Pulmonary Arterial Hypertension Medication

Updated: Apr 25, 2018
  • Author: Kristin E Schwab, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Medication

Medication Summary

Although treatment of pulmonary arterial hypertension (PAH) consists primarily of that necessary for the underlying disease, several medications are used in different clinical settings, as is oxygen supplementation. Currently, definite proof of effectiveness is lacking for several of these treatments.

Calcium channel blockers

Calcium channel blockers (CCBs) have been evaluated primarily in patients with idiopathic pulmonary arterial hypertension (IPAH). [34, 35] In a controlled study of 70 patients treated with these agents, approximately 50% maintained actual long-term New York Heart Association (NYHA) functional class improvement at 1 year, without the need for another treatment. [35] The most commonly observed adverse effects of these agents are systemic hypotension and lower-extremity edema. In one study, 10-14% of patients with IPAH were seen to develop Raynaud syndrome. CCBs act by inhibiting calcium ions from entering slow channels or select voltage-sensitive areas of vascular smooth muscle. CCBs may include nifedipine, diltiazem, and amlodipine.

Vasodilators

Prostacyclin analogues and agonists

Prostacyclin is a strong vasodilator of all vascular beds and a potent endogenous inhibitor of platelet aggregation. Platelet effects result from activation of intracellular adenylate cyclase and from increased cyclic adenosine monophosphate (cAMP) concentrations within platelets. Prostacyclin may decrease thrombogenesis and platelet clumping in the lungs by inhibiting platelet aggregation. These agents may include epoprostenol, treprostinil, iloprost, and selexipag.

Epoprostenol is a synthetic prostacyclin that is available only as an intravenous infusion. It induces relaxation of vascular smooth muscle and inhibits its growth and platelet aggregation through the increase in intracellular cyclic adenosine monophosphate (cAMP). [36, 37, 38] A prospective, randomized, open-label trial was conducted on 81 patients with PAH. 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 arterial pressure. [36] Intravenous epoprostenol improved exercise tolerance, hemodynamics, and long-term survival in another cohort of 178 patients with PAH, as compared with historical controls. [38] Another trial, in which a cohort of 162 patients was studied after 1 year of receiving epoprostenol therapy, confirmed that patients’ clinical function improved significantly, even though improvements in hemodynamic measures were modest. Improvement with epoprostenol has also been reported in patients who had PAH associated with congenital left-to-right cardiac shunts, portal hypertension, and HIV infection. [39] Of note, epoprostenol is also the only treatment that has shown a mortality reduction, although this was in a single randomized controlled trial. [36] Epoprostenol is administered only by continuous intravenous infusion via a portable infusion pump connected to a permanent catheter. Compared with other prostacyclin-based therapies, epoprostenol has a very short half-life (3-5 min) and is not stable at room temperature for more than 8 hours. Sudden drug interruption can thus be life-threatening. The dosage is determined during a dose-effect study performed in a catheterization laboratory or ICU. The selected dosage produces maximum vasodilation with minimum systemic hypotension. Common adverse effects of epoprostenol include jaw pain, headache, diarrhea, flushing, leg pain, and nausea, although these are generally mild and dose-related. Other complications include catheter-related sepsis, pump failure, or dislocation of the central venous catheter.

Treprostinil is a stable prostacyclin analogue that can be administered parenterally (Remodulin), as a continuous subcutaneous infusion delivered by a minipump (Remodulin), as an inhaled therapy (Tyvaso), or as an oral tablet (Orenitram). Treprostinil 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. A multicentric randomized trial evaluating treprostinil versus placebo over 12 weeks in 470 patients documented that patients with PAH had increases in 6-minute walk distances (6MWDs), dyspnea, and hemodynamic measurements. [40] A subsequent multicenter retrospective study of 122 patients with PAH or chronic thromboembolic pulmonary hypertension (CTEPH) treated over a 3-year period demonstrated significant improvement in long-term survival rates. [41] A randomized controlled trial by McLaughlin et al demonstrated the addition of inhaled treprostinil improved exercise capacity and quality of life among 212 patients with PAH, who remained symptomatic despite therapy with bosentan or sildenafil. [42] In December 2013, the FDA approved treprostinil extended-release tablets (Orenitram) for pulmonary arterial hypertension. The primary efficacy study, FREEDOM-M, demonstrated patients taking titrated treprostinil orally twice daily improved median 6MWD by +23 meters (P = .013) compared with placebo. [43] Two other phase 3 studies (FREEDOM-C and FREEDOM-C2) did not demonstrate a benefit in exercise with median 6MWD at week 16 (11 meters [P = .072] and 10 meters [P = .089], respectively). [44, 45] Adverse effects depend on the mode of administration (ie, infusion site pain is the most common adverse effect with the subcutaneous form), but are otherwise similar to epoprostenol. Compared with epoprostenol, treprostinil has gained more widespread use, largely because of its longer half-life and thus better safety profile.

Iloprost is a chemically synthetic analogue of prostacyclin that dilates systemic and pulmonary arterial vascular beds. It can be delivered through an inhaler by producing aerosol particles that deposit in the alveoli. It is indicated for patients with NYHA class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration. A 12-week trial involving 203 patients showed an increase in patient scores on a 6-minute walk test and an improvement in NYHA functional class, as well as improved hemodynamics. [46] The long-term efficacy of inhaled iloprost remains disappointing because the only trials performed exhibited a high dropout rate and no improvement in survival compared with conventional therapy. [46, 47] Adverse effects include cough, hypotension, and syncope associated with vasodilation. Its disadvantage is its short duration of action. Therefore, it must be inhaled as many as six times a day.

Selexipag is the first prostacyclin agonist approved in the United States. It is available in tablet form. It selectively activates the prostacyclin receptor (ie, IP-receptor), one of five types of prostanoid receptors. Unlike prostacyclin analogs, selexipag is selective for the IP receptor over other prostanoid receptors (ie, EP1-4, DP, FP, TP). Activating the IP receptor induces vasodilation and inhibits proliferation of vascular smooth muscle cells. It was approved in December 2015 for adults with PAH to delay disease progression and reduce the risk of hospitalization. Approval of selexipag was based on the phase 3 GRIPHON study (n=1156). Results showed that selexipag decreased the risk of morbidity/mortality by 39% compared with placebo (P <.0001). Efficacy observed was consistent across the key subgroups (eg, age, sex, WHO functional class, PAH etiology, and background PAH therapy). [48, 49, 50] Adverse effects are similar to the other prostacyclins and include headache, diarrhea, nausea, flushing, muscle aches, and jaw pain. Although these are mostly mild, they are reported in the majority of patients.

Endothelin-receptor antagonists

Endothelin-1 exerts a direct vasoconstrictor effect, leads to the proliferation of vascular smooth muscle cells, and is a proinflammatory mediator. Its effects are mediated through the EtA and EtB endothelin receptors: the former mediate sustained vasoconstriction and proliferation of vascular smooth muscle cells, and the latter result in clearance of endothelin and induce production of nitric oxide and prostacyclin by endothelial cells. Endothelin-receptor antagonists competitively bind to the endothelin-1 receptors EtA and EtB, causing reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. Agents may include bosentan, ambrisentan, and macitentan.

Bosentan is an orally active dual (EtA/EtB) endothelin-receptor antagonist used to treat PAH. [51, 52, 53, 54] It inhibits vessel constriction and elevation of blood pressure by competitively binding to EtA and EtB receptors in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. The efficacy of oral bosentan in patients with PAH has been evaluated in multiple randomized controlled trials, including the BREATHE trials. It has been found to increase 6MWD as well as cardiac index, right ventricular systolic function, and left ventricular function. Reduced clinical worsening (defined as death, lung transplantation, or hospitalization for PAH) has also been reported. Because of its teratogenic potential, bosentan can be prescribed only through the Tracleer Access Program (phone: 1-866-228-3546).Ten percent of patients may have liver function test (LFT) abnormalities with use of the drug, thus monthly LFT monitoring is recommended. [19]

Ambrisentan is a selective type A endothelin-1 antagonist [55] indicated for the treatment of PAH (1) to improve exercise ability and delay clinical worsening and (2) in combination with tadalafil to improve exercise ability, as well as reduce the risks of disease progression and hospitalization for worsening PAH. It inhibits vessel constriction and elevation of blood pressure by competitively binding to EtA and EtB receptors in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. While the incidence of LFT abnormalities is less with ambrisentan compared with bosentan, ambrisentan is available only 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).

Macitentan is a dual endothelin receptor antagonist that prevents binding of ET1 to both EtA and EtB receptors. It is indicated to delay disease progression of PAH (WHO group I) and was approved by the FDA in October 2013. In the SERAPHIN trial (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), macitentan was shown to lower the risk of clinical events in patients with PAH. According to the study, macitentan given at 10 mg/day led to a 45% reduction (P<.001) in a clinical primary endpoint that included death, initiation of intravenous or subcutaneous prostanoids, or worsening of PAH. The benefit was driven primarily by reductions in PAH worsening. A dosage of 3 mg/day was also shown to improve clinical outcome (P =.01) but to a lesser degree. [56, 57, 58] Anemia was observed in 4% of trial participants; LFT abnormalities were not noted.

Phosphodiesterase-5 enzyme inhibitors

The antiproliferative effects of the phosphodiesterase type 5 (PDE5) pathway, which regulates cyclic guanosine monophosphate (cGMP) hydrolysis, is significant in the long-term treatment of PAH. Agents may include sildenafil, tadalafil, and vardenafil.

Sildenafil promotes selective smooth-muscle relaxation in lung vasculature, possibly by inhibiting PDE5. This results in a subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output. It is dosed as a three-times-a-day medication. Its main adverse effects include headache, flushing, and epistaxis, which are likely related to its vasodilatory properties. Sildenafil has been studied as a single agent in PAH in multiple trials. [59, 60, 61, 62] In one randomized controlled trial evaluating 278 patients treated with sildenafil for 12 weeks, patients demonstrated improved 6-minute exercise capacity, reduced mean pulmonary arterial pressure, and a decrease in WHO functional class for a 12-month period. [59] An uncontrolled study of 104 CTEPH patients treated with sildenafil for 12 months documented significant improvements in WHO functional class and pulmonary vascular resistance. [61] It has also been studied as an additive agent with epoprostenol, and again showed improved 6MWD in this trial. [31]

Tadalafil is a PDE5 inhibitor indicated for improving exercise capacity in patients with PAH. [63] It increases cGMP, the final mediator in the nitric oxide pathway. It is indicated as a single agent for improving exercise capacity in patients with PAH, as well as in combination with ambrisentan based on the AMBITION trial (per above). It is dosed as a once-daily medication and has a similar adverse effect profile as sildenafil.

Vardenafil is a PDE5 inhibitor. This medication has been demonstrated to increase 6MWD. [64] It is dosed as once or twice daily.

Soluble guanylate cyclase stimulators

Soluble guanylate cyclase (sGC) is an enzyme in the cardiopulmonary system and the receptor for nitric oxide. PAH is associated with endothelial dysfunction, impaired synthesis of nitric oxide, and insufficient stimulation of the nitric oxide-sGC-cGMP pathway.

Riociguat is the first sGC stimulator approved in the United States. It elicits a dual mode of action. It sensitizes sGC to endogenous nitric oxide by stabilizing the nitric oxide-sGC binding, and it directly stimulates sGC via a different binding site, independently of nitric oxide. It is indicated for CTEPH and PAH. Approval was based on data from the two randomized, double-blind, placebo-controlled, global phase III studies, CHEST-1 and PATENT-1. In each study, riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with PAH. [65, 66]

Cardiac glycosides

Cardiac glycosides are used for prevention and treatment of supraventricular arrhythmias associated with PAH and for patients who have concomitant left-sided heart failure. Digoxin is not useful in the treatment of right-sided ventricular failure.

Digoxin is a cardiac glycoside with direct inotropic effects and indirect effects on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Its indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Loop diuretics

Diuretics should be used in 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 the function of the left ventricle, leading 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. Agents may include furosemide and bumetanide.

Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, thereby, in turn, inhibiting sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. The dosage must be individualized to the patient. Depending on the response, administer furosemide in increments of 20-40 mg, no sooner than 6-8 hours after the previous dose, until the desired diuresis occurs.

Bumetanide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in the ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs following administration, renal vascular resistance decreases, and renal blood flow is enhanced. The dose should be individualized to the patient. One milligram of bumetanide is equivalent to approximately 40 mg of furosemide.

Anticoagulants

Long-term anticoagulation with warfarin should be considered in selected patients with PAH. These include patients with pulmonary venoocclusive disease as well as those with low bleeding risk in who the benefit outweighs the risk (eg, those with cor pulmonale or immobility secondary to severe dyspnea).

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of deep venous thrombosis, pulmonary embolism, and thromboembolic disorders. It is also used to decrease the risk of embolic stroke in patients with atrial fibrillation. The practitioner typically tailors the dose to maintain an international normalized ratio in the range of 2-3. Recurrence of deep venous thrombosis and pulmonary embolism increases dramatically when the international normalized ratio drops below 2 and decreases when it is kept between 2 and 3. Serious bleeding risk (including hemorrhagic stroke) is approximately constant when the international normalized ratio is between 2.5 and 4.5, but rises dramatically when it exceeds 5.

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Calcium Channel Blockers

Class Summary

Calcium channel blockers act by inhibiting calcium ions from entering slow channels or select voltage-sensitive areas of vascular smooth muscle.

Nifedipine (Adalat, Procardia, Nifedical)

Nifedipine is a dihydropyridine calcium channel blocker. It is a vasodilator that dilates both systematic and pulmonary vascular beds. Higher doses of nifedipine are required for optimal vasodilation of pulmonary arteries.

Diltiazem (Cardizem, Dilacor, Cartia XT, Tiazac)

Diltiazem is a nondihydropyridine calcium channel blocker. During depolarization, diltiazem inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. The resultant decrease in intracellular calcium inhibits the contractile processes of myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. It decreases conduction velocity in atrioventricular node and increases refractory period via blockade of calcium influx.

Amlodipine (Norvasc)

Amlodipine is a dihydropyridine calcium channel blocker that has antianginal and antihypertensive effects. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

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Vasodilators

Class Summary

Prostacyclin is a strong vasodilator of all vascular beds and a potent endogenous inhibitor of platelet aggregation. Platelet effects result from activation of intracellular adenylate cyclase and from increased cyclic adenosine monophosphate (cAMP) concentrations within platelets. Prostacyclin may decrease thrombogenesis and platelet clumping in the lungs by inhibiting platelet aggregation.

Epoprostenol (Flolan, Veletri)

Epoprostenol has potent vasodilatory properties, an immediate onset of action, and a half-life of approximately 5 min. In addition to its vasodilator properties, this agent also contributes to inhibition of platelet aggregation and plays a role in inhibition of smooth muscle proliferation. The latter effect may have implications for beneficial remodeling of pulmonary vascular bed.

Treprostinil (Remodulin, Tyvaso, Orenitram)

The prostanoid treprostinil is used to treat PAH. It is structurally similar to epoprostenol but stable at room temperature and has a longer half-life; therefore, it can be given as an intravenous or subcutaneous continuous infusion via a smaller pump. This agent 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.

Iloprost (Ventavis)

Iloprost is a synthetic analogue of prostacyclin that dilates systemic and pulmonary arterial vascular beds. It is indicated for WHO class I PAH in patients with NYHA class III or IV symptoms to improve exercise tolerance and symptoms and to delay deterioration.

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PAH, Prostacyclin Agonists

Class Summary

Selexipag is the first prostacyclin agonist approved in the United States.

Selexipag (Uptravi)

Selexipag selectively activates the prostacyclin receptor (ie, IP-receptor), one of five types of prostanoid receptors. Unlike prostacyclin analogs, selexipag is selective for the IP receptor over other prostanoid receptors (ie, EP1-4, DP, FP, TP). Activating the IP receptor induces vasodilation and inhibits proliferation of vascular smooth muscle cells.

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Endothelin-Receptor Antagonists

Class Summary

Endothelin-receptor antagonists competitively bind to the endothelin-1 receptors EtA and EtB, causing reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure.

Bosentan (Tracleer)

Bosentan is indicated for the treatment of PAH in patients with WHO class III or IV symptoms to improve exercise ability and decrease the rate of clinical decline. It inhibits vessel constriction and elevation of blood pressure by competitively binding to EtA and EtB receptors in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. Because of its teratogenic potential, bosentan can be prescribed only through the Tracleer Access Program (phone: 1-866-228-3546).

Ambrisentan (Letairis)

Ambrisentan inhibits vessel constriction and elevation of blood pressure by competitively binding to EtA and EtB receptors in endothelium and vascular smooth muscle. This leads to a significant increase in cardiac index associated with significant reductions in pulmonary arterial pressure, pulmonary vascular resistance, and mean right atrial pressure. Ambrisentan is indicated for the treatment of WHO group 1 PAH in patients to improve exercise ability and delay clinical worsening. It is also indicated in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. Because of the risks of hepatic injury and potential teratogenesis, ambrisentan is available only 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).

Macitentan (Opsumit)

Macitentan is a dual endothelin receptor antagonist that prevents binding of ET1 to both EtA and EtB receptors. It is indicated to delay disease progression of PAH (WHO group I).

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Phosphodiesterase-5 Enzyme Inhibitors

Class Summary

The antiproliferative effects of the phosphodiesterase type 5 (PDE5) pathway, which regulates cyclic guanosine monophosphate (cGMP) hydrolysis, may be significant in the long-term treatment of PAH with PDE5 inhibitors such as sildenafil.

Sildenafil (Revatio)

Sildenafil promotes selective smooth-muscle relaxation in lung vasculature, possibly by inhibiting PDE5. This results in a subsequent reduction of blood pressure in pulmonary arteries and an increase in cardiac output.

Tadalafil (Adcirca)

Tadalafil is a PDE5 inhibitor indicated for improving exercise capacity in patients with WHO group 1 PAH. It increases cGMP, the final mediator in the nitric oxide pathway.

Vardenafil (Levitra, Staxyn ODT)

Vardenafil is a PDE5 inhibitor. This medication has been demonstrated to increase 6-minute walk distance. It is dosed as once or twice daily.

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Soluble Guanylate Cyclase (sGC) Stimulators

Class Summary

Soluble guanylate cyclase (sGC) is an enzyme in the cardiopulmonary system and the receptor for nitric oxide. PAH is associated with endothelial dysfunction, impaired synthesis of nitric oxide, and insufficient stimulation of the nitric oxide-sGC-cGMP pathway.

Riociguat (Adempas)

Riociguat elicits a dual mode of action. It sensitizes sGC to endogenous nitric oxide by stabilizing the nitric oxide-sGC binding, and it directly stimulates sGC via a different binding site, independently of nitric oxide. It is indicated for chronic thromboembolic pulmonary hypertension and PAH.

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Cardiac Glycosides

Class Summary

Cardiac glycosides are used for prevention and treatment of supraventricular arrhythmias associated with nonidiopathic pulmonary hypertension and for patients who have concomitant left-sided heart failure. Digoxin is not useful in the treatment of right-sided ventricular failure.

Digoxin (Lanoxin)

Digoxin is a cardiac glycoside with direct inotropic effects and indirect effects on the cardiovascular system. It acts directly on cardiac muscle, increasing myocardial systolic contractions. Its indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

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Diuretics, Loop

Class Summary

Diuretics should be used in 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 leading 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)

Furosemide increases excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule.

Bumetanide

Bumetanide increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in ascending loop of Henle. These effects increase urinary excretion of sodium, chloride, and water, resulting in profound diuresis.

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Anticoagulants

Class Summary

Long-term anticoagulation with warfarin should be considered in selected patients with PAH. These include patients with chronic pulmonary embolism, pulmonary veno-occlusive 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, Jantoven)

Warfarin interferes with hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.

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