Pulmonary Arterial Hypertension: Current Concepts and Clinical Applications

At an industry-sponsored symposium held in conjunction with CHEST 2002, the annual meeting of the American College of Chest Physicians, four leaders in pulmonary medicine, cardiology and the treatment of scleroderma presented information on the comprehensive diagnosis and treatment of pulmonary arterial hypertension (PAH). Topics included epidemiology, pathogenesis and
diagnosis of PAH, conventional and new strategies for its treatment as well as PAH secondary to systemic sclerosis.

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

Pulmonary Arterial Hypertension: Epidemiology, Pathogenesis and Diagnosis

Understanding the pathogenesis of pulmonary arterial hypertension is gaining momentum and that is translating into advances in disease management. This has reinforced the idea that successful treatment will require cooperation and collaboration between pulmonologists, cardiologists and rheumatologists.

“As we think about the pathogenesis of pulmonary hypertension, it is useful to go back to the pathology,” said Lewis J. Rubin, MD, FCCP, from the University of California-San Diego Medical Center at La Jolla.

All three layers of the vessel may show changes leading to pulmonary hypertension. There may be multiple layers of cells in the intima. Medial hypertrophy can lead to additional space between the internal and external lamina. Finally the adventita may show abnormal growth resulting in lessened elasticity.

“The single take-home message is that there is some stimulation for growth and proliferation of all layers of the vessel,” said Dr. Rubin. “That is the absolute key to the pathogenesis of PAH.”

When considering the mechanisms that might contribute to the pathogenesis of PAH, Dr. Rubin sees three compartments.

The pulmonary system is the one area that gets the entire cardiac output and is continually bathed by whatever is in the bloodstream. This makes it particularly susceptible to circulating vasoactive substances.

Endothelial cells may show evidence of both growth and dysfunction. Of particular interest is endothelin, a key pathogenic mediator in PAH that is responsible for deleterious effects of vasoconstriction, hypertrophy, fibrosis and cell proliferation.

Finally there are changes in the smooth muscles. Among these are calcium kinetics that lead to an increase of intercellular calcium. This, in turn, accounts for vasoconstriction and for growth and proliferation in the smooth muscle layer.

“The single most important determinant of survival in these patients isn’t their pulmonary artery pressure,” noted Dr. Rubin. “It is how well, or poorly, their right ventricle is functioning.”

A study published several years ago in Germany looked at asymptomatic patients with the familial variant of primary pulmonary hypertension (PPH). They underwent stress echocardiography and fell into two distinct groups. The first had a normal response. The others had normal resting results, but progressive increases in pulmonary hypertension under stress (Grunig, et al. Circulation. 2000;102:1145).

“It emphasized two important points,” said Dr. Rubin. “One, is that you can be asymptomatic, have a normal echocardiogram and still have early pulmonary hypertension. The other is that you can be symptomatic, still have an unremarkable echo and stress may unmask it.”

All forms of pulmonary hypertension are serious, but scleroderma is particularly lethal. If you have pulmonary hypertension with this disease, there is about a 50% one-year survival rate.

Hemodynamic abnormalities impact on prognosis. A study of the NIH Registry indicated that survival in right-sided heart failure with right arterial pressures greater than 20 mm mercury was measured in months. The same was seen in those with a depressed cardiac index. In contrast, those with mean pulmonary artery pressures above 55 mm of mercury had average survival of 4 years or more if right-sided function remained normal (D’Alonzo, et al. Ann Intern Med. 1991;115:343).

Exercise is an important component of assessing patients with pulmonary hypertension. The six-minute walk test (SMW) has been shown to be a good marker of disease severity.

The PPH Study Group found a good correlation between six-minute walk, functional class hemodynamics and survival in patients on prostacyclin therapy. Marius Hoeper confirmed these findings in a study evaluating iloprost (Hoeper, et al. NEJM. 2000;342: 1866).

PAH Secondary to Systemic Sclerosis: The Global View

Scleroderma is more common than many physicians realize. New epidemiological studies are finding perhaps 24 new cases per million people per year.

“The prevalence is way up because of two phenomena,” said James R. Seibold, MD, from the University of Medicine and Dentistry of New Jersey- Robert Wood Johnson Medical School in New Brunswick “One is that the rheumatologists have gotten better at making the diagnosis. The other is that survival has dramatically improved, largely through specific organ support.”

Scleroderma, particularly regarding lung involvement is, “a hopelessly complex disease”. There are elements of immune activation, inflammation, fibrosis, and vascular injury. The major clinical issue is defining the relative contribution of these processes and choosing an appropriate therapy.

There have been case series suggesting that treating the alveolitis with cyclophosphamide may help prevent fibrosis. While suggesting an association with stabilizing lung function, these are largely uncontrolled studies, which lessens their value (White BA, et al. Ann Intern Med. 2000;132:947).

The NHLBI/NIAMS study examines cyclophosphamide versus placebo in scleroderma alveolitis (SA). Patients with FVCs under 85% and less than seven years into their disease are screened using high resolution CT scans (HRCT) and bronchoalveolar lavage (BAL).

Although the trial is ongoing, it is becoming known that even those with the mildest level of impairment still have abnormal interstitial HRCT about 82% of the time and abnormal BALs in about 57%. Dr. Seibold notes that alveolitis appears to be rather common in the early years of scleroderma.

“What is going on with lung function during that period of time?” asked Dr. Seibold. “Not all that much.”

A study from his center by Broder looked at the frequency of decline in FVC >10% from baseline. Over ten years, the event frequency was 30.0%. Progressive loss of FVC appears to be uncommon in scleroderma patients even though 8 in 10 will have alveolitis.

“Look at data like this and then review some of the cyclophosphamide studies to see how frequently failure to lose pulmonary function was touted as a clinical benefit,” noted Dr. Seibold. “In fact, what we might be seeing is the natural history of the disease.”

Series of case studies of patients with advanced disease indicates that progressive loss of lung function is not the leading cause of death. Over 500 patients were followed for 20 years if they had at least three sets of pulmonary function tests at any time during the study. The population with a ratio of FVC to diffusing capacity >1.8 had longer survival compared to a group with ratios <1.8 (Broder A, et al., Arthritis Rheum in press). (Figure 1)

“This data argues that they die of a progressive impact on gas exchange,” said Dr. Seibold. “The vascular lesion is seen as the major influence on survival.”

An important concern is stimulating the production of endothelin-1 (ET-1), which induces the scleroderma fibroblast phenotype. In addition, ET-1 is proinflammatory and endothelin B receptors are overexpressed in the scleroderma lung.

Dr. Seibold sees promise in early-stage research into the use of L-arginine supplements to increase PDE-5 inhibitor substrates. Diminished prostacyclin synthase and locally bioavailable prostacyclin at the site of a vascular injury would make replacing prostacyclin a reasonable strategy. Targeting the vasoconstrictive and proliferative effects of endothelin would be relevant to both pulmonary hypertension and other aspects of scleroderma.

With the advent of approved efficacious treatment options, there is an increased need to find scleroderma patients earlier. One method might be an increase in echocardiography with Doppler as a routine screening test. Available figures indicate that 25 percent of patients being seen by rheumatologists may have preclinical pulmonary hypertension. In Dr. Siebold’s view Doppler echocardiography is useful not only in diagnosis, but also in monitoring patients with connective tissue disease.

“All newly diagnosed scleroderma patients should have a baseline echocardiogram and pulmonary function tests,” said Dr. Seibold. “Patients with a known diagnosis should have annual echocardiograms independent of their level of dyspnea. That is the current recommendation of the World Health Organization.”

“With modern therapy changing the field and enhancing awareness, I think we should consider how to foster formation of PAH multidisciplinary teams that include cardiopulmonary and rheumatology components,” said Dr. Seibold.

Conventional Therapies for the Treatment of PAH

Prior to initiating therapy for PAH, it is important to test for a response to vasodilators and to confirm the diagnosis with a right heart catheterization for all patients with suspected PAH. According to Vallerie V. McLaughlin, MD, FCCP, from Rush-Presbyterian-St. Luke’s Medical Center in Chicago, about 20% of patients with PPH might respond to calcium channel blockers.

Right heart catheterization and vasoreactivity testing is done using inhaled nitric oxide (NO), IV adenosine or prostacyclin. If there is a dramatic reduction in mean pulmonary artery pressure, pulmonary vascular resistance and an increase in cardiac output with no increase in right atrial pressure, they are likely to be responders and should be further tested using oral calcium channel blockers.

IV epoprostenol, a synthetic form of prostacyclin, was the initial FDA-approved therapy. Released in 1996, it is indicated for PPH and PAH associated with scleroderma in patients who are New York Heart Association (NYHA) functional Class III and IV.

The US PPH Study Group trial looked at 81 patients who were randomized to receive epoprostenol plus conventional therapy or conventional therapy alone. There was a significant improvement in the six-minute walk test (SMW) as well as improvements in hemodynamics, dyspnea, NYHA class and survival at 12 weeks (Barst RJ, et al. NEJM1996;334:296).

A subsequent study was completed of 113 patients with scleroderma and pulmonary hypertension but without significant interstitial lung disease. Those randomized to epoprostenol had an improvement in the 6MW while those in the conventional therapy arm deteriorated (Badesch DB, et al.. Ann Internal Med. 2000;132:425).

“We’ve noticed over the long term that chronic therapy with epoprostenol results in more improvement than one would expect from acute vasodilator testing,” noted Dr. McLaughlin. “This suggests that maybe there are some chronic remodeling effects at work.”

Epoprostenol has been shown to increase survival in patients with PPH. Dr. McLaughlin recently published an article showing that observed survival was significantly higher than estimated using the National Institutes of Health Registry Equation. This was maintained up to three years (McLaughlin VV, et al. Circulation. 2002;106:1477). A large study from France showed similar results (Sitbon O, et al. J Am Coll Cardiol.2002; 40:780).

An alternative is the prostacyclin analog treprostinil. It can be given subcutaneously using premixed syringe and mini-med pump.

A trial of over 400 patients using treprostinil showed an increase in six-minute walk of 17 meters versus essentially no change in the placebo group. Although the result looks unimpressive compared to other interventions, Dr. Mc-Laughlin says this might be due to inadequate dosing. Those in the highest dose quartile had substantial improvement in the walking test (Simmoneay et al. Am J Resp Crit Care Med. 2002;165:800).

The initial randomized studies of bosentan versus placebo in patients with PAH showed an increase in SMW distance of 70 meters after 12 weeks. There was essentially no change in placebo-treated patients. There were also improvements in hemodynamics, a subtle decrease in pulmonary artery pressure and a reduction in pulmonary vascular resistance (Channick RN, et al. Lancet. 2001;358: 1119).

The BREATHE-1 (Bosentan Ran-domized Trial of Endothelin Receptor Antagonist Therapy for Pulmonary Hypertension) study included 213 patients with either PPH or pulmonary hypertension associated with scleroderma. Again patients were randomized to bosentan or placebo and then followed for 16 weeks. The six-minute walk results had increased by 36 meters in the treatment group versus a decrement eight meters in the placebo group for a net treatment effect of 44 meters (P>0.001) (Rubin LJ, et al. NEJM. 2002;346:896).

A secondary endpoint was time to clinical worsening, a composite of death, lung transplantation, initiation of epoprostenol or atrial septostomy in countries where available. Over the 16-week double-blind period, only 5% of those randomized to bosentan met one of those endpoints as compared to nearly a quarter in the placebo arm. In a smaller number followed out up to 28 weeks, the curves continued to separate.

“These two trials have demonstrated that bosentan improved exercise capacity, dyspnea, functional class and reduces the risk of clinical worsening,” said Dr. McLaughlin. “The bottom line is that the very sick patients should go on epoprostenol, those who respond should be placed in calcium channel blockers and a majority of the rest should be initiated on oral bosentan.”

New Strategies for the Comprehensive Management of PAH

Although there have been great advances in treatment of PAH recently, there are many other options being examined. New forms of prostacyclin are being explored. NO replacement therapies are under active study. Combination therapies using different agents that work in a complementary fashion is yet another area being intensely scrutinized.

“It should be obvious by now that pathogenesis can occur via a variety of mechanisms such as prostacyclin abnormalities, NO abnormalities and others,” said Richard N. Channick, MD, UCSD Medical Center in La Jolla. “Because of this, it certainly follows that combination therapy might provide additional benefit.”

One new medication is iloprost. Data from Germany shows that inhalation leads to significant reductions in pulmonary arterial pressures and improvement in cardiac index. The effects are seen at baseline and after three months (Olschewski H, et al. Ann Intern Med. 2000;132:435). However, iloprost is not available or under investigation in the US.

“There are a small number of uncontrolled reports indicating a long-term benefit to use of inhaled NO,” said Dr. Channick. “There has not yet been a randomized, prospective trial in PAH.”

Another option is giving a drug that poteniates the effect of endogenous NO. Sildenafil is one possible candidate. Some reports suggest sildenafil may have a selective pulmonary vasodilator effect. Although there are currently only uncontrolled reports showing potential benefits, a Phase III trial of sildenafil
versus placebo is ongoing.

Endothelin (ET) is an endogenously produced peptide in endothelial cells that is a key pathogenic mediator in PAH. ET is known to mediate its effects via the ET-A and ET-B receptors. Activation of these receptors ultimately results in vasoconstriction and cell proliferation. In pathological conditions, up-regulation of ET-B receptors on smooth muscle cells and fibroblasts is responsible for the vasoconstrictive and pro-fibrotic effects.

There are currently two compounds that are ET-A agonists. A randomized trial for sitaxsentan has recently been completed and the results are pending. The other, ambersentan, is in Phase II trials.

“I also want to touch on something that’s probably of interest to most physicians who have patients on epoprostenol,” said Dr. Channick. “Will the addition of bosentan provide added benefit or allow me to decrease or wean the epoprostenol?”

A study sponsored by the manufacturer to answer that question has recently been completed and the results may be available early in 2003. The patients were randomized to either bosentan or placebo. The main endpoints were the six-minute walk and hemodynamic measurements.

“While there is no hard data yet to report, it appeared that those therapies were safe,” said Dr. Channick. “I can tell you there was a trend toward improved efficacy with the combination. This was small study and the effect did not reach significance, likely due to the small numbers.”

The BREATHE-3 study looked at the addition of bosentan to epoprostenol in pediatric patients. Although the official results are still pending, the combination appeared to provide added benefits in terms of hemodynamic improvements.

Another small study in press by Dr. Channick looked at who could be weaned off epoprotenol. Four patients with normal or near normal pulmonary hemodynamics were weaned after the addition of other medications including bosentan, as well as calcium channel blockers and sildenafil in some patients.

Dr. Channick stressed that this was done as part of a protocol. It is not approved therapy as of yet.

“I think as we gain more data about this therapy, we’re going to be able to identify which patients on other therapies can be safely transitioned,” said Dr. Channick. “The answer is not here yet, but it is definitely coming.”