Current management strategies: New vasodilators and genetic therapies are being investigated

Current management strategies: New vasodilators and genetic therapies are being investigated – Pulmonary Hypertension, part 2

Gokhan M. Mutlu

ABSTRACT: Management of pulmonary hypertension (PH) includes not only treatment of PH itself but also specific therapy for any underlying cause. An empiric trial with a vasodilator, such as nitric oxide or epoprostenol, is an essential step in the management of primary pulmonary hypertension (PPH). Right heart catheterization during this trial helps direct therapy. Patients with PPH who respond to vasodilators can benefit from long-term therapy with calcium channel blockers, such as diltiazem and nifedipine. Anticoagulants, such as warfarin, are warranted in most patients who have thrombi in small pulmonary arteries. Supplemental oxygen benefits patients who have resting hypoxemia and those with parenchymal lung disease and intracardiac shunt. When right-sided heart failure develops, consider diuretics. Spironolactone is especially effective when there is liver congestion. Lung transplantation is reserved for patients in whom medical treatment fails. (J Respir Dis. 2001;22(11):641-645)

In the treatment of pulmonary hypertension (PH), every effort has to be made to identify an underlying disease. After an underlying disease has been either excluded or specifically treated, the patient should be evaluated to assess the risks versus the benefits of treating PH itself.

In the October 2001 issue of The Journal of Respiratory Diseases, we reviewed the clinical presentation and the diagnosis of primary pulmonary hypertension (PPH). In this article, we will discuss treatment strategies.

Vasodilator therapy

An essential step in the management of PPH is an empiric trial with a vasodilator (Figure). Right heart catheterization during this trial helps with treatment decisions. Based on their response to various vasodilators (such as nitric oxide and epoprostenol), patients can be categorized as “responders” or “nonresponders.” A positive response is defined as a decrease of 10 mm Hg or more in mean pulmonary artery (PA) pressure with an increase or no change in cardiac output. (1)

Responders are thought to have early disease with increased pulmonary vascular tone due to vasoconstriction, whereas nonresponders are in the late stage of the disease with fixed and irreversible changes in pulmonary vasculature. Unfortunately, only 20% of patients with PPH respond to vasodilators.

Nonresponders who have New York Heart Association (NYHA) functional class III or IV symptoms may warrant continuous epoprostenol therapy. (2) However, patients with NYHA functional class I or II symptoms do not warrant long-term treatment and should be observed. Epoprostenol has been shown to improve hemodynamics and survival in patients with PPH who are nonresponders, and pulmonary vascular resistance diminishes slowly in patients receiving this therapy. (3,4)

Epoprostenol is approved for use only in patients who have PPH and PA hypertension (PAH) due to scleroderma. Continuous epoprostenol infusion improves symptoms, exercise capacity (improved NYHA functional class and increased distance in a 6-minute walk test), and hemodynamics in PAH due to scleroderma. Although the impact of long-term epoprostenol therapy on the mortality of patients with PAH due to scleroderma is still unknown, one study demonstrated that 12 weeks of therapy provided no survival benefit for these patients; this finding was attributed to the unfeasibility of enrolling enough patients to detect statistically significant differences. (5)

* Calcium channel blockers: Patients with PPH who are responders can benefit from long-term therapy with calcium channel blockers (6); however, it is imperative to determine hemodynamic responses before such therapy is started. Basing treatment decisions on the clinical response to empiric use of these agents without vasodilator trials has several consequences, including giving the drugs to nonresponders who are unlikely to benefit and to patients with contraindications (such as a cardiac index of less than 2 L/min/[m.sup.2]).

These agents have been shown to decrease morbidity and improve survival in patients with PPH. (7) Five-year survival in responders who receive both calcium channel blockers and anticoagulation therapy is at least 90%. (7)

Nonresponders who do not have an acute hemodynamic response during the vasodilator trial are unlikely to benefit from long-term therapy and, therefore, are not considered candidates for this treatment. Although a few small studies showed modest beneficial effects with calcium channel blockers in PH other than PPH, additional studies are needed to identify their role.

Calcium channel blockers have their effect by inhibiting calcium influx into smooth muscle cells via slow channels. We recommend starting with low-dose therapy and increasing to higher doses slowly, as tolerated. To achieve beneficial effects, very high dosages (such as diltiazem, up to 720 mg/d; or nifedipine, up to 300 mg/d) may be necessary. Since little is known about the dose-response relationship, it is difficult to choose a dosage for a given patient. Another approach to optimal dosing is to titrate the dosage while evaluating the hemodynamic response with a PA catheter in place. (7)

The main limitation of calcium channel blockers is a negative inotropic effect on myocardial contractility. These agents may be contraindicated if the patient has severe right-sided heart failure (such as right arterial pressure greater than 15 mm Hg and a cardiac index less than 2 L/min/[m.sup.2]). Other side effects include peripheral edema and hypoxemia from worsening ventilation-perfusion (V/Q) imbalance following vasodilatation in areas with a low V/Q, It is important to remember that abrupt discontinuation can result in rebound PH and, consequently syncope and death.

* Prostacyclin analogues: An imbalance between thromboxane, prostacyclin ([PGI.sub.2]), and reduced [PGI.sub.2] synthase provides a rationale for the use of [PGI.sub.2] analogues (such as epoprostenol) in PPH. Prospective, randomized clinical trials have shown improved exercise tolerance, pulmonary hemodynamics, and survival in patients who are in NYHA functional classes III and IV. (3,4) Lack of an acute response to epoprostenol does not preclude a benefit when it is given on a long-term basis. The impact of continuous epoprostenol therapy on PPH can be substantial, deferring the need for lung transplantation almost indefinitely. (8)

The precise mechanism of action for long-term epoprostenol therapy is unknown. Acutely, it lowers PA pressure and improves cardiac output and systemic oxygen delivery, and when administered early in the course of disease, it may facilitate pulmonary vascular remodeling. Some benefits may be attributed to its antiplatelet properties. (9) [PGI.sub.2] therapy improves endothelial injury and altered hemostasis by decreasing P-selectin (a leukocyte adhesion receptor) and increasing thrombomodulin levels, respectively. (8)

Since epoprostenol has a short half-life, continuous administration through a tunneled, central venous catheter is required. Although optimal dosage is unknown, the dosage should be increased at regular intervals during the first year of therapy to overcome tolerance. Abrupt discontinuation, even for a few seconds, can lead to syncope and death as a result of rebound PH. Common adverse effects of epoprostenol include flushing, jaw pain, diarrhea, and foot pain.

Only patients who have PAH are considered candidates for this therapy. While receiving epoprostenol, patients with parenchymal disease may have worsened V/Q mismatching and shunt as a result of improved blood flow to poorly ventilated areas. Pulmonary edema can develop in patients with pulmonary venous hypertension while they are taking epoprostenol.

* Nitric oxide: This vasodilator activates guanylate cyclase in pulmonary vascular muscle cells, with a subsequent increase in cyclic guanosine monophosphate and a decrease in intracellular calcium, leading to smooth muscle relaxation. When inhaled, nitric oxide is potent and avoids undesired systemic vasodilatation. Despite well-described acute effects of this agent on pulmonary vasculature, (11) its role in long-term therapy is unknown–currently, because its method of delivery is in continuous gaseous form, it is not an option.

Anticoagulation therapy

Data regarding the use of anticoagulation therapy in PPH are limited but supportive. In most patients, thrombus in small pulmonary arteries warrants its use. When anticoagulants are combined with vasodilator therapy, they provide additional survival benefit. (12,13) Warfarin has been associated with improved survival in PAH caused by anorexigen use. The optimal dose is unknown, but an international normalized ratio above 2 is recommended. The role of anticoagulants in PH other than PAH and chronic thromboembolic disease (CTED) is uncertain.

Nonspecific medical therapy

Supplemental oxygen benefits patients with PH who have resting hypoxemia and those with parenchymal lung disease and intracardiac shunt. Long-term oxygen therapy has not been shown to have a beneficial effect on pulmonary hemodynamics. (14) Although there is no clear evidence supporting its benefits in patients with exertional oxygen desaturation, supplemental oxygen may prevent the negative impact of hypoxemia on pulmonary vasculature that is already compromised.

Use of inotropic agents (such as digitalis) in PH is controversial. These agents improve contractility by increasing intracellular cyclic adenosine monophosphate and calcium. Currently, there are no data supporting the use of inotropic agents in chronic PH, but short-term use has been shown to improve cardiac output and decrease circulating catecholamines. (15) Drugs that improve right ventricular performance seem reasonable options for adjunctive therapy in PH, particularly in those with signs of right-sided heart failure.

Diuretics should be considered when right-sided heart failure develops. Both loop and potassium-sparing diuretics are effective. Use diuretics judiciously to avoid dehydration because overdiuresis can lead to underfilling of the left or the right ventricle and, consequently, hypotension and cardiovascular collapse. Avoidance of dehydration, which may reflect left or right ventricular underfilling rather than diminished total body water, is mandatory. Spironolactone is especially effective when there is liver congestion, and it can be used with loop diuretics.


Atrial septostomy has not been studied in large clinical trials but can be used as a palliative procedure for patients who have severe PPH with recurrent syncope and/or intractable right ventricular failure that is resistant to medical management. This procedure improves left ventricular filling and cardiac output by decompressing the right side of the heart and increasing left ventricular preload. (15)

Thromboendarterectomy is a surgical technique used to treat PH secondary to CTED. It is generally indicated for patients with advanced disease who have NYHA functional class III or IV symptoms. Markedly impaired right ventricular function and tricuspid insufficiency increase risk but do not preclude surgery. Lifelong anticoagulation therapy is necessary after this operation.

Since procedure-related mortality is high, atrial septostomy and throm boendarterectomy must be performed at select centers with highly experienced personnel.

Single or bilateral lung transplantation is performed in selected patients with PH who do not respond to medical therapy On lung transplantation, right ventricular function improves following the reduction in pulmonary vascular resistance. Therefore, simultaneous heart transplantation should be reserved for those with left-sided heart disease or PH due to congenital heart disease other than atrial septal defect.

One-year survival after lung transplantation ranges from 70% to 75%; 3-year survival ranges from 55% to 60%; and 5-year survival ranges from 40% to 45%. Guidelines for referral include NYHA functional class III or IV symptoms despite medical therapy and failure of [PGI.sub.2] therapy or intolerable adverse effects of such therapy.

Investigational medications

To overcome the limitations of continuous epoprostenol therapy, new vasodilators, particularly [PGI.sub.2] analogues that do not need to be administered intravenously, have been developed. Iloprost and beraprost are 2 new [PGI.sub.2] analogues that can be inhaled (iloprost) or given orally (beraprost). Iloprost, which is effective at lower doses than epoprostenol, minimizes systemic side effects. Unfortunately, short half-life is a major limitation; both medications need to be administered frequently.

Although studies of each drug have shown beneficial effects with long-term treatment,(16,17) recent data showed no hemodynamic improvement after long-term use of iloprost.(18,19) These conflicting findings were partly a result of patient selection bias, with more responders included in one of the earlier studies.(16) Controlled, randomized clinical trials are needed to determine the role of these expensive drugs in the treatment of patients with PPH.

Uniprost (UT-15) is another investigational analogue of [PGI.sub.2] that can be given via an insulin pump.(20) Results from a prospective, randomized multicenter trial that included 470 patients with PAH demonstrated improved exercise capacity, assessed by a 6-minute walk test, in those who received UT-15 compared with those who received placebo. In addition, UT-15 improved hemodynamic parameters and clinical signs and symptoms and was well tolerated.(21)

Given the potential pathogenetic role for endothelin-l (ET-1) in PPH, bosentan, an endothelin antagonist, has been evaluated in PPH. Short-term use of bosentan is associated with improved pulmonary hemodynamics.(22) Preliminary data on bosentan demonstrated improvement in exercise capacity at 12 weeks (increased distance in a 6-minute walk test and improved NYHA functional class) and improved hemodynamics and symptoms compared with placebo.(23)

Genetic therapies aimed at pulmonary vasculature to express and enhance the activity of nitric oxide synthase, [PGI.sub.2] synthase, potassium channels, and bone morphogenetic protein receptor type 2 and to inhibit ET-1 and metalloproteinases are other potential treatments that may be available in the future.

Dr Mutlu is assistant professor of medicine in the division of pulmonary and critical care medicine at Northwestern University Medical School, Chicago. Dr Rubinstein is professor of medicine in the section of respiratory and critical care medicine at the University of Illinois College of Medicine, Chicago.


(1.) Rich S, ed. Executive Summary From the World Symposium on Primary Pulmonary Hypertension 1998 [WHO Web site]. Available at: Accessed September 25,2001.

(2.) Criteria Committee, New York Heart Association. Physical capacity with heart disease. In: Diseases of the Heart and Blood Vessels. Nomenclature and Criteria for Diagnosis. 6th ed. Boston: Little, Brown, and Company, Inc; 1964:110-114.

(3.) 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

(4.) McLaughlin W, Genthner DE, Panella MM, Rich S. Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med. 1998; 338:273-277.

(5.) Badesch DB, Tapson VF, 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.

(6.) 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.

(7.) Rich S, Kaufmann E. High dose titration of calcium channel blocking agents for primary pulmonary hypertension: guidelines for short-term drug testing. J Am Coll Cardiol. 1991;18:1323-1327.

(8.) 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.

(9.) O’Grady J, Warrington S, Moti MJ, et al. Effects of intravenous infusion of prostacyclin ([PGI.sub.2]) in man, Prostaglandins. 1980;19:319-332.

(10.) Sakamaki F, Kyotani S, Nagaya N, et at. Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy. Circulation. 2000;102:2720-2725.

(11.) Hart CM, Nitric oxide in adult lung disease, Chest. 1999;115:1407-1417.

(12.) Rich S, Levy PS, Characteristics of surviving and nonsurviving patients with primary pulmonary hypertension. Am J Med. 1984;76:573-578.

(13.) Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis, Circulation. 1984; 70:580-587.

(14.) 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.

(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.) Hoeper MM, Schwarze M, Ehlerding S, et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med. 2000;342:1866-1870.

(17.) Nagaya N, Uematsu M, Okano Y, et al. Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension. J Am Coll Cardiol. 1999;34:1188-1192.

(18.) Machherndl S, Kneussl M, Baumgartner H, et at. Long-term treatment of pulmonary hypertension with aerosolized iloprost. Eur Respir J. 2001;17:813.

(19.) Schenk P, Petkov V, Madl C, at al. Aerosolized iloprost therapy could not replace long-term IV epoprostenol (prostacyclin) administration in severe pulmonary hypertension. Chest. 2001;119:296-300.

(20.) Gaine SP, Barst RJ, Rich S. Acute hemodynamic effects of subcutaneous UT-15 in primary pulmonary hypertension [abstract]. Am J Respir Crit Care Med. 1999;159. Abstract 161.

(21.) Barst RJ, Simonneau G, Rich S, et al. Uniprost PAH Study Group. Efficacy and safety of chronic subcutaneous infusion UT-15 in pulmonary arterial hypertension (PAH) [abstract], Circulation. 2000;102:ll-100-101. Abstract 477.

(22.) Williamson DJ, Wallman LL, Jones R, et al. Hemodynamic effects of Bosentan, an endothelin receptor antagonist, in patients with pulmonary hypertension. Circulation. 2000;102:411-418.

(23.) Channick RN, Rubin LJ, Simonneau G, at al. Bosentan, a dual endothelin receptor antagonist improves exercise capacity and hemodynamics in patients with pulmonary arterial hypertension: results of a double blind, randomized, placebo-controlled trial [abstract]. Circulation. 2000;102:ll-100. Abstract 476.

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