Drugs Trail Back Scratching and Blood Thinners

Pricey new blood thinners to prevent strokes are in high demand, thanks in part to doctors who recommend them – and who are often paid by drug companies. A Handelsblatt investigation reveals the relationships at play.
Some drugs have highly respected pushers.

Things could scarcely be going better for Bayer chief executive Marijn Dekkers. At the end of July, the chemical and pharmaceutical giant presented a flawless financial statement for the first half of the year.

Mr. Dekkers owes a lot of his company’s success to a product that has not been on the market for long – the blood-clotting inhibitor Xarelto. In 2014, it was Bayer’s top pharmaceutical money-maker. The Leverkusen-based company had sales of almost €1.7 billion, or about $1.9 billion, with Xarelto alone.

But the drug’s success might be more than just medical. A Handelsblatt investigation shows Xarelto and two other anti-coagulants benefited from the vigorous advocacy of prestigious doctors, some of whom were paid by drug manufacturers.

This is evident in a report published in early 2015 on guidelines for preventing strokes. These sorts of guidelines are drawn up by commissions of experts and serve as the major resource for doctors looking for the right medication for patients.

In the current report on strokes, 16 of the 23 authors of the guidelines were linked to the pharmaceutical industry as advisors or experts, as well as through research money. Fourteen of those authors had links with Bayer.

Since mid-2013, these well-paid authors have been calling for a switch to new stroke medications, including those made by Bayer.

A recent study reveals that out of 2,190 medical guideline writers, 85 percent acknowledged conflicts of interest.

The cozy alliance between pharmaceutical companies and doctors is apparently still not a thing of the past. Even today, advanced training for doctors is permeated with dubious offerings from the drug industry. The pharma industry's approach is often subtle and appears to be based on the premise of “whoever takes our money today will remember us later.”

A recent study of 234 medical guidelines published in the German medical magazine Deutsches Ärzteblatt reveals that out of 2,190 guideline writers, 85 percent acknowledged conflicts of interest. Only one scientist excluded himself from participating in the guidelines.

Medical guidelines, which are drawn up by professional associations of doctors, basically pursue an honorable goal. They provide orientation to doctors, hospitals and patients about how to handle certain diseases. Its recommendations are not binding, but they carry weight. Not least of all, doctors can cite guidelines in order to fend off legal challenges from patients.

“Guidelines are always the ultimate argument when the question is: Do we do it this way or that way?” said Thomas Lempert, head of neurology at Schlosspark Clinic in Berlin.

The guidelines also have a big impact on the medication market – and with anti-coagulants they have been a gold mine. Worldwide revenues for blood thinners are around €38.7 billion, or $43.2 billion. In Germany alone, according to the most recent Barmer Report on Medicine, more than 5.5 million packages of blood thinners were prescribed in 2012.

Since mid-2013, there has been a new strategy in using blood thinners to help prevent strokes. Professional associations recommended a shift from Marcumar – the drug from the Meda company that up to now was most widely used in Germany – to significantly more expensive products. Those pricey new medicines include Eliquis from Pfizer/Bristol-Myers Squibb, Pradaxa from Boehringer Ingelheim and Xarelto from Bayer.

This is documented in the new guidelines by the German Neurology Association and German Stroke Association. It says: “The new anti-coagulants (i.e. Dabigatran, Rivaroxaban and Apixaban) constitute an alternative to the Vitamin-K antagonists and should be used because of the more favorable use-risk profile.”

Dabigatran, Rivaroxaban and Apixaban are the active ingredients in Pradaxa, Xarelto and Eliquis, respectively.

Handelsblatt looked at the way the medical authors voted on the stroke guidelines –  including many who are chief physicians at university hospitals – and their links to the pharmaceutical industry.

One is Hans-Christoph Diener, a neurologist at the University Hospital Essen and spokesman for the German Neurology Association.

In an article in the news magazine Der Spiegel, he called Dabigatran for treating atrial flutter “the greatest success in stroke prevention in the last 10 years.”

But Mr. Diener seems to be anything other than an independent expert. He is one of 16 out of the total 23 guideline voting authors who also served simultaneously as an advisor, evaluator or advisory-committee member for numerous pharmaceutical companies – including Bayer, Boehringer Ingelheim and Pfizer/Bristol-Myers Squibb.

Mr. Diener also received lecture fees and research funding from those companies. This emerges from the transparency chapter of the guideline report itself, in which the authors declared their conflicts of interest from 2008 to the end of 2012.

Quelle: dpa
Drugs companies often fund research for medical professionals.
(Source: dpa)


Others among the experts were linked to all three manufacturers of the new drugs – and a few even held stock in the companies. But that apparently did not keep them from casting votes regarding the important recommendation on blood thinners.

The stroke guidelines report stated that, in the case of conflicts of interest, “there was a requirement that the affected individual refrain from participating in this vote.”

But only six of the 16 authors who had a conflict of interest obeyed their own rule. In the crucial second ballot, there were only four abstentions.

The result was a subtle victory for the pharmaceutical lobby. Ultimately the recommendation in favor of the new anti-coagulants was decided by a 10-9 vote, with four abstentions. Of the 16 authors with conflicts, at least three must have voted in favor of the recommendation – with a single vote determining the outcome.

In response to an inquiry, Mr. Diener said he abstained from voting.

Joachim Röther, spokesman of the German Stroke Association and the chief physician at the hospital, Asklepios Klinik Altona, was also financially linked to all three manufacturers. He would not comment on specifics of the vote.

But a statement issued by the German Stroke Association asserted that in the case of conflicts, it was simply “suggested” to individuals authorized to vote that they abstain. The decision of whether they were subject to bias “was left to the holders of the mandates themselves.”

Neither doctor is willing to reveal how much money he received from the drug companies. And no light can be shed on who among the 16 did not abstain. Mr. Diener said that information was “not recorded for each vote.”

Concerning collaboration with doctors, all three pharmaceutical companies say they have always obeyed the law, as well as self-imposed rules of the pharmaceutical industry.

“Without cooperation between the pharmaceutical industry and doctors in research and development, ... it is not conceivable that new drugs could be introduced or already-existing ones could be further developed,” Bayer said in a statement.

Boehringer Ingelheim noted that the guidelines and their preparation corresponded to specifications of the German Association of Scientific Medical Societies.

But those specifications are considered inadequate by Transparency International, which monitors and reports on corporate and public corruption, as well as by associations of doctors such as Neurology First and Mezis.

They call for authors with conflicts of interest to be entirely excluded over the long term from establishing guidelines. But up to now, the medical societies association has not developed compulsory rules.

Niklas Schurig of Mezis argues that influence from the drug industry must be “just as strictly prohibited as with Stiftung Warentest,” a consumer protection agency that evaluates products and services.

Progress has been made internationally, said the neurologist Mr. Lempert – U.S. professional medical associations, for example, don’t allow the author in charge of guidelines to have any relationships to the drug industry.

“And if they don’t want to do without the opinion of a particular expert, that can occur in a hearing,” said Mr. Lempert.

Without a doubt, the widespread use primarily serves to bolster the revenues of the pharmaceutical industry. Barmer Medical Report 2014

The case of the new anti-coagulants shows how necessary it is for medical guideline authors to be totally independent, in order to remove doubts concerning use of medicines. Massive use of blood thinners is controversial among some medical experts.

Thinning blood with Marcumar is also considered dangerous. In contrast to the new drugs, patients must be continuously supervised. But in the case of Pradaxa, for example, there is not a quickly effective counter-agent to stop blood from thinning. Boehringer Ingelheim said a medicine of this sort is currently being developed.

The new blood thinners are also suspected of leading to a higher risk of bleeding and, in some cases, death. An inquiry on the subject was submitted to the German government by the Left Party. The response in April 2015 cited, among other things, investigations by Bremen scientist Gerd Glaeske that a causal connection in individual cases had not been “established with certainty.”

The manufacturers emphatically reject such accusations. Boehringer Ingelheim and Pfizer say large-scale studies prove that their preparations have a “positive safety profile” and are “significantly better in reducing the risk of serious bleeding.”

Bayer emphasized that for Xarelto, “a positive use-risk relationship has been proven in the authorized areas of use.”

Not all patients or their families are convinced. In the United States, all three manufacturers face lawsuits for allegedly related health impairments or deaths. Bayer alone is dealing with 1,200 lawsuits. The companies reject the demands of claimants as unfounded.

German health insurance funds are likewise headed on a confrontation course. For example, the 2014 Barmer Medicine Report argues that “so widespread a use, as is the case in Germany, is not justified by current evidence for the new preparations.”

“Without a doubt, it primarily serves to bolster the revenues of the pharmaceutical industry,” the report said.


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The report also provides detailed information about the financial impact of the prescriptions being issued. Germany’s health insurance companies paid €675.4 million for Xarelto and similar blood thinners in 2014. According to the Barmer report, costs for the new medicines per patient are around €1,000 higher annually.

Wolf-Dieter Ludwig, head of the Medicine Commission of the Association of German Doctors, said earlier this year in a report by the TV broadcaster ARD: “There are opinion leaders who have no scruples about promoting these drugs, although there is no clear justification at the moment.”

He said there are programs of ongoing education for doctors in which so-called “opinion leaders” with conflicts of interest make statements that “have a strong impact on promoting uncritical behavior with regard to writing prescriptions.”

Handelsblatt recently described how pharmaceutical companies and doctors act in this field. The article cited a two-day seminar organized by Pfizer and certified by the Berlin Medical Association – in which Pfizer offered to reimburse the participants’ expenses for air travel and accommodations up to €760.

The official title of the seminar was “A Matter of the Heart: Stroke Prevention.”

The internal working title, which inadvertently ended up on the homepage of the Berlin Medical Association, was more revealing: “Eliquis-CardiCampus-2015.”


Jan Keuchel is a Handelsblatt correspondent covering the German legal system. To contact the author: [email protected]