Pulmonary hypertension (PH) is a hemodynamic condition defined by pulmonary arterial systolic pressure (PASP) above an upper limit of 35mmHg, or by pulmonary arterial mean pressure (PAMP) exceeding 25mmHg at rest.1,2 Pulmonary arterial hypertension (PAH) is present when pre-capillary pulmonary vascular pressure is elevated in the absence of pulmonary capillary wedge pressure >15mmHg, such as that associated with left ventricular dysfunction or valve disease, or obstruction of the pulmonary veins. PH can be suspected on the basis of symptomatic presentation (though may be present in the absence of symptoms), physical examination and transthoracic Doppler-echocardiogram. Chest X-ray and electrocardiogram, while important for assessment of co-existing conditions, may be supportive of a diagnosis of PH but is not definitive in determining the presence of PH.3 Echocardiography, by assessment of the tricuspid and pulmonary regurgitant velocities and application of the modified Bernoulli equation, estimates PASP and pulmonary artery diastolic pressure. Although the estimated value correlates well with invasively measured hemodynamics,4 individual variation and inaccuracy requires that right heart catheterization be performed for definitive evaluation of pulmonary hemodynamics, including response to vasoactive agents.
Pulmonary hypertensive disorders have been classified according to the World Health Organization (WHO) definition of 1998 and modified by an international symposium in 2003 (see Table 1).5 The schema of classification is based on a combination of pathological features, clinical constellation, hemodynamics, and management strategies. Idiopathic pulmonary arterial hypertension (IPAH; also called primary pulmonary hypertension (PPH)) is a rare illness affecting all ages, but predominantly young to middle-aged women. A genetic type of IPAH has been identified, associated with mutations of the gene coding for the bone morphogenic protein receptor.6,7 The low incidence of both sporadic and familial IPAH (approximately one to five per million in the US) and subtle signs at early stages makes it difficult to recognize. Improving physician awareness and widespread availability of non-invasive screening by echocardiography, however, are shortening the delay to the time of diagnosis. When other types of PAH are considered, the prevalence increases substantially. Moreover, the diagnosis of PH based on echocardiography includes patients who may have left-sided cardiac abnormalities, hypoxemic or parenchymal lung disease, or chronic pulmonary thromboembolic disease. Since the management of PAH (idiopathic or in association with connective tissue disease, HIV infection, prior appetite suppressant use or other toxic exposures, EisenmengerÔÇÖs syndrome, or portal hypertension) differs from PH due to chronic thromboembolic disease, lung disease, and left heart etiologies, accurate diagnostic distinction is essential.A general process for evaluating PH is illustrated in Figure 1.
The untreated natural history of PAH is one of progressive symptoms of dyspnea and right heart failure culminating in a markedly curtailed survival (mean 2.8 years). Medical treatment can now provide improved life expectancy with more stable and tolerable symptoms. Because of their complex nature, however, the use of these agents has been largely focused in multidisciplinary referral centers with dedicated PH clinics and specialized personnel who provide follow-up including careful reassessment and modification of treatment.
Therapeutic Strategy
Treatment is dictated by multiple factors:
- severity of disease and symptoms;
- specific type of PAH;
- access to and ability to use expensive, complex medications; and
- acute vasodilator responsiveness.
Vasodilator Assessment
Right heart catheterization, including assessment of response to pulmonary vasodilators, is a pivotal component of the evaluation of PH.8 Following careful assessment of baseline hemodynamics and confirmation of pre-capillary pulmonary hypertension, a pulmonary vasodilator (inhaled nitric oxide, or infused prostacyclin or adenosine) is administered and the peak effect is noted. Patients with PAH who acutely respond to vasodilators (by demonstration of a decrease in PAMP and pulmonary vascular resistance by >20%) have improved survival when treated with calcium channel blockers (CCB). Patients with a vasodilator response of this magnitude who are treated with a CCB have a reported survival of up to 94% at five years (compared with 38% in those who failed to respond and were not treated with a CCB).9 A decrease of PAMP by at least 10mmHg to less than or equal to 40mmHg, with an increased or unchanged cardiac output has been adopted as a criterion for portending a beneficial response to CCBs.8 The likelihood of demonstrating an acute response in IPAH is less than 10%, however, and even less in patients with substrates such as connective tissue disease or congenital heart disease. Patients who are unstable have WHO Class IV symptoms or severe right heart failure never do well with calcium channel blockers and need not undergo vasodilator assessment. These patients and vasodilator nonresponders require treatment with an alternative agent.
Approve d Treatment
Since 1996, three drugs have been approved by the US Food and Drug Administration (FDA) for use in patients with PAH (see Table 2).
Epoprostenol
Prostacyclin, a potent endogenous vasodilator with platelet anti-aggregatory effects, is deficient in patients with PAH. Randomized studies and subsequent reports have shown that epoprostenol sodium, a synthetic prostacyclin analog, improves exercise capacity, quality of life, hemodynamics in IPAH and PAH related to scleroderma, and improved survival in patients with IPAH.10,11 Survival of IPAH patients treated with epoprostenol therapy is 85% to 88%, 70% to 76%, and 63% at one, two, and three years, respectively (compared with expected survival of 59%, 46%, and 35%).12,13 Epoprostenol treatment is complicated.The drug must be given by continuous intravenous infusion through an indwelling central line. It is unstable at room temperature, so the supply must be changed frequently (at least three times a day) or kept cool, necessitating somewhat bulky ice packs surrounding an administration pump. Epoprostenol (Flolan®; GlaxoSmithKline) is extremely expensive (up to US$100,000 or more per year in commonly used dose ranges). Finally, patients are exposed to significant side-effects and risks. Common side-effects of epoprostenol include headache, flushing, jaw pain, diarrhea, nausea, dermatitis, and painful leg discomfort. Infection of the central venous catheter may occur. Sudden interruption of the infusion may cause rebound severe PH and death.
Despite the improvement in symptoms, longevity, and exercise capacity (as measured by the distance an individual can walk on level ground in six minutes) seen in many patients, hemodynamic improvement tends to be relatively modest. Benefit in some, if not most, patients may be due to stabilization and prevention of progression of the disease with its attendant right heart failure. Many investigators feel that much of the benefit over time may result from anti-proliferative properties of the drug which lead to beneficial vascular reverse remodeling. A salutary inotropic effect of the drug has also been postulated.
Treprostinil
Treprostinil (Remodulin®; United Therapeutics Corporation) is a prostacyclin analog with a half-life of three hours. In contradistinction to epoprostenol, it is stable at room temperature. Because of its stability, longer half-life, and a documented equivalent hemodynamic effect when administered subcutaneously, it avoids the use of an intravascular catheter. Instead, it is given via a tiny subcutaneous catheter using a small pump that does not require an ice-pack.The medication is provided in usable form, rather than requiring daily mixing of active compound with a diluent (as epoprostenol does) by the patient. Compared with placebo, treprostinil tends to improve exercise capacity on six-minute-walk testing, quality of life, and hemodynamics, but the benefits are quite limited.14,15 At higher doses and among more symptomatic patients, the beneficial effects are more pronounced. Treprostinil exhibits a similar side-effect profile to epoprostenol, but an additional concern is the frequent occurrence of pain at the infusion site. This may limit the ability to raise doses to a level most likely to produce optimal benefit.The expense of treprostinil is also similar to epoprostenol. Thus, the advantages of treprostinil are the absence of a central venous catheter, a smaller infusion pump set-up, and availability of drug that does not require reconstitution by the patient. The feasibility and efficacy of using treprostinil intravenously to take advantage of its ease of use while avoiding site pain is being explored.
Bosentan
Bosentan (Tracleer®; Actelion, Inc.) is a nonselective endothelin receptor antagonist, blocking the action of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen, at endothelin receptor sub-types A and B (ETA and ETB). Its therapeutic effect is due to reduction of vasoconstriction and pulmonary vascular hypertrophy caused by increased plasma levels of ET-1 in patients with PAH,and mediated predominantly via ETA receptors. As with the prostanoids above, the demonstrable clinical vasodilatory effect of the drug is quite modest in patients with established PAH,16 but clinical studies of bosentan have demonstrated an augmented six-minute-walk distance compared with placebo and improved functional classification over 16 weeks,17 leading to FDA approval of the medication. Some of its benefit may be related to anti-proliferative and anti-fibrotic effects that stabilize the disease process and promote remodeling. Side-effects associated with bosentan include dose-dependent elevation of transaminases reflecting hepatic toxicity, syncope and flushing.
Drug interactions with glyburide and cyclosporine are recognized; bosentan may interfere with the action of hormonal contraceptives. The medication is administered orally in pill form twice daily and liver function tests are monitored monthly. Like the prostanoids, it is extremely expensive, costing over US$30,000 annually.
Other Medications
In addition to the FDA-approved agents and CCBs, other agents have been and are currently being used or investigated as treatment modalities (see Table 2).
Other Prostanoids
Iloprost is a stable prostacyclin analog available for intravenous, oral, and aerosolized administration. Inhaled therapy delivers drugs to ventilated alveolar units where local pulmonary arteries vasodilate, thereby enhancing ventilation-perfusion matching. Iloprost improves functional class, exercise capacity, and pulmonary hemodynamics in open and randomized studies, with side-effects of flushing, headache, and cough in some patients.18,19 The relatively short duration of action of inhaled iloprost requires between six and nine five- to 15-minute inhalations daily to obtain a sustained clinical benefit. Co-administration of iloprost with other pulmonary vasoactive agents such as sildenafil reportedly augments and prolongs the duration of action.20-22 Iloprost is approved in Europe for symptomatic IPAH and studies in the US are in the early stages. Beraprost is a stable oral prostacyclin analog that has been used clinically in Japan based predominantly on uncontrolled studies suggesting improved hemodynamics and six-minute-walk distance.23,24 Subsequent randomized studies have yielded variable results,25,26 suggesting an early modest clinical benefit that markedly attenuates or vanishes during follow-up of six to 12 months. FDA approval ultimately was not sought.
Other Endothelin Receptor Antagonists
Sitaxsentan and ambrisentan are ETA receptor-selective agents currently undergoing randomized studies. Initial Phase III study results suggest that sitaxsentan improves exercise capacity, functional class, and pulmonary hemodynamics at 12-week follow-up.27 Ambrisentan Phase II pilot studies have recently been completed and suggested sufficient benefit28 to proceed with Phase III international clinical investigation.
Nitric Oxide, Nitric Oxide Donors and Phosphodiesterase Inhibitors
Nitric oxide (NO) is an endogenous vasodilator produced from L-arginine by nitric oxide synthase in endothelial cells. NO has a pivotal function in regulating basal vascular resistance. In vascular smooth muscle cells, it promotes conversion of GTP to cyclic GMP. Cyclic GMP is a second messenger that leads to a cascade of events that reduces entry of calcium ions into smooth muscle cells, thereby producing vasodilation. Intracellular cyclic GMP levels are regulated by phosphodiesterases that catalyze its degradation to 5ÔÇÖGMP. Agents that inhibit the predominant phosphodiesterase (PDE) in the pulmonary vasculature (PDE5) consequently have a net effect of boosting the pulmonary vascular response to endogenous NO. Sildenafil (Viagra┬«; Pfizer) is a potent and highly specific PDE5 inhibitor used for treatment of erectile dysfunction since PDE5 is present in the corpus cavernosum. Since PDE5 is the predominant PDE in the pulmonary vascular bed, the use of sildenafil to generate pulmonary vasodilation is conceptually attractive. Animal studies, anecdotal reports, uncontrolled case series, and small controlled trials suggest that sildenafil may have salutary effects in PAH, either alone or in combination with other medications.21 A larger prospective multicenter blinded controlled study has been completed and the results are expected in late 2004.The possibility that other PDE5 inhibitors, such as tardalafil (Cialis┬«; Lilly) or vardenafil (Levitra┬«; Bayer/GlaxoSmithKline) may be efficacious has not been tested.
Studies have shown that inhaled NO is a vasodilator in a variety of pulmonary hypertensive states, supporting its use in pulmonary vasodilator testing29,30 and acute pulmonary hypertensive states post-operatively.31 Rare patients have been treated chronically with inhaled NO therapy.32,33 Studies of L-arginine administered to supplement the substrate for NO production are limited, but may suggest a hemodynamic benefit.34
Combination Therapy
Combining medications with different mechanisms of action has not been systematically explored, but growing experience suggests that empirical multidrug therapy may produce additive benefit in some patients, or allow use of doses less likely to produce adverse effects.
Adjunctive Therapy
In general, patients with PAH are treated with warfarin in conservative doses aiming for an international normalized ratio (INR) of 2.0-2.5.The use of chronic anticoagulation is predicated on the results of two retrospective studies that demonstrate an apparent survival benefit,35,36 possibly due to minimization of in situ small vessel thrombosis. PAH results in right ventricular pressure overload and eventual right ventricular failure. Inotropic support with digoxin is appropriate under these circumstances, and diuretics are frequently required to manage resulting intravascular volume overload, peripheral edema, ascites and hepatic congestion. Hypoxemia due to reduced diffusing capacity, low cardiac output and low mixed venous oxygen saturation, suboptimal ventilation-perfusion matching, and right-to-left shunting of blood through a patent foramen ovale may necessitate the use of supplemental oxygen.
Speculative Therapy
Hypothetical considerations, cellular studies, and/or early anecdotal reports have raised possible new avenues of treatment for patients with or at risk of developing PAH (see Table 2). Whether appropriately rigorous clinical studies are ever performed examining these approaches remains an open question.
Summary
The spectrum of medical treatment for PAH has expanded in the last decade. While providing benefits including increased longevity for many patients, the available therapies remain essentially palliative. Moreover, the options of various medications and investigational protocols has made treatment more complex rather than simpler. Because of this, management of most patients seems to be most appropriately directed to facilities with expertise, experience and involvement in clinical studies.