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Secondary Pulmonary Hypertension Treatment & Management

  • Author: Nader Kamangar, MD, FACP, FCCP, FCCM; Chief Editor: Ryland P Byrd, Jr, MD  more...
 
Updated: Jan 27, 2016
 

Approach Considerations

The therapy of secondary pulmonary hypertension (SPH) is primarily directed at the 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 PAH (SPAH) has been established, management consists of specific interventional therapy, specific medical therapy, or general supportive therapy.

Ongoing clinical trials may prove the benefit of vasodilator therapy in patients with various forms of PAH. Preliminary data with inhaled Iloprost, a prostacyclin analogue, appear promising, although frequent inhalations are required.

Patients with an atrial septal defect, mitral stenosis, or chronic thromboembolic pulmonary hypertension (CTEPH) should be considered for surgical management. PH typically resolves after early successful surgical procedures, unless it is too far advanced.

Balloon atrial septostomy has been employed with success in patients without evidence of right ventricular (RV) failure. The benefit (improved exercise function) occurs at the cost of a fall in arterial oxygen saturation (SaO2). The technique has been performed via a femoral catheter, with a Brockenbrough septal needle and Mansfield balloons to dilate the septostomy.

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Oxygen Supplementation

Oxygen has proved beneficial for reducing patient mortality in selected patients with PH. Two large trials demonstrated a definite mortality benefit for patients with chronic obstructive pulmonary disease (COPD), the most common cause of PH. Survival rates are highest in COPD patients who have less severe PH, 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, it appears that oxygen administration may also benefit other groups of patients with PH. Accordingly, long-term oxygen therapy should be prescribed for patients whose arterial oxygen tension (PaO2) is lower than 55 mm Hg at rest from any cause, those who have desaturation during exercise, and those who perform better on oxygen therapy.

Medicare indications for continuous long-term oxygen therapy include the following:

  • PaO 2 of 55 mm Hg or less than or SaO 2 of 88% or less.
  • PaO 2 of 56-59 mm Hg or SaO 2 of 89%, in the presence of evidence of cor pulmonale, right-sided heart failure, or erythrocytosis (hematocrit >55%).
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Pharmacologic Therapy

Calcium channel blockers

Calcium channel blockers have been used to treat idiopathic pulmonary arterial hypertension (IPAH).[12, 13] 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.[13] The most commonly observed adverse effects of these agents are systemic hypotension and lower-extremity edema. In one study, 10-14% of patients with idiopathic PAH (IPAH) were seen to develop Raynaud syndrome.

Phosphodiesterase type 5 inhibitors

Sildenafil

Sildenafil has also been used to treat PAH.[14, 15, 16, 17] In a controlled study evaluating 278 group 1 PAH patients treated with sildenafil for 12 weeks, patients demonstrated improved 6-minute exercise capacity, reduced mean pulmonary arterial pressure, and a decrease in World Health Organization (WHO) functional class for a 12-month period.[14] An uncontrolled study of 104 CTEPH patients treated with sildenafil for 12 months documented significant improvements in WHO functional class and pulmonary vascular resistance.[16]

A double-blind, multicenter, placebo-controlled, dose-ranging, parallel-group study determined that intravenous (IV) sildenafil reduced pulmonary artery pressure and shortened time to extubation and intensive care unit stay in children with postoperative pulmonary hypertension.[18]

Tadalafil

Tadalafil is another phosphodiesterase type 5 inhibitor used to treat IPAH.[19] It is indicated for improving exercise capacity in patients with WHO class 1 PAH.

Vardenafil

Vardenafil is a phosphodiesterase type-5 inhibitor currently undergoing study. This medication has been demonstrated to increase 6-minute walking distance.[20]

Combination therapy

In a controlled study of 25 patients with IPAH and scleroderma-associated PAH in whom monotherapy with bosentan (see below) had failed and sildenafil was added, a significant improvement in WHO functional status and exercise capacity was observed in patients with IPAH but not in the patients with scleroderma-associated PAH.[21]

In another controlled trial, sildenafil 80 mg was added to an IV epoprostenol regimen, and the combination proved to be more effective than placebo for improving exercise capacity and pulmonary arterial pressure.[22] 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.

Combination therapy of ambrisentan (an ERA) with tadalafil (a PDE-5 inhibitor) was approved as first-line treatment by the FDA in October 2015. The combination decreased disease progression and hospitalization, and more effectively improved exercise ability. Approval of the first-line ambrisentan/tadalafil combination for PAH is based on results of the ambrisentan and tadalafil in patients with pulmonary arterial hypertension (AMBITION) trial involving 605 patients with World Health Organization functional class II or III PAH. Patients were randomly assigned to receive once-daily ambrisentan plus tadalafil or to either drug alone. Doses were titrated from 5-10 mg/day for ambrisentan and from 20-40 mg/day for tadalafil. Treatment with the combination was associated with ~50% reduction in risk for clinical failure compared with either drug alone (P = 0.0002).[23]

Endothelin-receptor antagonists

Bosentan

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.

Bosentan is an orally active dual (EtA/EtB) endothelin-receptor antagonist used to treat PAH.[24, 25, 26, 27] The efficacy of oral bosentan in patients with PAH 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, RV systolic function, and left ventricular (LV) function. Reduced clinical worsening (defined as death, lung transplantation, or hospitalization for PAH) was reported.

Ambrisentan

Ambrisentan is a selective type A endothelin-1 antagonist[28] indicated for treatment of WHO group 1 PAH in patients to 1) improve exercise ability and delay clinical worsening; and 2) in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. However, because of the associated risks, it is available only through a restricted program developed by the manufacturer and the US Food and Drug Administration (FDA). Also see above discussion on combination therapy with tadalafil.

Macitentan

Macitentan is a dual endothelin receptor antagonist that 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.[29, 30]

Prostacyclins

Prostacyclin therapies for PAH have included epoprostenol, treprostinil, and Iloprost.[31]

Epoprostenol

IV prostacyclin (epoprostenol) induces relaxation of vascular smooth muscle and inhibits its growth and platelet aggregation through the increase in intracellular cyclic adenosine monophosphate (cAMP).[32, 33, 34]

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.[32] However, no long-term randomized trial of epoprostenol in patients with PAH has been conducted.

IV epoprostenol improved exercise tolerance, hemodynamics, and long-term survival in a cohort of 178 patients with PAH, as compared with historical controls.[34] 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.[35]

Epoprostenol is administered only by continuous IV infusion via a portable infusion pump connected to a permanent catheter. Common adverse effects of epoprostenol include jaw pain, headache, diarrhea, flushing, leg pain, and nausea, though these 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.

Treprostinil

Treprostinil is a stable prostacyclin analogue administered as a continuous subcutaneous infusion delivered by a minipump. 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, dyspnea, and hemodynamic measurements.[36] A subsequent multicenter retrospective study of 122 patients with PAH or CTEPH treated over a 3-year period demonstrated significant improvement in long-term survival rates.[37]

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.[38]

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 PO BID improved median 6-minute walk distance (6MWD) by +23 meters (p=0.013) compared with placebo.[39] 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=0.072] and 10 meters [p=0.089], respectively).[40, 41]

Iloprost

Iloprost is a chemically stable prostacyclin analogue that can be delivered through an inhaler by producing aerosol particles that deposit in the alveoli. Its disadvantage is its short duration of action. Therefore, it must be inhaled as many as six times a day. A 12-week trial involving 203 patients showed an increase in patient scores on a six-minute walk test and an improvement in NYHA functional class, as well as improved hemodynamics.[42] Adverse effects included cough, hypotension, and syncope associated with vasodilation.

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.[42, 43]

Prostacyclin agonists

Selexipag

The FDA approved selexipag (Uptravi) in December 2015 for adults with WHO group I PAH to delay disease progression and reduce the risk of hospitalization for PAH. It selectively activates the prostacyclin receptor (ie, IP-receptor), one of 5 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.

Approval of selexipag was based on the phase 3 GRIPHON study (n=1,156). Results showed that selexipag decreased the risk of morbidity/mortality by 39% compared with placebo (P<0.0001). Efficacy observed was consistent across the key subgroups (eg, age, gender, WHO Functional Class, PAH etiology, and background PAH therapy).[44]

 

Soluble guanylate cyclase (sGC) stimulators

Riociguat

Soluble guanylate cyclase (sGC) is an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). Pulmonary arterial hypertension (PAH) is associated with endothelial dysfunction, impaired synthesis of NO, and insufficient stimulation of the NO-sGC-cGMP pathway.

Riociguat is the first sGC stimulator approved in the United States. Approval was based on data from the two randomized, double-blind, placebo-controlled, global phase III studies CHEST-1 and PATENT-1, as well as long-term data from these studies. In each study, riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension.[45, 46]

Riociguat elicits a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding, and it directly stimulates sGC via a different binding site, independently of NO. It is indicated for chronic thromboembolic pulmonary hypertension and PAH.

Digoxin

Digoxin has been demonstrated to be beneficial for patients with supraventricular tachycardia–associated LV dysfunction,[47] but verapamil has been proved to be better than digoxin for controlling the heart rate.

Anticoagulants

Anticoagulation (specifically, with warfarin) may be helpful.[48] There is evidence to suggest that in patients with IPAH, thrombotic arteriopathy (abnormalities of blood coagulation factors, antithrombotic factors, and the fibrinolytic system) forms, contributing to a prothrombotic state. In a review of seven observational studies evaluating anticoagulation in PAH, five demonstrated a mortality benefit.[49] A benefit to anticoagulation, however, has not documented for secondary forms of PH.

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 six antibiotics and five 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, chickpeas), turnip greens, parsley, green onions, spinach, and lettuce.

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Lung Transplantation

Although lung transplantation is reserved for patients with severe PAH, a number of SPH patients have undergone successful transplantation at several centers. These patients had SPH due to collagen-vascular disease, drug-induced PH, or pulmonary veno-occlusive disease. The stability of the underlying causative disorder and the ability of the patient to tolerate an extensive operation are prerequisites. Heart-lung transplantation has been performed in patients with SPH due to congenital cardiac disease or severe LV dysfunction.

Although lung transplantation has historically been the treatment of choice for severe PAH, at present it is typically needed only for patients who are still in NYHA functional class IV after three months of therapy with epoprostenol. The long-term outcomes of lung transplantation remain disappointing, with 50% survival at five years.

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Pulmonary Endarterectomy

CTEPH is a potentially treatable form of PAH that, though not extremely common, is more prevalent than is generally appreciated. Pulmonary endarterectomy offers a cure for the condition. Excellent results can be obtained with proper patient selection, meticulous surgical technique, and careful postoperative management. Wider recognition of the prevalence of CTEPH and the efficacy of the operation performed to treat it are important.[50]

Pulmonary endarterectomy is a technically demanding procedure that is currently performed with success at only selected centers. The procedure is carried out during cardiopulmonary bypass and periods of circulatory arrest. Careful dissection of chronically endothelialized material from the native intima is performed to restore pulmonary arterial patency (see the image below). All affected parts of the lung are explored in order to clear all affected areas of the pulmonary vasculature.

During pulmonary arterial thromboendarterectomy, b During pulmonary arterial thromboendarterectomy, bilateral proximal thrombus was carefully dissected and extracted, leading to resolution of secondary pulmonary arterial hypertension.

Although pulmonary endarterectomy has proved to be permanently curative, an inferior vena caval filter should nevertheless be placed in all patients to prevent recurrence, and a lifelong anticoagulation regimen should be instituted.

Postoperative complications of pulmonary endarterectomy include pulmonary artery steal, which is the redistribution of pulmonary arterial blood flow away from previously well-perfused segments and into the newly operated segments. Another potential complication is reperfusion pulmonary edema, which may range in severity from a mild form that results in hypoxemia to a more severe form that results in hemorrhage and fatal complications.

A large case series of thromboendarterectomies for thromboembolic pulmonary hypertension reviewed the outcomes of 743 patients who underwent this operation between 1999 and 2004 and demonstrated that the procedure could be performed safely in patients with severe thromboembolic pulmonary hypertension, regardless of the magnitude of the preoperative systolic pressure in the pulmonary artery.[51]

A published series reported a perioperative mortality rate of 8.6% in 1200 patients. Among survivors of thromboendarterectomy, marked reductions in pulmonary artery pressures and pulmonary vascular resistance have been observed. Most patients who were New York Heart Association (NYHA) class III or IV improved to NYHA class I or II status. This procedure is performed in a few centers where surgical teams have gained sufficient experience in the perioperative care of these patients.

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Contributor Information and Disclosures
Author

Nader Kamangar, MD, FACP, FCCP, FCCM Professor of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Chief, Division of Pulmonary and Critical Care Medicine, Vice-Chair, Department of Medicine, Olive View-UCLA Medical Center

Nader Kamangar, MD, FACP, FCCP, FCCM is a member of the following medical societies: Academy of Persian Physicians, American Academy of Sleep Medicine, American Association for Bronchology and Interventional Pulmonology, American College of Chest Physicians, American College of Critical Care Medicine, American College of Physicians, American Lung Association, American Medical Association, American Thoracic Society, Association of Pulmonary and Critical Care Medicine Program Directors, Association of Specialty Professors, California Sleep Society, California Thoracic Society, Clerkship Directors in Internal Medicine, Society of Critical Care Medicine, Trudeau Society of Los Angeles, World Association for Bronchology and Interventional Pulmonology

Disclosure: Nothing to disclose.

Coauthor(s)

Sat Sharma, MD, FRCPC Professor and Head, Division of Pulmonary Medicine, Department of Internal Medicine, University of Manitoba; Site Director, Respiratory Medicine, St Boniface General Hospital

Sat Sharma, MD, FRCPC is a member of the following medical societies: American Academy of Sleep Medicine, American College of Chest Physicians, American College of Physicians-American Society of Internal Medicine, American Thoracic Society, Canadian Medical Association, Royal College of Physicians and Surgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, World Medical Association

Disclosure: Nothing to disclose.

Kelvin Chan, MD Resident Physician, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Olive View-UCLA Medical Center

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Ryland P Byrd, Jr, MD Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Ryland P Byrd, Jr, MD is a member of the following medical societies: American College of Chest Physicians, American Thoracic Society

Disclosure: Nothing to disclose.

Acknowledgements

Oleh Wasyl Hnatiuk, MD Program Director, National Capital Consortium, Pulmonary and Critical Care, Walter Reed Army Medical Center; Associate Professor, Department of Medicine, Uniformed Services University of Health Sciences

Oleh Wasyl Hnatiuk, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Shahriar Pirouz, MD Resident Physician, Department of Internal Medicine, Olive View-UCLA Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

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Gross pathology on patient who died of severe pulmonary arterial hypertension secondary to persistent patent ductus arteriosus.
Close-up view of gross pathology on patient who died of severe arterial pulmonary hypertension secondary to persistent patent ductus arteriosus.
During pulmonary arterial thromboendarterectomy, bilateral proximal thrombus was carefully dissected and extracted, leading to resolution of secondary pulmonary arterial hypertension.
Chest radiograph of patient with secondary pulmonary arterial hypertension shows enlarged pulmonary arteries. This patient had atrial septal defect.
54-year-old woman with history of scleroderma (CREST variety—ie, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) developed dyspnea that worsened upon exertion. The patient was found to have severe pulmonary arterial hypertension.
54-year-old woman with history of scleroderma (CREST variety—ie, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia) developed dyspnea that worsened on exertion. Spiral CT showed enlarged pulmonary arteries but no evidence of thromboembolism.
Ventilation-perfusion scan of bilateral mismatched segmental and subsegmental defects, suggesting chronic thromboembolic hypertension.
Left pulmonary arterial angiogram shows large central pulmonary arteries and attenuation of peripheral vessels, but thrombosis cannot be identified, because it has organized along vessel walls.
Bilateral angiography should be performed in patients suspected of having chronic thromboembolic pulmonary arterial hypertension. This right pulmonary arterial angiogram shows no evidence of filling defect, therefore excluding acute thrombosis. Angioscopy is potentially useful in this setting.
 
 
 
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