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Catching air


Catching air

A deadly disease, a problematic health-care system, a happy ending

In health care there are many heroes and few villains. Working together, patients, health-care providers, researchers and insurers can overcome what would have seemed impossible odds.

Yet, while their interests largely coincide — in a good doctor-patient relationship, they are identical — aspects of the alliance can come into conflict. The experiences of Americans with rare, deadly diseases illustrate the greatest strengths of the complex super-organism that is our health-care system, as well as its vulnerabilities. Here’s the story of one doctor-patient team that prevailed.

One Saturday in 2004,

Karen Lindemann, 38, took a BART train into San Francisco to see a musical production and collapsed halfway up the steps from the station. “I thought I was going to die right there,” she says. “I finally crawled up the rest of the stairs and made it to the theater right across the street and watched The Lion King. That was probably the dumbest thing I ever did in my life.”

Lindemann hadn’t been feeling well for years, but no doctor could nail down the nature of her problem. She would finally find out that Monday, and the news wouldn’t be good. She was going to learn she had a rare condition called pulmonary arterial hypertension, or PAH, which destroys blood vessels carrying oxygen from the lungs, leaving people gasping for breath. Even if they receive appropriate treatment, a big if, only 60 percent of patients survive more than five years after diagnosis.

No pulmonary arterial hypertension success story comes without an asterisk. Lindemann has lived to tell hers. Raised in San Francisco’s eastern suburbs, where she still resides, she started suffering blackouts in 2001. “For years, I was complaining to my doctor of having this general run-down feeling. I was tired all the time, and short of breath when I exercised. It was really hard for me to walk 20 or 30 yards.”

At first her doctors told her it was her weight. That’s ironic, as she would eventually find out that her PAH came from the use, for 72 days in 1997, of “fen-phen” (fenfluramine-phentermine), a diet-drug combination prescribed to her for weight loss. Fen-phen was subsequently withdrawn from the market.

At some point, Lindemann was diagnosed with asthma. “Pretty much everybody I know with PAH is,” she says.

In 2004, her symptoms started to worsen, and came to a crisis in the San Francisco train station. When she saw her doctor in Hayward, Calif., the following Monday, he immediately sent her for an electrocardiogram. She’d already had several, and they’d always come back normal. Not this time, though. She ferried her results back from the uncharacteristically unsmiling technician who’d run the test. “My doctor opens the envelope, looks at the EKG, runs out of the office, personally gets a wheelchair, puts me in it and runs me down to the emergency department with my poor mother trailing behind.”

At least this time the diagnosis was correct.

A place where pulmonary arterial hypertension isn’t rare

PAH is a subset of a spectrum of diseases collectively known simply as PH, or pulmonary hypertension. This latter, broader category includes all cases of high blood pressure in the lungs, whether caused primarily by damage to pulmonary blood vessels, as in PAH, or by other problems in the lungs, left side of the heart or elsewhere.

Stanford’s Vera Moulton Wall Center for Pulmonary Vascular Disease, which opened in 2000, is one of about 50 U.S. pulmonary hypertension centers, treating patients from all over the western United States. Directed by Jeffrey Feinstein, MD, PhD, associate professor of pediatrics, the center’s faculty members conduct laboratory and patient research, run a physician training program (one of only five PH traineeships in the world) and care for patients.

“We see the sickest of the sick,” says Roham Zamanian, MD, who directs the center’s adult pulmonary hypertension service. “Half of our new patients are on track to die within a year. By the time someone with PAH becomes symptomatic, 60 percent to 70 percent of their lung vasculature has been injured already. So we’re way behind the curve when our patients come into the clinic. We ask them to think back, and on average it’s about 18 months from the point that they first had symptoms they realized were abnormal until their accurate PAH diagnosis. They’ve often been misdiagnosed as having asthma, or told that it’s all in their head, that there’s nothing wrong with them,” adds Zamanian, an assistant professor in the Division of Pulmonary and Critical Care Medicine.

Thus, the PAH verdict comes as a shock, says Zamanian. “They’re devastated, because it is a disease that doesn’t have a cure, a disease they’ll live and die with.”

Only one or two in a million people, most of them otherwise healthy women of childbearing age, develop the disease out of the blue. The risk is substantially higher for people with certain autoimmune diseases (such as scleroderma or lupus), HIV, congenital heart disease or liver disease; for those who have used street drugs such as amphetamines or cocaine; or for those like Lindemann, who used the diet drug fen-phen. People with scleroderma are especially at risk, with 10 percent to 20 percent developing PAH.

In the United States today, roughly 20,000 to 30,000 people are known to have pulmonary arterial hypertension, although it’s likely that many more are undiagnosed because the chief symptom, shortness of breath, is so non-specific. Doctors can diagnosis the disease definitively only by right-heart catheterization, the threading of a thin tube through a vein and into the right side of the heart.

“We see the sickest of the sick. Half of our patients are on track to die within a year.”

- Roham Zamanian, MD

What all cases share is the narrowing of blood vessels in the lungs when, for mysterious reasons, the smooth muscle cells that ring the lungs’ blood vessels start proliferating. As their walls thicken, the vessels become increasingly occluded, choking off blood flow.

It’s like stepping on a garden hose. The pump — the right side of the heart — has to work harder, and it’s not very good at it. It was designed by evolution to operate under low pressure. The heart muscle thickens, trying to adjust to its new job description, but it does so only imperfectly. Within a few years it gives out.

“Initially, the symptoms are minimal. But full-blown PAH is a terrible disease,” Zamanian says.

If left untreated, newly diagnosed patients are looking at a 50/50 chance of surviving 2.8 more years. Barely over a third will live for five years. That gives even the more aggressive types of cancer a run for their money.

Until the mid-1990s, there were no treatments at all for pulmonary hypertension, beyond palliative care. “We’ve improved on that,” Zamanian says. The first drug therapy, an intravenous infusion, came in 1995. It has lengthened survival times, for some lucky patients by a decade or more, he notes. “But there’s still no effective cure, except for lung transplantation, which itself has a dismal outcome.”

Still, the medical and pharmaceutical fields have made extraordinary strides. The past decade or so has brought significant advances, with eight new drugs to combat the disease. These therapies aren’t cures either, but they have extended survival. “With active treatment, we’re now seeing a two-year survival rate of nearly 75 percent to 80 percent for some patient populations,” says Zamanian. Half of all appropriately treated patients now live for five years post-diagnosis.

How much would you pay to save your life?

Roham Zamanian
Roham Zamanian

The first treatment licensed for PAH — and still the treatment of last resort — is a continuous intravenous infusion of a drug, epoprostenol, that has to be mixed fresh every morning from a powder and saline, then delivered by an electrically powered pump. Epoprostenol has a six-minute half-life, so a delivery line that clogs or gets pulled loose by accident is a life-threatening emergency: 15 minutes to cardiac arrest, according to Zamanian.

Like epoprostenol, the newer drugs available in the United States are vasodilators: They cause smooth muscle cells to relax, permitting more blood flow through the vessels ringed by them.

The expanded pharmacopeia is beneficial, because if one drug loses its potency it’s possible to switch or add another. But none of them is perfect. Some are delivered via IV tubes and pumps or painful subcutaneous injection, others through five- to 15-minute-long bouts of inhalation six to nine times a day. Even a couple of pill formulations require frequent dosage adjustments due to interactions with other drugs, or blood tests to make sure there’s no liver toxicity.

One big reason for the rash of new PAH drugs is that they fetch huge prices, ranging from about $15,000 annually for the cheapest oral compounds to well over $100,000 for the mainstay, intravenous epoprostenol, and even more — up to $200,000 or $300,000 for another, similar drug with a much longer half-life. (These prices vary, depending on what deal a particular insurance company in a particular state has negotiated with the drug’s maker.)

Drug companies charge more because they can charge more.

“Once you have a marketable therapy that’s life-saving, how much would you pay to save your life?” asks Zamanian. The reality is that the audience is captive. Some of these companies make a tremendous profit. True, they have taken tremendous risks in developing some of these drugs for a very small population of patients. And they provide more backing for clinical research on PH than the National Institutes of Health does. But how do you justify a drug’s costing $300,000 a year?

The economist

In the United States, a drug developer has the exclusive right to market a new drug for a period of time after it’s approved (typically around seven to 10 years, depending on how long development took), so companies can charge monopoly prices during that period to recoup their investment. As a further incentive to drug makers, the FDA often gives candidate treatments for rare diseases “orphan drug” status, a combination of grants to defray testing costs, expedited review, a lower threshold for approval (for instance, acceptance of what in other cases might be considered insufficient numbers of subjects participating in a pivotal trial) — and two additional years of marketing exclusivity.

“It’s very easy to characterize the pharmaceutical companies as the bad guys here because they’re exploiting their monopoly power,” says health economist and associate professor of medicine Jay Bhattacharya, MD, PhD. “But their rationale is that if you undercut that monopoly pricing power you’d have less drug research. The argument is that you’re trading off the social costs of monopoly power — more-expensive drugs now — and the social benefit of new and better drugs later, thanks to the research investments these companies presumably will be making with their profits.”

“That one winner has to make up for the investments in the 249 other efforts that didn’t pan out.”

Maybe one out of every 250 experimental drug research programs pays off, Bhattacharya says. “That one winner has to make up for the investments in the 249 other efforts that didn’t pan out.” The first pill that rolls off a drug company’s assembly line can cost the company on the order of $800 million or so in total development expenditures (when you take the failed efforts into account), but the second and every subsequent pill cost only a few cents apiece. The prices charged for drugs for rare diseases such as PAH are, in part, an inevitable result of dividing the drug-development cost by the small number of patients who will buy it.

The runaround

Zamanian and Wall Center nurse practitioner Juliana Liu, who often goes head to head with balky insurers, have been frustrated by companies that don’t answer the phone, return calls or even provide working phone numbers connected to voicemail. “Most companies will eventually cover the drug if you’re willing to fight the battle,” Liu says. “But authorizations are typically only good for three months, and then the battle has to be fought all over again.”

Insurers’ reticence is hardly diminished by the fact that many patients are on combination therapies, based on growing but not completely definitive evidence that combination therapies can better stave off worsening symptoms. Yet, to the extent that these hints and glimmers find their way into medical practice, the already substantial cost of therapy for a given patient is going to go up. That spells sticker shock to insurers trying to keep their expenses, and their customers’ premiums, down. There’s no easy way out.

Does it have to be this way? As chief of cardiology at Jewish General Hospital in Montreal, Quebec, David Langleben, MD, runs the second-biggest PH center in Canada. The cost of PH drugs there is comparable to that in the United States, Langleben says. But in the single-payer Canadian system, the government picks up the tab, not insurance companies.

“I have to say — and I can only speak for pulmonary hypertension, and for Quebec — that the government has gone above and beyond in supporting these patients,” says Langleben. “The availability has been easy, limitless and very generous. All they ask is that there be some science to support the benefit, and that these drugs be used in a controlled fashion. What’s reassured the government is that, unlike Europe and the United States, not every doctor can prescribe these drugs. PH medications here have to be prescribed by approved PH centers.”

But, Langleben notes wryly, “we’re going broke.” In April, Quebec’s government imposed (for the first time) the equivalent of co-payments for doctor visits, in order to make up for its budget shortfall.

The price problem confronting PAH patients, providers, insurers and drug manufacturers mirrors the one facing the United States at large. Who’s at fault for the high cost of health care in general, and drugs in particular? Greedy pharmaceutical companies? Callous insurers? Care providers understandably trying to secure slight to moderate gains in their patients’ conditions or quality of life? A payer system in which patients rarely see the bills for the services they receive, let alone have to make decisions trading off costs versus estimated benefits?

“I don’t believe there are any villains,” says Bhattacharya, “only trade-offs.”

Hooked up

Karen Lindemann spent four days in the hospital in Hayward hooked up to monitors. She was fitted with oxygen tanks and a 50-foot hose so she could wander around the house when she went home.

“Constantly wearing this thing 24/7 definitely took some getting used to,” Lindemann says. “People could always find me, because they would just follow the hose. I didn’t mind that, but sometimes they would stand on the hose, or close the door on it. It would get tangled on things. I had a portable tank for when I went out. But it’s only good for four hours. You kind of plan your life around your oxygen usage.”

Within a month or so, Lindemann hooked up to a San Jose-based support group where Zamanian — “Dr. Z,” she calls him — sometimes showed up to speak and give advice and encouragement. Later that year she participated in the Race against Pulmonary Hypertension, an annual Wall Center-organized event benefiting PH research.

She went to the race again the next year. “Dr. Z was there. He saw me, came up, took one look at me and said, ‘You’re blue.’ I said, ‘What?’ He said, ‘Your lips are blue. I’m admitting you. Right now.’ People around me every day hadn’t noticed because it was so gradual. From then on we were glued at the hip. Dr. Z kind of kept tabs on me after that.”

For a couple years more, Lindemann cycled through new drugs and new doctors in the San Francisco area and even Los Angeles, almost 500 miles away. (Stanford’s pulmonary hypertension service, with Zamanian, wasn’t in her insurance network.) But her disease continued to progress. By late 2007 it was time to go to the last-gasp regimen: intravenous epoprostenol. “This is a serious drug,” says Lindemann. “You have to mix a new batch every day. And it involves needles.” Her husband, whom she’d met in 2006 and married in 2007, shouldered those burdens.

As soon as she began IV therapy, Lindemann felt better. It was not to last. In March 2008, she was admitted on an emergency basis to Stanford Hospital with blood sepsis from her IV line. She stayed for 11 days.

By now, Zamanian was adamant about getting Lindemann treated at Stanford as a regular, non-emergency patient. He and Marc Nicolls, MD, associate professor of medicine in the pulmonary and critical-care division, ganged up on her insurance provider and finally got approval for her to be treated at the Wall Center.

The spring of 2009 saw a big decline in Lindemann’s condition. That May, Stanford’s transplant division put her on the active list. “I saw Dr. Z the Friday before Memorial Day. He wanted to admit me into the hospital on the spot, but I didn’t want to just be stuck there until a suitable set of lungs came along.” She asked if she could stay home that weekend for a family barbecue. He answered, “OK. But if you feel anything, you call me and I will come get you with the helicopter.” (He wasn’t kidding. Stanford has a helicopter for such purposes.)

At the barbecue, “I was thinking, this is the last time I’m going to see all these people. I knew in my soul I was dying. And I was at peace with that.”

Found in translation

The hope for lowering PAH’s toll lies in attaining a better grasp of its underlying causes, and in converting such knowledge into clinical treatments — a process called translation within the drug industry. If the disease can be attacked early and on multiple fronts, it may be possible to save lives and money.

Research on pulmonary hypertension overall is racing full tilt on multiple fronts: epidemiological, biological, diagnostic and therapeutic. The number of human studies of PH in the last decade has almost doubled from the decade before. Since 2002, PH has had its own quarterly journal, Advances in Pulmonary Hypertension.

As scientific understanding of PAH’s molecular underpinnings grows, the arsenal of available drugs appears set to broaden from its current vasodilator focus. Seeing an analogy to cancer, investigators are looking at antiproliferative agents often used to treat cancer as a possible way to block the proliferating smooth muscle cells surrounding PAH patients’ pulmonary blood vessels.

The Wall Center’s research director, Marlene Rabinovitch, MD, is pursuing a new course for stopping the cell proliferation. She has identified a variant of an enzyme that’s produced in unusually large amounts by smooth-muscle cells in the walls of PAH patients’ blood vessels. The enzyme degrades a key blood-vessel wall component, reducing the walls’ elasticity and unleashing growth factors that can both attract inflammatory cells to the vessel wall and stimulate cell proliferation there. “When that happens, the vessels become stiff, blood pressure goes up and the load on the right heart is greatly increased,” Rabinovitch says. In several studies using animal models, she has shown that changing the enzymatic activity can inhibit and, in many cases, reverse the course of disease. That could eventually translate into promising “root-cause” therapies, she says.

Other research explores the tie between PAH and insulin resistance — an inability to control blood sugar, which can lead to type-2 diabetes. Rabinovitch used a high-fat diet and low-oxygen environment to cause experimental animals to develop PAH and insulin resistance, then administered a compound known to combat insulin resistance. The drug not only affected the insulin resistance but improved PAH.

Zamanian himself is hardly sitting on his hands between patient visits. Taking his cue from Rabinovitch’s findings, he has shown that insulin resistance is unusually prevalent in patients with PAH. He is now conducting an early investigational study to see if pioglitazone, an approved insulin-sensitizing drug, can influence the course of PAH in patients.

Zamanian is also the principal investigator for a randomized combination drug trial — a small pilot study in which one group of so-far-untreated patients will be given one approved vasodilator drug and a second group will be given that drug plus another one from a different category. “We hope to begin to enroll patients by July of this year,” he says.

Meanwhile, Stanford is the lead site of a trial of Rituxan, a drug that has been approved for treating certain cancers of the immune system caused by hyperproliferating immune cells, in 80 PAH patients who have scleroderma. Nicolls, Zamanian’s colleague, designed the randomized, placebo-controlled trial’s protocol and is the principal investigator. The trial will begin to enroll patients in the next few months.

On the diagnostic front, Zamanian is investigating whether new, noninvasive imaging technologies, such as cardiac MRI, might not only speed detection but allow more frequent monitoring of disease progression, which would in turn guide treatment by letting clinicians see whether a particular drug regimen is succeeding at slowing, arresting or even reversing PAH’s course.

Karen then and now

On June 3, 2009, the Wednesday after Lindemann went home to stand by for new lungs or die waiting, she got the call from Stanford. Late that night, she was rolled into surgery and took ownership of a new pair of lungs. By November, she was able to walk the full 5 kilometers in the ninth annual Race Against PH at Stanford. Fifteen hundred people showed up. Dr. Z was there, cheering her on.

“She’s reset herself,” says Zamanian of Lindemann. “She’s active, she’s enjoying herself. I think she’s healthier than I am.”

“I’ll always have to be careful of germs: bacteria, fungus, viruses,” Lindemann says. “And rejection. Unfortunately, with a lung transplant the chances of surviving five years are 50 percent. That’s why I’m trying to make the most of it now.”

She goes to the gym four days a week. She rides her bike. “I can’t do gardening anymore, because I’m not allowed to play in the dirt.” She goes shopping, goes for long drives to wine country with her husband. And she remembers.

“I was so sick it took me 30 minutes to get dressed. We had to load four oxygen tanks into the car just so I could take a ride around town.” Now, she’s healthy enough to sing in a choir — literally. A one-time music major, she’s looking for a new choir to join, and reforming a trio with a friend.

She can’t leave her PAH community behind. “Doctors, nurses, patients, caregivers. Everybody. They’re my family now. I decided I want to give something back, because of all these miracle workers who helped me out along the way.”

And she’s decided the biggest bang for the buck will come from adding more fuel to the research fire that Zamanian, Rabinovitch and others have sparked. So she’s starting the Karen Lindemann Foundation, with Zamanian as her co-director. “My goal is to raise money for PH research at Stanford,” she says. “Community education is also big on my list. Because there are still doctors out there who are misdiagnosing this disease. And there’s no reason, in this day and age, that we should be missing it.”

She recalls that doctor who told her, “You are going to die.” But she didn’t. “No doctor needs to be saying that anymore. Nobody should have to hear a doctor saying that, anywhere, ever.”


E-mail Bruce Goldman






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