Practical Management of Pulmonary Arterial Hypertension

This program was supported by an unrestricted educational grant from Actelion Pharmaceuticals Ltd.

Faculty disclosures for this summary are provided on page 28 of this publication.

Epidemiology, Pathogenesis, and Natural History

Lewis Rubin, MD, Professor of Medicine, University of California, San Diego, began by explaining that pulmonary arterial hypertension encompasses “a number of conditions that share clinical and pathological features in common,” and often respond to the same types of therapy, although they are not identical.

In 1998, at a World Health Organ-ization (WHO) meeting on pulmonary hypertension, a definition of pulmonary arterial hypertension (PAH) was agreed upon. A committee of experts agreed that the category of PAH would include primary pulmonary hypertension (PPH), both idiopathic and familial, and PAH related to other causes. These secondary causes include the use of drugs (i.e., Fen-Phen), exposure to toxins, HIV, collagen vascular disease (e.g., scleroderma, lupus, rheumatoid arthritis), chronic liver disease with portal hypertension, congenital systemic to pulmonary shunts, and persistent pulmonary hypertension of the newborn.

Dr. Rubin discussed various types of pulmonary venous hypertension, the most common being left-sided heart disease. This type of pulmonary hypertension can also be caused by extrinsic compression of central pulmonary veins seen in fibrosing mediastinitis, adenopathy or tumors, and pulmonary venoocclusive disease.

Pulmonary hypertension associated with respiratory disease or hypoxemia is different from PAH, he explained. Other types of pulmonary hypertension that should be considered as differential diagnoses include COPD, interstitial disease, severe sleep disordered breathing, as well as pulmonary hypertension due to thrombotic or embolic disease, for example in IV drug abusers or people with sickle cell disease.

“Those are the conditions you need to work through in establishing the etiology for pulmonary hypertension,” Dr. Rubin concluded. “The natural history of pulmonary hypertension is important to understand as you begin to approach management.”

When a patient first has the disease, there is a period of time during which he or she has no symptoms. The right ventricle is able to handle the increased pressure so no symptoms appear. By the time symptoms do occur, because the right ventricle can no longer boost flow to meet oxygen demands during exercise, the disease is established.

“Patients will present with exertional dyspnea as their consistent, most common, albeit non-specific, complaint,” said Dr. Rubin. At this point, chances are best for intervening successfully. “Disease progression is not defined by increasing pressure, but by decreasing right ventricular function.”

“Strategies for diagnosing PAH early have not improved much in the last 20 years,” he said. “We need to develop new strategies for earlier diagnosis,” such as considering pulmonary vascular disease in patients with unexplained dyspnea.

He went on to discuss the pathology of pulmonary arterial hypertension. “The important point to emphasize is that there is growth and proliferation of all components of the vessel wall: the intima, the media, and the adventitia,” Dr. Rubin said. This implies that injury to and dysfunction of the endothelium plays a critical role in the pathogenesis of the disease.

There are several potential mechanisms that could cause this growth and proliferation within the vessel wall, including abnormalities of the circulating blood space, abnormalities of the endothelium, abnormalities of the smooth muscle cell or all of the above.

Research is underway to begin to define these mechanisms. For example, one study showed overexpression of the serotonin transporter in pulmonary arterial hypertension. Serotonin is a vasoconstrictor and also promotes growth and proliferation of cells. The fenfluramine diet drugs tied to PPH also boost expression of the serotonin transporter.

Research has also shown overexpression of endothelin, which mediates hypertrophy, proliferation, and vasoconstriction in the lungs of pulmonary arterial hypertension patients. Endothelin concentrations have been linked to disease severity.

“Levels of endothelin are important prognostically,” Dr. Rubin said. “They are associated with poor survival in pulmonary arterial hypertension.”

Prostacyclin activity abnormalities are also at work in pulmonary arterial hypertension, Dr. Rubin noted. Prosta-cyclin, produced in the endothelium, is a vasodilator and antiplatelet aggregator and also inhibits growth and proliferation. One study showed that levels of the enzyme that makes prostacyclin from arachidonic acid are lower in blood vessels in pulmonary arterial hypertension, but especially in the small muscular pulmonary arteries. “This is where, we believe, the site of disease is,” he added.

Hereditary PPH has been tied to a defect in the bone morphogenic protein receptor -1 gene (BMPR 1), part of the transforming growth factor (TGF) signaling pathway that plays a key role in apoptosis. Inhibiting the programmed cell death process, Dr. Rubin noted, leads to proliferation of endothelial and smooth muscle cells.

A number of conditions can cause pulmonary arterial hypertension, but the condition is more severe in some people than in others. “We think that they are different diseases but may work by a final common pathway,” he added.

He cited studies by Thistlethwaite and colleagues that showed angiopoetin upregulation in PPH, Eisenmenger syndrome, thromboembolism and scleroderma, all conditions in which pulmonary arterial hypertension occurs (N Engl J Med. 2003;348(6):500-9). Thistlethwaite also showed that angiopoetin downregulates BMPR 2 regulation.

“A final common pathway of disease process, in a variety of forms of pulmonary arterial hypertension, could be the stimulation of angiopoetin that leads to altered BMPR expression, altered apoptosis, growth and proliferation,” Dr. Rubin said.

In terms of prognosis, exercise capacity is a good marker of disease severity. “Non-invasively, it tells us how the right ventricle is handling the pulmonary arterial hypertension during a dynamic stress,” said Dr. Rubin. A number of exercise tests have been shown to be clinically meaningful, such as the six-minute walk test and the maximal cardiopulmonary stress test.

“Some assessment of hemodynamics, either invasive or non-invasive, is very important,” he said. Functional status is also a good measure of disease prognosis and survival, he added.

Dr. Rubin concluded by emphasizing that understanding the etiology of pulmonary arterial hypertension is critical for management, as is determining the severity of disease and assessing it globally. “Clarification of the pathogenic mechanisms of pulmonary arterial hypertension is quite exciting and is leading to newer and more effective therapeutic strategies,” he said.

Evaluation and Diagnosis

Vallerie McLaughlin, MD, Associate Professor of Medicine, University of Michigan, Ann Arbor, discussed evaluation and diagnosis of PAH. She noted that the disease is difficult to diagnose, as symptoms are non-specific, such as shortness of breath, dyspnea upon exertion, pre-syncope, syncope, chest pain, edema, and ascites. Patients also tend to be young and are predominantly female.

“You can imagine a 35- or 40-year-old woman going to her primary care physician’s office complaining about these symptoms,” Dr. McLaughlin said. “PPH is not the first thing to jump out in their mind.” Making the diagnosis can take quite a bit of time, she added; according to NIH registry data from the 1980s, the average time from symptom onset to diagnosis was over two years. “I’d like to think we’re doing better today,” she said.

“Some of the findings on physical exam can be subtle,” Dr. McLaughlin pointed out. For example, patients with right heart failure will have jugular venous distension. Other signs can include right ventricular heave, right-sided fourth heart sound and a loud pulmonic valve closure sound.

“Some of these signs, although familiar to many in this audience, may not be easily perceptible to the primary care physician,” she said.

Echocardiograms are important in the diagnosis of pulmonary arterial hypertension. For example, these patients have tricuspid regurgitation that is more advanced than that seen in the general population. Right ventricular and right atrial enlargement and right ventricular hypertrophy are also seen. Observing the movement of the intraventricular septum is also important; it begins to move with the right ventricle rather than the left.

The echocardiogram is also useful for identifying other causes of pulmonary arterial hypertension such as left ventricular systolic dysfunction, congenital heart disease, and mitral valve disease.

“The estimation of PA pressure is what gets a lot of people into our center,” Dr. McLaughlin said. She reviewed the method for estimating PA pressure: placing a Doppler jet through the tricuspid regurgitation, which reveals the pressure gradient between the right ventricle and the right atrium. It’s not always possible to get this measurement, however, for example, if a patient has poor acoustic windows or if patients don’t have tricuspid regurgitation.

Echocardiography can also have flaws, Dr. McLaughlin said. It can underestimate or overestimate PA pressure. “Although this is a good test and it is one of the first tests that should be done in a patient with unexplained dyspnea, it’s not perfect,” she said. “I urge you to evaluate the results of echo very carefully.”

Electrocardiograms will show right ventricular hypertrophy, she added, while in X-rays of patients with pulmonary arterial hypertension the cardiopericardial silhouette is often enlarged, with a reduction of retrosternal airspace. Central pulmonary arteries may be large, with some peripheral pruning. With pulmonary function tests, most commonly a reduced capacity for diffusing carbon monoxide is seen in patients with pulmonary arterial hypertension.

When patients present with unexplained dyspnea and pulmonary arterial hypertension, Dr. McLaughlin added, evaluation for thromboembolic disease should always be performed. If clots or mosaic perfusion patterns are seen on a CT or lung scan, the patient should have a pulmonary angiogram to look for thromboembolic disease. This, she noted, is often a “surgically curable form of pulmonary arterial hypertension.”

When using cardiac catheterization to evaluate patients, she added, it’s crucial to evaluate left heart pressures by wedge pressure or by a left ventricular end diastolic pressure, to establish the severity of disease and the prognosis.

And while measuring pulmonary artery pressure is essential, cardiac output is also important, especially in determining the patient’s state of disease.

Some patients with pulmonary arterial hypertension have a substantial amount of vasoconstriction, at which treatment should be targeted, Dr. McLaughlin added. Three agents are used to test for vasodilator reserve: IV adenosine, IV prostacyclin and inhaled nitric oxide. All will help to determine whether the patient might respond to calcium channel blockers. Such responders, Dr. McLaughlin added, are those whose mean pulmonary artery pressure and pulmonary vascular resistance will fall substantially.

While functional assessment is not how pulmonary arterial hypertension is diagnosed, Dr. McLaughlin noted, it is important for determining prognosis and how patients should be followed. This can include establishing functional class and the six-minute walk test. “One thing that I think is important is to follow the exercise tolerance on the treatment,” she concluded, to assess response to therapy.

New Strategies for Optimizing the Management of Pulmonary Arterial Hypertension

Richard Channick, MD, Associate Professor of Medicine, University of California at San Diego, discussed the current best strategies for treating PAH. He noted that while pulmonary arterial hypertension used to be a fatal disease, it is now “one of the most treatable diseases.”

Functional class and exercise capacity, as measured by the six-minute walk test, are taken into consideration when determining the best therapy for a patient with pulmonary arterial hypertension, as well as indices of right ventricular function, he said.

Although no prospective studies have been done on warfarin, Dr. Channick noted, it is considered the standard of care as background therapy. Patients also achieve substantial improvement on diuretics.

In terms of lifestyle, patients are cautioned not to overexert, and women are counseled to avoid pregnancy, as mortality during and after delivery is quite high. Pulmonary arterial hypertension patients are also advised to avoid prolonged periods at high altitude.

Lung transplantation is a “changing target” in terms of treating pulmonary arterial hypertension, Dr. Channick noted. Waiting times can be two to three years or more, and the rejection rate is high, with over two-thirds of patients rejecting the organs at three years. Survival is between 50% and 60% at five years. Therefore, lung transplantation may be no better—or perhaps even worse—than drug therapy, he said.

Currently, he added, he and his colleagues may put a patient on the lung transplant waiting list when he or she begins medical therapy, and inactivate the patient or put them on hold if the medical therapy is successful.

In terms of medical therapy, Dr. Channick continued, only about 10% of patients will benefit from calcium channel blockers. These drugs should not be used in patients who are not so-called vasoreactive, because they can worsen their condition.

The goal of therapy for most patients, therefore, is not to treat vasoconstriction but to improve right ventricular function and block vascular tissue proliferation, as well as targeting endothelial defects seen in the disease. The three drugs that do this are epoprostenol, treprostinil, and bosentan.

Epoprostenol has been shown to improve hemodynamics and exercise capacity. It also acts quickly. “When you start a patient on intravenous prostacyclin, you can get therapeutic benefit almost immediately,” Dr. Channick said. In some patients, he added, the drug may remodel the blood vessels, making their structure more normal. The drug also has been shown to have functional and survival benefits.

Drawbacks, he noted, include cost, problems with the catheter and pump, and occlusion. Patients on average develop one to two infections per year. Side effects include peripheral neuropathy, weight loss, chronic diarrhea, rashes, jaw pain, thrombocytopenia, and wasting illness.

The second drug is subcutaneous treprostinil. It has been shown to improve six-minute walk distance and hemodynamics, but does not work as quickly as epoprostenol. The main problem with the drug is pain and irritation at the infusion site, which can require painkillers, and its cost.

The third drug approved for treating PAH is oral bosentan, a dual endothelin receptor antagonist. The drug has been proven to decrease the rate of clinical worsening, increase exercise capacity and improve hemodynamics in patients with pulmonary arterial hypertension, he said.

The primary concern with this drug, Dr. Channick added, is the potential for liver injury. Studies have found that about 10% to 11% of patients develop transaminase elevations more than triple the normal level while on the drug. This normally occurs during the first four months of treatment. But every case has been reversible with discontinuation or reduction of dose, he said, with patients very rarely developing symptoms.

In terms of which drug to use, Dr. Channick noted that oral bosentan is clearly the top choice in terms of its ease of administration, compared to subcutaneous or IV medications. However, is starting patients on oral therapy detrimental to outcome? No, he concluded, noting that studies have shown that at 36 months 57% of patients on the oral drug were failure-free, and “patients on this drug had a very good survival as far out as three years,” at close to 90%.

To summarize, in terms of a treatment algorithm, Dr. Channick said, patients in class III or IV should be tested for vasoreactivity, and put on calcium channel blockers if deemed vasoreactive. It is important to note that the vasorecactive patients represent the minority. All other patients can be started on bosentan, with the exception of severe class IV patients who should go on epoprostenol immediately. These patients should also be evaluated for transplant. Patients with contraindications to oral therapy, such as serious liver function abnormalities, should be started on treprostinil or epoprostenol at that point.

Over the next few years, treatment may be directed toward patients with earlier stage disease, he added. Combination therapy with prostacyclin, other prostanoids and bosentan may be possible, and transitioning patients on parenteral therapy to oral therapy will also be a goal. Five years from now other agents for treating PAH could include sildenafil and other endothelin receptor antagonists.

“Since I’ve been doing this we’ve come a long way,” Dr. Channick concluded. “Now we have all these options. I think it’s a wonderful time.”

Faculty Disclosures:

Richard Channick, MD
Research support, consultancy, speaker: Actelion, Pfizer

Vallerie McLaughlin, MD
Consultant: Actelion, United Therapeutics; Speaker: Actelion, United Therapeutics
Research Support: United Therapeutics, TBC, Myogen, Pfizer

Lewis Rubin, MD
Consultant/Investigator: Actelion, Pfizer, Schering, Myogen
Off-Label Use: Sildenafil for Pulmonary Hypertension