Reports

Revisiting ß-Blockers for the Treatment of Uncomplicated Hypertension
Unpredictability of aHUS and Benefit of Early Therapy Supports High Index of Suspicion

Recent Trial Data Foster New Definitions of Optimal Management for Pulmonary Arterial Hypertension

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

MEDICAL FRONTIERS - CHEST 2013

Chicago, Illinois / October 26-31, 2013

Chicago - As a reflection of progress in the treatment of pulmonary arterial hypertension (PAH), experts speaking at the 2013 Chest meeting contend that they consider normalization of right ventricle function a viable therapeutic goal in at least some patients. This is a major step forward. The right ventricle overload produced by pulmonary vasoconstriction is a key part of the terminal pathophysiological process that was once considered irreversible. The goals of treatment in PAH have moved from improving quality of life over the course of survival to improving survival itself. The reorientation is captured in recent and ongoing clinical trials that have abandoned symptomatic improvement as a primary measure of efficacy for protection against hard measures of progression, including PAH-related hospitalization and death. While it is unclear what proportion of the improving rates of survival in PAH is due to earlier diagnosis relative to better therapy, there is growing consensus that current treatments are not simply palliative.

Chief Medical Editor: Dr.Léna Coïc, Montréal, Quebec

A fundamental change in the therapeutic goals of pulmonary arterial hypertension (PAH) is being driven by evidence that effective control of pulmonary hypertension slows or in some cases halts the cascade of pathological events that produce pulmonary dysfunction and right heart failure. According to experts speaking at a series of symposia at the 2013 Chest meeting, the greatest opportunity to change the natural history of PAH occurs at the earliest stages, but PAH treatment has moved beyond transient functional improvements.

“I would agree that you can normalize right ventricle function and hemodynamics in some patients. This is a minority of individuals, but I think you can move it in the right direction in most patients, with the goal of preventing PAH-associated hospitalizations,” reported Dr. Charles D. Burger, Chair, Pulmonary and Critical Care Medicine, Mayo Clinic, Jacksonville, Florida. Speaking at a symposium on PAH, Dr. Burger acknowledged that this is a major shift in orientation. Other experts made similar assertions.

“My goal today, particularly at early stages of PAH, is to normalize the right heart,” agreed Dr. Rajan Saggar, Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at the University of California, Los Angeles. “In treatment trials, I think we are in the position to look at hard end points rather than just quality of life.”

The clinical trials in PAH have already moved in this direction, replacing the 6-minute walk distance (6MWD) test with event-driven end points as the primary outcome. The first such trial, called SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcomes) was recently completed (Pulido et al. N Engl J Med 2013;369;9:809-18). It associated the most effective dose of a novel agent called macitentan with a 45% risk reduction (P<0.001) in the composite morbidity and mortality end point. Macitentan was recently approved for the treatment of PAH in the U.S. and in Canada.

At least two other large, multicenter studies are ongoing. One, called GRIPHON (Selexipag in Pulmonary Arterial Hypertension), is comparing a novel oral prostacyclin receptor agonist to placebo. The other, called AMBITION (First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension) is comparing a combination of an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE-5) inhibitor with either alone for an event-driven time to clinical failure.

Markers of Benefit

“We need to evaluate the impact of current therapies on outcomes, not just functional improvements, and that is what we are now seeing with large trials following patients over long periods,” reported Dr. Sean Studer, Chief of Medicine, Woodhull Medical Center, New York University, New York City. “For too long, we have been focused on the 6MWD test, but this just measures effect on functional capacity. If you start with the concept of changing outcomes, then we need event-driven trials.”

In the SERAPHIN trial, which was the source of several new substudies presented at the 2013 Chest meeting, the median follow-up was approximately 2.2 years. The primary composite end point included death, atrial septostomy, lung transplantation, initiation of prostanoids, or worsening of PAH. Relative to placebo, both the 3 mg and 10 mg doses of macitentan significantly reduced the risk of reaching the primary end point, but the 10 mg dose was more effective with comparable tolerability (See Figure 1). For the secondary combined end point of PAH-related hospitalizations and deaths, the 10 mg dose produced a 50% reduction (P<0.001) relative to placebo over the course of the trial.

Figure 1. 

 

SERAPHIN is the longest and among the largest multicenter phase 3 studies ever conducted in PAH. A number of preplanned substudies, including several presented at the 2013 Chest meeting, are already generating new information about PAH, including a clearer identification of the most useful pathophysiological and clinical markers of progression. In one substudy presented at the 2013 Chest meeting, the data provided support for the prognostic value of an improving World Health Organization (WHO) functional class.

 “The clinical implication from this substudy is that gaining improvement in functional class is a meaningful therapeutic goal and a simple marker of therapeutic benefit,” reported Dr. Rogerio Souza, Pulmonary Department, University of Sao Paulo, Brazil. “The data indicate that maintaining patients in class III should not be considered optimal. Such patients should be considered for additional therapy with the goal of achieving class II or better.”

In this substudy, patients were stratified by change in functional class from baseline and then compared for the relative risk of reaching the readily measured, hard clinical combined outcome of PAH-related hospitalization or death.  At baseline, slightly more than half of patients were in functional class II with almost all of the remaining in functional class III (<2% in class IV).

Reducing Hospitalization Rates

Over the course of more than 2 years of therapy, those starting and remaining in functional class II or improving to functional class I were significantly less likely to be hospitalized for PAH or die relative to those who progressed. For those starting in class III, improving to class II relative to staying in class III or worsening also produced a more favourable survival curve for the end point of hospitalization and death, although this difference was a trend (See Figure 2).

“The greater likelihood of avoiding hospitalization or death by staying or improving to functional class II was evaluated in this substudy independent of therapy, but macitentan, relative to placebo, increased the proportion of patients who improved in functional class and reduced the proportion of patients who worsened,” reported Dr. Souza. Although this study has no active comparator arm, he noted that the dual receptor binding and greater relative tissue penetration of macitentan relative to currently available ERA agents provided the basis for its clinical development.

 

Figure 2.

 

Beyond 6MWD

The value of placing or keeping patients in functional class II differs pointedly from improving 6MWD. Even though baseline measures of both functional class and 6MWD are powerful prognostic indicators, change in 6MWD, unlike improvement to or sustaining functional class II, has not been found to correlate with key outcomes such as hospitalization and death. The inability of change in 6MWD on therapy to predict improved outcomes, first convincingly demonstrated in a meta-analysis (Savarese et al. J Am Coll Cardiol 2012;60:1192-201), was reinforced from a SERAPHIN substudy presented at the 2013 European Society of Cardiology annual meeting (Galiè et al. Abstract 1061).

“Patients who improve their 6MWD on therapy feel better, but the data suggest that this does not tell you how they will do long-term,” explained Dr. Souza, indicating that 6MWD may be a relatively transient measure that does not closely reflect the cascade of pathophysiology leading to right ventricular overload. Pulmonary vasoconstriction, the defining signal of PAH, is thought to be fundamental to this pathophysiology, which includes the vicious cycle of an upregulated inflammatory response, intimal fibrosis, and hypertrophy.

In fact, all of the available therapies for PAH, including ERA agents, PDE-5 inhibitors, prostacyclin analogues, and riociguat, the first and recently approved soluble guanylate cyclase (sGC) stimulator, reduce pulmonary vasoconstriction. Many of the therapeutic targets, including endothelin-1 and prostacyclin, are involved in well-documented imbalances in patients with PAH and are directly implicated in pathological events, such as proliferation of smooth muscle cells and fibroblasts, which underlie the vascular and cardiac hypertrophy that characterized disease progression.

The vasodilating activity of current therapies are fundamental to the symptomatic relief that they provide, but the current effort to seek improvements in long-term outcome are based on the expectation that these agents can change the natural history of PAH, particularly if initiated early. Improvement in cardiac function is potentially one of the most potent measures of treatment effect because of the major role played by right heart failure in clinical deterioration. While cardiac function has long been monitored in clinical trials in PAH, sustained improvement could not be adequately measured in the study periods of 12 or 16 weeks typical of past studies. Long-term outcome studies, such as SERAPHIN, AMBITION, and GRIPHON, not only provide an opportunity to monitor the effect of the specific treatment strategy on cardiac function but better correlate the importance of change in cardiac function to outcome.

According to data from a SERAPHIN substudy presented at the 2013 Chest meeting, baseline values of markers of cardiopulmonary hemodynamic function are significant predictors of outcome, but the substudy was unable to correlate change after 6 months of therapy with the primary study end point. In this evaluation, the values evaluated were cardiac index, pulmonary vascular resistance (PVR), and N-terminal pro-brain natriuretic peptide (NT-proBNP). While these data do not rule out a benefit from changes evaluated after a longer period of treatment or longer period of follow-up, they suggest more data are needed to define the key drivers of clinical events.

In this substudy, 145 patients of the 742 patients who participated in SERAPHIN underwent right heart catheterization at baseline and again after 6 months of treatment. Among those randomized to placebo, cardiac index, PVR, and NT-proBNP worsened relative to baseline at the 6-month interval. In contrast, all three improved in the patients randomized to either the 3 mg or 10 mg dose of macitentan. When stratified into quartiles by baseline or 6-month cardiac index, PVR, and NT-proBNP, there was a stepwise correlation between worse values and worse end-of-study outcomes. However, when stratified into quartiles by change at 6 months and end-of-study outcomes, differences were not significant.

“This study provides evidence that absolute values of cardiac index, PVR, and NT-proBNP are prognostic of long-term outcomes and supports the importance of assessing these parameters in PAH patients,” reported Dr. Richard N. Channick, Director of the Pulmonary Hypertension and Thromboendarterectomy Program, Massachusetts General Hospital, Boston. “However, although macitentan improved all of these parameters after 6 months of treatment, the changes did not appear to determine risk of morbidity and mortality.”

The key variable may, again, be early treatment. In yet another SERAPHIN substudy presented at the 2013 Chest meeting, outcomes were stratified in 267 treatment-naïve patients by whether they had incident PAH, defined as a diagnosis within
6 months of randomization, or prevalent PAH, defined as symptomatic PAH for a longer period. As with previously reported registry data, those with incident disease had a poorer prognosis than those with prevalent disease in the placebo group despite similar severity at baseline. Still, macitentan improved outcomes in both.

Figure 3. 

 

“Macitentan 10 mg reduced the risk of PAH-related hospitalization and death by 77% in incident patients and by 62% in prevalent patients,” reported Dr. Gerald Simonneau, Head, Department of Pulmonology and Critical Care, Hospital Kremlin-Bicetre, University Paris Sud, France (See Figure 3). He said these data demonstrate that incident patients benefit as much from macitentan as prevalent patients, but he also called them important for the role in “supporting earlier diagnosis and treatment.”

The Evolution of PAH Management

The landscape for PAH management has been evolving because of a number of variables, including earlier diagnosis, a broader selection of therapeutic options, and better supportive care. In general, patients with PAH are living longer, according to Dr. Vallerie McLaughlin, Director, Pulmonary Hypertension Program, University of Michigan, Ann Arbor. She acknowledged that PAH is still best characterized as a progressive, incurable disorder, but she believes optimal treatment strategies are changing outcomes even in those with advanced disease.

“Only a proportion of patients probably have reversible PAH, but preservation of right ventricle function has the potential to improve survival even in individuals with advanced pulmonary fibrosis,” said Dr. McLaughlin, concurring that treatment has moved from the era when functional improvements were the key treatment goal to a modern focus on improved outcomes.

Conclusion

An important evolution has taken place in the treatment of PAH, according to expert opinion delivered in a series of symposia and scientific sessions at the 2013 Chest meeting. This change is most vividly reflected in advent of event-driven clinical trials. While change in the 6MWD test, a marker of improvement functional capacity, was the dominant end point for more than a decade, there is now evidence that current therapeutic options are capable of reducing morbidity and mortality. The first event-driven trial, which tested a novel ERA agent against placebo, has been completed. Future studies, similar to some studies already underway, will increasingly compare two active arms in a quest to identify which strategies provide the best opportunity to control the underlying processes leading to terminal events.  

 

We Appreciate Your Feedback

Please take 30 seconds to help us better understand your educational needs.