Boehringer Ingelheim has systematically rebutted claims in the BMJ that the company withheld analyses of its blockbuster anticoagulant Pradaxa from regulators and played down the risk of bleeding.

The journal has devoted considerable space to analysis which it claims “illuminates a lack of transparency about the safety of unmonitored Pradaxa (dabigatran), compounded by the drug’s fickle pharmacokinetics, which can cause a fivefold variation of plasma concentration”. It goes on to reference “data integrity issues”, speaking of “clinical concerns” which include “potentially higher than reported bleeding risk, the possibility of undertreating or overtreating with fixed doses…the unknown value of monitoring dabigatran levels and adjusting the dose; and the lack of a specific reversal agent”.

The BMJ argues that “a more transparent process of data collection and review would make important clinical data available without waiting for litigation and subpoenas, which is what it took to unearth some of Boehringer’s early concerns with dabigatran”. The company reluctantly agreed to pay $650 million to settle 4,000 lawsuits in the USA, frustated by a legal system where “lawyers run advertising campaigns to find clients”.

'Set record straight' using Twitter

Over the past few days, Boehringer has taken to Twitter to bat aside the claims made by the BMJ one by one. After publication, the firm said it “wants to set the record straight following misleading statements” made by the BMJ as “we are concerned that the reporting might put patients at risk of stopping their important stroke-preventing medication”.

Boehringer noted that a couple of months ago, the US Food and Drug Administration once again reaffirmed the positive efficacy-safety profile of Pradaxa when it issued results from one of the largest real-world analyses of its kind which included more than 134,000 patients, who were 65 years or older and were not monitored.

The company has provided regulators “with the complete data set and analyses of clinical evidence” and as for the accusation of withholding analyses, in 2012, “our scientists performed preliminary, exploratory simulations with mathematical models to understand whether dose adjustments based on plasma concentrations might further improve the efficacy and safety profile of Pradaxa”.

However, the initial hypothesis could not be supported when applied to the data from the patient population involved in the 18,000-patient RE-LY trial on which approval was based. Therefore, they were not provided to regulators, Boehringer notes, adding that “the totality of scientific evidence does not support dosing decisions for Pradaxa based solely on blood levels”. Characteristics, such as age, kidney function and certain medications, “are critical factors in contributing to the risk of bleeding”.

Correct patient selection the key

The company’s UK unit quoted David Keeling, haematology consultant at Oxford University Hospitals as saying that “an important advantage of all the new oral anticoagulants is that you don’t need to monitor and adjust the dose based on plasma levels. The important thing is correct patient selection and patient education.”

Charles De Wet, medical director UK and Ireland, pulled no punches in his response, saying the company made a robust effort to find ways to utilise plasma levels to further improve the risk-benefit profile and it is irrational to suggest otherwise”. He added that “we are deeply concerned that the BMJ’s skewed reports are an effort to distort the facts and generate public attention”, noting that “the accusation that we should have done more than one trial are absurd”.

Dr De Wet stressed that post-market data assessments from the FDA comparing the drug to warfarin reinforce the favourable risk/benefit profile shown in RE-LY, stating that “boldly demonstrating a biased agenda, the BMJ failed to inform its readership of this research”.

Channel 4 was scheduled to transmit a report earlier this week based on the BMJ analysis but nothing has been broadcast as yet.