NEW YORK: For millions of heart patients, a pair of new blood thinners have been heralded as the first replacements in 60 years for warfarin, a pill whose hardships and risks have deterred many from using the stroke-prevention medicine.
But growing complaints of risks and deaths tied to the new crop of drugs have made some top U.S. cardiologists hesitant to prescribe them. Some are proposing a more rigorous monitoring regimen for when they are used.
Most concerns revolve around Pradaxa, a twice daily pill from Boehringer Ingelheim that was approved by the U.S. Food and Drug Administration in October 2010 to prevent strokes in patients with an irregular heartbeat called atrial fibrillation. It was the first new oral treatment for that use since warfarin was introduced in the 1950s.
"The good news is you now have an alternative to warfarin," said Dr. Alan Jacobson, director of anti-coagulation services at the Veterans Administration (VA) healthcare system in Loma Linda, California. "The bad news is you can kill a patient as easily with the new drug as you could with the old drug" if it is not handled properly.
"The average patient doesn't understand anything about the new drug, or what the risks are, or what other medicines he can or can't take," said Jacobson, citing interactions with common painkillers and other drugs that can alter Pradaxa blood levels.
Xarelto, a once daily pill that Johnson & Johnson developed with Bayer AG, was approved last November for atrial fibrillation. The condition affects about 3 million Americans, causing blood to pool in a storage chamber of the heart, where it can clot and travel to the brain.
Both new drugs were designed to sidestep risks of warfarin, including brain hemorrhages and other dangerous bleeding, and become mainstays of a new therapeutic market worth at least $10 billion a year. Patients taking warfarin require close monitoring and regular blood tests as well as dietary and lifestyle changes.
Doctors have less data and familiarity with Xarelto, which is still being rolled out.
But Jacobson and another dozen physicians interviewed by Reuters expressed similar concerns about both Pradaxa and Xarelto.
They say that real world use of Pradaxa and Xarelto, which do not require regular blood monitoring or frequent doctor follow-up, raises concerns about the risk of stroke, serious bleeding and blood clots if not taken properly, particularly in patients with poor kidney function.
The nonprofit Institute for Safe Medication Practices estimated last month that 542 reports of deaths associated with Pradaxa were reported to the FDA in 2011, topping all other medicines, including warfarin, with 72 deaths. Adverse event reports on Xarelto were not available.
A case study published in March raised alarm in particular, showing an elderly Utah patient on Pradaxa developed a massive brain hemorrhage and died after a minor fall.
European regulators have instructed Boehringer Ingelheim to add warnings about the bleeding risk to Pradaxa's package insert. Almost two dozen U.S. federal lawsuits have been filed against Boehringer Ingelheim alleging harm from Pradaxa.
Boehringer declined to comment on the lawsuits. The German company also declined to comment about the deaths, but said the number of reports of bleeding with Pradaxa were within Boehringer's expectations, given the incidence of bleeding seen in the drug's largest study.
"Research has shown that the number of reported adverse events for a drug peaks during its first few years on the market," when doctors are most likely to file voluntary reports to regulators and drugmakers, company spokeswoman Emily Baier said.
Dr. Robert Temple, a top official in the FDA's Center for Drug Evaluation and Research, said few doctors notify the agency about incidents from warfarin because its risks are already well known. So the lopsided number of Pradaxa reports compared with warfarin may not indicate an elevated risk, he said.
"We don't necessarily believe it is real," he said. "But we're watching it. We can't help but notice it."
A SHIFT IN PRACTICE
The makers of Pradaxa and Xarelto say it takes time for doctors to get up to speed on new types of treatments and how to best administer them outside the controls of clinical trials.
"This is a shift in medical practice," said Dr. John Smith, senior vice president for clinical development at Boehringer. "Individual physicians have to determine what the follow-up plan will be, to use common medical-sense judgment."
Dr. Peter Wildgoose, a senior director of clinical development at J&J, said the company has not provided special advice on follow-up care for patients on Xarelto.
"There's nothing more than for any other drug that people regularly take," he said, adding that most atrial fibrillation patients probably see their doctors on a regular basis. "These drugs have been tested long term, for several years at a time, with very good outcomes."
Boehringer Ingelheim and Johnson & Johnson officials stressed there was far less evidence in trials of brain bleeding - the most worrisome side effect of anti-coagulants - in patients taking Pradaxa and Xarelto than those taking warfarin.
In the meantime, warfarin is holding its own, with 33 million U.S. prescriptions filled for atrial fibrillation and other uses last year, according to IMS Health, a healthcare information and services company. Some 2.2 million prescriptions were filled for Pradaxa.
About 130,000 U.S. prescriptions were written for Xarelto in the first three months of 2012. Pradaxa and Xarelto each cost about $3,000 a year, versus just $200 for generic warfarin.
Prominent U.S. heart doctors stress that neither new drug has a known antidote for a bleeding emergency, as warfarin does.
They also say that patients using them should undergo testing ahead of time to ensure good kidney function, be carefully taught potential pitfalls of the drugs and be seen by doctors periodically, especially after a switch is made.
"I have received a dozen phone calls from local colleagues in the last couple of months about bleeding on Pradaxa and have yet to find a single case where that bleeding was not related to improper use of the drug," said Dr. Sanjay Kaul, a cardiologist at Cedars-Sinai Medical Center in Los Angeles.
Kaul found that many of the doctors failed to test patient kidney function before prescribing Pradaxa, though 80 percent of the drug is excreted in that organ. Weak kidneys allow the medicine to build to unsafe levels in the bloodstream. About two thirds of Xarelto is eliminated by the kidneys. Other doctors failed to ask patients whether they had a history of gastrointestinal bleeding, which raises the risk for Pradaxa.
"What really compounds the matter is the lack of a specific antidote to reverse life-threatening bleeding" from Pradaxa, said Kaul, who served on independent panels that advised the FDA on both new medications. Kaul said he had written only one prescription for Pradaxa and none for Xarelto.
Boehringer Ingelheim said it is working on an antidote, but declined to elaborate. Johnson & Johnson said it is not developing an antidote, but is monitoring early efforts by other drugmakers to come up with one. Bristol-Myers Squibb Co, which is developing a blood clot drug called Eliquis that is similar to Xarelto, declined to comment on the antidote issue.
HOPES FOR A THIRD NEW DRUG
Warfarin thins the blood by blocking Vitamin K, while Pradaxa directly inhibits thrombin - a protein involved in clotting. Xarelto and Eliquis - which Bristol-Myers is developing with Pfizer Inc - interferes with a protein called Factor Xa.
Richard Purkiss, an analyst with Atlantic Equities, sees the new blood clot drugs reaching combined global annual sales of $10 billion for stroke prevention and other uses, with Eliquis commanding up to a 60 percent market share, based on data showing it was more effective and safer than warfarin, including less bleeding and risk of death from all causes.
Neither Pradaxa nor Xarelto were able to claim both superiority and better safety than warfarin, or reduced risk of death.
Eliquis is eliminated mainly by the liver, which some doctors say could make it more appropriate than Pradaxa or Xarelto for older patients and those with kidney problems. The FDA is expected to make a decision on Eliquis by June 28.
Michael Liss, portfolio manager at American Century Investments, predicts Eliquis will overtake Pradaxa and Xarelto within six months after it is introduced. He expects it to capture peak annual sales of up to $4 billion, with Pradaxa and Xarelto dividing up another $3 billion.
Dr. Kenneth Bauer, head of hematology for the Veterans Administration health system in Boston, said the FDA should never have approved Pradaxa and Xarelto for patients with severe kidney dysfunction, since such patients were excluded from large studies. Nor should the agency have approved an untested 75-milligram half dose of Pradaxa for such patients, he said.
"These are people whose kidneys are already damaged ... and even at the smaller dose (of Pradaxa), you risk overdosing yourself," Bauer said.
The FDA said it routinely approves adjusted doses of medicines, and noted that patients with severe liver dysfunction were included in smaller studies of Xarelto and Pradaxa.
Boehringer Ingelheim's Smith said the FDA cleared the lower dose of Pradaxa after conducting its own analysis of how it performs in the bloodstream.
FRAIL ELDERLY 'CANARY IN COAL MINE'
Almost 15 percent of Americans over the age of 80 are believed to have atrial fibrillation and face a fivefold higher risk of stroke if untreated.
Dr. Richard Besdine, director of the Center for Gerontology at Brown University, said he had switched only two of his approximately 100 elderly patients from warfarin. He is unlikely to switch many others for at least a few years.
"If there's an adverse event lurking in the closet for a new drug, it's most likely to come out in patients that are old and frail and taking multiple medications. They're the canary in the coal mine," he said.
Even so, Besdine - like many other doctors now on the sidelines - believes the new drugs may eventually displace warfarin as doctors become familiar with them.
Others note that warfarin's disadvantages have led as many as 70 percent of prospective patients to refuse to take it, leaving plenty of room for the new drugs.
Dr. Robert Califf, a Duke University cardiologist who headed the largest study of Xarelto, noted warfarin is still one of the biggest causes of U.S. emergency room fatalities.
"We shouldn't lose sight of what warfarin is like in the real world," he said. (Reuters)
N'DJAMENA: A frail 65-year-old woman sitting under the mango trees in a rural village in Chad suffers from a tropical disease that eats into the brain, and the locals blame on witchcraft.
"I've been suffering for more than two months now. I have headaches, fever, and I just feel very tired," said Lea Sadene, who has just been tested and diagnosed.
She has Human African trypanosomiasis, commonly known as sleeping sickness, which is transmitted by tsetse flies found in 36 sub-Saharan African countries.
Sadene is in the first phase of the often fatal illness. Without treatment in four months to a year, "the parasite penetrates into the brain, causing serious neurological symptoms, until death," said Doctor Benedict Blaynay, head of neglected tropical diseases at French pharmaceutical giant Sanofi.
"The symptoms can cause a change in personality, mental deterioration, leading to a long sleep or coma," which gives the illness its name, he said.
Chadian health officials say around 3,300 people were infected between 2001 and 2011 in several areas of the landlocked central African nation, one of the poorest in the world.
"With more than 100 cases per year Chad is considered an endemic country," said Doctor Peka Mallaye, who is in charge of the national programme to fight against sleeping sickness.
In Kobitoi in southern Chad recently, village women lined up with their children, many with swollen bellies, in the scorching sun as temperatures hit 43 degrees Celsius (109 degrees Fahrenheit) to undergo tests for the disease organised with Sanofi.
The team found 14 cases of sleeping sickness out of 120 people examined, Mallaye said.
"This village is located next to a forest where the tsetse flies live. During the rainy season, people pass through the forest to go fishing or hunting," he said.
Fighting the disease, however, takes more than testing and drugs. For the people living in Chad's rural communities, the strange symptoms of sleeping sickness have long been shrouded in superstition about witchcraft and demonic possession.
"Before we didn't know that it was the disease that was killing people. People died like flies, they blamed witches," said Alngar Legode, a village mother trying to comfort her eight-month child still crying after being pricked for the blood test for the disease.
"Witchcraft is seen as a real phenomenon in traditional societies," said sociologist Serferbe Charlot. "They think that a man or a woman suspected of witchcraft is eating away at a person's soul."
In the advanced stages of the disease the infected person experiences severe neurological problems.
"When this disease reaches the brain, the patient loses control of his life, he even becomes violent. That is when the villagers believe that the sick person is possessed by evil spirits," said Charlot.
"It is up to the health specialists to prove" to the population that it is not witchcraft, he said, adding: "The fight against sleeping sickness calls for raising awareness."
But the World Health Organisation says it is not a losing battle.
After continued control efforts, the most recent statistics available show the number of cases in 2009 dropped below 10,000 for the first time in 50 years, and the trend continued in 2010 with 7139 new cases reported, the WHO reported on its website.
WHO estimates the number of actual cases is currently 30,000. The most affected country has been the Democratic Republic of Congo, which declared 500 new cases in 2010.
The WHO has established public-private partnerships with Sanofi and also Bayer Healthcare to create a surveillance team and provide support to endemic countries in their control efforts as well as a free supply of drugs to treat the sick.
Diagnosis should be made as early as possible before the disease reaches the neurological stage, which calls for more complicated and risky treatment.
The chief executive of Sanofi, Christopher Viehbacher, said the main challenge ahead "is to keep up the expertise in diagnosis and treatment in the medical centres, so that the monitoring for sleeping sickness is maintained."
Sleeping sickness figures on the WHO's list of 10 neglected tropical diseases. In January in London, the UN health agency brought together the US, British and United Arab Emirates governments along with 13 pharmaceutical companies and international organisations like the World Bank and the Bill & Melinda Gates Foundation to make a new push to eliminate these diseases by the end of the decade.
"If we keep doing the right things better, and on a larger scale, some of these diseases could be eliminated by 2015, and others by 2020," WHO Director General Margaret Chan has said.
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