Afib: Causes, Symptoms, and Treatment Options

As PAH Science Advances, Trial Design Comes Under Microscope

Investigators are considering how best to interpret the results of potential new therapies.

The science of pulmonary arterial hypertension (PAH) has advanced significantly in recent years. However, as the push for new and better therapies gains momentum, clinical trial investigators are thinking long and hard about how best to demonstrate and interpret patient improvement.

One issue has to do with the question of which end points are best to meaningfully track patient responses to therapies.

Marius Hoeper, MD, of Germany's Hannover Medical School, said in clinical practice, physicians tend to use a variety of measures to track patient improvement.

"PH physicians usually take a holistic view," he said, "i.E., they consider the broad picture."

That broad picture includes everything from patient's exercise capacity, assessed by 6-minute walking distance (6MWD); to serum levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP); to right heart function; and simply how the patient feels.

In clinical trials, though, figuring out the best way to track patient improvement across a broad study population is more complicated—and even more critical.

Michael Lewis, MD, who directs respiratory care services at the Cedars Sinai Medical Center, in Los Angeles, said there are currently two primary end points the Food and Drug Administration (FDA) will accept. One is 6MWD, the other is time to clinical worsening, which measures the time between therapy administration and clear signs of worsening like death, hospitalization, or the need to escalate therapy.

However, he said time to clinical worsening is used less often in clinical trials, because you generally need a larger patient population and a longer time frame in order to accurately capture it.

"In some of the earlier studies, they only went about 12 to 16 weeks," he explained. "...So that's not a lot of time to show that."

The phase III trial of sotatercept (Winrevair), for which Hoeper was the corresponding author, used 6MWD as its primary end point, and time to clinical worsening as a secondary end point. However, they also used a newer end point—multicomponent improvement—as one of their secondary end points.

In the trial, multicomponent improvement was measured by the percentage of patients who met criteria for improvement in 6MWD, maintenance or achievement of an NT-proBNP level under 300 pg per milliliter, and improvement in World Health Organization (WHO) functional class. Hoeper said these variables reflect functional capacity and right ventricular strain.

"At the same time, these variables are powerful predictors of outcomes," he said.

However, Hoeper added that the multicomponent improvement end point remains an "arbitrary" measure, in the sense that it has not been fully validated and is not accepted by the FDA as a primary end point.

Lewis is currently investigating a potential cell-based therapy for PAH. He said a different issue of trial design is generating interest.

"What's being emphasized a lot now is the issue of responders and non-responders," he said.

While a trial might have positive data in terms of the overall number of people who respond to a particular therapy, Lewis said the picture might actually be more complicated.

"If you look at it in tremendous detail, there are going to be groups of patients that are great responders, groups that are modest responders, and groups that don't respond or actually do worse," he said. "The pendulum is swinging towards trying to identify who are—quote—'significant' responders."

Gaining a better understanding of which patients respond most strongly to which types of therapies could pave the way for more personalized approaches to PAH care, he said. That will be an increasingly important topic and more studies are published and more therapies are approved.

In the meantime, decisions about which therapies work best for which patients will depend on doctor-patient conversations and ultimately how the patient feels about particular therapies. Lewis said for most patients, exercise capacity remains one of the biggest signs of improvement, or deterioration.

As for the multicomponent improvement end point, Hoeper said there has not been much in the way of studies designed to validate the end point. He said it has been used occasionally, but does not seem to be gaining traction.

Prescribers Face Growing Web Of Restrictions On PAH Therapies

A new report finds commercial insurers are adding more restrictions on therapies for pulmonary arterial hypertension.

As treatment options for people with pulmonary arterial hypertension (PAH) expand, the path to insurance coverage for new therapies is becoming more complicated, according to a new report published in the Journal of Managed Care & Specialty Pharmacy.

A team of investigators used the Tufts Medical Center Specialty Drug Evidence and Coverage database to analyze how 17 major insurance plans treated PAH drugs, and to note changes in coverage provisions over time. The 17 health plans represented 70% of the commercially insured population in the United States, about 188 million people.

The analysis was based on 13 PAH drugs, including phosphodiesterase-5 inhibitors (PDE5is), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) stimulators, and prostacyclin pathway agents (PPAs). It was based on rules in place between August 2017 and August 2022, and thus the analysis did not include sotatercept (Winrevair), Merck's latest PAH therapy, which was just approved in March of this year.

In broad terms, the report found payers instituted more coverage restrictions as time went on. In 2017, 38% of policies had at least one restriction on PAH prescriptions. By 2022, 73% of policies included at least one restriction. In particular, the investigators found step therapy protocols increased significantly over time, from 29% of plans including step therapy requirements, to 46%. Such requirements mandate that patients try particular drugs in a certain order, only moving to another "step" if the previous therapy fails.

Corresponding author James Chambers, PhD, MPharm, MSc, told Managed Healthcare Executive, that although there was a trend toward more step therapy requirements, it was not universal.

"It was surprising to observe the wide variation in step therapy protocols," he said. "Four payers included step therapy protocols in all coverage policies for PAH drugs, while three payers did not have any such requirements."

Chambers, an associate professor at the Tufts Medical Center Institute for Clinical Research and Health Policy Studies, said the variance means that patients with PAH will experience unequal access to therapies, depending on which health plan they have.

The investigators also found that 10 plans required at least one drug to be prescribed by a specialist (cardiologist or pulmonologist), while seven plans had no specialist prescribing requirements.

Chambers said payers generally do not publicly disclose their reasons for imposing restrictions, but the report notes that generics were the most common step required, and the proportion of plans with step requirements in a given class increased as generics became available in that class.

"I think it is fair to say that plans often use step therapy to control costs and that the increased use of step therapy may reflect pharmaceutical budgets becoming increasingly stretched," he said.

Chambers added that step therapy can also be a tool when payers negotiate coverage for drug companies; with payers offering preferential coverage for products with the largest rebates.

Another key finding from the study, though, is that policies and coverage are changing rapidly. The report found that between 40% and 75% of PAH coverage policies underwent revision each year of the analysis. They said that was consistent with previous research showing payers frequently review and revise their policies. Chambers and colleagues wrote that there appeared to be a lull in revisions in 2020, which they said may have been related to shifting priorities associated with the COVID-19 pandemic.

For providers, Chambers said the shifting policies amount to an added layer of complication.

"Instead of basing treatment decisions solely on a patient's clinical presentation, prescribers must also consider the patient's insurance coverage," he said. "These restrictions often result in more paperwork (including appeals) and additional time spent navigating the plan's coverage requirements."

Though such complications might be frustrating, Chambers said they are likely to increase over time.

"Our research has found that plans' use of step therapy (and other utilization management tools) is on the rise, and I would expect to see that trend continue," he said.

'Little Hospital In The Middle Of Nowhere' To Be Clinical Site For New Doctors

PUNXSUTAWNEY — A tiny Jefferson County hospital will be the first clinical practice site for a new medical school that's taking shape at Indiana University of Pennsylvania, extending a lifeline to a rural pocket of the state.

IUP and the 49-bed Punxsutawney Area Hospital signed an agreement Monday that will eventually allow 120 medical students to use the hospital for the on the job training part of their medical education, addressing a critical physician recruitment problem in rural Pennsylvania. PAH, part of the three health system Pennsylvania Mountain Care Network collaborative, will be the first of many clinical sites that IUP's college of osteopathic medicine anticipates using, university president Michael Driscoll said.

"We are in a rural health care crisis," Mr. Driscoll said.

Fourteen percent of Jefferson County's population of 44,000 is impoverished — 20% higher than the state average — and 21% is over age 65, he said, and recruiting doctors to practice in small town Pennsylvania can be difficult. The university-hospital alliance will help address that need, PAH President Jack Sisk said.

Typically, medical students spend the first two years of their education in the classroom, then train at clinical sites the third and fourth years. IUP is seeking accreditation for the new medical school from the American Osteopathic Association, a three- to five-year process that's occurring as PAH undergoes a $25 million expansion and renovation project.

The IUP-PAH affiliation also comes as a five-year-old program intended to help stabilize finances and improve care at rural hospitals starts to wind down. The Pennsylvania Rural Health Model, which gives small hospitals global payments for care from insurers to compensate for revenue variability, is scheduled to end in December.

Medicare will continue making global payments to the 18 participating hospitals for a few more years, including PAH, but commercial insurers are likely to drop out at the end of the year, said Hospital and Healthsystem Association of Pennsylvania President and CEO Nicole Stallings.

A full-service hospital is key to any region's economic development, she said in an interview Monday.

"No company wants to locate where their employees can't deliver babies and can't get the care they need," she said. "We think these issues really go hand in hand."

Affiliating with a medical school is a unique way for PAH to assure its future at a time when many rural Pennsylvania hospitals are cutting services and closing. Most recently, Penn Highlands Healthcare's 163-bed hospital in Elk County, shuttered its maternity unit May 1, creating a six-county swath of northern Pennsylvania without a hospital obstetrics unit.

Ridgway councilman Zack Pontious is among a group of residents who have been meeting with Penn Highlands' executives to try to get the unit reopened. Economic development hinges on the availability of a full range of health care services, he said.

"We have a lot of people invested in our community who want to see it grow and be viable," Mr. Pontious said. "We need an actual hospital, not a glorified Band-Aid station, for people to think about moving here or staying here."

At the signing ceremony Monday, PAH Chief Medical Officer Clark Simpson said the closing of the unit in Elk County would result in higher mortality rates for expectant moms, an assertion that Penn Highlands' officials have denied.

"For a man, it's not a big deal" to have a hospital nearby that's prepared for childbirth, Dr. Simpson said. "For women, it's crucial."

Among the services at PAH, which hospital president Mr. Sisk called a "small, little hospital in the middle of nowhere," is an obstetrics unit, a service line Punxsutawney Area Hospital planned to continue. The hospital traces its roots to 1888.

Only 5% of medical students are from rural areas, Dr. Simpson said, and the "disparity is only getting worse." The IUP-PAH affiliation is a way to introduce tomorrow's physicians to the rewards of practicing in small towns.

Meanwhile, Harrisburg-based HAP is pressing the General Assembly for a $25 million general fund investment that could leverage $80 million in additional federal funds to help prop up struggling hospitals. Gov. Josh Shapiro has been developing a plan to address rural health problems, but Ms. Stallings said the $25 million is not part of his budget proposal, which is currently being negotiated.

"Long term, sustainable funding support is needed, especially in our rural communities," she said. "That funding would be really timely. Now is the time to start action."

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