Chest
Volume 126, Issue 1, Supplement, July 2004, Pages 35S-62S
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Medical Therapy For Pulmonary Arterial Hypertension: ACCP Evidence-Based Clinical Practice Guidelines

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Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. This chapter will provide evidence-based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center.

Section snippets

Overview of the Approach to the Patient With PAH

The treatment of PAH begins with a thorough evaluation seeking underlying causes and contributing factors. The diagnosis of PAH is thoroughly discussed in Chapter 2. Initial therapy may be directed at the underlying cause or contributing factor, with examples including supplemental oxygen for hypoxemia, continuous positive airway pressure therapy and supplemental oxygen for obstructive sleep apnea, anticoagulation, and consideration of pulmonary thromboendarterectomy for PAH due to

Vasodilator Testing

Patients with IPAH who respond to vasodilators acutely have an improved survival with the long-term use of a CCB. As such, testing of vasoreactivity is an important part of the evaluation of any patient with PAH. Over the years, investigators have used a number of agents to acutely test vasodilator responsiveness, and have used various definitions of a response including reductions in either pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), or both. These different

Introduction/Rationale

Prostacyclin is a metabolite of arachidonic acid produced primarily in vascular endothelium. It is a potent vasodilator, affecting both the pulmonary and systemic circulations. It also has antiplatelet aggregatory effects, and the pathology of the disease may include microscopic in situ thromboses. There is evidence to suggest that a relative deficiency of prostacyclin may contribute to the pathogenesis of PAH. In a landmark study, Christman et al9 reported a deficiency of prostacyclin and

Introduction/Rationale

Endothelin-receptor antagonism is a promising therapeutic approach supported by increasing evidence of the pathogenic role of endothelin-1 in PAH.38 Endothelin-1 is a potent vasoconstrictor and a smooth-muscle mitogen that might contribute to the increase in vascular tone and the pulmonary vascular hypertrophy associated with PAH.39 In addition, endothelin-1 expression, production, and concentration in plasma4041 and lung tissue42 are elevated in patients with PAH, and these levels are

Rationale

Mechanisms that modulate cyclic guanosine 3′-5′ monophosphate (cGMP) content in vascular smooth muscle play critical roles in the regulation of vascular tone, growth, and structure. The vasodilator effects of NO are dependent on its ability to augment and sustain cGMP content in vascular smooth muscle. Once produced, NO directly activates soluble guanylate cyclase, which increases cGMP production. cGMP then activates cGMP kinase, opens potassium channels, and causes vasorelaxation. The effects

Rationale

NO contributes to the maintenance of normal vascular function and structure. Recognition of the importance of NO as an endogenous vasodilator77 was followed by experimental and clinical observations indicating its physiologic roles in the maintenance of normal basal vascular resistance.777879 That deficient function of the NO signaling system may be an important contributor to the pathogenesis of diverse cardiovascular disorders has come from abundant observations of impaired

Combination Therapy

With the development of therapeutic agents with different mechanisms of action, considerable interest has developed in the possibility of combination therapy, similar to the strategies utilized in the treatment of systemic hypertension and many forms of cancer. Some agents, such as phosphodiesterase inhibitors, might enhance and prolong the effects of others, like the prostanoids. Other combinations might simply approach the problem of PAH from different mechanistic angles, and therefore have

Children

In decades past, the early presentation of severe PAH during infancy or early childhood was typically associated with a rapidly progressive disease and fatal outcome. The National Institutes of Health PPH Registry in the 1980s initially suggested a worse survival in children < 16 years of age, with a mean survival of 10 months in contrast to adults, in whom the mean survival was 2.8 years after diagnosis.135 However, this study135 included only small numbers of pediatric cases, and preceded the

Summary

The treatment of PAH is advancing rapidly. Multicenter RCTs have provided a basis for evidence-based practice. The treatment algorithm (Fig 1) attempts to summarize the current approach to therapy for PAH. Recommendations regarding therapy obviously need to be applied in light of the individual patient's specific situation. The importance of a thorough diagnostic evaluation, looking for underlying causes and contributing factors, cannot be overemphasized. Educational efforts have contributed to

Summary of Recommendations

  • 1.

    Patients with IPAH should undergo acute vasoreactivity testing using a short-acting agent such as IV epoprostenol, adenosine, or inhaled NO. Level of evidence: fair; benefit: substantial; grade of recommendation: A.

  • 2.

    Patients with PAH associated with underlying processes, such as scleroderma or congenital heart disease, should undergo acute vasoreactivity testing. Level of evidence: expert opinion; benefit: small/weak; grade of recommendation: E/C.

  • 3.

    Patients with PAH should undergo vasoreactivity

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