Group 4 Pulmonary Hypertension Treatment & Management

Treatment in chronic thromboembolic pulmonary hypertension (CTEPH) is unique in that surgery is able to provide definitive and curative outcomes without having to proceed to transplantation. Thus, the goal of treatment is to assess for surgical candidacy (see the image and patient history caption below). Medical therapy is offered to nonoperative candidates or patients with residual pulmonary hypertension postsurgery.

Ventilation perfusion scan showing bilateral large wedge-shaped mismatched perfusion defects and areas of gray indicating decreased perfusion. Right-sided heart catheterization for this patient showed combined precapillary and postcapillary pulmonary hypertension and the following: right atrial pressure 10 mm Hg, right ventricular pressure 82/8 mm Hg, pulmonary artery wedge pressure 22 mm Hg, and pulmonary artery pressure 83/27 mm Hg with a mean of 49 mm Hg. He was referred to an expert center for pulmonary endarterectomy evaluation, where he underwent pulmonary angiography. Findings from the right side showed an occluded upper lobe anterior segment, a proximal web in the upper lobe, and disease in all lower segments. Findings from the left side showed an occluded superior segment of the lower lobe with disease in basal segments, proximal web in lingula, and intact upper lobe vessels. He underwent pulmonary endarterectomy with intraoperative University of California San Diego classification of thrombus as right 1 and left 2. Postoperatively, he has had dramatic improvement in his symptoms and is off all pulmonary arterial hypertension therapy.

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Preoperative assessment

With the diagnosis confirmed or suspected, assessment of surgical candidacy for pulmonary thromboendarterectomy (PTE) should be performed at centers with expertise in the management of CTEPH. Proximal organized thrombi represent the ideal surgical circumstance, but patients with more distal obstruction (isolated segmental disease) often also derive hemodynamic benefit. ^[43] Because the increase in pulmonary vascular resistance (PVR) arises not only from central surgically accessible lesions but also from distal, small-vessel arteriopathy, patients with a significant component of small-vessel arteriopathy may not experience a significant decrease in PVR following PTE. Determining the presence and extent of small-vessel arteriopathy before surgery remains challenging. Poor subpleural perfusion on pulmonary angiography may suggest distal vessel disease but remains to be explored. ^[44]

Comorbid diseases must also be assessed as part of the preoperative evaluation. Coronary artery disease and valvular heart disease can be corrected at the time of PTE. Severe underlying parenchymal disease, particularly involving regions of the lung anticipated to be reperfused with an endarterectomy, is a contraindication to surgery, which has the potential to increase ventilation-perfusion (V/Q) mismatch and worsen hypoxemia and postoperative respiratory failure.

Pulmonary thromboendarterectomy

PTE should be offered to all eligible patients with CTEPH (see the image below and patient history caption). The international registry of incident cases of CTEPH reported 3-year survival of 90% in those operated and 70% in those not having surgery. ^[27] Characteristics that favor good long-term outcomes for PTE include the following:

• History of deep venous thrombosis/pulmonary embolism (PE)
• Absence of right-side heart failure and other comorbidities
• Clear concordance on all images
• Bilateral lower-lobe disease
• PVR less than 1,000 dyn·s·cm−5, in proportion to site and number of obstructions on imaging
• Higher pulmonary artery pulse pressure
• Good functional capacity (New York Heart Association functional class II or III)

The most important surgical advance has been in redefining the distal limits of endarterectomy, ^[45] as well as perioperative and postoperative care, which have resulted in a reduction of perioperative mortality from almost 20% in the early years to less than 2% at University of California San Diego. ^[43]

Intraoperative clot during pulmonary endarterectomy. This is a 42-year-old woman with a history of multiple pulmonary emboli and protein S deficiency who initially presented with severe dyspnea (New York Heart Association functional class IV) and was initiated on multiple pulmonary arterial hypertension medications, including intravenous prostacyclin. Preoperative right-sided heart catheterization showed right atrial pressure of 16 mm Hg, pulmonary artery pressure of 124/29 mm Hg with a mean of 67 mm Hg, cardiac output of 4.53, and pulmonary vascular resistance of 12 Wood units. Immediate postoperative right-sided heart catheterization showed right atrial pressure of 9 mm Hg, pulmonary artery pressure of 40/15 mm Hg with a mean of 25 mm Hg, cardiac output of 5.15, and pulmonary vascular resistance of 2.9 Wood units. She came off all her pulmonary arterial hypertension therapy immediately postoperatively and continues to do well.

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In expert centers, surgery can be performed successfully in patients with distal chronic thromboembolism. ^[46] The advances in diagnostics and growing surgical experience have contributed to this success and have led to an intraoperative classification of the specimens retrieved during pulmonary endarterectomy. ^[11]

University of California San Diego surgical classification is as follows:

• Surgical level 0: No evidence of thromboembolic disease in either lung
• Surgical level I: Chronic thromboembolism starting in the main pulmonary arteries (Level IC: Complete occlusion of one main pulmonary artery with chronic thromboembolism)
• Surgical level II: Chronic thromboembolism starting at the level of the lobar arteries or in the main descending pulmonary arteries
• Surgical level III: Chronic thromboembolism starting at the level of the segmental arteries
• Surgical level IV: Chronic thromboembolism starting at the level of the subsegmental arteries

A median sternotomy with use of cardiopulmonary bypass with periods of hypothermic circulatory arrest is the crucial element of the surgical procedure. Deep hypothermia provides for tissue protection, whereas intermittent circulatory arrest periods avoid back-bleeding from the bronchial artery to pulmonary artery anastomoses and provides the necessary bloodless field to allow the optimal dissection of chronic thromboembolic material from the pulmonary vessels.

Immediately following surgery, a reduction in mean pulmonary arterial pressure (mPAP) with augmentation in cardiac output has been a consistent observation. Some patients do not achieve normal pulmonary pressures and right-side heart function following PTE surgery, although the definition of residual pulmonary hypertension varies among reporting centers. Occurrence estimates vary between 5% and 35%. Possible explanations for this postoperative outcome include (1) chronic thromboembolic disease (CTED) that could not be surgically resected and (2) a significant amount of coexisting distal vasculopathy. Mortality rates reported from centers performing PTE surgery have steadily declined over the years, currently in the range of 2.2-11.4%, with the lower perioperative mortality figures at centers with more extensive experience. ^[28] Intraoperative and postoperative extracorporeal membrane oxygenation is often done at CTEPH centers to help avoid reperfusion injuries and to assist with right ventricular pump failure. ^[47]

Balloon pulmonary angioplasty

Balloon pulmonary angioplasty (BPA) should be considered for symptomatic CTEPH patients ineligible for PTE due to distal chronic thromboembolism or persistent/recurrent pulmonary hypertension after surgery. ^[2] BPA has evolved into an important component of the CTEPH treatment algorithm since the 2012 reports from Japan ^[48] and is part of the European Society of Cardiology/European Respiratory Society recommended guidelines. ^[31] This involves treatment of vascular CTEPH lesions with semicompliant balloons at relatively low pressures (about 6-10 atm), over several sessions. BPA has been reported to improve hemodynamics, symptoms, exercise capacity, and right ventricular function, with significantly lower rates of major complications compared with the report from 2001. ^[2] BPA patient selection is important and requires a multidisciplinary review of all available and pertinent data, with anatomical and functional assessment of pulmonary arteries and lung perfusion to identify the target vessels, and, possibly, a selective pulmonary angiogram or other intravascular imaging and pressure gradient analysis to aid in lesion assessment and balloon sizing of the target vessels. ^[49] In experienced hands, BPA has emerged as a promising and established treatment for inoperable CTEPH.

Pulmonary hypertension - targeted medical therapy

While PTE remains the treatment of choice for most patients with CTEPH, around 40% of the patients in the international CTEPH registry were considered inoperable because of concerns over inaccessible vascular obstruction, pulmonary artery pressure out of proportion to morphological lesions, and significant prohibitive comorbidities. ^[15] A large number of small studies and three large randomized controlled trials (BENEFIT, CHEST, MERIT-1) have demonstrated varying improvements with targeted medical therapy in technically inoperable patients. Riociguat is the currently approved medical therapy in the United States for inoperable CTEPH based on the CHEST trials. ^[50] In 2017, the MERIT-1 trial of macitentan in the treatment of inoperable CTEPH showed improvements of the primary endpoint, PVR, and of other endpoints (eg, 6-minute walk distance, N-terminal pro-brain natriuretic peptide). ^[51] This study provided the first evidence on combination drug therapy in inoperable CTEPH. Of the included patients, 61% were already treated with phosphodiesterase type 5 inhibitors and/or oral/inhaled prostanoids at inclusion, and the addition of macitentan showed similar efficacy compared with the drug-naïve patients. Accordingly, macitentan is being considered for potential CTEPH registration. Patients with persistent/residual postoperative pulmonary hypertension were also included in the BENEFIT and CHEST-1 trials, representing around 30% of the study population. ^{[50, 52]}

Using medical therapy as a bridge to PTE is more controversial and is believed to delay timely surgical referral and, therefore, definitive treatment. In the international registry and in a University of California San Diego cohort, 28% and up to 37%, respectively, of the patients were on some form of pulmonary hypertension–targeted drug(s) at the time of surgical referral. ^[15] In both cohorts, the delay between diagnosis and surgery was doubled in the pretreated patients, without demonstrable clinical benefit. In the international registry, pretreatment even independently predicted worse outcome (hazard ratio 2.62; P = .0072). ^[27] Key limitations of these reports are the inherent referral bias and the possibility of medical therapy potentially stabilizing otherwise deteriorating cases (unknown and not tested). Event-driven morbidity/mortality studies have not been performed in CTEPH, and the role of medical treatment prior to and following PTE and BPA is still being investigated.

The use of intravenous epoprostenol, a prostacyclin derivative, in patients with inoperable CTEPH has also been examined, with limited studies showing improvement in hemodynamics, 6-minute walk distance, WHO functional class, ^[53] and, in some instances, survival. ^[42]

Diuretics

Diuretics (eg, furosemide, bumetanide) should be used in patients who develop right-side heart failure and those who have systemic congestion manifested by hepatomegaly, ascites, and marked lower extremity edema. Severe right-side heart failure may also compromise function of the left ventricle (ventricular interdependence, reverse Bernheim effect), 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 and worsen renal dysfunction. Thus, a careful balance with close clinical follow up is required.

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 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.

Anticoagulation

Lifelong anticoagulation is recommended for patients with CTEPH, and vitamin K antagonists have been studied the most and are the therapy of choice. ^[31]

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

Patients who undergo PTE may develop complications that are common to other types of cardiothoracic surgery (eg, arrhythmias, atelectasis, wound infection, pericardial effusions, delirium). They may also experience two very unique complications that impair gas exchange resulting in profound hypoxic respiratory failure. The first is pulmonary artery steal, where redistribution of pulmonary arterial blood flow to the newly endarterectomized areas causes a severe V/Q mismatch. The second is reperfusion pulmonary edema, where high-permeability shift of fluids develops in the areas where the thromboendarterectomy occurred. Usually, the treatment is supportive (oxygen supplementation, mechanical ventilation) and inhaled nitric oxide. ^[54]

If the patient is not a surgical candidate, pharmacologic regimens are also a possible source of adverse effects and possible complications. The guanylate cyclase stimulant, riociguat, can trigger hypotension, bleeding, and numerous gastrointestinal complaints. If endothelin receptor antagonists such are bosentan are used, possible hypotension, edema, headaches, respiratory tract infections, and transaminitis can develop. If phosphodiesterase type 5 inhibitors are used, flushing, headaches, and hypotension can result. If prostanoids are used, in severe inoperable disease, multiple adverse effects can occur, including flushing, hypotension, chest pain, headaches, anxiety, jaw pain, and catheter-associated sepsis.

While no specific guidelines exist, patients with CTEPH, especially with right-side heart failure, should generally follow a low-sodium diet to minimize excessive fluid retention.

Guidelines recommend that patients with pulmonary arterial hypertension (PAH) remain active, although they should avoid excessive activity that precipitates symptoms. Supervised exercise rehabilitation should also be recommended to deconditioned patients, as this has been shown to increase functional capacity and quality of life. ^[55]

The majority of cases of PAH are not preventable. Patients should avoid using anorexigen drugs, as well as illicit stimulant drugs such as amphetamine-derivatives and cocaine, which can increase risk of group 1 PAH. To minimize potential contributions from WHO group 3 disease, patients should not smoke. Those with obstructive sleep apnea or other lung disease should be optimally treated for these diseases to avoid further insults from hypoxemia/chronic pulmonary disease.

Once a diagnosis of CTEPH has been made, patients should be evaluated by a center specializing in CTEPH. Medical assessment including 6-minute walk distance testing should be performed at least twice a year to assess for a decline in functional status. Transthoracic echocardiography is often performed on at least an annual basis as well, with right-sided heart catheterization undertaken for patients who have a change in clinical status.