Pulmonary arterial hypertension: newer treatments are improving outcomes.
* Echocardiography is useful for screening high-risk patients (SOR: A).
* The New York Heart Association classification of dyspnea has been modified by the World Health Organization to categorize pulmonary hypertension by the severity of symptoms, which, unlike pulmonary arterial pressure, correlates well with survival (SOR: A).
* Calcium channel blockers are useful only for patients who respond to vasodilator testing in a cardiac catheterization laboratory (SOR: A).
* Therapeutic modalities now include parenteral prostanoids, oral endothelin receptor antagonists, PDE5 inhibitors, and lung transplantation (SOR: A; for PDE5 inhibitors, SOR: B)
* Early referral to expert centers is crucial to patient survival (SOR: B).
Recent progress in understanding the pathobiology of pulmonary arterial hypertension (PAH) has been tremendous, and treatment options have multiplied to include prostanoids, endothelin antagonists, phosphodiesterase-5 inhibitors, anticoagulants, and surgical options such as lung transplantation and atrial septostomy.
Although idiopathic pulmonary arterial hypertension, formerly called "primary," is rare, other forms of PAH and associated cor pulmonale are more prevalent than conventionally believed. It is a life-threatening disease best managed within a diagnostic framework such as the one reviewed here with a treatment algorithm and recommendations from evidence-based guidelines.
* PATIENTS MOST LIKELY TO EXPERIENCE PULMONARY ARTERIAL HYPERTENSION
Pulmonary arterial hypertension may be idiopathic and sporadic (IPAH), familial (FPAH), or associated with (APAH) connective tissue diseases, congenital systemic to pulmonary shunts, portal hypertension, HIV, drugs including anorexigens or cocaine, and other disorders (Table 1). (1)
Annually, 1 to 2 cases of IPAH occur per million Population. (2) The mean age at diagnosis is 36 years, and women are affected more often than men by a ratio of 1.7-3.5:1. This female predominance has also been noted in PAH associated with scleroderma, (3) congenital heart disease, (4) and anorexigen-induced PAH. (5) The incidence among users of anorexigens such as fenfluramine, dexfenfluramine, and aminorex is estimated to be 25 to 50 per million per year. (2)
The prevalence of portopulmonary hypertension is about 0.73% in cirrhosis. (6) In scleroderma, the incidence is between 6% to 60%, (7,8) while in systemic lupus erythematosus (SLE) it is reported to be 4% to 14%. (9,10) In one study, 21% of rheumatoid arthritis patients without underlying cardiopulmonary disease had mild pulmonary hypertension (PH). (11) PAH occurs in about 0.5% of patients with HIV infection. (12)
Included in the "others" group are hemoglobinopathies such as sickle cell anemia. This classification does not include PH due to end-stage renal disease, a recently described entity in patients with arteriovenous fistulae that portends a poorer prognosis. (13) PH was present in a surprising 40% of hemodialysis patients.
* CLINICAL PRESENTATION
Pulmonary arterial hypertension manifests the following symptoms and signs:
* Progressive onset of exertional dyspnea (60%) (14)
* Chest pain or discomfort (17%)
* Palpitations (5%)
* Dizziness and light-headedness. There may be a history of near-syncope or syncope (13%)
* Fatigue (19%)
* Ortner's syndrome: hoarseness from compression of left recurrent laryngeal nerve by enlarged pulmonary artery (<1%) (See Ortner's syndrome)
* Raynaud's phenomenon (10%)
* Loud P2 (93%)
* Tricuspid regurgitation murmur (40%)
* Right ventricular heave
* Jugular venous distention with a prominent "a" wave
* Graham Steell's murmur: diastolic pulmonary regurgitation murmur best heard at upper left sternal border (13%)
* Signs of right heart failure including S3 gallop, "v" wave in central venous pressure tracing, hepatojugular reflux, peripheral edema, and ascites
* Cutaneous telangiectasia.
* AN EFFICIENT DIAGNOSTIC FRAMEWORK
Proceed with a stepwise assessment (Figure 1) of any patient exhibiting signs or symptoms suggestive of PH, particularly if there is an associated underlying condition or suggestive imaging study. Echocardiography (ECG) is usually the first test ordered, to detect thickening of the right ventricle or regurgitation of blood into the right atrium. ECG is neither sensitive nor specific for PAH. Not every patient will require the full work-up outlined in Figure 1. The sequence and extent of testing depend on the clinical scenario. Cardiac catheterization is sometimes the last procedure, given its risks of invasiveness. A surface echocardiogram has a sensitivity of 79% to 100% and specificity of 60% to 98% for detecting PAH. (15)
Functional assessment most important
Mean blood pressure above 25 mm Hg at rest or systolic pressure over 40 mm Hg in the pulmonary circulation constitutes pulmonary hypertension (see Pulmonary hypertension criteria). However, the correlation of mean pulmonary arterial pressure to disease severity is not straightforward. (16) Higher pulmonary artery pressure may portend better survival. The severity of pulmonary arterial hypertension is better determined by functional assessment. The New York Heart Association (NYHA) classification of dyspnea has been modified by the World Health Organization (WHO) to categorize PH by the severity of symptoms, which, unlike pulmonary arterial pressure, correlates well with survival. Even with epoprostenol treatment, functional class III patients have a survival of 60% at 7 years compared with less than 20% for class IV. (17)
Class I: Patients with pulmonary hypertension but without limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.
Class II: Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class III: Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.
Class IV: Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea or fatigue may be present even at rest. Discomfort increases with any physical activity.
* CHOOSING FROM AMONG IMPROVED THERAPEUTIC OPTIONS
Main therapeutic goals are to prevent or reverse vasoconstriction, inhibit smooth muscle proliferation, impede thrombosis, and thereby reduce right ventricular failure. Newer pharmacologic agents have improved outcomes for patients and may even obviate the need for surgery. Treating the underlying cause of PH may be helpful, such as immunosuppression for SLE (18) or positive pressure in sleep-disordered breathing. (19) Table 2 outlines therapeutic options, and Figure 2 presents a strategy for applying these options.
[FIGURE 2 OMITTED]
Calcium channel blockers. Calcium channel blockers (CCBs) are useful only for PAH patients who respond to vasodilator testing in a cardiac catheterization laboratory (SOR: B). Criteria for vasoresponsiveness have changed and it is now generally agreed that the mean PA pressure must fall by at least 10 mm Hg to [less than or equal to] 40 mm Hg with increased or unchanged cardiac output. CCB use for nonresponders leads to higher morbidity and mortality. (20)
Digoxin. In left ventricular failure, digoxin relieves symptoms, but without mortality benefit (SOR: A). (21) Only 1 study has shown a hemodynamic benefit in PAH in the intensive-care setting. (22) Therefore, experts do not agree that digoxin is useful in right ventricular failure from PAH. Digoxin may be warranted in the presence of concomitant left ventricular dysfunction or digoxin-responsive arrhythmias.
Warfarin. Two retrospective studies have shown a decrease in mortality with warfarin in PAH. (23,24) There is no consensus, though, on the degree of anticoagulation, with recommendations of INR ranging from 1.5 to 4.0.
Diuretics. Judicious use of diuretics is recommended in PAH. Loop diuretics, thiazides, and spironolactone are commonly titrated to achieve symptomatic relief.
Ambulatory oxygen therapy. This option is indicated for resting and exercise-induced hypoxia. Experts usually recommend titration to achieve a P[O.sub.2] >60 mm Hg.
Prostanoids: Epoprostenol, treprostinil, iloprost
Prostanoids cause vasodilation, inhibit platelet aggregation, prevent smooth muscle proliferation, decrease inflammation, and increase cardiac output. (25) Epoprostenol improves exercise tolerance, hemodynamics and quality of life in patients with IPAH and PAH secondary to scleroderma (SOR: A). (3,26) Treprostinil and iloprost show similar benefits. A survival advantage has only been shown for epoprostenol and treprostinil. (27) Epoprostenol is useful in both vasodilator "responders" and "nonresponders." (28)
Administration. Epoprostenol is administered with a central venous catheter. Usual starting dose is 2 ng/kg/min or higher with increase by 1 ng/kg/min every 1 to 2 weeks until the desired clinical improvement is manifested, or side effects preclude dose escalation. (29)
Treprostinil is given subcutaneously and is under investigation as an intravenous agent. The optimal dose for treprostinil is 13.8 ng/kg/min and above. (30)
Iloprost is delivered via inhalation, although it has also been used intravenously. Iloprost is not approved by the Food and Drug Administration but is available in clinical trials. Inhaled iloprost is short-lived and only provides intermittent hemodynamic benefit. (31)
Side effects. Side effects include jaw pain, nausea, anorexia, diarrhea, flushing, and headache. With the exception of jaw pain, these side effects are dose-related. The risk of catheter sepsis with epoprostenol is 0.1% to 0.4% per patient-year. More serious side effects include arrhythmia with sudden interruption of drug delivery. Treprostinil causes infusion site pain (85%), necessitating discontinuation in 8% of the patients.
Endothelin receptor antagonists: Bosentan, sitaxsentan, ambrisentan
In the lung parenchyma of patients with PH, expression of endothelin-1, a 21-amino-acid peptide, increases. (32) Higher levels of serum endothelin-1 correlate directly with severity of PH and poorer outcomes. (33) Endothelin-1 mediates vasoconstriction and smooth muscle proliferation primarily through endothelin type A (ETA) receptors and vasodilatation mostly through endothelin type B (E[T.sub.B]) receptors, although a dynamic relationship exists between the two. (34)
Oral formulation a plus. Bosentan is the only endothelin antagonist currently approved by the FDA. It is a low-molecular-weight, nonpeptide, competitive, dual receptor antagonist. Sitaxsentan and ambrisentan are available in clinical trials only. They are E[T.sub.A]-selective with the premise that sparing the E[T.sub.B] receptor, which is responsible for pulmonary vasodilation, will lead to better clinical outcomes. All these compounds can be given orally, a major advantage over prostanoids.
Bosentan improves exercise capacity, hemodynamics, symptoms, and time to clinical worsening. (35,36) Patients studied in bosentan trials had NYHA class III or IV dyspnea due to IPAH, APAH due to scleroderma, and others. Bosentan is not approved by the FDA for functional class II patients, but has been used for such patients.
Indicated for milder PAH. Bosentan outcome data were presented at the American Thoracic Society Meeting (2003) but have not been published so far. At 3 years, 86% of patients were still alive when only 48% were expected based on historical data from the NIH registry. (37) Epoprostenol survival at 3 years is about 63%? (16,17) However, only patients with milder PAH receive bosentan, while the more seriously ill ones require prostanoids. This selection may explain the survival difference.
Administration. Recommended starting dose of bosentan is 62.5 mg twice daily for 4 weeks. It is then increased to 125 mg twice daily if there is no elevation of aminotransferases. Bosentan is now known to be safe in children. (38) Ambrisentan and sitaxsentan should to be available in 2005 or later.
Side effects. The most common side effect of bosentan is hepatic aminotransferase elevation (9% of patients), usually occurring within 16 weeks (90%). All elevations have resolved upon drug withdrawal (97% within 8 weeks). The FDA mandates monthly monitoring of aminotransferase for bosentan. Furthermore, bosentan is teratogeuic (39) and absolutely contraindicated in pregnancy. There may be significant fluid retention. Sitaxsentan and ambrisentan have similar side effects and their eventual clinical use is expected to require similar monitoring.
Phosphodiesterase-5 inhibitors: Sildenafil, vardenafil, tadalafil
Phosphodiesterases (PDEs) are a group of isoenzymes widely distributed in various organs. PDE5 is found in the corpus cavernosum, pulmonary vasculature, muscle, and platelets.
Use for PAH off-label. Sildenafil, vardenafil, and tadalafil are cyclic guanosine monophosphate-specific PDE5 inhibitors with potent, selective pulmonary vasodilatory and antiplatelet effects. Sildenafil and vardenafil have relatively short half-lives (4-6 hours). Tadalafil has a longer half-life (17.5 hours) with potential for once-daily administration. All these compounds are only available orally. The FDA has approved these for erectile dysfunction only, but they have been used off-label.
A phase III study of sildenafil in PAH has been completed, but has not been published. One randomized study has shown clinical efficacy. (40) Small series have also shown clinical improvement. (41,42)
Due to their short half-lives, sildenafil and vardenafil require multidose regimens, with potential for noncompliance leading to rebound pulmonary vasoconstriction. Retinopathy at high dose, from inhibition of PDE6, remains a concern for sildenafil. (43) Priapism has not been reported in the PAH population so far, but may be a relevant consideration in sickle cell anemia.
Lung transplantation should be considered if functional class II is not achieved despite optimal medical therapy. (44) Improved medical therapy has decreased the need for this surgical option, lengthened the time to transplantation, or even eliminated the requirement altogether. (45) The 5-year survival of patients on epoprostenol is comparable with, or better than, that with lung transplant. (46) Patient selection and early referral for transplantation are crucial to success in this process. Published international guidelines help guide this process. (47) In general, PAH patients in WHO functional class II, III, or IV should be medically treated. Concurrently, referral for transplantation should be considered, even before there are signs that functional class I or II cannot be achieved. This is because transplant evaluation is a fairly lengthy process and it is not unusual for patients to die while on the long waiting list. If medical therapy is successful, the patient can be inactivated. In case medical therapy begins to fail subsequently, listing can be reactivated.
Lung transplantation remains the surgical treatment of choice for refractory PAH. Heart-lung transplants tend to be reserved for patients with structural cardiac abnormalities. Single lung transplantation has the advantages of less complex surgery and more efficient use of harvested organs to benefit more patients, thereby leading to shorter waiting periods. However, most transplant centers in the US prefer double lung transplantation, mainly because there is greater pulmonary reserve should the patient sustain rejection or infection. (48)
The operative mortality range is between 16% to 29%. (48) The 1-year survival rate after lung transplantation (single as well as double) is approximately 70% to 75%, 2-year survival is 50% to 60%, and 5-year survival is 40% to 45%. (49) The International Society of Heart and Lung Transplantation database shows that overall survival for both single and double lung transplantation is nearly equal up to 3 years postsurgery. After that, there is a significant survival advantage for double lung transplant. (50) Although several studies have documented a significant improvement in the quality of life after transplantation for PH, cost-effectiveness has not yet been addressed.
Balloon atrial septostomy
Balloon atrial septostomy reduces strain on the right ventricle and improves cardiac output. Its use is limited by systemic hypoxemia caused by the fight-to-left shunt and perioperative morbidity. It may be used as a bridge procedure while awaiting lung transplantation. (51) Functional improvement has been demonstrated in a small series. (52) Patient selection, improvement in hemodynamics, and clinical outcomes vary from center to center. (53,54) It is likely that patient selection, technique, and experience influence the outcome considerably. This procedure should only be performed in experienced centers on carefully selected patients.
Combination therapy increasingly used
There are no prospective data on combination therapy for PAH. Whether combination therapy has an additive, synergistic, or even antagonistic effect is uncertain. However, there is pathophysiologic rationale for this approach, especially in therapeutic failure following monotherapy. Addition of sildenafil to epoprostenol reduces PA pressure and PVR without hypotension or desaturation. (42) When iloprost failed as monotherapy for 14 patients with PAH, addition of sildenafil reversed clinical deterioration, increased functional capacity, and yielded favorable hemodynamics at 3 months, with sustained efficacy up to 12 months. (55) There are no data showing whether sildenafil will have synergistic benefits with bosentan. Despite lack of evidence, combination therapy has been used increasingly in clinical practice.
TABLE 1 The 2003 Venice clinical classification of pulmonary hypertension * 1. Pulmonary Arterial Hypertension 1.1. Idiopathic (IPAH) 1.2. Familial (FPAH) 1.3. Associated with (APAH): 1.3.1. Collagen vascular disease 1.3.2. Congenital systemic-to-pulmonary shunts 1.3.3. Portal hypertension 1.3.4. HIV infection 1.3.5. Drugs and toxins 1.3.6. Others (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) 1.4. Associated with significant venous or capillary involvement 1.4.1. Pulmonary veno-occlusive disease (PVOD) 1.4.2. Pulmonary capillary hemangiomatosis (PCH) 1.5. Persistent pulmonary hypertension of the newborn 2. Pulmonary hypertension with left heart disease 2.1. Left-sided atrial or ventricular heart disease 2.2. Left-sided valvular heart disease 3. Pulmonary hypertension associated with lung diseases and/or hypoxemia 3.1. Chronic obstructive pulmonary disease 3.2. Interstitial lung disease 3.3. Sleep-disordered breathing 3.4. Alveolar hypoventilation disorders 3.5. Chronic exposure to high altitude 3.6. Developmental abnormalities 4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease 4.1. Thromboembolic obstruction of proximal pulmonary arteries 4.2. Thromboembolic obstruction of distal pulmonary arteries 4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material) 5. Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis) * Classification does not include pulmonary hypertension due to end-stage renal disease. (13) TABLE 2 Treatment options for pulmonary arterial hypertension Cost Medication SOR * Route Adverse effects [dagger] Prostanoids Epoprostenol A Intravenous Line-related sepsis $$$$ and thrombosis, jaw pain, fatal arrhythmia with sudden interruption Treprostinil B Subcutaneous Site pain (85%), $$$$ jaw pain Iloprost# B Inhaled Short half-life with intermittent benefit Endothelin antagonists Bosentan A Oral Hepatotoxicity, $$$ teratogenicity, Sitaxsentan# B fluid retention Ambrisentan# C PDE5 inhibitors Sildenafil B Oral Short half-life, retinopathy Vardenafil I Short half-life $$ Tadalafil I Surgical options Lung Complicated proce- $$$$ transplant C dure, lifelong immunosuppression Atrial Invasive procedure, $$ septostomy C hypoxemia Diuretics C Electrolyte $ imbalance, dehydra- tion, etc Conventional therapy Digoxin C Higher mortality $ with high serum level Warfarin C Bleeding diathesis, $ dosing difficult in liver disease Calcium channel Harmful in $ blockers C vasodilator nonresponders Note: The level of evidence implied by the strength of recommendation must not be confused with level of efficacy. Medications not currently approved by the FDA for any indication are listed in italics. Only epoprostenol, bosentan, and treprostinil are approved specifically for pulmonary arterial hypertension. * SOR = strength of recommendation. A = Data derived from multiple randomized clinical trials or meta-analyses; B = Data derived from single randomized clinical trials or from multiple randomized clinical trials with heterogeneous results; C = Data derived from small randomized studies or consensus opinion of experts; (59) I = indeterminate, no data available, theoretical basis only. See "Evidence-based medicine terms" on page 995. Note: Medications not currently approved by the FDA for any indication are listed indicated with #.
Ortner's syndrome was first described in 1897. The commonest cause has been thought to be mitral valve stenosis or prolapse leading to left atrial dilatation that compresses the recurrent laryngeal nerve as it hooks around the aorta next to the ligamentum arteriosum and courses up in the groove between the trachea and esophagus. However, other vascular structures can also compress this nerve, including a thoracic aortic aneurysm, or a dilated pulmonary artery from pulmonary arterial hypertension.
Pulmonary hypertension criteria
Pulmonary hypertension (PH) refers to elevated blood pressure within the pulmonary circulation. The term pulmonary arterial hypertension (PAH) encompasses a spectrum of disorders that cause PH with a common histopathology and pathobiology. (56) The hallmark histopathologic lesion is plexogenic pulmonary arteriopathy. (57)
Normal mean pulmonary artery (PA) pressure is 12 to 16 mm Hg. PH is defined as a mean PA pressure greater than 25 mm Hg at rest, or greater than 30 mm Hg on exertion. Alternatively, systolic PA pressure greater than 40 mm Hg is also considered to be PH. (58) Pulmonary arterial hypertension (PAH) is defined as a mean PA pressure greater than 25 mm Hg at rest (or 30 mm Hg with exercise), with a concomitant pulmonary capillary wedge pressure less than 15 mm Hg and a pulmonary vascular resistance (PVR) greater than 3 Woods units (14) or 240 dyn*sec*cm- (5).
(1.) Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43:5S-12S.
(2.) Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998; 352:719-725.
(3.) Badesch DB, Tapson VK, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132:425-434.
(4.) Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 1999; 99:1858-1865.
(5.) Fishman AP. Aminorex to fen/phen: an epidemic foretold. Circulation 1999; 99:156-161.
(6.) McDonnell PJ, Toye PA, Hutchins GM. Primary pulmonary hypertension and cirrhosis: are they related? Am Rev Respir Dis 1983; 127:437-441.
(7.) Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest 1996; 110:1515-1519.
(8.) Stupi AM, Steen VD, Owens GR, et al. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum 1986; 29:515-524.
(9.) Asherson RA, Higenbottam TW, Dinh Xuan AT, et al. Pulmonary hypertension in a lupus clinic: experience with twenty-four patients. J Rheumatol 1990; 17:1292-1298.
(10.) Shen JY, Chen SL, Wu YX, et al. Pulmonary hypertension in systemic lupus erythematosus. Rheumatol Int 1999; 18:147-151.
(11.) Dawson JK, Goodson NG, Graham DR, et al. Raised pulmonary artery pressures measured with Doppler echocardiography in rheumatoid arthritis patients. Rheumatology (Oxford) 2000; 39:1320-1325.
(12.) Mehta NJ, Khan IA, Mehta RN, et al. HIV-Related pulmonary hypertension: analytic review of 131 cases. Chest 2000; 118:1133-1141.
(13.) Yigla M, Nakhoul F, Sabag A, et al. Pulmonary hypertension in patients with end-stage renal disease. Chest 2003; 123:1577-1582.
(14.) Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987; 107:216-223.
(15.) Denton CP, Cailes JB, Phillips GD, et al. Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis. Br J Rheumatol 1997; 36:239-243.
(16.) 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.
(17.) McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002; 106:1477-1482.
(18.) Groen H, Bootsma H, Postma DS, et al. Primary pulmonary hypertension in a patient with systemic lupus erythematosus: partial improvement with cyclophosphamide. J Rheumatol 1993; 20:1055-1057.
(19.) Thalhofer S, Dorow E [Effect of n-BiPAP therapy on the hemodynamics in patients with central sleep apnea]. Pneumologie 1995; 49 Suppl 1:165-166.
(20.) Farber HW, Karlinsky JB, Faling LJ. Fatal outcome following nifedipine for pulmonary hypertension. Chest 1983; 83:708-709.
(21.) The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997; 336:525-533.
(22.) 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.
(23.) Frank H, Mlczoch J, Huber K, et al. The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension. Chest 1997; 112:714-721.
(24.) 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.
(25.) Rich S, McLaughlin VV. The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension. J Am Coll Cardiol 1999; 34:1184-1187.
(26.) Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996; 334:296-302.
(27.) Gibbs J, Arneson C, Mottola D. Chronic infusion of Treprostinil is safe, and appears to prolong survival over a three-year period in patients with Pulmonary Arterial Hypertension. Abstract presented at American Thoracic Society Meeting, 2003.
(28.) McLaughlin VV, Genthner DE, Panella MM, et al. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 1998; 338:273-277.
(29.) Hoeper MM, Galie N, Simonneau G, et al. New treatments for pulmonary arterial hypertension. Am J Respir Crit Care Med 2002; 165:1209-1216.
(30.) Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165:800-804.
(31.) Fruhwald FM, Kjellstrom B, Perthold W, et al. Continuous hemodynamic monitoring in pulmonary hypertensive patients treated with inhaled iloprost. Chest 2003; 124:351-359.
(32.) Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelm-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993; 328:1732-1739.
(33.) Rubens C, Ewert R, Halank M, et al. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001; 120:1562-1569.
(34.) Zuccarello M, Boccaletti R, Rapoport RM. Does blockade of endothelinB1-receptor activation increase endothelinB2/ endothelinA receptor-mediated constriction in the rabbit basilar artery? J Cardiovasc Pharmacol 1999; 33:679-684.
(35.) Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001; 358:1119-1123.
(36.) Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346:896-903.
(37.) D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115:343-349.
(38.) Barst RJ, Ivy D, Dingemanse J, et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther 2003; 73:372-382.
(39.) Actelion Pharmaceuticals. Package insert. Tracleer (bosentan). Physician's Desk Reference (www.pdr.net). South San Francisco, Calif, 2002.
(40.) Sastry BK, Narasimhan C, Reddy NK, et al. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004; 43:1149-1153.
(41.) Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med 2000; 343:1342.
(42.) Stiebellehner L, Petkov V, Vonbank K, et al. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension. Chest 2003; 123:1293-1295.
(43.) Behn D, Potter MJ. Sildenafil-mediated reduction in retinal function in heterozygous mice lacking the gamma-subunit of phosphodiesterase. Invest Ophthalmol Vis Sci 2001; 42:523-527.
(44.) Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997; 336:111-117.
(45.) Conte JV, Gaine SP, Orens JB, et al. The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation. J Heart Lung Transplant 1998; 17:679-685.
(46.) Rich S, McLaughlin VV. Lung transplantation for pulmonary hypertension: patient selection and maintenance therapy while awaiting transplantation. Semin Thorac Cardiovasc Surg 1998; 10:135-138.
(47.) Maurer JR, Frost AE, Estenne M, et al. International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. J Heart Lung Transplant 1998; 17:703-709.
(48.) McLaughlin VV, Rich S. Severe pulmonary hypertension: critical care clinics. Crit Care Clin 2001; 17:453-467.
(49.) Hosenpud JD, Bennett LE, Keck BM, et al. The Registry of the International Society for Heart and Lung Transplantation: sixteenth official report--1999. J Heart Lung Transplant 1999; 18:611-626.
(50.) Hertz MI, Mohacsi PJ, Taylor DO, et al. The registry of the International Society for Heart and Lung Transplantation: introduction to the Twentieth Annual Reports--2003. J Heart Lung Transplant 2003; 22:610-615.
(51.) Rich S. Primary Pulmonary Hypertension. Curr Treat Options Cardiovasc Med 2000; 2:135-140.
(52.) Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. J Am Coll Cardiol 1998; 32:297-304.
(53.) Reichenberger F, Pepke-Zaba J, McNeil K, et al. Atrial septostomy in the treatment of severe pulmonary arterial hypertension. Thorax 2003; 58:797-800.
(54.) Nihill MR, O'Laughlin MR Mullins CE. Effects of atrial septostomy in patients with terminal cor pulmonale due to pulmonary vascular disease. Cathet Cardiovasc Diagn 1991; 24:166-172.
(55.) Ghofrani HA, Rose F, Schermuly RT, et al. Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 2003; 42:158-164.
(56.) Chatterjee K, De Marco T, Alpert JS. Pulmonary hypertension: hemodynamic diagnosis and management. Arch Intern Med 2002; 162:1925-1933.
(57.) Tuder RM, Groves B, Badesch DB, et al. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994; 144:275-285.
(58.) Maloney JP. Advances in the treatment of secondary pulmonary hypertension. Curr Opin Pulm Med 2003; 9:139-143.
(59.) Galie N, Seeger W, Naeije R, et al. Comparative analysis of clinical trials and evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43:81S-88S.
DRUG BRAND NAMES
Amlodipine * Norvasc
Bosentan * Tracleer
Digoxin * Lanoxin
Epoprostenol * Flolan
Iloprost * Ventavis
Nifedipine * Adalat, Procardia
Sildenafil * Viagra
Sitaxsentan * Thelin
Spironolactone * Aldactone
Tadalafil * Cialis
Treprostinil * Remodulin
Vardenafil * Levitra
Warfarin * Coumadin
Kasem Sirithanakul, MD, and Kamal K. Mubarak, MD
Wayne State University, Detroit, Mich
Corresponding author: Kamal K. Mubarak, MD, Wayne State University, 3990 John R, 3937 Hudson, Detroit, MI 48201. E-mail: firstname.lastname@example.org.
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||New Research Findings That Are Changing Clinical Practice|
|Author:||Sirithanakul, Kasem; Mubarak, Kamal K.|
|Publication:||Journal of Family Practice|
|Date:||Dec 1, 2004|
|Previous Article:||Atorvastatin delays first MI for patients with diabetes.|
|Next Article:||Acting on synergies between clinic and community strategies to improve preventive medicine.|