eMedicine Specialties > Pulmonology > Pulmonary Hypertension
Pulmonary Hypertension, Secondary: Treatment & Medication
Updated: Aug 21, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
The treatment of pulmonary hypertension (PH) is primarily directed at treatment of the underlying disease. Effective therapy should be instituted in the early stages, before irreversible changes in pulmonary vasculature occur. Once the cause of secondary pulmonary arterial hypertension (SPAH) has been established, the management consists of specific interventional therapy, specific medical therapy, or general supportive therapy.
Oxygen supplementation
Oxygen has a proven benefit in reducing patient mortality in selected patients with pulmonary arterial hypertension (PAH). Two large trials have demonstrated a definite mortality benefit for patients with COPD, the most common cause of pulmonary arterial hypertension. Survival rates are highest in patients who have less severe SPAH, patients in whom the pulmonary arterial pressure decreases, or patients in whom exercise capacity improves with oxygen therapy.
Although long-term study results are not available, oxygen administration may also benefit other groups of patients with SPAH. Therefore, patients who have PaO2 of less than 55 mm Hg at rest from any cause, those who have desaturation during exercise, and those who perform better on oxygen therapy should be prescribed long-term oxygen therapy.
Medicare indications for continuous long-term oxygen therapy include the following:
- Arterial PaO2 of less than or equal to 55 mm Hg or an arterial oxygen saturation (SaO2) of less than or equal to 88%
- PaO2 of 56-59 mm Hg or an SaO2 of 89%, in the presence of evidence of cor pulmonale, right-sided heart failure, or erythrocytosis (hematocrit >55%)
In a controlled study of 70 patients treated with calcium channel blockers (CCBs), approximately 50% maintained actual long-term New York Heart Association (NYHA) functional class improvement at 1 year, without the need for another treatment
The most commonly observed adverse effects with the CCBs are systemic hypotension and lower limb edema. In one study, 10-1414% of idiopathic pulmonary arterial hypertension patients were seen to develop Raynaud syndrome.
Sildenafil15,16,17,18
In one controlled study evaluating 278 patients with group 1 pulmonary arterial hypertension treated with sildenafil for a 12-week period, the trial showed improvements in 6-minute exercise capacity, decrease in mean pulmonary artery pressures, and decrease in World Health Organization (WHO) functional class for a 12-month period.
One uncontrolled study of 104 patients with chronic thromboembolic pulmonary hypertension (CTEPH) treated with sildenafil for a 12-month period showed significant improvements in WHO functional class and pulmonary vascular resistance.
Bosentan19,20,21,22
Endothelin-1 exerts a direct vasoconstrictor effect and leads to the proliferation of vascular smooth muscle cells and is a proinflammatory mediator. The effects of endothelin-1 are mediated through the EtA and EtB endothelin receptors. EtA receptors mediate sustained vasoconstriction and proliferation of vascular smooth muscle cells. EtB receptors result in clearance of endothelin and induce the production of nitric oxide and prostacyclin by endothelial cells. Bosentan is an orally active dual (EtA and EtB) endothelin-receptor antagonist.
The efficacy of oral bosentan in patients with pulmonary arterial hypertension that was either primary or associated with scleroderma was demonstrated in terms of a significant increase in walking distance. Bosentan also improved the cardiac index, right ventricular systolic function, and function of the left ventricle. Less clinical worsening, defined as death, lung transplantation, or hospitalization for pulmonary hypertension, was present.
Combination therapy
In one controlled study of 25 patients with idiopathic pulmonary arterial hypertension and scleroderma-associated pulmonary hypertension in whom monotherapy with bosentan had failed, a significant improvement in WHO functional status and exercise capacity was observed in patients with idiopathic pulmonary arterial hypertension, but not in the patients with scleroderma-associated pulmonary hypertension.23
In one controlled trial, sildenafil at 80 mg was added to patients already receiving intravenous epoprostenol, and insufficient improvement was observed. This trial proved that the combination was more effective than the placebo for improving exercise capacity and pulmonary arterial pressure. It also demonstrated a significant reduction in the number of patients showing clinical worsening and an improvement of survival among the patients with the most severe disease.24
Prostacyclin therapy25
Epoprostenol26,27,28
Intravenous prostacyclin (epoprostenol) induces relaxation of vascular smooth muscle and inhibits its growth and platelet aggregation through the increase in intracellular cyclic adenosine monophosphate
A prospective, randomized, open-label trial was conducted on 81 patients with primary pulmonary hypertension. After 12 weeks, epoprostenol therapy led to functional improvement, as shown by an improved 6-minute walk test and a decrease of 8% in mean pulmonary artery pressure. However, no long-term randomized trial of epoprostenol in patients with pulmonary arterial hypertension has been conducted.
Intravenous epoprostenol improved exercise tolerance, hemodynamics, and long-term survival in a cohort of 178 patients with primary pulmonary hypertension as compared with historical controls. Another trial, in which a cohort of 162 patients was studied after 1 year of receiving epoprostenol therapy, confirmed that the patients' clinical function improved significantly, even though improvements in hemodynamic measures were modest. Improvement with epoprostenol has also been reported in patients who had primary pulmonary hypertension associated with congenital left-to-right cardiac shunts, portal hypertension, and HIV infection.29
Epoprostenol is administered only by continuous intravenous infusion with the use of a portable infusion pump connected to a permanent catheter. Common adverse effects of epoprostenol include jaw pain, headache, diarrhea, flushing, leg pain, and nausea, although they are generally mild and dose related. Other complications include catheter-related sepsis, pump failure, or dislocation of the central venous catheter. Sudden drug interruption may be life threatening.
Treprostinil30,31
Treprostinil is a stable prostacyclin analogue administered as a continuous subcutaneous infusion delivered by a minipump. A multicentric randomized trial evaluated treprostinil versus placebo over 12 weeks in 470 patients. The study showed that patients with pulmonary arterial hypertension had increases in 6-minute walk distances, dyspnea, and hemodynamic measurements. A subsequent multicenter retrospective study of 122 patients with pulmonary arterial hypertension or CTEPH treated over a 3-year period showed significant improvement in long-term survival rates. To date, no prospective studies have been performed.
Iloprost32,33
Iloprost is a chemically stable prostacyclin analogue that can be delivered by inhaler by producing aerosol particles that deposit in the alveoli. The disadvantage of iloprost is its short duration of action; therefore, it must be inhaled as many as 6 times a day. One 12-week trial involving 203 patients showed an increase in patient scores on a 6-minute walk test and improvement in NYHA functional class, as well as improved hemodynamics. Adverse effects included cough, hypotension, and syncope associated with vasodilation. The long-term efficacy of inhaled iloprost remains disappointing because the only trials performed show a high dropout rate and no improvement in survival compared with conventional therapy.
Digoxin34
Digoxin has been shown to be beneficial for patients with supraventricular tachycardia – associated left ventricular dysfunction, but verapamil has been proven to be better than digoxin for controlling the heart rate.
Anticoagulation35,36
Current evidence suggests that in patients with idiopathic pulmonary arterial hypertension (IPAH), thrombotic arteriopathy (abnormalities of blood coagulation factors, antithrombotic factors, and the fibrinolytic system) forms, contributing to a prothrombotic state. In a review of 7 observational studies evaluating anticoagulation in pulmonary arterial hypertension, 5 showed a mortality benefit.
Surgical Care
Patients with an atrial septal defect, mitral stenosis, or chronic pulmonary thromboembolic disease should be considered for surgical management. Pulmonary arterial hypertension resolves following successful surgical procedures, unless it is too far advanced.
Although lung transplantation is reserved for patients with severe primary pulmonary hypertension, a subset of patients with secondary pulmonary arterial hypertension (SPAH) has undergone successful transplantation at several centers. These patients had SPAH due to collagen-vascular disease, drug-induced pulmonary arterial hypertension, or pulmonary venous obstruction. Stability of the underlying causative disorder and the patient's ability to tolerate an extensive surgical procedure are prerequisites. Heart-lung transplantation has been performed in patients with SPAH due to congenital cardiac disease or severe left ventricular dysfunction.
Lung transplantation, which has historically been the treatment of choice for severe pulmonary arterial hypertension, in recent years has only been needed for patients who are still in NYHA functional class IV after 3 months of therapy with epoprostenol.
Long-term benefits of lung transplantation remain disappointing, with 50% survival at 5 years.
Chronic pulmonary hypertension from thromboembolism is much more prevalent than is generally appreciated. Pulmonary endarterectomy offers a cure for the condition, and wider recognition of the efficacy of the operation and the entity are important.37 Pulmonary endarterectomy is a technically demanding procedure, now performed with success at only selected centers. However, excellent results can be obtained with proper patient selection, meticulous surgical technique, and careful postoperative management. An endarterectomy (not an embolectomy) of all affected parts of the lung is performed, and cardiopulmonary bypass, systemic cooling, and circulatory arrest are essential to clear all affected areas of the pulmonary vasculature. Pulmonary endarterectomy has proven to be permanently curative, although an inferior vena caval filter should be placed in all patients to prevent recurrence, and the patients must have life-long anticoagulation.
The largest of the case series for thromboendarterectomy operations for thromboembolic pulmonary hypertension reviews the outcomes of 743 patients who underwent this operation between 1999 and 2004. The outcomes showed that the procedure can be performed safely in patients with severe thromboembolic pulmonary hypertension, regardless of the magnitude of the preoperative pulmonary artery systolic pressure.38
Medication
Although treatment of secondary pulmonary hypertension consists primarily of that necessary for the underlying disease, several medications and oxygen are used in different clinical settings. Currently, definite proof of effectiveness is lacking for several of these treatments.
Anticoagulants
Long-term anticoagulation with warfarin should be considered in selected patients with SPAH. These include patients with chronic pulmonary emboli, pulmonary venoocclusive disease, and atrial fibrillation induced by left- or right-sided heart failure who are at high risk for developing venous thromboembolism (eg, those with cor pulmonale or immobility secondary to severe dyspnea).
Warfarin (Coumadin)
Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.
Tailor dose to maintain an INR in the range of 2-3. Tailor dose to maintain desired INR. Recurrence of DVT and PE increases dramatically when INR drops to <2 and decreases when INR is kept at 2-3. Serious bleeding risk (including hemorrhagic stroke) is approximately constant when INR is 2.5-4.5 but rises dramatically when INR is >5.
Procoagulant vitamin K–dependent proteins are responsible for a transient hypercoagulable state when warfarin is first started and when it is stopped. This phenomenon occasionally causes warfarin-induced necrosis of large areas of skin or of distal appendages. Heparin is always used to protect against this hypercoagulability when warfarin is started; however, when warfarin is stopped, the problem resurfaces, causing an abrupt temporary rise in the rate of recurrent venous thromboembolism.
At least 186 different foods and drugs have been reported to interact with warfarin. Clinically significant interactions have been verified for a total of 26 common drugs and foods, including 6 antibiotics and 5 cardiac drugs. Every effort should be made to keep the patient adequately anticoagulated at all times because procoagulant factors recover first when warfarin therapy is inadequate.
Patients who have difficulty maintaining adequate anticoagulation while taking warfarin may be asked to limit their intake of foods that contain vitamin K. Foods that have moderate-to-high amounts of vitamin K include Brussels sprouts, kale, green tea, asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, liver, soybean oil, soybeans, certain beans, mustard greens, peas (black-eyed peas, split peas, chick peas), turnip greens, parsley, green onions, spinach, and lettuce.
Adult
5-15 mg/d PO; adjust dose according to desired INR
Pediatric
Administer weight-based dose of 0.05-0.34 mg/kg/d PO; adjust dose according to desired INR
Infants may require doses at high end of range
Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate
Medications that may increase anticoagulant effects of warfarin include oral antibiotics, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac
Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Do not switch brands after achieving therapeutic response; caution in patients with active tuberculosis or diabetes; patients with protein C or protein S deficiency are at risk of developing skin necrosis
Calcium channel blockers
Efficacy has been evaluated primarily in patients with primary pulmonary hypertension. Efficacy of these agents is unclear in patients with SPAH. In selected patients (ie, patients with scleroderma), these agents may be tried only after a vasodilator response is demonstrated. Act by inhibiting calcium ions from entering slow channels or select voltage-sensitive areas of vascular smooth muscle.
Nifedipine (Adalat, Procardia)
Vasodilator that dilates both systematic and pulmonary vascular beds. Higher than usual doses are required for optimal vasodilation of pulmonary arteries.
Adult
10-20 mg IR cap PO tid initially; gradually increase as BP allows (not <90-100 mg Hg systolic)
Pediatric
0.6-0.9 mg/kg/d PO divided tid/qid
Caution with coadministration of any agent that can lower BP, including beta-blockers and opioids; H2 blockers (cimetidine) may increase toxicity; decreases levels of phenobarbital, quinidine, and rifampin; increases levels of theophylline and vincristine
Documented hypersensitivity; severe CHF, sick sinus syndrome, second- or third-degree AV block, and hypotension (<90 mm Hg systolic)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
May cause lower extremity edema; allergic hepatitis has occurred but is rare; caution in patients with angina, CHF, or patients on concomitant therapy with beta-blockers or digoxin; monitor for hypotension; adverse effects include flushing, lightheadedness, nausea, and weakness
Diltiazem (Cardizem, Dilacor)
During depolarization, inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium. Produces vasodilation but causes less reflex tachycardia compared with nifedipine. May be useful if patients develop excessive hypotension with nifedipine.
Adult
30 mg PO tid/qid initially; increase gradually to 360 mg/d as BP allows
Pediatric
Not established
May increase carbamazepine, digoxin, and cyclosporine or theophylline levels; when administered with amiodarone, may cause bradycardia and a decrease in cardiac output; when given with beta-blockers, may increase cardiac depression; cimetidine may increase levels; moricizine may decrease levels
Documented hypersensitivity; severe CHF, sick sinus syndrome, second- or third-degree AV block, and hypotension (<90 mm Hg systolic)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in patients with impaired renal or hepatic function (may increase LFT levels, hepatic injury may occur); caution in patients with hypotension, CHF, and those concomitantly using digoxin and beta-blockers; adverse effects include bradycardia, AV block, peripheral edema, nausea, headache, and weakness; rarely, CHF, angina, tachycardia, palpitations, and insomnia may develop
Amlodipine (Norvasc)
Longer duration of action and requires less frequent dosing compared with nifedipine and diltiazem. Experience in pulmonary hypertension not as extensive as with other agents. Fewer effects on conduction and infrequent AV block.
Adult
2.5-5 mg PO qd; not to exceed 10 mg/d
Pediatric
Not established
Increases cyclosporine levels; hypotensive effects increase with benazepril; increased myocardial depression with concomitant use of beta-blockers
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in patients with impaired renal or hepatic function, CHF, sick sinus syndrome, and those on concomitant therapy with beta-blockers and digoxin; adverse effects include peripheral edema, headache, dizziness, rash, nausea, and shortness of breath
Peripheral vasodilators
Strong vasodilator of all vascular beds and potent endogenous inhibitor of platelet aggregation. Platelet effects result from activation of intracellular adenylate cyclase and increase in cyclic adenosine monophosphate concentrations within platelets. May decrease thrombogenesis and platelet clumping in the lungs by inhibiting platelet aggregation.
Epoprostenol (Flolan)
Long-term infusion improves outcome in patients with primary pulmonary hypertension and selected patients with secondary pulmonary hypertension. Short-term vasodilator response appears unrelated because favorable impact on disease progression occurred with long-term therapy.
Dose is determined during dose/effect study performed in catheter laboratory or ICU. Selected dose produces maximum vasodilation with minimum systemic hypotension.
Adult
4 mg/kg/min IV initially; adjust dose by 1-2 mg/kg/min for persistent or worsening symptoms
Pediatric
Not established
Coadministration with anticoagulants may increase bleeding risk because of shared effects on platelet aggregation; hypotension may be exacerbated by other vasodilators and diuretics
Documented hypersensitivity; hyaline membrane disease, presence of dominant left-to-right shunt, respiratory distress syndrome
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Whenever possible, coadminister with anticoagulants to reduce risk of thromboembolism; sudden discontinuation or reduction in therapy may result in rebound pulmonary hypertension; during a vasodilator study, some patients developed pulmonary edema (venoocclusive disease); adverse effects include flushing, tachycardia, shock, fever, chills, headache, diarrhea, nausea, jaw pain, myalgia, paresthesia, hypoxia, and flulike symptoms
Treprostinil (Remodulin)
Used to treat PAH. Elicits direct vasodilation of pulmonary and systemic arterial vessels and inhibits platelet aggregation. Vasodilation reduces right and left ventricular afterload and increases cardiac output and stroke volume.
Adult
1.25 ng/kg/min SC via continuous infusion initially; may increase by 1.25 ng/kg/min each wk for 4 wk, then may increase by 2.5 ng/kg/min each wk; not to exceed 40 ng/kg/min
Note: If initial dose not tolerated, decrease to 0.625 ng/kg/min, then slowly titrate upward; must taper slowly if discontinued
Pediatric
Not established
Additive hypotensive effect with antihypertensive agents or diuretics; may increase risk of bleeding with other antiplatelet drugs (eg, aspirin) or anticoagulants (eg, warfarin, heparin)
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
May cause pain or irritation at infusion site; common adverse effects include diarrhea, jaw pain, edema, vasodilatation, and nausea; do not discontinue abruptly
Iloprost (Ventavis)
Synthetic analogue of prostacyclin PGI2 that dilates systemic and pulmonary arterial vascular beds. Indicated for pulmonary arterial hypertension (WHO class I) in patients with NYHA class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration.
Adult
Initial: 2.5 mcg via nebulizer
Maintenance: If first dose tolerated, increase to 5 mcg/dose via nebulizer 6-9 times/d; do not administer more frequently than q2h
Note: Administration studied only with Prodose AAD system nebulizer
Pediatric
Not established
May increase hypotensive effect of vasodilators and antihypertensives; may increase bleeding risk when coadministered with anticoagulants
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Monitor vital signs during initial treatment to decrease syncope risk; avoid eye and skin contact and oral ingestion; inhibits platelet function, but clinical relevance is unclear
Diuretics
For patients who develop right-sided heart failure and those who have systemic congestion manifested by hepatomegaly, ascites, and marked lower extremity edema. Severe right-sided heart failure may also compromise function of left ventricle and may lead to pulmonary congestion. Therefore, judicious use of diuretics helps reduce systemic congestion and edema. However, excessive hypovolemia may lower cardiac output further and interfere with tissue oxygenation.
Furosemide (Lasix)
Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Dose must be individualized to patient. Depending on response, administer at increments of 20-40 mg, no sooner than 6-8 h after the previous dose, until desired diuresis occurs. When treating infants, titrate with increments of 1 mg/kg/dose until a satisfactory effect is achieved.
Adult
20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous states
Pediatric
PO: 1-2 mg/kg/dose; not to exceed 6 mg/kg/dose; do not administer >q6h
IV/IM: 1 mg/kg slowly under close supervision; not to exceed 6 mg/kg
Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently; increased plasma lithium levels and toxicity are possible when taken concurrently
Documented hypersensitivity; hepatic coma, anuria, and state of severe electrolyte depletion
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter
Endothelin receptor antagonists
Competitively bind to endothelin-1 (ET-1) receptors ETA and ETB, causing reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP).
Bosentan (Tracleer)
Endothelin receptor antagonist indicated for the treatment of PAH in patients with WHO class III or IV symptoms to improve exercise ability and decrease rate of clinical decline. Inhibits vessel constriction and elevation of BP by competitively binding to ET-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index associated with significant reduction in PAP, PVR, and mean RAP. Due to teratogenic potential, can only be prescribed through the Tracleer Access Program (phone: 1-866-228-3546).
Adult
<40 kg: 62.5 mg PO bid; not to exceed 125 mg/d
>40 kg: 62.5 mg PO bid for 4 wk initially, then increase to 125 mg PO bid
Pediatric
Not established; 62.5 mg PO bid recommended if <40 kg or >12 y; not to exceed 125 mg/d
Toxicity may increase when administered concomitantly with inhibitors of isoenzymes CYP450 2C9 and CYP450 3A4 (eg, ketoconazole, erythromycin, fluoxetine, sertraline, amiodarone, cyclosporine A); induces isoenzymes CYP450 2C9 and CYP450 3A4, causing decrease in plasma concentrations of drugs metabolized by these enzymes (eg, glyburide and other hypoglycemics, cyclosporine A, hormonal contraceptives, simvastatin, and possibly other statins); hepatotoxicity increases with concomitant administration of glyburide
Documented hypersensitivity; coadministration with cyclosporine A or glyburide
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Causes at least 3-fold elevation of liver aminotransferase levels (ie, ALT, AST) in approximately 11% of patients; may elevate bilirubin levels (serum aminotransferase levels must be measured prior to initiation of treatment and then monthly); caution in patients with mildly impaired liver function (avoid in patients with moderate or severe liver impairment); not recommended while breastfeeding; monitor hemoglobin levels after 1 and 3 mo of treatment and every 3 mo thereafter; exclude pregnancy before initiating treatment and prevent thereafter by use of reliable contraception; headache and nasopharyngitis may occur
Ambrisentan (Letairis)
Endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with WHO class II or III symptoms. Improves exercise ability and decreases progression of clinical symptoms. Inhibits vessel constriction and elevation of blood pressure by competitively binding to ET-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index associated with significant reduction in PAP, PVR, and mean RAP. Because of the risks of hepatic injury and teratogenic potential, only available through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).
Adult
5 mg PO qd initially; may increase to 10 mg PO qd if 5 mg/d tolerated; do not chew, crush, or split tab
Pediatric
Not established
Glycoprotein-P, OATP, UGTs (ie, 1A9S, 2B7S, 1A3S), CYP2C19, and CYP3A substrate; coadministration with CYP3A (eg, cyclosporine, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) or 2C19 inhibitors (eg, omeprazole) may decrease elimination and therefore increase serum levels; CYP3A and 2C19 inducers (eg, rifampin) may increase metabolism and therefore decrease serum levels
Pregnancy
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Common adverse effects include peripheral edema, nasal congestion, sinusitis, and facial flushing; caution with mild hepatic impairment or history of moderate-to-severe hepatic impairment; hepatic injury may occur (monitor bilirubin, ALT, and AST values at baseline and then monthly); may use in women of childbearing potential only after negative pregnancy test result and must use 2 reliable methods of contraception (unless tubal sterilization or Copper T 380A or LNg 20 IUD inserted); may decrease hemoglobin and hematocrit values (monitor at baseline, 1 mo, and then periodically)
Phosphodiesterase (type 5) enzyme inhibitors
The antiproliferative effects of the phosphodiesterase type 5 (PDE5) pathway, which regulates cyclic guanosine monophosphate hydrolysis, may be significant in the chronic treatment of pulmonary hypertension with PDE5 inhibitors such as sildenafil.39,15
Sildenafil (Revatio)
Promotes selective smooth muscle relaxation in lung vasculature possibly by inhibiting PDE5. This results in subsequent reduction of BP in pulmonary arteries and increase in cardiac output.
Adult
20 mg PO tid
Pediatric
Not established
Potentiates vasodilatory effect of nitric oxide, resulting in potentially fatal drop in BP; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma concentrations; coadministration with rifampin decreases plasma levels
Documented hypersensitivity; concurrent or intermittent use of organic nitrates in any form
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adverse effects include headaches (16%), flushing (10%), upset stomach (7%), nasal congestion (4%), and a blue haze at the periphery of vision (3%); adverse effects occur more often in men taking the 100-mg dose; serious adverse effects occur in patients with severe heart disease and those who are taking nitrates; rates of MI were 1.7 and 1.4 per 100 man-years for sildenafil and placebo groups
Tadalafil (Adcirca)
PDE5 inhibitor indicated for improving exercise capacity in patients with WHO class 1 pulmonary arterial hypertension. Increases cyclic guanosine monophosphate, which is the final mediator in the nitric oxide pathway.
Adult
40 mg PO qd (dividing dose to give more than once daily is not recommended)
CrCl 51-80 mL/min: 20 mg PO qd initially; may increase to 40 mg PO qd based on individual tolerability
CrCl <30 mL/min and on hemodialysis: Avoid use
Mild-to-moderate hepatic impairment (Child-Pugh class A or B): 20 mg PO qd initially
Severe hepatic impairment (Child-Pugh class C): Avoid use
Use with strong CYP3A4 inhibitors (eg, ritonavir): 20 mg PO qd initially; may increase to 40 mg PO qd based on individual tolerability
Pediatric
Not established
CYP450 3A4 inhibitors (eg, erythromycin, ketoconazole, itraconazole, indinavir, ritonavir) may significantly increase levels of vardenafil; vardenafil potentiates hypotensive effect of nitrates or alpha-blockers; concurrent alcohol consumption may increase orthostatic hypotension risk
Documented hypersensitivity; concurrent or intermittent use of alpha-blockers (eg, doxazosin, terazosin, prazosin) or organic nitrates in any form
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Common adverse effects include headache, flushing, rhinitis, dyspepsia, or indigestion; assess cardiovascular status before use; caution with left ventricular outflow obstruction or conditions aggravated by hypotension; caution with hepatic or renal impairment (decrease dose); may cause prolonged or painful erection; may cause back pain or myalgias; sudden vision loss caused by nonarteritic anterior ischemic optic neuropathy (NAION) has been associated with PDE5 inhibitors following use for ED, analysis is ongoing to determine causality; sudden decreases or loss of hearing has been reported
Cardiac glycosides
For prevention and treatment of supraventricular arrhythmias associated with SPAH and for patients who have concomitant left-sided heart failure. Digoxin not useful in treatment of right-sided ventricular failure.
Digoxin (Lanoxin)
Cardiac glycoside with direct inotropic effects and indirect effects on the cardiovascular system. Acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.
Adult
0.125-0.375 mg PO qd
Pediatric
<5 years: Not established
5-10 years: 20-35 mcg/kg PO TDD
>10 years: 10-15 mcg/kg PO TDD
Maintenance dose: 25-35% of PO loading dose
Medications that may increase levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem, aminoglycosides, oral amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and verapamil; medications that may decrease serum levels include aminoglutethimide, antihistamines, cholestyramine, neomycin, penicillamine, aminoglycosides, oral colestipol, hydantoins, hypoglycemic agents, antineoplastic treatment combinations (including carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, or procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid
Documented hypersensitivity; beriberi heart disease, idiopathic hypertrophic subaortic stenosis, constrictive pericarditis, and carotid sinus syndrome
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Hypokalemia may reduce positive inotropic effect of digitalis; IV calcium may produce arrhythmias in digitalized patients; hypercalcemia predisposes to digitalis toxicity, and hypocalcemia can make digoxin ineffective until serum calcium levels are normal; magnesium replacement therapy must be instituted in patients with hypomagnesemia to prevent digitalis toxicity; patients diagnosed with incomplete AV block may progress to complete block when treated with digoxin; exercise caution in patients with hypothyroidism, hypoxia, and acute myocarditis
More on Pulmonary Hypertension, Secondary |
| Overview: Pulmonary Hypertension, Secondary |
| Differential Diagnoses & Workup: Pulmonary Hypertension, Secondary |
 Treatment & Medication: Pulmonary Hypertension, Secondary |
| Follow-up: Pulmonary Hypertension, Secondary |
| Multimedia: Pulmonary Hypertension, Secondary |
| References |
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References
[Guideline] Martin JK, Luthra MG, Wells MA, Watts RP, Hanahan DJ. Phospholipase A2 as a probe of phospholipid distribution in erythrocyte membranes. Factors influencing the apparent specificity of the reaction. Biochemistry. Dec 16 1975;14(25):5400-8. [Medline].
[Guideline] Mockrin SC, Byers LD, Koshland DE Jr. Subunit interactions in yeast glyceraldehyde-3-phosphate dehydrogenase. Biochemistry. Dec 16 1975;14(25):5428-37. [Medline].
[Guideline] Goss DJ, Parkhurst LJ, Gorisch H. Kinetic light scattering studies on the dissociation of hemoglobin from Lumbricus terrestris. Biochemistry. Dec 16 1975;14(25):5461-4. [Medline].
[Guideline] Cassatt JC, Marini CP, Bender JW. The reversible reduction of horse metmyoglobin by the iron(II) complex of trans-1,2-diaminocyclohexane-N,N,N,n-tetraacetate. Biochemistry. Dec 16 1975;14(25):5470-5. [Medline].
Speich R, Jenni R, Opravil M, Pfab M, Russi EW. Primary pulmonary hypertension in HIV infection. Chest. Nov 1991;100(5):1268-71. [Medline].
Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. Jan 1 2008;177(1):108-13. [Medline].
Kessler R, Chaouat A, Weitzenblum E, et al. Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences. Eur Respir J. Apr 1996;9(4):787-94. [Medline].
Elwing J, Panos RJ. Pulmonary hypertension associated with COPD. Int J Chron Obstruct Pulmon Dis. 2008;3(1):55-70. [Medline].
Battle RW, Davitt MA, Cooper SM, et al. Prevalence of pulmonary hypertension in limited and diffuse scleroderma. Chest. Dec 1996;110(6):1515-9. [Medline].
Hyduk, A, Croft, JB, Ayala, C, et al. Pulmonary hypertension surveillance--United States, 1980-2002. MMWR Surveill Summ. 2005;54:1.
Partinen M, Guilleminault C. Daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnea patients. Chest. Jan 1990;97(1):27-32. [Medline].
Sitbon O, Humbert M, Jagot JL, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J. Aug 1998;12(2):265-70. [Medline].
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. Jul 9 1992;327(2):76-81. [Medline].
Sitbon O, Humbert M, Jaïs X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation. Jun 14 2005;111(23):3105-11. [Medline].
Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. Nov 17 2005;353(20):2148-57. [Medline].
Lee AJ, Chiao TB, Tsang MP. Sildenafil for pulmonary hypertension. Ann Pharmacother. May 2005;39(5):869-84. [Medline].
Reichenberger F, Voswinckel R, Enke B, et al. Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension. Eur Respir J. Nov 2007;30(5):922-7. [Medline].
Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J. Apr 2006;151(4):851.e1-5. [Medline].
Hughes RJ, Jais X, Bonderman D, et al. The efficacy of bosentan in inoperable chronic thromboembolic pulmonary hypertension: a 1-year follow-up study. Eur Respir J. Jul 2006;28(1):138-43. [Medline].
Kenyon KW, Nappi JM. Bosentan for the treatment of pulmonary arterial hypertension. Ann Pharmacother. Jul-Aug 2003;37(7-8):1055-62. [Medline].
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. Mar 21 2002;346(12):896-903. [Medline].
Sharma S, Kashour T, Philipp R. Secondary pulmonary arterial hypertension: treated with endothelin receptor blockade. Tex Heart Inst J. 2005;32(3):405-10. [Medline].
Mathai SC, Girgis RE, Fisher MR, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J. Mar 2007;29(3):469-75. [Medline].
[Best Evidence] Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. Oct 21 2008;149(8):521-30. [Medline].
Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation. Apr 13 1999;99(14):1858-65. [Medline].
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. Feb 1 1996;334(5):296-302. [Medline].
Rubin LJ, Mendoza J, Hood M, et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. Apr 1 1990;112(7):485-91. [Medline].
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. Aug 21 2002;40(4):780-8. [Medline].
Aguilar RV, Farber HW. Epoprostenol (prostacyclin) therapy in HIV-associated pulmonary hypertension. Am J Respir Crit Care Med. Nov 2000;162(5):1846-50. [Medline].
Lang I, Gomez-Sanchez M, Kneussl M, et al. Efficacy of long-term subcutaneous treprostinil sodium therapy in pulmonary hypertension. Chest. Jun 2006;129(6):1636-43. [Medline].
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. Mar 15 2002;165(6):800-4. [Medline].
Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. Aug 1 2002;347(5):322-9. [Medline].
Opitz CF, Wensel R, Winkler J, et al. Clinical efficacy and survival with first-line inhaled iloprost therapy in patients with idiopathic pulmonary arterial hypertension. Eur Heart J. Sep 2005;26(18):1895-902. [Medline].
Rich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest. Sep 1998;114(3):787-92. [Medline].
Johnson SR, Granton JT, Mehta S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest. Aug 2006;130(2):545-52. [Medline].
Johnson SR, Mehta S, Granton JT. Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review. Eur Respir J. Nov 2006;28(5):999-1004. [Medline].
Mellemkjaer S, Ilkjaer LB, Klaaborg KE, et al. Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Ten years experience in Denmark. Scand Cardiovasc J. Feb 2006;40(1):49-53. [Medline].
Thistlethwaite PA, Kemp A, Du L, Madani MM, Jamieson SW. Outcomes of pulmonary endarterectomy for treatment of extreme thromboembolic pulmonary hypertension. J Thorac Cardiovasc Surg. Feb 2006;131(2):307-13. [Medline].
Galie N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. Jun 9 2009;119(22):2894-903. [Medline].
Alexopoulos D, Lazzam C, Borrico S, Fiedler L, Ambrose JA. Isolated chronic mitral regurgitation with preserved systolic left ventricular function and severe pulmonary hypertension. J Am Coll Cardiol. Aug 1989;14(2):319-22. [Medline].
Ashutosh K, Dunsky M. Noninvasive tests for responsiveness of pulmonary hypertension to oxygen. Prediction of survival in patients with chronic obstructive lung disease and cor pulmonale. Chest. Sep 1987;92(3):393-9. [Medline].
Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. Jul 9 1992;327(2):70-5. [Medline].
Fletcher EC, Miller J, Divine GW, Fletcher JG, Miller T. Nocturnal oxyhemoglobin desaturation in COPD patients with arterial oxygen tensions above 60 mm Hg. Chest. Oct 1987;92(4):604-8. [Medline].
Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet. Aug 29 1998;352(9129):719-25. [Medline].
Himelman RB, Struve SN, Brown JK, Namnum P, Schiller NB. Improved recognition of cor pulmonale in patients with severe chronic obstructive pulmonary disease. Am J Med. May 1988;84(5):891-8. [Medline].
Hosenpud JD, Novick RJ, Bennett LE, Keck BM, Fiol B, Daily OP. The Registry of the International Society for Heart and Lung Transplantation: thirteenth official report--1996. J Heart Lung Transplant. Jul 1996;15(7):655-74. [Medline].
Klinger JR, Hill NS. Right ventricular dysfunction in chronic obstructive pulmonary disease. Evaluation and management. Chest. Mar 1991;99(3):715-23. [Medline].
Langleben D, Hirsch AM, Shalit E, Lesenko L, Barst RJ. Sustained symptomatic, functional, and hemodynamic benefit with the selective endothelin-A receptor antagonist, sitaxsentan, in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest. Oct 2004;126(4):1377-81. [Medline].
Morgan JM, Griffiths M, du Bois RM, Evans TW. Hypoxic pulmonary vasoconstriction in systemic sclerosis and primary pulmonary hypertension. Chest. Mar 1991;99(3):551-6. [Medline].
Moser KM, Auger WR, Fedullo PF. Chronic major-vessel thromboembolic pulmonary hypertension. Circulation. Jun 1990;81(6):1735-43. [Medline].
Palevsky HI, Fishman AP. Chronic cor pulmonale. Etiology and management. JAMA. May 2 1990;263(17):2347-53. [Medline].
Raiesdana A, Loscalzo J. Pulmonary arterial hypertension. Ann Med. 2006;38(2):95-110. [Medline].
Rich S, Levitsky S, Brundage BH. Pulmonary hypertension from chronic pulmonary thromboembolism. Ann Intern Med. Mar 1988;108(3):425-34. [Medline].
Rogers TK, Howard P. Pulmonary hemodynamics and physical training in patients with chronic obstructive pulmonary disease. Chest. May 1992;101(5 Suppl):289S-292S. [Medline].
Ungerer RG, Tashkin DP, Furst D, et al. Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis. Am J Med. Jul 1983;75(1):65-74. [Medline].
Weitzenblum E, Apprill M, Oswald M, Chaouat A, Imbs JL. Pulmonary hemodynamics in patients with chronic obstructive pulmonary disease before and during an episode of peripheral edema. Chest. May 1994;105(5):1377-82. [Medline].
Zielinski J, Hawrylkiewicz I, Gorecka D, Gluskowski J, Koscinska M. Captopril effects on pulmonary and systemic hemodynamics in chronic cor pulmonale. Chest. Oct 1986;90(4):562-5. [Medline].
Further Reading
Keywords
secondary pulmonary artery hypertension, SPAH, pulmonary artery hypertension, pulmonary arterial hypertension, PAH, cardiac disorders, pulmonary disorders, chronic obstructive pulmonary disease, COPD, high-altitude disorders, hypoventilation disorders, obstructive sleep apnea, OSA, collagen-vascular diseases, systemic scleroderma, CREST syndrome, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, telangiectasia, left-sided heart disorders, atrial septal defects, ventricular septal defects
