 13% of patients have a positive response; of these, half will have a sustained response with CCB therapy.¹⁷ CCBs should be considered first-line therapy in patients with a positive acute vasodilator response. Although trials suggest reduced mortality in PH with CCB use, evidence suggesting their benefit is limited by the lack of randomized trials comparing CCB therapy versus placebo in vasoreactive patients only.^13,17 Trials with data supporting CCB use in PH used high-dose, sustained-release therapy with titrations up to nifedipine 240 mg, amlodipine 20 mg, or diltiazem 900 mg daily. Verapamil is generally avoided due to its negative inotropic effects. Nonresponders to vasodilator testing or responders who remain in NYHA functional Class III or IV should be considered for treatment with prostanoids, ET receptor antagonists, or PDE5 inhibitors. The use of these agents for PH other than PAH has been investigated in small, uncontrolled, and often open-label studies and, as such, is often more art than science for these indications.

Mechanistically, the prostanoids overcome dysfunction in the endothelial SMCs' prostacyclin pathway to increase cAMP levels. The synthetic prostacyclin epoprostenol (Flolan) is indicated for the treatment of patients with NYHA functional Class III or IV PAH and is considered first-line therapy in functional Class IV given the small number of patients in trials of alternative agents. Compared with historical control groups, epoprostenol increased absolute three-year survival rates by approximately 20%.^6,18 Epoprostenol is given via an IV portable cassette infusion pump. It may be administered peripherally, but central venous line administration is preferred to maintain IV line integrity. Considering the drug's three- to-five-minute half-life, line loss or pump malfunction can be a life-threatening emergency, and a second drug cassette should always be prepared and a cassette pump be available to the patient. If the backup cassette is not needed as a replacement, it should be used the following day. The dose generally starts at 2 ng/kg/min and is titrated as tolerated to as high as 200 ng/kg/min, although doses of 10 ng/kg/min to 50 ng/kg/min are more commonly seen. Adverse reactions include headache, flushing, jaw pain, nausea, vomiting, diarrhea, hypotension, and anxiety. Epoprostenol is supplied in 0.5-mg and 1.5-mg vials of powder for injection. It must be diluted only with the special diluent. All of the prostanoid products must be obtained through specialty pharmacy-distribution programs.

Treprostinil (Remodulin) is another synthetic prostanoid used to treat PAH functional Class II–IV. It may be administered by continuous subcutaneous infusion--which frequently causes injection-site pain--or IV infusion. Treprostinil recently has been shown to prolong survival in patients with PAH.¹⁹ Dosing and adverse reactions are similar to those for epoprostenol. Treprostinil has two main advantages over epoprostenol: (1) its four-hour half-life allows for restarting the infusion with less urgency if the line is accidentally discontinued, and (2) its commercially available solution is simpler to prepare at home compared with the sterile manipulations required for the powdered epoprostenol. Treprostinil solution for injection should be diluted only with normal saline. Bacterial line infections, a serious consequence of IV prostacyclin therapy, may occur more commonly with treprostinil.²⁰

Iloprost (Ventavis) is an inhaled prostacyclin that has been shown to improve NYHA functional class and the six-minute walk test in doses of 2.5 mcg to 5 mcg nebulized six to nine times daily.²¹ It has not been shown to increase survival in PH. The FDA has approved iloprost for patients with PAH in NYHA functional Class III–IV. Its adverse effects are similar to those of epoprostenol and also include cough. Iloprost must be administered using a special nebulizer that calibrates the specific dose.

The nonselective ET receptor antagonist bosentan (Tracleer) and the selective ET_A receptor antagonist ambrisentan (Letairis) are oral agents used to treat PAH. Sitaxsentan (Thelin), another selective ET_A receptor antagonist, is currently undergoing FDA review. Bosentan 62.5 mg to 125 mg twice daily and ambrisentan 5 mg to 10 mg daily are indicated to improve exercise tolerance and delay clinical progression in patients with WHO functional Class III–IV and Class II–III symptoms, respectively. Bosentan also appears to have a mortality benefit compared with historical controls.²² The main adverse effect of ET receptor-antagonist therapy is hepatotoxicity, necessitating frequent monitoring with liver-function tests. These agents are teratogenic; women of childbearing potential should use two forms of contraception while taking them. Ambrisentan, a CYP450 substrate at 3A4 and 2C19, has fewer drug interactions than bosentan, a substrate and inhibitor of 3A4 and 2C9. This difference is noteworthy in that bosentan decreases the efficacy of both oral contraceptives and warfarin, whereas ambrisentan is not known to do so. Both of these ET receptor antagonists require physician, patient, and pharmacy enrollment in specialty pharmacy direct-shipment programs to ensure ongoing monitoring for hepatotoxicity and pregnancy.

The PDE5 inhibitor sildenafil (Revatio) inhibits metabolism of cGMP, resulting in relaxation and antiproliferation of pulmonary endothelial SMCs, and is FDA-approved to improve exercise tolerance in patients with PAH. Mortality rates with sildenafil have not been assessed. Doses of 20 mg and up to 80 mg three times daily have been tested in clinical trials.²³ Adverse reactions include headache, flushing, epistaxis, and dyspepsia; as in erectile dysfunction, sildenafil for the treatment of PAH is contraindicated with nitrates due to the possibility of severe hypotension. Interestingly, the PDE5 inhibitors tadalafil and vardenafil did not improve arterial oxygenation as sildenafil did in patients with PAH and NYHA functional Class II–III during short-term right heart catheterization.²⁴

WHO Clinical Class II: Treatment of PH due to left-sided cardiac disease (WHO Class II) centers on correcting the underlying valvular, atrial, or ventricular abnormality. Chronic pulmonary vasodilator therapy may be beneficial in select patients, such as those who have undergone mitral valve replacement but still have PH postprocedurally. Caution should be used, however; one trial of patients with severe left ventricular dysfunction receiving standard therapy (n = 471) noted a trend toward increased mortality in the epoprostenol group versus placebo. Potentially, the positive inotropic effect of epoprostenol is detrimental to an already-stressed heart, or the heart cannot compensate for the increased flow across a newly dilated pulmonary vascular bed.^25,26 Bosentan also has been evaluated in PH that is due to systolic dysfunction and has not been found to be beneficial.^27,28

WHO Clinical Class III: In WHO Class III PH, therapy consists of treating the underlying hypoxemia and correcting it with chronic oxygen administration. For patients with PH and obstructive sleep apnea, continuous positive airway pressure should be used. Patients with PH secondary to living at high altitude should relocate to sea level. Two trials in patients with chronic obstructive pulmonary disease and partial pressure of oxygen (PaO₂) between 55 mmHg and 60 mmHg found that oxygen therapy decreases three- and five-year mortality.^29,30 If these treatments are not completely successful and a patient remains in WHO functional Class III–IV, chronic pulmonary vasodilator therapy may be utilized. Small studies have shown benefit with sildenafil, NO, and iloprost, whereas epoprostenol may increase hypoxemia.^31-33

WHO Clinical Class IV: Up to 3% of survivors of acute pulmonary embolism develop WHO Class IV PH.³⁴ Anticoagulation to a goal INR of 2.0 to 3.0 is the primary therapy for these patients. Thromboendarterectomy is an option for patients who are still symptomatic despite anticoagulation. In addition, chronic pulmonary vasodilator therapy may be used if these treatment modalities are suboptimal, or as a bridge to surgery.

WHO Clinical Class V: The treatment of WHO Class V PH is directed at the underlying etiology whenever possible. Small studies have reported the use of prostanoids and ET receptor antagonists.^35,36

Conclusion
The treatment of PH continues to evolve as additional drug-therapy targets are found. The severity of the PH should always be determined prior to initiating treatment so that patients' responses can be compared with baseline values. Primary therapy (structural cardiac repair, chronic oxygen, anticoagulation, etc.) should be directed at the underlying cause of the PH. If this is not possible, as in PAH, or if the patient remains in WHO or NYHA functional Class II–IV, vasoreactivity testing should be performed and a CCB prescribed if appropriate. For patients with negative vasodilator tests or who become nonresponsive to CCB therapy, prostanoids, ET antagonists, or PDE5 inhibitors should be considered. Rarely, lung or heart–lung transplantation also has been performed successfully in a curative manner.

REFERENCES
1. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417-1431.
2. Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(suppl 12S):40S-47S.
3. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med.1987;107:216-223.
4. Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004;126(suppl 1):7S-10S.
5. Simonneau G, Galiè N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43(suppl 12S):5S-12S.
6. Barst RJ, Rubin LJ, McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. 1994;121:409-415.
7. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002;106:1477-1482.
8. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780-788.
9. Kuhn KP, Byrne DW, Arbogast PG, et al. Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med. 2003;167:580-586.
10. Macchia A, Marchioli R, Marfisi R, et al. A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology. Am Heart J. 2007;153:1037-1047.
11. Johnson SR, Mehta S, Granton JT. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review. Eur Respir J. 2006;28:999-1004.
12. Mereles D, Ehlken N, Kreuscher S, et al. Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation. 2006;114:1482-1489.
13. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-
channel blockers on survival in primary pulmonary hypertension. N Engl J Med.1992;327:76-81.
14. Aubier M, Murciano D, Viirès N, et al. Effects of digoxin on diaphragmatic strength generation in patients with chronic obstructive pulmonary disease during acute respiratory failure. Am Rev Respir Dis. 1987;135:544-548.
15. Rich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest. 1998;114:787-792.
16. Fleming T, ed. Red Book 2007: Pharmacy's Fundamental Reference. Montvale, NJ: Thomson Healthcare; 2007.
17. Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. 2005;111:3105-3111.
18. Shapiro SM, Oudiz RJ, Cao T, et al. Primary pulmonary hypertension: improved long-term effects and survival with continuous intravenous epoprostenol infusion. J Am Coll Cardiol. 1997;30:343-349.
19. Barst RJ, Galiè N, Naeije R, et al. Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil. Eur Respir J. 2006;28:1195-1203.
20. Bloodstream infections among patients treated with intravenous epoprostenol or intravenous treprostinil for pulmonary arterial hypertension--seven sites, United States, 2003–2006. MMWR. 2007;56:170-172.
21. Olschewski H, Simonneau G, Galiè N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347:322-329.
22. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J. 2005;25:244-249.
23. Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med.2005;353:2148-2157.
24. Ghofrani HA, Voswinckel R, Reichenberger F, et al. Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study. J Am Coll Cardiol. 2004;44:1488-1496.
25. Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1997;134:44-54.
26. Montalescot G, Drobinski G, Meurin P, et al. Effects of prostacyclin on the pulmonary vascular tone and cardiac contractility of patients with pulmonary hypertension secondary to end-stage heart failure. Am J Cardiol. 1998;82:749-755.
27. Packer M, McMurray J, Massie BM, et al. Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study. J Card Fail. 2005;11:12-20.
28. Kaluski E, Cotter G, Leitman M, et al. Clinical and hemodynamic effects of bosentan dose optimization in symptomatic heart failure patients with severe systolic dysfunction, associated with secondary pulmonary hypertension--a multi-center randomized study. Cardiology. 2007;109:273-280.
29. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med. 1980;93:391-398.
30. Medical Research Council Working Party. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet. 1981;1:681-686.
31. Ghofrani HA, Wiedemann R, Rose F, et al. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002;360:895-900.
32. Olschewski H, Ghofrani HA, Walmrath D, et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med. 1999;160:600-607.
33. Strange C, Bolster M, Mazur J, et al. Hemodynamic effects of epo­ prostenol in patients with systemic sclerosis and pulmonary hypertension. Chest. 2000;118:1077-1082.
34. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257-2264.
35. Fisher KA, Serlin DM, Wilson KC, et al. Sarcoidosis-associated pulmonary hypertension: outcome with long-term epoprostenol treatment. Chest. 2006;130:1481-1488.
36. Steiner MK, Preston IR, Klinger JR, et al. Conversion to bosentan from prostacyclin infusion therapy in pulmonary arterial hypertension: a pilot study. Chest. 2006;130:1471-1480.

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