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Pulmonary Arterial Hypertension
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Improvement in cardiopulmonary hemodynamics, exercise capacity, functional class, survival, and prevention of clinical worsening are the goals of PAH treatment. General measures in the management of PAH include symptom-limited, regular exercise to maintain skeletal muscle conditioning and overall cardiovascular fitness. Intense exercise should be avoided, especially if the patient with PAH has a history of exercise-induced syncope or presyncope. Patients should avoid high altitudes, and supplemental oxygen should be provided for air travel. Since patients with PAH have reduced cardiopulmonary reserve, immunization against influenza and pneumococcus is recommended.
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Pregnancy in PAH deserves special attention. Patients with PAH should be counseled to avoid pregnancy because it is associated with significant (30%) mortality. Birth control should be discussed and contraceptive methods prescribed in women of childbearing age. Hemoglobin levels should be monitored regularly. In patients with Eisenmenger syndrome, erythrocytosis should be treated with phlebotomy only if symptoms of hyperviscosity develop. Patients with PAH should refrain from smoking and adhere to a sodium-restricted diet in the setting of right heart failure.
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Patients with PAH require supplemental oxygen if they exhibit arterial oxygen desaturation at rest or with minimal exertion. Patients with PAH, particularly idiopathic PAH, should receive oral anticoagulant therapy with a goal international normalized ratio (INR) of 1.5 to 2.5. This recommendation is based on several nonrandomized clinical trials showing improved survival in patients with idiopathic PAH treated with warfarin.
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Diuretic therapy is the mainstay of treatment for symptomatic PAH with volume overload. Digoxin may also help improve right-sided hemodynamics and is the preferred rate-controlling agent in the setting of atrial tachyarrhythmia. Digoxin has also been shown to reduce circulating catecholamine levels in patients with chronic PAH. However, no other data exist regarding the efficacy of cardiac glycosides (ie, digoxin) in PAH with right ventricular failure. Digoxin toxicity, especially in patients with severe hypoxia, renal insufficiency, or hypokalemia, is well recognized and warrants vigilance.
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In patients with PAH and decompensated right heart failure, strategies to improve clinical status and restore end-organ perfusion include (1) afterload reduction with pulmonary vasodilators, such as oxygen, inhaled nitric oxide, prostanoids, endothelin receptor antagonists, and phosphodiesterase inhibitors; (2) preload reduction with diuretics or ultrafiltration; and (3) augmentation of right ventricular function with inotropic therapy. Intravenous inotropes such as low-dose dobutamine or dopamine (1–2 mcg/kg/min) are of particular benefit in patients with right ventricular failure and hypotension in whom diuretic therapy is ineffective or in whom renal failure has developed (Figure 30–12).
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Until 1996, high-dose calcium channel blockers were the only vasodilators available to treat PAH. Calcium channel blocker therapy may reduce PA pressure and right ventricular afterload, thereby improving right ventricular hemodynamics and increasing CO. Vasoreactivity testing identifies a subset of idiopathic PAH patients (less clear for the general PAH cohort) who may benefit from calcium channel blocker therapy. If a patient with PAH has a favorable response to acute vasodilator testing, a hemodynamically monitored trial of an oral calcium channel blocker, such as nifedipine, amlodipine, or diltiazem, may be undertaken. If a reduction in PA pressures occurs with preservation of CO, then the patient can be considered for long-term therapy. Verapamil is contraindicated due to its significant negative inotropic properties. Response to calcium channel blocker therapy should be assessed during a repeat RHC.
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There are several limitations to calcium channel blocker therapy. Use of a calcium channel blocker is not advisable in patients with severe right ventricular failure or hypotension. Calcium channel blocker therapy is contraindicated in the absence of a positive vasoreactivity trial or a favorable hemodynamic response. Lastly, only a small percentage (< 7%) of patients with PAH who have acute vasoreactivity will have a sustained response to long-term calcium channel blocker therapy; therefore, close monitoring during calcium channel blocker therapy is needed.
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Fortunately, the following drugs have been approved as alternatives for the treatment of PAH: oral bosentan and ambrisentan, oral sildenafil and tadalafil, inhalational iloprost and treprostinil, subcutaneous/intravenous treprostinil, and intravenous epoprostenol. These agents target the endothelin, nitric oxide, and prostacyclin pathways (Figure 30–13). These pathways are thought to mediate vascular tone and arterial remodeling. When used appropriately, these pulmonary vasodilators can improve symptoms and exercise capacity. Most of these agents delay time to clinical worsening. Only epoprostenol has been shown to improve survival in a randomized trial (Table 30–4).
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Endothelin-1 is secreted by vascular endothelial cells and is a potent vasoconstrictor and mediator of smooth muscle cell proliferation. In addition, endothelin-1 enhances vascular fibrosis, increases platelet aggregation, promotes cardiac myocyte hypertrophy, and increases aldosterone production. Endothelin-1 is secreted in response to a variety of stimuli, including hypoxemia, endothelial sheer and pulsatile stress, and neurohormonal activation, as well as PH-related growth factors and cytokines.
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Bosentan is an endothelin-A and -B receptor antagonist approved for the treatment of functional class III and IV PAH. Bosentan has been shown to increase 6-minute walk distance, decrease symptom burden, and delay clinical worsening in patients with idiopathic PAH and patients with associated PAH secondary to scleroderma (see Table 30–4). Bosentan also appears to have benefit in symptomatic patients with PAH secondary to congenital heart disease and Eisenmenger syndrome.
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Transaminitis develops in approximately 11% of patients treated with bosentan, and monthly liver function testing in patients treated with bosentan is required. Transaminitis is usually reversible with cessation of treatment. A drop in hemoglobin is common and is usually not clinically significant; however, periodic monitoring of hemoglobin is recommended. Bosentan is highly teratogenic, and treated patients of childbearing potential must reliably utilize approved contraception and undergo monthly pregnancy testing. Side effects associated with bosentan include nasal congestion, flushing, anemia, and lower extremity edema.
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Ambrisentan is a selective endothelin-A receptor antagonist that has recently been approved in the United States for PAH for functional class II and III patients. Ambrisentan significantly improves exercise capacity, delays time to clinical worsening, and improves cardiopulmonary hemodynamics. The incidence of transaminitis is approximately 3% at 1 year. Monthly liver function testing is no longer mandatory, but most experts still monitor liver function every 3–6 months. Importantly, ambrisentan has no significant interactions with warfarin or sildenafil. The drug is teratogenic, and so, as with bosentan, pregnancy must be avoided. Ambrisentan can cause peripheral edema, nasal congestion, and flushing.
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In patients with PAH, nitric oxide bioavailability is significantly reduced. Nitric oxide is secreted by the endothelial cell and diffuses to the smooth muscle cell where it mediates vasodilation and exerts an antiproliferative effect via activation of the cyclic guanyl monophosphate (cGMP) pathway.
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The nitric oxide pathway can be enhanced by administering exogenous inhaled nitric oxide. It can also be enhanced by inhibiting phosphodiesterase isoform-5, the enzyme responsible for the degradation of cGMP. Sildenafil and tadalafil are oral phosphodiesterase-5 (PDE-5) inhibitors known to dilate the PA bed without increasing left-sided filling pressures. They are approved for treatment of PAH patients with functional class II–IV symptoms. When administered long term, both agents improve exercise capacity, reduce symptom burden, and improve cardiopulmonary hemodynamics (see Table 30–4). Tadalafil but not sildenafil has been shown to delay clinical worsening. Tadalafil is dosed once daily compared to three times daily dosing for sildenafil. PDE-5 inhibitors can cause headache, flushing, dyspepsia, epistaxis, and visual changes.
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Prostacyclin (PGI2) is a direct pulmonary and systemic vasodilator as well as an inhibitor of vascular remodeling and platelet aggregation. Prostacyclin is secreted by the endothelial cell and exerts its vascular effect by stimulating smooth muscle cell cyclic adenyl monophosphate (cAMP). The PGI2 pathway is downregulated in PAH. To enhance this pathway, exogenously synthesized epoprostenol (prostacyclin) and other prostanoids can be administered. Currently, Food and Drug Administration–approved prostanoids for PAH are administered through intravenous, subcutaneous, or inhalational routes. A summary of the pivotal trials that have led to approval of these agents for PAH is provided in Table 30–4.
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Epoprostenol has a short half-life and is unstable if exposed to room temperature or light. It is degraded by gastric pH and must therefore be administered via continuous intravenous infusion. When added to conventional therapy, epoprostenol has been shown to improve exercise capacity, reduce symptom burden, improve cardiopulmonary hemodynamics, and reduce mortality in patients with PAH who have NYHA class III–IV symptoms. Major adverse effects of this agent relate to its complex delivery system and include infection, thrombosis, and pump malfunction. Due to its short half-life, brief interruption of epoprostenol infusion can result in rebound PH and cardiopulmonary collapse. Prostanoids, as a class, are known to cause headache, flushing, nausea, vomiting, diarrhea, arthralgias, myalgias, and jaw pain. Newer temperature-stable formulations of epoprostenol may simplify administration.
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Treprostinil is a prostanoid that is premixed, stable at room temperature, and has a longer half-life than epoprostenol. Treprostinil can be administered subcutaneously as well as intravenously. In patients with NYHA class II–IV PAH, treprostinil improves exercise capacity, reduces symptoms, and improves cardiopulmonary hemodynamics (see Table 30–4). Inhalational iloprost has also been shown to improve clinical outcomes in patients with symptomatic PAH. Iloprost must be administered six to nine times daily to maintain efficacy. Treprostinil can also be administered by inhalation and is dosed four times daily. While iloprost and treprostinil have advantages over epoprostenol, epoprostenol is the only prostanoid shown to reduce mortality in advanced PAH.
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Choosing the correct treatment regimen for the patient with PAH relies on an understanding of the underlying disease and of patient-specific factors. Disease severity, as assessed by integration of hemodynamic, clinical, and laboratory parameters, is crucial in selecting the appropriate treatment (Table 30–5; see Figure 30–11). Individual patient factors, such as comorbidities (ie, liver disease), concomitant drug therapy, or a history of medication nonadherence, may all influence treatment choice (Figure 30–14).
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Invasive treatment options for PAH include atrial septostomy, lung transplantation, and combined heart-lung transplantation. Atrial septostomy has been performed as a palliative measure for patients with PAH and right heart failure or recurrent syncope. It is postulated that a right-left shunt in this setting improves left ventricular filling and CO. Atrial septostomy can, however, worsen hypoxia and increases the likelihood of paradoxical embolization. As such, it is recommended that atrial septostomy be performed only at experienced centers. Outcomes with lung and combined heart-lung transplantation are improving. One-year survival posttransplantation is 70%, and 5-year survival is 50%. Transplantation is reserved for PAH patients with heart failure and poor quality of life who continue to deteriorate despite maximal medical therapy.
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Pulmonary Hypertension with Left-Sided Heart Disease
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PH occurs in 25–30% of patients with left-sided heart disease and is associated with worse outcomes in this population. Treatment is dictated by the underlying disease process. Surgical or percutaneous treatment of aortic or mitral valve disease and treatment of coronary artery disease should be aggressively pursued as these interventions can improve left-sided filling pressures, reduce PA pressure, and improve symptoms. Standard therapy for systolic and diastolic heart failure is recommended. Supplemental oxygen is required for those who exhibit systemic oxygen desaturation.
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Although limited data are available, oral or intravenous vasodilators (eg, nitrates or sildenafil, nitroprusside, nesiritide, milrinone) are sometimes used for the management of refractory cases of PH with left-sided heart disease. Calcium channel blocker therapy, with the possible exception of amlodipine, is contraindicated in systolic heart failure with PH. Endothelin-receptor antagonists are also contraindicated in left-sided heart failure because they have been shown to worsen heart failure and increase mortality. Intravenous epoprostenol is also contraindicated in the treatment of advanced systolic heart failure because it has been shown to increase mortality. Mechanical circulatory-assist devices and heart-lung transplantation are other therapies available for PH due to left-sided heart disease.
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Pulmonary Hypertension Associated with Lung Disease or Hypoxemia
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PH in persons with lung disease or hypoxemia, or both, is best relieved by treating the underlying disease. In this cohort, correction of hypoxemia is especially important. Bronchodilator therapy should be optimized for patients with obstructive pulmonary disease. Continuous positive airway pressure and weight loss often aid in the treatment of PAH patients with sleep-disordered breathing. Inflammatory conditions that lead to ILD should be sought and aggressively treated with anti-inflammatory agents. Specific pulmonary vasodilator therapy is controversial for PH associated with lung disease on the basis of insufficient evidence.
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Cor pulmonale, or right heart failure secondary to lung disease, often develops in patients with PH. As previously outlined for PAH, sodium restriction and diuretics are the mainstays of right heart failure therapy. Digoxin and vasodilator therapy may be considered, although outcome data are lacking. For select, severely symptomatic patients with PH and lung disease, lung transplantation can improve quality of life and survival.
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Pulmonary Hypertension Due to Chronic Thrombotic or Embolic Disease
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Mortality in patients with CTEPH is high, and CTEPH should be excluded in all patients undergoing evaluation for PH. Patients with CTEPH in whom conventional pulmonary angiography demonstrates proximal surgically accessible disease may be candidates for PTE. At experienced centers, perioperative mortality following PTE is as low as 4.4%. Following PTE, most patients experience marked improvement in PAP, right heart function, NYHA class, and exercise capacity.
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Residual PH occurs in approximately 10% of patients after PTE and appears to be linked to the degree of small vessel arteriopathy. Pathophysiologic similarities between PAH and CTEPH have prompted investigation into the usefulness of pulmonary vasodilator therapy for PH that persists after PTE and as bridging therapy. Encouraging data are emerging from small nonrandomized trials showing hemodynamic improvement in chronic thromboembolic PH patients with vasodilator therapy. The role for medical treatment in chronic thromboembolic PH is as yet incompletely defined and is an area of ongoing research.
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