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Sunday Star Times wrote:Pharmac attacked for rushing drug
http://www.stuff.co.nz/national/health/ ... shing-drug

Dozens of elderly patients have suffered bleeds – and at least two have died – after taking an anti-blood clotting drug which was rushed onto the market by Pharmac in a deal worth more than $100m.

Some doctors say Pharmac, the government drug funding agency, may have put lives at risk by funding Pradaxa, also known as dabigatran, before more was known about managing its side effects.

Pradaxa is a new oral blood-thinning drug used to reduce the risk of stroke in people with heart rhythm disorder, and can also be used to prevent clots following hip or knee replacements.

The Centre for Adverse Reactions Monitoring (Carm) has received around 50 reports of people experiencing bleeding since the drug was introduced two months ago as a replacement for the standard blood-thinning drug warfarin. Around 56,000 people take warfarin and thousands have been switched to Pradaxa.

It is unclear how many deaths have resulted, but the Sunday Star-Times has heard of two elderly patients, a man and a woman, dying after bleeds.

Other patients, mostly [older] than 75, have experienced symptoms including coughing up blood, rectal bleeding and bleeding around the brain. Some improved after they stopped taking Pradaxa but others needed multiple blood transfusions and in some cases there were major surgery complications. An 84-year-old man had to wait nine days for surgery on a fractured hip because of complications associated with Pradaxa.

Bleeding is a known risk of blood-thinning drugs but doctors are concerned that there is no treatment to reverse the effects of Pradaxa, unlike warfarin, which can be quickly revesed by administering another drug. One surgeon, who asked not to be named, said he did not believe clinicians should be prescribing Pradaxa.

Pharmac declared Pradaxa was a "game changer" when it announced in June it was fully funding it without restriction, meaning any clinician can prescribe it. Pharmac had signed a deal with drug company Boehringer Ingelheim which could cost $155m over five years, although this will drop through rebates.

"We do have concerns about the way it was rolled out," said Humphrey Pullon, of the Haematology Society. "It was rolled out very rapidly without a lot of forethought and planning. In particular the fact that general practitioners could have widespread access to this drug from day one was a concern to us, when some of them did not know how to use it."

Research by haematologists has found that GPs have been prescribing the drug to people who should never have been given it, such as those with poor kidney function.

Medsafe said in a statement that it considered the benefits of Pradaxa outweighed the risks. It was "closely monitoring the safety of dabigatran (Pradaxa)" and would follow the results of a number of ongoing safety studies being undertaken by Boehringer Ingelheim. Any suspected adverse reactions should be reported to Carm and patients who had concerns should discuss it with their doctor.

Pharmac said in a statement that Medsafe had decided Pradaxa was safe to register in New Zealand.

"As with all adverse events, both Pharmac and Medsafe take these reports very seriously. In addition to the normal safety nets, the haematologists' reporting system is proving to be invaluable and the results are being monitored by all agencies."

The reporting system is being run by Palmerston North haematologist Paul Harper, who said it was a bit late to be starting efforts to manage adverse effects when the drug had been on the market two months.

"The drug came in much quicker than we expected and there hasn't been much opportunity to really educate people about how to use it," Harper said. "We haven't really got anything helpful to reverse the effects of the drug, and that's the big concern. If someone does have a significant bleed we haven't got a good way of managing that."

Although Pradaxa is no more effective than warfarin, it does not require the regular blood tests which people on that drug must undergo, which Pharmac sees as a major cost-saver.

But Harper said there was not much known about Pradaxa internationally as there had only been one clinical trial. There had been reports of deaths in Japan and the US.

New Zealand is one of the only countries that has fully funded the drug. Some doctors are concerned that Pharmac has put commercial concerns ahead of patient safety.

Pullon said: "I think there were certain commercial pressures whereby in order to generate adequate volumes and generate the savings they really had to open it up to ... GP prescribing," he said. "That's a commercial risk that Pharmac entered into. It certainly wasn't done with any consultation with the society."

Pharmac's statement said: "There is no incentive for any clinician to maximise prescribing of this medicine. There is a substantial cost to the pharmaceutical budget from the prescribing of this medicine."

It said decision-making around Pradaxa took 14 months and included seeking clinical advice.

Harper's research has found that Pradaxa is unsuitable in certain doses for people over 75, those with poor kidney function, people of low weight and those with replacement heart valves. There have also been problems with people switching between Warfarin and Pradaxa too quickly.

Pullon said the haematology society had warned Pharmac the drug could cause bleeding.

"They then gathered a group of haematologists ... and generated some guidelines as to how the drug should be used. It was a bit of an afterthought."

Do you know anyone who has had an adverse reaction to Pradaxa? Email tony.wall@star-times.co.nz

- Sunday Star Times

Its value as a warfarin alternative for patients with atrial fibrillation was addressed in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study detailed below.


STUDY SUMMARY: At higher dose, dabigatran prevents more strokes than warfarin

RE-LY included 18,113 patients from 951 facilities in 44 countries. To be eligible for the study, patients had to have atrial fibrillation documented on an electrocardiogram and at least one additional risk factor for stroke.

Participants were randomized into one of 3 groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily (both administered in a blinded fashion), or warfarin (administered in an unblinded fashion and dosed to maintain an INR between 2 and 3). Baseline characteristics, such as age, sex, and CHADS2 (congestive heart failure, hypertension, age, diabetes, prior stroke) score, were similar across all 3 groups. The median duration of follow-up was 2 years, and complete follow-up occurred in 99.9% of participants.

The primary outcome of the study was stroke or systemic embolism. The primary safety outcome was major hemorrhage, defined as a reduction in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of blood, or symptomatic bleeding in a critical area/organ. Other outcomes were death, myocardial infarction (MI), pulmonary embolism, transient ischemic attack, and hospitalization.

For the primary outcome of prevention of stroke or systemic embolism, the 150-mg dose of dabigatran was superior to warfarin (1.11% vs 1.69% per year, relative risk [RR], 0.66; 95% confidence interval [CI], 0.53-0.82; P<.001 for superiority). The major bleeding rates were similar for dabigatran 150 mg and warfarin, although major gastrointestinal bleeding rates were significantly higher with this dose of dabigatran compared with warfarin (TABLE). Minor bleeding was more common in the warfarin group (16.37% vs 14.84%; RR, 0.91; 95% CI, 0.85-0.97; P=.005).

The 110-mg dose of dabigatran (which is not available in the United States) was neither inferior nor superior to warfarin for the prevention of stroke or systemic embolism. This dose of dabigatran had a lower risk of major bleeding compared with warfarin.