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Saturday, December 22, 2018

FDA Approves New Enzyme Product for ALL


The US Food and Drug Administration (FDA) has approved a new drug for the treatment of acute lymphoblastic leukemia (ALL), a cancer of the blood and bone marrow.
The agency has granted approval for calaspargase pegol-mknl (Asparlas, Servier Pharmaceuticals), an asparagine-specific enzyme, to be used as part of a multi-agent chemotherapeutic regimen in pediatric and young adult patients (age 1 month to 21 years). This new product differs from other available pegaspargase products, such as pegaspargase (Oncaspar, Sigma-Tau Pharmaceuticals) and asparaginase (Erwinaze, Jazz Pharmaceuticals), in that it provides for a longer interval between doses. It also has an extended shelf-life beyond that of the current pegylated asparaginase treatment, which helps ensure availability to patients.
Calaspargase contains an asparagine-specific enzyme derived from Escherichia coli and depletes plasma asparagine, selectively killing leukemic cells that are unable to synthesize asparagine because of a lack of asparagine synthetase. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize L-asparagine, and therefore depend on an exogenous source of L-asparagine for survival.
The approval was based on demonstration of the achievement and maintenance of nadir serum asparaginase activity (NSAA) above 0.1 U/mL when using a dose of 2500 U/m2 given intravenously every 3 weeks. The pharmacokinetics were studied in a cohort of 124 patients with B cell lineage ALL who were a median age of 11.5 years (range, 1-26). Within this group, 62 (50%) were male, 102 (82%) white, six (5%) Asian, five (4%) Black or African American, two (2%) Native Hawaiian or Pacific Islander, and nine (7%) other or unknown.
When calaspargase was administered with multi-agent chemotherapy, the results showed that 123 of the 124 patients (99%, 95% CI, 96 – 100) maintained NSAA > 0.1 U/mL at weeks 6, 12, 18, 24, and 30.
The recommended dosage is 2500 units/m2 intravenously administered no more frequently than every 21 days.
The most common (incidence ≥ 10%) grade ≥ 3 adverse reactions associated with this agent were elevated transaminase, increased bilirubin, pancreatitis, and abnormal clotting studies. In a randomized trial, the safety profile of calaspargase pegol-mknl administered every 3 weeks was similar to that of pegaspargase administered every 2 weeks, according to the FDA.
Calaspargase pegol-mknl has received FDA orphan drug designation.

A Christmas Carol: A Psychiatric Primer on Character and Redemption


Forty-three years before Freud arrived on the scene with The Interpretation of Dreams, Charles Dickens wrote A Christmas Carol. In this exemplar of psychotherapy, Dickens taught us all we need to know about character formation, the effects of trauma, and the healing process of mourning.
This most illuminating story prefigures the psychotherapy of character and shows that each of us has his own unique story. We adapt to trauma through our temperament as we write the plot of our play of consciousness. This story-plot crystallizes into our adult character. Dickens had the wisdom to write all of this into a profound understanding of Ebenezer Scrooge’s character, whom he then takes through a transformational journey to the recovery of his authentic being.

Scrooge and the Ghost of Psychotherapy’s Future

As his vehicle, Dickens employs the visitations of the three Ghosts of Christmas Past, Present, and Future. The ghosts take Scrooge back to the future, through a kind of a time travel, by which he comes face to face with his life. As such, he mourns the trauma of his life, which allows him to emerge as a truly changed man. The ghosts are the analog of the processes of psychotherapy, which we are familiar with 160 years later.
What do we know of Scrooge’s character? Dickens writes, “Oh! But he was a tight-fisted hand at the grindstone, Scrooge! A squeezing, wrenching, grasping, scraping, clutching, covetous old sinner! Hard and sharp as flint, from which no steel had ever struck out generous fire; secret, and self-contained, and solitary as an oyster. The cold within him froze his old features, nipped his pointed nose, shriveled his cheek, stiffened his gait; made his eyes red, his thin lips blue; and spoke out shrewdly in his grating voice.”
The ghosts are the analog of the processes of psychotherapy, which we are familiar with 160 years later.
On Christmas Eve, Scrooge’s deceased business partner, Marley, appears as an apparition, warning Scrooge that if he does not change his ways, he will live an afterlife of ongoing torment, just like him. Marley is a horror show of dirty gauze, ugliness, chains, moans, and physical and emotional pain. Although Scrooge’s character is a carbon copy of Marley’s, he argues that Marley was a successful businessman, a great man. Marley answers, “Business! Mankind was my business. The common welfare was my business; charity, mercy, forbearance, and benevolence, were, all, my business. The dealings of my trade were but a drop of water in the comprehensive ocean of my business!”
He tells Scrooge that he still has a chance to escape his fate through the visitation of the three Christmas ghosts. Scrooge, of course, does not listen and dismisses him as an undigested piece of meat. He pays no heed to Marley’s warning, although it leaves him a bit unnerved.
Scrooge has been firmly set in his ways for a long, long time. How in the world could such a man as he ever change? Is it possible for him to reverse his hostile and judgmental attitudes? Can he rejoin the human race and feel and care about his fellow man? Can he reach out and engage in a loving way instead of nastily? Can he use his intelligence and gifts in the service of humanity rather than in the service of selfishness and pitilessness?

Ghost of Christmas Past

The Ghost of Christmas Past arrives, just as Marley had prophesized. He takes Scrooge back to his old school where he finds himself alone, a solitary child neglected by his friends. He sits in a melancholy room reading near a small fire. He “wept to see his poor forgotten self as he had used to be.” He wept again when “there he was, alone again, when all the other boys had gone home for the jolly holidays.”
In point of fact, Ebenezer was an abandoned child. He had been totally rejected by his father and sent off to school, never to come home again. His younger sister remained at home with the father.
Ebenezer was a sweet little boy who became so damaged by the deprivation of a home and love.
Parental love and guidance is the source of our inner sustenance. It nourishes us and serves as the foundation that carries us through the trials of life. Ebenezer was a sweet little boy who became so damaged by the deprivation of a home and love.
His sister surprised him and arrived at his school to bring him home after begging her father, who finally softened and agreed to her request. She tells him he’ll never come back to this school and they’ll be together all Christmas long and be merry. The memory of his sister was the only source of love in his life. There certainly wasn’t any from his father. There’s no mention of a mother.
Nonetheless, it was too late. As an abandoned child, the pain informs the writing of his inner story. The hurt, the anger, the lack of self-worth, and the shame it generated would leave its indelible mark later.
The next scene takes place during Christmas Eve at the office of Old Fezziwig, to whom he was apprenticed. His mentor was a kind, warm, generous, and loving man. Old Fezziwig treated his employees like family. He was loved by everybody, including Ebenezer. He rejoiced at the memories of the old Christmas party, where he was a happy participant.
Scrooge had two models: his father and Fezziwig. But because of the abandonments and emotional deprivation, he, predictably, would reject the model of his mentor. He didn’t have a real choice. He lacked the foundation of internal love from which to build a loving life. He was too angry. He turned bitter and teamed up with the older Marley as the empty promises of gold and egotism became his false idols. He would eventually settle into his ways of hardness, mendacity, and judgmental anger.
As it turned out, the next loss was the last straw. His beloved sister died while giving birth to his nephew, whom Scrooge blamed for her death. This is the same nephew who invited Scrooge to Christmas every year and was rejected by the famous declaration of “Bah! Humbug!”
In the context of Christmas Past, his old self began to remember about real giving. In the course of mourning the pain of these memories, Scrooge began to soften. He acknowledged and genuinely regretted not being kind to his clerk, Bob Cratchit, Tiny Tim’s father.
The final crystallization of his character solidified when his fiancée released him from his vow to marry. She said, “Another idol has displaced me…A golden one. You are changed. When your vow was made, you were another man… I release you. With a full heart, for the love of him you once were.”
She had realized that the old Ebenezer was gone. His character changed into one that she no longer recognized or loved. It was too late. Scrooge would play out his character story of hardness, cruelty, and the inability to love.
With the Ghost of Christmas Past, Scrooge visited his ex-fiancée and her family. He realized that he missed out on love and being a father with a happy home. He saw that he would die like Marley, all alone. He saw her daughter. “He thought that such another creature, quite as graceful and as full of promise, might have called him father.” This brought out such regret and pain.
Scrooge was deeply affected by his formative past. He wept and mourned his pain. He began to feel genuine regret for his life decisions. He regretted hardening his heart to love. He regretted how he conducted himself with a meanness of spirit. He had lost all of the pleasures of life that the innocent, little Ebenezer had once relished. He missed out on the warmth and comfort of a family and children. He was lost and empty. Mourning the trauma began to allow him to reopen his heart.

Ghost of Christmas Present

With the second ghost, who also appeared early Christmas morning, Scrooge visits Tiny Tim’s house, his nephew’s, and many of the poor and bereft homes throughout the world. There is Christmas joy and giving in all of them, in contrast to his solitary and joyless state of misery. Scrooge is a miser in matters of both money and spirit. They are, in fact, inseparable.
Psychotherapy is not only about mourning and facing the formative past, but also about our present relationships. We need to mourn the pain that we give and receive in the present. Facing the truth is what sets us free.
As Scrooge starts to feel, he begins to care about Tiny Tim and learns that the boy will die. The ghost quotes Scrooge from his earlier disposition: “If he be like to die, he had better do it, and decrease the surplus population.”
The real mensch in this story is Bob Cratchit. He never complains and will not criticize Scrooge. Even at Christmas, the family is so poor (due to Scrooge) that they wear threadbare clothes and make do with a tiny Christmas goose. His tender devotion to his family and to Tiny Tim shows Scrooge a richness he never dreamed of.
Cratchit suffers the unbearable pain of Tiny Tim’s death, the cherished child he lost because he couldn’t afford medical care. And yet he still takes the blow with such grace and a generosity of feeling for others. The model of Bob Cratchit stands in contrast to Scrooge’s response to the death of his sister. He couldn’t mourn and was filled with bitterness, as he blamed and rejected his innocent nephew.
With the visitation to the nephew’s house, Scrooge sees that he is viewed as the ogre of the family. Even so, his nephew, his dear sister’s son, still loves him. Scrooge had cut him off in his unforgiving anger. His niece looks exactly like Scrooge’s sister and awakens memories of the feeling of loving her. Likewise, he wants to participate in the celebrations, the loving games that he so recently considered “humbug.”
Finally, Scrooge has to confront the dual evils of the world—two gaunt, neglected, and starved children hidden under the robes of the Ghost of Christmas Present: The girl is Want and the boy is Ignorance. Most of all, the boy represents his own doom. The ghost again quotes Scrooge’s old heartless attitude: “Are there no prisons?” said the Spirit, turning on him for the last time with his own words. “Are there no workhouses?”
Starvation is not just physical hunger; it is also a metaphor for the absence of loving nurturance. It’s worth noting that Scrooge didn’t live well off of his own wealth; he continued to eat gruel in the dungeon of his rundown home. He horded his money. He accumulated the gold and deprived others of it, but he didn’t actually enjoy it or spend it. He lived a dark, empty, unhappy, and mean life.

Ghost of Christmas Future

With the arrival of the final ghost, Scrooge now sees the future. One cannot really predict the specifics of the future, but on the other hand, the future is very predictable. Character always plays true unless it is mourned and dealt with. Wisdom understands that character is destiny. Of course, Dickens understood this as well.
Nobody comes to mourn Scrooge’s death. Three robbers steal his belongings and sell them to a bottom-of-the-barrel broker. Scrooge does not yet know that the loathsome man who died in this vision was indeed him. “If this man could be raised up now, what would be his foremost thoughts? Avarice, hard dealing, griping cares? They have brought him to a rich end, truly!…If there is any person in the town, who feels emotion caused by this man’s death,” said Scrooge, quite agonized, “show that person to me, Spirit, I beseech you!”
One cannot really predict the specifics of the future, but on the other hand, the future is very predictable. Character always plays true…
The upshot of our Dickensian psychotherapy: “Men’s courses will foreshadow certain ends, to which, if persevered in, they must lead,” said Scrooge. “But if the courses be departed from, the ends will change. Say it is thus with what you show me!”
Finally, in desperation, Scrooge begs, “Assure me that I yet may change these shadows you have shown me, by an altered life! I will honour Christmas in my heart, and try to keep it all the year. I will live in the Past, the Present, and the Future. The Spirits of all Three shall strive within me. I will not shut out the lessons that they teach. Oh, tell me I may sponge away the writing on this stone!”

Back to the Land of the Living

The therapy works. Scrooge recovers his lost and authentic self. This joyless, judgmental, hateful man now walks around transformed, back to the sweet and innocent boy he always was but couldn’t be. He laughs, he cries, he feels, he cares, he loves, he gives. His laughing is almost embarrassing, because the lightness of his being is so new. He’s come back from the dead.
He makes up for lost time by giving a large sum of money to the men he had browbeaten for wanting to help the poor. He buys the Cratchit family the biggest goose in town. He plays a joke on Bob Cratchit, pretending that he is mad that Cratchit has come to work late and that he is going to dock his pay. Instead, he raises Cratchit’s salary. Scrooge ends the joke quickly because he doesn’t want Cratchit to suffer. Scrooge hadn’t joked in decades. He also supplies the funds needed for Tiny Tim’s medical care, which allows the boy to walk again and thrive. Although it is too late for Scrooge to have children, he becomes like a second father to Tiny Tim, loving him as his own.
One cannot undo the past but one can live and love well now. Scrooge forgives his nephew and reunites with his family. He joins them in celebrating Christmas with cheer and kindness. He gets to be with his niece, who reminds him so much of his deceased sister. He laughs and joins the games and fun he had as a child. Scrooge now participates fully in life and leaves the world of the walking dead. His old life was empty; now he is alive.
Scrooge’s character was forged from his own emotional pain. Indeed, we can change the course of our lives by facing and mourning that pain. Want, deprivation, and cruelty create the evils of the world. Mourning and trust, in the context of love, are its antidotes. Dickens teaches us that we must rediscover this truth over and over again, as he helps us all to find our way.
There is a reason why so many people of all ages read and watch A Christmas Carol every year. It is a sacrament of renewal of the human spirit.

The Best Cardiovascular Drug Many Physicians Won’t Prescribe


Many effective drugs have been developed to prevent and treat cardiovascular diseases. Certain drugs have striking benefits to reduce death and disability. The vast majority are widely prescribed by practitioners.
But there is one exception: beta-blockers.
Beta-blockers inhibit the effects of activation of the sympathetic nervous system on an important receptor (the beta-adrenergic receptor). By doing so, they protect the heart from overstimulation. They were first synthesized in the early 1960s by Sir James Black, who (in 1988) won the Nobel Prize in Medicine for his groundbreaking role in their development.
Beta-blockers have been widely prescribed for the treatment of a broad spectrum of cardiovascular diseases. Initially, they were used to control certain rhythm disturbances of the heart and to reduce the frequency of anginal attacks in patients with coronary artery disease. Then they became one of the main treatments for hypertension. Subsequently, they were routinely prescribed to patients who had survived a heart attack in order to prevent a second event. Finally, they were given to patients with heart failure to prevent death and disease progression.
No other class of drugs in cardiovascular medicine has such a broad list of clinical indications. And for many years, the drugs were exceptionally popular.
But over the last decade, the use of beta-blockers has experienced a major decline. Currently, these drugs are infrequently used for cardiac arrhythmias, because other interventions have supplanted them. They are sparsely prescribed for exertional angina, because most patients with angina now undergo a revascularization procedure. They are no longer popular for the treatment of hypertension, because other drugs are often more effective and better tolerated. And many physicians neglect to prescribe beta-blockers following a heart attack, perhaps because we no longer understand their role in the modern era, where efforts are focused to maintain coronary artery patency. In nearly all indications for their original use, the prescribing of beta-blockers has plummeted.
Because they are generic, beta-blockers are no longer promoted by the pharmaceutical industry. Last year, AstraZeneca sold all European rights to its iconic beta-blocker metoprolol, presumably because the annual sales of the drug had dropped to a mere $110 million annually.
There is only one therapeutic area in which the role of beta-blockers remains paramount — heart failure.
That is incredibly ironic, since for most of the past five decades, physicians were toldto avoid the use of beta-blockers in patients with heart failure who had impaired ventricular function. That belief was wrong.
Studies in the 1970s by investigators in Sweden challenged the prohibition against the use of beta-blockers in heart failure. Led by Finn Waagstein and Karl Swedberg, these reports suggested that beta-blockers produced dramatic results in patients whose hearts were damaged, because they were susceptible to further injury as a result of being stimulated by their own sympathetic nervous system. These promising results were ignored by mainstream cardiology for years.
The tide began to turn in the late 1980s and early 1990s. Several small trials showed improvements in pump function when beta-blockers were given to patients with heart failure whose contractile function was impaired. Then, several large-scale clinical trials (reported from 1996-2001) demonstrated that beta-blockers reduced the risk of death, the frequency of hospitalizations, and prevented disease progression. The magnitude of the benefit was unexpectedly large, and the results across trials were amazingly consistent. (I had the incredible privilege of leading two of these trials, published in the New England Journal of Medicine in 1996 and 2001.)
In fact, in some patients with heart failure, beta-blockers actually led to a normalization of heart function, which was sustained for years. In 2018, beta-blockers are arguably our most effective drug for the treatment of heart failure in patients with a reduced ejection fraction.
So in the 1960s, physicians were told NEVER to prescribe beta-blockers for heart failure. Now, 50 years later, the treatment of heart failure is one of the primary reasons that beta-blockers are still used in cardiovascular medicine.
It is a great story, but there is a catch.
Despite overwhelming evidence of efficacy, most patients with heart failure do not receive proper doses of beta-blockers in clinical practice. There is no good reason for the lack of prescribing. There is no dispute about their efficacy. Patients with heart failure typically tolerate them very well. And they are not expensive. (The beta-blockers used for heart failure are all generic.)
Yet, a large proportion of patients with heart failure are not being treated with beta-blockers, even though they are life-saving. Heart failure specialists prescribe them enthusiastically, but most patients with heart failure are not treated by specialists. In primary care, beta-blockers are not consistently used. In one survey, only one-third of patients with heart failure received these drugs.
To make matters worse, even when patients are treated with beta-blockers, the drugs are often prescribed in low doses — despite considerable evidence that higher doses produces better results and are strongly preferred.
What proportion of patients with heart failure are receiving beta-blockers at appropriate doses? I do not know. But I fear that the number may be less than 20%.
Sounds bad? It is bad. But the situation is even worse than you think.
There is one group of patients with heart failure who are being deprived of beta-blockers entirely — even though they are treated by specialists in cardiology.
Children.
Sadly, some children develop heart failure. For most, it results from a genetic condition, a viral infection or after the treatment of cancer. Many children with a cardiomyopathy would benefit from treatment with a beta-blocker. These drugs are considered accepted therapy in children, but typically, pediatric cardiologists do not prescribe beta-blockers to children with cardiomyopathy.
Why not? In 2007, a small trial reported that beta-blockers did not work in children, but it enrolled only 157 patients and treated them for only 8 months. However, to show dramatic benefits in adults with heart failure, the trials needed to enroll tens of thousands of patients who were treated for many years. That kind of evidence does not exist with beta-blockers in children. Yet, children with heart failure routinely receive other drugs (e.g., digitalis, diuretics, and ACE inhibitors), even though none of them have ever been evaluated in a pediatric clinical trial.
The story of beta-blockers in cardiovascular medicine is unique. Fifty years after their introduction, they remain the cornerstone of treatment for a life-threatening cardiovascular disorder — and deservingly so. But physicians are not financially incentivized to prescribe drugs, and drug companies have no reason to advertise the use of low-cost off-patent versions. As a result, millions of people with heart failure who would benefit from beta-blockers do not receive them in an appropriate way.
The generic form of the beta-blocker carvedilol costs about $3 per month. If properly used, it would save about 100,000 lives in the U.S. each year.
Ever see commercials for it on television? Nope.

Friday, December 21, 2018

Novartis wraps pharma’s first big global pot deal


In a watershed moment for medical cannabis advocates in the United States, Swiss giant Novartis’ $NVS Sandoz AG unit has tied up with Canadian medical cannabis producer Tilray, marking the first big endorsement of the controversial plant by a large, multinational pharmaceutical company.
The deal exemplifies changing attitudes in the US, where more Americans live in states that have legalized the sale of medical and/or recreational cannabis than in anti-cannabis jurisdictions. Tilray, which supplies cannabis flower and extract products to patients, physicians, healthcare facilities and researchers in 12 countries, has an existing alliance with Sandoz Canada.
Under the so-called framework agreement, Sandoz AG may support Tilray in commercializing and branding the Nanaimo, British Columbia-based company’s non-smokable/non-combustible products; the Canadian pot producer may supply and/or license such products to and from Sandoz AG; and significantly, the two may collaborate in developing such products.
“The (expanded) partnership also helps legitimize cannabis in international markets, which could impact prevalence within existing markets as well as help influence countries considering medical cannabis legalization,” Cowen’s Vivien Azer wrote in a note.
The landmark FDA approval of GW Pharma’s $GWPH cannabis-derived medicine Epidiolex earlier this year paved the way for a plethora of small and mid-sized drug developers — including Insys Therapeutics $INSY, Zynerba $ZYNE, InMed Pharma, Kannalife and Axim Biotech $AXIM — that are hoping to hitch their wagon to the cannabis star, either by developing synthetic or natural cannabis-derived therapeutics or devising novel delivery mechanisms for its absorption.
Two big deals over the course of this year have also underscored the lucrative potential of the plant, with alcohol giant Constellation Brands $STZ spending a mammoth $4 billion to secure a 38% stake in Canadian cannabis company Canopy Growth $CGC, and cigarette maker Altria $MO forking out $1.8 billion to take a 45% stake in another Canadian pot company Cronos $CRON.

Meanwhile, the US federal government continues to consider cannabis as a schedule 1 substance — on par with LSD and heroin — with no medical value, infuriating researchers who contend the classification has dramatically slowed the scientific and medical investigation of the plant. Nevertheless with House Democrats taking back seats this November, pro-marijuana legislation is expected to heat up.
“There is ample evidence that the cannabis plant has numerous useful applications in medicine and the law is obsolete,” said Marc Feldmann, an Oxford professor and immunologist whose work  led to the discovery and subsequent commercialization of the world’s largest selling drug class, anti-TNF. “This classification is changing around the world – it has already happened in Canada and will happen in more states in the US in due course,” he said in a previous interview with Endpoints News. Feldmann also serves as CEO of CannBioRex, a Canada-based company that is developing synthetic cannabis-derived medicines.

As healthcare providers merge, states look to supersede FTC


As providers merge and morph into behemoth health systems with market share to match, a debate is unfolding over whether competition has served consumers well and whether states should play a greater role in regulating the new entities.
Some states have in effect concluded that relying on competition alone has failed their communities. Multiple players in a market wasn’t enough to limit rising prices or ensure access to care, particularly in rural areas.  
Tennessee, Virginia and West Virginia all recently passed laws to protect mergers from being blocked by federal antitrust regulators — in exchange for state regulation and prolonged oversight.
In some cases, states have secured limits on price increases and commitments to keep certain facilities open after the merger. To shelter mergers from antitrust action, states passed laws, sometimes referred to as COPAs, or certificates of public advantage.
But some legal experts warn that allowing providers to form effective monopolies — even in exchange for regulation — will only pose more harm to consumers. And some states later back away, leaving the merger in place without the oversight.
“That’s a conversation we all need to have, which is best: competition or active state regulation?” Chris Garmon, a former economist with the Federal Trade Commission, told Healthcare Dive.

Tennessee and Virginia shelter merger

A new health system now dominates a large swath of rural Appalachia. The Federal Trade Commission had characterized it as a near monopoly, but the merger was greenlit by state regulators earlier this year after lawmakers previously passed a law immunizing the deal from antitrust intervention.
The system, now known as Ballad Health, was the result of a merger between Mountain States Health Alliance and Wellmont Health System. Ballad Health straddles northeast Tennessee and southwest Virginia, and operates 21 hospitals and employs more than 815 physicians that serve about 20 counties. The merger received final state approval earlier this year after a lengthy review process.
The FTC was adamantly opposed to the deal after conducting a yearlong investigation, calling the two systems serving as “each other’s closest, most-intense competitor.” The antitrust agency warned that together the two would have a near-monopoly on inpatient services and significant market share in outpatient services. That sizable market share would likely lead to higher costs, the FTC warned.
Both Tennessee and Virginia lawmakers agreed that as long as the deal was actively supervised, or in other words, regulated by the two states, they would approve a law to shelter the deal from antitrust regulators. From there, the merging entity had to apply for a COPA and gain approval from state regulators before the deal could be finalized.
In large part, the rationale behind the approval was the fear about rural hospital closures. Ensuring rural residents have continued access to hospitals within Ballad Health’s 20-county service area serves two purposes, according to Tennessee state regulators.
“The existing threat to these hospitals is substantial, which affects not only access to care, but also the economic vitality of their respective communities,” the approval letter from the Tennessee Department of Health states.
Some of the terms of the deal include placing a limit on future price increases, a large financial commitment to improve access to care and improving the health markers of the overall region — not just the health system’s patients.
As the deal was formed, state regulators regularly consulted with the FTC, which strengthened the states’ hand in negotiating, Erin Fuse Brown, a legal expert in healthcare issues and professor at Georgia State University, told Healthcare Dive.
While some healthcare economists tend to dismiss the idea of COPAs, characterizing them as state-sanctioned monopolies, Brown said the reality is providers in rural areas are facing significant headwinds that put their continued viability in doubt.
This particular region faces numerous challenges from dismal health statistics, bad payer mix and an ongoing opioid epidemic.
“We don’t have a perfect world where we can create all this competition,” Brown said. “We’re not going to get more competition back in the market.”
COPAs at least provide some oversight and guarantees, Brown said.
Across the country, the healthcare market has consolidated to the point that, “no hospital market in the United States remains ‘highly competitive,'” according to a 2018 report by Brown on COPAs and commissioned by the Millbank Memorial Fund.
“To me, the only thing left is the regulation,” Brown said.

A cautionary tale in North Carolina

But this idea has failed to work in some places, or has served as a cautionary tale.
More than two decades ago, North Carolina agreed to shield two merging hospitals in Asheville from antitrust scrutiny in exchange for some long-term commitments geared toward protecting consumers.
At the time, Asheville’s two largest hospitals agreed to a number of conditions including caps on profit margin, costs and the amount of area physicians it could directly employ.
Each year, Mission Health was required to submit reports showing whether it was in compliance with the agreed upon terms.
But North Carolina’s COPA didn’t work as intended, some legal experts say.
The deal was rescinded in 2015 when North Carolina lawmakers repealed its COPA statute. For Mission Health, it meant retaining monopoly power but with no oversight.
Now, hospital chain giant HCA is buying Mission Health for $1.5 billion, creating an even bigger system.
And that’s the precise scenario economists fear: allowing a system to carve out a monopoly because it’s nearly impossible to unwind in the future, many have likened it to unscrambling an egg.
“Antitrust law has an important, constrained, role to play but is especially inept in dealing with extant market power,” Tim Greaney, a legal expert in antitrust law, wrote in Health Affairs. Greaney is a professor at the University of California Hastings College of Law in San Francisco.

What separates COPAs from consent decrees?

But for all the criticism of COPAs, some question the FTC’s decision to allow blockbuster mergers with certain conditions in consent decrees, or a settlement with the merging parties.
“It really isn’t different from a consent decree,” Robert Berenson, a fellow at the Urban Institute, said of COPAs.
For example, the FTC decided not to block the megamerger of Beth Israel Deaconess Medical Center and Lahey Health System, citing the seven-year pricing cap deal, secured by the Massachusets attorney general in November.
The Massachusets Health Policy Commission had warned that the deal would likely raise prices as the merger would create a rival to Partners Healthcare, the state’s largest provider. The two will have nearly equal market share, the commission reported.
If both consent decrees and COPAs are able to secure concessions from the merging entities, some question the difference between the two, and the FTC’s stance against COPAs.
Still, the Trump administration is wary of COPAs, too, citing the influence of special interests and the difficulty of ongoing monitoring of the deal, according to a recent report on choice and competition from the Department of Health and Human Services.
“Things are going to get worse not better and I don’t see any alternative than some forms of regulation,” Berenson told Healthcare Dive.

JAMA: ‘unintended harm’ from Hospital Readmissions Reduction Program


  • New evidence links CMS’ Hospital Readmissions Reduction Program to unintended harm in some patients, a JAMA editorial suggests.
  • Researchers analyzed 8.3 million hospitalizations of Medicare enrollees for heart failure, acute myocardial infarction and pneumonia over four periods from April 2005 through March 2015. Thirty-day post-discharge mortality for heart failure patients rose following announcement of HRRP and after implementation.
  • The findings raise concerns about whether the program is a reliable measure of hospital quality and basis for financial penalties, writes Gregg Fonarow of Ronald Reagan UCLA Medical Center.

Part of the Affordable Care Act, HRRP seeks to curb healthcare costs and improve care by incentivizing hospitals to reduce 30-day risk-standardized readmissions for six conditions: heart failure, AMI, pneumonia, chronic obstructive pulmonary disease, hip/knee replacement and coronary artery bypass graft surgery. Hospitals with higher-than-expected readmission rates risk being docked up to 30% of their normal reimbursement.
In fiscal 2018, eight in 10 hospitals subject to HRRP were penalized, resulting in $564 million less in payments, Fonarow notes.
In the new study, published Friday in JAMA, HRRP was associated with a 0.49% increase in 30-day post-discharge mortality in heart failure patients between 2007-2010 and 2010-2012, and a 0.52% jump from 2010-2012 to 2012-2015. No significant change was seen in heart attack patients, but there was also a significant increase in pneumonia patients following announcement and implementation of the program.
Previous studies have differed on whether HRRP puts vulnerable patients at risk. A 2017 study in JAMA Cardiology found that while the program reduced heart failure readmissions, mortality in those patients went up. However, a JAMA study published this fall found no link between the HRRP and increases in in-hospital or post-discharge mortality rates among Medicare beneficiaries.
Fonarow points to a separate analysis of clinical data from the American Heart Association’s Get With the Guidelines – Heart Failure that found 30-day mortality rose under HRRP. The risk of harm was consistent across multiple subgroups and sensitivity analyses.
The findings provide “important new insights into the association of the HRRP with increases in mortality among patients hospitalized for heart failure, and raises additional concerns regarding potential unintended harms among patient with pneumonia,” Fonarow writes. “Irrespective of the intent of the policy, there is no evidence that patients have benefited from the HRRP.”
He urges lawmakers and CMS to consider alternative strategies to reduce avoidable readmissions and improve patient outcomes.

FDA Warns on Aortic Aneurysms With Fluoroquinolones


Manufacturers of fluoroquinolones such as ciprofloxacin (Cipro) must now warn about risk of aortic dissection or aneurysm in certain patients associated with systemic use of these antibiotics, the FDA said Thursday.
It’s the latest in a series of warnings related to this class of antibiotics. In July, the FDA required manufacturers to update labeling to warn about mental health issues and potential low blood sugar adverse reactions; and before that, the agency had warned about adverse musculoskeletal effects and peripheral neuropathy. The FDA had also indicated that this class of agents should not be used for uncomplicated infections owing the risk of adverse effects.
It also represents a backtrack from a May 2017 announcement, in which the FDA, responding to reports of a possible aneurysm risk, said it could not find solid evidence to support them.
In Thursday’s statement, the agency said a review found fluoroquinolones were linked to “an increase in occurrence” of aortic dissections. The review included cases reported to the FDA Adverse Event Reporting System, as well as four observational studies that hazard or odds ratios of about 2 to 3 among users of fluoroquinolones relative to the general population. “[T]he results of all four studies provide consistent evidence of an association between fluoroquinolone use and aortic aneurysm or dissection,” the FDA said. However, the agency also noted that the background risk of aortic aneurysm is very low: about 9 per 100,000 overall up to 300 per 100,000 in high-risk groups such as the very elderly.
The new label warning states that fluoroquinolones should not be used in patients “with a history of blockages or aneurysms (abnormal bulges) of the aorta or other blood vessels, high blood pressure, certain genetic disorders that involve blood vessel changes, and the elderly.” These warnings must be added to the prescribing information and the patient medication guide, the FDA said.
Moreover, the FDA said that healthcare professionals should avoid prescribing these antibiotics to patients with aortic aneurysm or those at risk for aortic aneurysm, unless no other treatment options are available. These patient groups at increased risk include “patients with peripheral atherosclerotic vascular diseases, hypertension, certain genetic conditions such as Marfan syndrome and Ehlers-Danlos syndrome, and elderly patients,” the agency said.