Dr. Steve Wong (biography and disclosures)
What I did before
I recognized that atrial fibrillation is the most common arrhythmia in the world, affecting nearly 3-5% of patients older than 70. Most are asymptomatic, yet atrial fibrillation can account for up to 30% of strokes in patients > 80 years old. In addition, strokes from atrial fibrillation tend to be larger and more prone to hemorrhagic transformation.
I routinely recommend warfarin for stroke prophylaxis for patients with a CHADS score ≥ 2 (see below) given its much greater stroke reduction vs aspirin (~66% relative risk reduction with warfarin vs. ~33% relative risk reduction with ASA). Warfarin, although very effective, is hardly anyone’s favorite drug: its narrow therapeutic window is a challenge, and the need for laboratory testing (patient & clinician time, lost productivity), dose adjustment, accounting for food and drug interactions are huge challenges. The low cost of warfarin itself belies its larger cost to society and the health care system in general.
What changed my practice
Over the years, several different agents to replace warfarin were disappointing: they were associated with major adverse bleed risks, liver failure or were inferior. Dabigatran is the first oral direct thrombin inhibitor to make it to the market. This drug does not require monitoring, has few food & drug interactions, and is currently being used in the post-orthopedic surgery prophylaxis arena as an alternative to low molecular weight heparin.
In late 2009, the RE-LY study was published. This was the largest-ever trial of anticoagulation in atrial fibrillation (n=18,113), comparing warfarin against dabigatran at doses of 110 mg bid or 150 mg bid. Patients were followed for 2 years, comparing the primary endpoint of stroke & systemic embolization as well as bleeding rates.
RE-LY demonstrated that dabigatran 110 mg bid was noninferior to warfarin (relative risk (RR) 0.91 (CI 0.74-1.11)) yet had a 22% reduction in total bleeding (RR 0.78, p <0.001) and a 32% reduction in life-threatening bleeding (RR 0.68, P <0.001). At 150mg BID, dabigatran was actually superior to warfarin, achieving a 34% reduction in the primary endpoint (RR 0.66, NNT 200, p<0.001) and met criteria for superiority over warfarin (not ‘just’ non-inferiority). At the 150 mg bid dose, dabigatran was associated with a 9% reduction in total bleeding (RR 0.91, p=0.002) and a 19% reduction in life-threatening bleeding (RR 0.81, P=0.037).
It should be noted that RE-LY did show more GI side effects with dabigatran (dyspepsia, ~11-12% vs 5.8% on warfarin) and GI bleeding (1.12% per year at 110 mg bid, 1.51% per year at 150 mg bid vs 1.02%/yr warfarin). Again, note that life-threatening bleeding was lower in both dabigatran groups.
Although not in the scope of this article, the RE-COVER trial looked at dabigatran 150mg bid vs warfarin in thromboembolic disease with very similar findings (equal to warfarin, lower bleed rate).
What I do now
I now strongly consider using dabigatran instead of warfarin in patients with a CHADS score of 2 or higher (see below). The 2 doses allow a choice of efficacy vs bleeding with both doses (110mg bid vs 150 mg bid) being either much safer or somewhat safer than warfarin.
CHADS score in non-valvular Atrial Fibrillation:
1 point for: CHF, Hypertension, Age >75, Diabetes,
2 points for prior Stroke.
Suggest warfarin or dabigatran for CHADS score ≥2, Warfarin or dabigatran > ASA for CHADS score = 1, ASA for CHADS score = 0.
| CHADS score 0 1 2 3 4 6 |
Annual Stroke risk % 1.9 2.8 4 5.9 8.5 18.2 |
I feel the time savings to patients and clinicians (no monitoring required), clinical efficacy and safety vs warfarin and fewer drug interactions make this a huge innovation in clinical practice.
Although not specifically studied, given its cost, dabigatran may be a very reasonable option for patients who need a temporary refrain from testing (eg. traveling abroad). I’ve had many patients express anxiety over how they would monitor their INRs when traveling – a special challenge given costs, time constraints, lack of access to medical care and changing diet and bowel habits.
While my opinion may seem enthusiastic for a new drug based on a single trial, it should be noted that the RE-LY study is the largest ever done, encompassing more patients than all the warfarin studies to date. It will not be repeated.
In addition, a preview of the Canadian Cardiovascular Society’s new 2011 Atrial fibrillation guidelines endorses dabigatran in preference to warfarin (we await the final publication):
- Based on its safety and efficacy profile, dabigatran is preferred over warfarin. Overall, the 150-mg dose of dabigatran is preferred over the 110-mg dose (conditional recommendation, high-quality evidence).
- For patients at low risk of stroke (CHADS2 score=1), treatment should include either warfarin or dabigatran (strong recommendation, high-quality evidence). However, based on individual risk/benefit considerations, aspirin is a reasonable alternative (conditional recommendation, moderate-quality evidence).
- For patients at moderate to high risk of stroke (CHADS2>2), treatment should include either warfarin or dabigatran (strong recommendation, high-quality evidence).
Dabigatran just received approval for use in Canada for atrial fibrillation at the end of October 2010. The monthly cost will be around $100 at either dose (not currently covered by Pharmacare nor via special authority).
References: (Note: Article requests require a login ID with UBC)
- RE-LY trial (dabigatran in AFib). N Engl J Med 2009;361. (10.1056/NEJMoa0905561) (View article with UBC or http://www.nejm.org/doi/pdf/10.1056/NEJMoa0905561)
- RE-COVER trial (dabigatran in PE & DVT). N Engl J Med 2009;361.(10.1056/NEJMoa0906598) (View article with UBC or http://www.nejm.org/doi/pdf/10.1056/NEJMoa0906598)
- CCS guideline preview: http://www.theheart.org/article/1141079.do
- Dabigatran cost-effectiveness: http://www.theheart.org/article/1142417.do
CHADS score:
Article request form with CPSBC Library: https://www.cpsbc.ca/library/library-article-requests
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Until the cost is less or covered by Pharmacare I will only be able to realistically offer this to a small number of my patients. One hundred dollars a month will be an unsupportable financial burden for most.
Sure, dabigatran will change my practice too, once the archaic and medieval government Blue Cross plans start to cover it. Nobody in my practice will pay >$100/month for it. PERIOD. Right now, I still have to get special authorization for Flomax, Proscar and Andriol. I will be dead and in my grave before Blue Cross covers dabigatran.
This will certainly change my practice.
If he can afford $100/month, who would not prefer it?
I would have liked a few more details in the review, such as are INRs required at initiation of therapy, or periodically?
This is an excellent alternative to Warfarin. The problem with monitoring INRs for snowbirds has been quite difficult. Many of these travellers will be willing to pay for dabigratrin. It will definitely be a challenge for those patients who are tied to “Unfair Pharmacare” and who don’t have an extra $1200 around.
Article is very interesting but cost will prohibit use in a majority of my patients. I would also like to know if INR’s ever have to be done, how would one start the medication and what ARE the drug interactions to be careful of? Thanks!
A simple anticoagulation treatment such as dabigatran is something we’ve all been waiting for. Warfarin costs $15 a month and dabigatran is $100, but what is the real cost to the patient when he or she must go to the lab 2 or three times a month for INR checks. Warfarin is also the grand champion for interacting with other drugs. All that said, as a FP I’ll likely move to the new treatment slowly, for those who can afford it, for fear of after market side effects. Of note, my one patient on this treatment, started by his cardiologist, got the drug approved by his extended drug plan!
Thanks for all the comments.
Cost is obviously an issue with all new drugs: in my experience, almost every new agent these days comes in around $3 per day. Whether or not they are worth it is obviously a very personal decision between you & your patient.
Although $100/month seems steep — before the drug was approved for A fib, its monthly cost was a whopping $260 – $520 per month if used BID for A fib! “Back then” the pills were sized and priced for once daily usage in post op patients.
As with Dr. Edworthy’s experience, I started it on a few patients particularly at risk of consequences of bleeding (one is a Jehovah’s witness who had a recent stroke with A Fib) and another spends 1/3 of their time travelling. Both were covered by their private health plans (at the high price before approval!).
My other portfolio at UBC is the Director of Clinical Practice Reviews — this is a new initiative where the BC Ministry of Health is directly seeking (and paying for) direct physician input (specialist and GP) on all new drugs to the Pharmacare formulary. If you’re interested in joining our panel of reviewers, please email me at doc@stevewongmd.com
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More info on the drug’s actions:
1. In terms of monitoring: there is none required. INRs, PTTs are VARIABLY and UNRELIABLY affected by the drug, so these won’t be useful. There are tests to measure directly the thrombin activity (Ecarin clotting time (ECT)), but these aren’t available widely. The Thrombin Time (TT) is may be overly sensitive to dabigatran.
2. It reaches anticoagulant activity (Cmax) within 2 hours, with a half life about 11-17h (thus BID dosing for Afib and DVT), steady state in 2-3 days.
3. Renal failure or Cr clearance <30: consider lowering the dose or use the lower 110mg bid regimine
4. Drug interactions: from the safety notes at the RE-LY investigator website (https://www.rely-trial.com/RELYWeb/resources/jsp/emergency/dabigatran_bg.jsp:)
Concomitant use of aspirin, and presumably other platelet inhibitors, significantly increase the risk of bleeding with dabigatran.
Results of specific drug interaction studies with selected drugs that inhibit different cytochromes P-450 revealed that dabigatran should not alter the metabolism of drugs being substrates of the major CYP isoenzymes CYP2C9 and 3A4, and of the drug efflux transporter P-gp. Dabigatran is not metabolized by and does not induce or inhibit cytochrome P-450 drug metabolizing enzymes and is moderately bound (25-35%) to plasma proteins.
There are no known food interactions. When dabigatran is taken with food, the time to peak plasma concentrations is delayed.
This morning, theheart.org has a great Q&A with an expert in the field. I think answers most of the questions people may have:
http://www.theheart.org/article/1142899.do
Cost-effective Stroke Prevention Through New Drug…
”Dabigatran is the first new drug in 20 years to be approved for stroke prevention in atrial fibrillation, and we wanted to see if it could be cost-effective even before it made its debut in the United States,” stated cardiac electrophysiol…
I would also love to make this change, but the pharmacies in my area are still quoting about $250+/month as direct cost to the patient.
This is just unrealistic for most, if not all, of my patients.
Good clear opinion and assessment of dabigatran, and review of CHADS2 scoring. For those who can afford it, it is an ideal option. Perhaps the overall cost savings will some time be apparent to Pharmacare. I wonder too if it could prevent recurrant PE in patients with malignancies where warfarin is ineffective, saving those patients daily injections.
I am concerned with the higher rates of GI bleeding and heart attacks compared to warfarin. Hardly seems worth the cost. And the problems with reversibility of anticoagulation as compared to warfarin (Vit K, if needed).
To whom it may concern,
I am disappointed with the presentation of drug sponsored trials with what appears to be articles written by the pharma firms themselves. Dr. Wong’s review of the RE-LY trial is a glaring example of bias reporting. To use the relative risk reductions for this is grossly inflating the benefits if this very very expensive drug. The use of bold wording of superior and not reporting the absolute risk reductions is also misleading. It is a classic pharma marketing tool and puts into question Dr. Wong’s unbiased appraisal. I also have trouble relying (pun intended) on the opinions of individuals with multiple relationships to the pharmaceutical industry as Dr. Wong has acknowledged. It is very apparent that the pharmaceutical industry cannot be trusted in the dissemination of information regarding their products. The criminal activity surrounding the false promotion of gabapentin is a perfect example of how the industry uses vehicles such as this to influence the behavior of physicians.
A more accurate description of the RE-LY trial would be as follows:
RE-LY demonstrated that dabigatran 110 mg bid was noninferior to warfarin (absolute risk reduction 0.16% per year, relative risk (RR) 0.91 (CI 0.74-1.11)) and had a 3.53% reduction in total bleeding (18.15% vs 14.62% RR 0.78, p <0.001) and a 0.58% absolute reduction (1.80% vs 1.22%) 32% relative reduction) in life-threatening bleeding (RR 0.68, P <0.001). At 150mg BID, dabigatran was superior to warfarin, achieving a 0.58% absolute reduction in the primary endpoint of stroke or systemic embolism (RR 0.66, NNT 200, p<0.001) or 65 additional out of 12,098 patients. There was no difference in the clinically significant end point of disabling, (rankin score of 3 or more) or fatal stroke. At the 150 mg bid dose, dabigatran was associated with a 1.73% absolute reduction in total bleeding ( 18.15% v 16.42% RR 0.91, p=0.002) and a 0.35% absolute reduction (19% relative reduction (RR 0.81, P=0.037) in life-threatening bleeding. The RE-LY website states that there is no antidote for Dabigatran overdose. Cost implications Warfarin 5 mg daily for one year $80.00, Dabigatran 150 mg bid for one year $1500.00. Absolute cost increase $1420, Relative cost increase 1900%!
So my take is that Dabigatran seems to provide the same or a very very tiny increased benefit in preventing strokes in AF patients with nearly the same rate of significant bleeding. Its advantage is that there is no testing, and so far minimal interacts as compared to warfarin but it comes with a big price tag and no easy means to reverse its effects in an overdose situation.
Sincerely Dr. Drew Digney
Nanaimo
One of the limitations (by design) of This Changed My Practice postings is their short length: indeed, the full discussion and final decision about a novel agent (especially an expensive one) requires much more space than the usual article length here. That said, I hope even dissenting opinions help drive learning, no matter which side the reader agrees with.
To clarify conflicts of interest, I stress that all of my disclosures relate to speaking at accredited and nonaccredited CMEs regarding hypertension, diabetes, lipids and renal disease. I have not received honoraria for CMEs directly related to dabigatran as of the time of this posting. UBC CME has not received any pharma funding for any aspect of This Changed My Practice.
One objection is the trial is paid for by the manufacturer. Unfortunately, this is the reality of megatrials and in general, the publicly funded trials (eg NIH-funded) happen typically ~10+ years after a drug is on the market, and drugs won’t get regulatory approval without a large trial beforehand. Yes, there have been many recent examples of issues in the regulatory process and whether or not an individual physician chooses to disregard large trials due to funding source is again a personal decision. We should balance these issues with careful inspection, as Dr. Digney has.
I definitely agree with Dr. Digney that the absolute risk reductions are small (this is reflected in my original post as an NNT of 200, but I acknowledge I could have also added the absolute risk reduction — in my own mind these are directly calculated from each other (NNT = 1/ARR x 100) thus I personally self-convert to NNTs). Since the 110 mg bid dose is not statistically better, I personally don’t calculate or consider NNTs when not statistically significant.
I also agree that the absolute reductions in bleeding rates would have been useful, and I agree with your amplification of these to understand the ‘net benefit’ of this new agent.
I do feel this drug will be a practice changer regardless of the cost: this is the first time any oral drug has been as good as warfarin (if not a little bit better) with less (or similar) bleeding rates and no monitoring required. The biggest objection to this drug is predictably cost, and the final decision as to whether or not it is worth it is (as I stated) a very personal decision.
We should also keep in mind that, in the context of a clinical trial, the control arm typically gets better care than in the ‘real world’: in this study, the warfarin patients were in the therapeutic window 64% of the time (which is in line with other warfarin trials, and generally better than real-world control levels).
Recent studies suggest that:
1. Patients seem to do best if INRs are maintained in the therapeutic window > 68% of the time (Intern Med. 2010;49(16):1711-6. Epub 2010 Aug 13.)
2. In ‘real world’ practice, INRs are maintained in the therapeutic range < 50% – 55% of the time (Adv Ther. 2010 Sep;27(9):623-33. Epub 2010 Jul 30.)(J Am Geriatr Soc. 2010 Aug;58(8):1475-80. doi: 10.1111/j.1532-5415.2010.02967.x. Epub 2010 Jul 19.)
The Cost-effectiveness analysis:
http://www.annals.org/content/early/2010/11/01/0003-4819-154-1-201101040-00289.full
The cost analysis is funded by the American Heart Association and Veterans Affairs Health Services Research & Development Service. See their conclusions (editors notes copied below).
I realize drug cost is a huge consideration for any therapy, but there are other costs: some of which are directly borne by the patient (time to go to the lab, blood testing discomfort, side/under effects of under or over dosing) and others are borne by the system and physicians (lab costs, physician time & liability, payments for adjusting INRs, hospitalizations for side/under effects of under or over dosing), etc. The challenges of maintaining INRs in the therapeutic window (thus achieving the studied risk reductions) are outlined above.
I am certainly not qualified to make a global cost assessment, thus would depend on others' ability to do this.
Although this is a US $ analysis, this cost effectiveness analysis suggests dabigatran could be cost effective below a drug cost of $9.36/d (110 bid) and $13.70/d (150 bid). This is considerably higher than the established BC cost of around $3.50 /day at either dose.
——— (from the Annals cost analysis) —–
Editors' Notes
Context
* Dabigatran is a direct thrombin inhibitor shown to be about as safe and effective as warfarin for preventing thromboembolism in patients aged ≥65 years with nonvalvular atrial fibrillation.
Contribution
* This analysis suggests that dabigatran is also generally cost-effective as an alternative to warfarin. Treatment seems to become less cost-effective when daily costs exceed $9.36 for low-dose therapy and $13.70 for high-dose therapy.
Caution
* Much of the analysis relies on data from the single available manufacturer-sponsored study of dabigatran.
Implication
* Dabigatran could be a cost-effective alternative to warfarin for treating atrial fibrillation depending on how it is priced.
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Finally, dabigatran is addressed in the guidelines from the Canadian Cardiovascular Society (now available on the website) and the European Society of Cardiology (ESC). These are cited below, with quotes pulled from their documents. I would leave it to the reader to decide if these guideline groups are unduly influenced by industry.
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The current Canadian Cardiovascular Society guideline executive summary for AF has just been posted on their site (the full guideline is in press currently):
http://www.ccsguidelineprograms.ca/index.php?option=com_content&view=category&id=50%3Aafib-guidelines&Itemid=59
Chapter 5: Prevention of Stroke and Systemic Embolization in Atrial Fibrillation and Flutter
On Page 16 of the summary, item 5, they do state:
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5. We suggest, that when OAC therapy is indicated, most patients should receive dabigatran in preference to warfarin. In general, the dose of dabigatran 150 mg po bid is preferable to a dose of 110 mg po bid (exceptions discussed in text). (Conditional Recommendation, High Quality Evidence)
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Another interesting point is on page 18:
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10.We suggest that patients with AF or AFL who have stable CAD should receive antithrombotic therapy selected based upon their risk of stroke (aspirin for CHADS2 = 0 and OAC for CHADS2 ≥ 1). Warfarin is preferred over dabigatran for those at high risk of coronary events. (Conditional Recommendation, Moderate Quality Evidence).
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The ESC has also released their AF guidelines:
http://eurheartj.oxfordjournals.org/content/early/2010/08/28/eurheartj.ehq278.full.pdf+html
While they are not specifically recommending dabigatran over warfarin, they do state:
Page 16, in the text below the table:
(a) Where oral anticoagulation is appropriate therapy, dabigatran may be considered, as an alternative to adjusted dose VKA therapy. (i) If a patient is at low risk of bleeding (e.g. HAS-BLED score of 0–2; see Table 10 for HAS-BLED score definition), dabigatran 150 mg b.i.d. may be considered, in view of the improved efficacy in the prevention of stroke and systemic embolism (but lower rates of intracranial haemorrhage and similar rates of major bleeding events, when compared with warfarin); and (ii) If a patient has a measurable risk of bleeding (e.g. HAS-BLED score of ≥3), dabigatran etexilate 110 mg b.i.d. may be considered, in view of a similar efficacy in the prevention of stroke and systemic embolism (but lower rates of intracranial haemorrhage and of major bleeding compared with VKA). (b) In patients with one ‘clinically relevant non-major’ stroke risk factor, dabigatran 110 mg b.i.d. may be considered, in view of a similar efficacy with VKA in the prevention of stroke and systemic embolism but lower rates of intracranial haemorrhage and major bleeding compared with the VKA and (probably) aspirin.
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I hope your points and the discussion above from all of the commenters helps people in their learning.
I hope people continue to vote and comment.
– Steve Wong
I have read all the discussion with interest. But if any of my patients CAN afford this, how soon do they need to stop it before some surgeries when they will be required to go on LMW Heparin OR do they need to stop it??
Also, if Pharmacare and MSP consider the cost of laboratory INR payments, payments to physicians for monitoring INR’s and the cost of hospitalizations for drug interactions and other Warfarin complications, I suspect we will see this covered by Pharmacare in years to come.
The problem for anesthesia and surgery is not the handiness of dabigatran’s lack need for monitoring, but the very fact that it is difficult to monitor at all. The test is not widely available and I understand the drug is not reversible as warfarin is. Guess what, in this cohort of patients, falls and fractures and broken hips are very common as are bowel obstructions and other unplanned trips to the OR. So we cannot reverse the drug and in fact have no idea what its level of activity is. Obviously this is not going to serve patients well who need urgent operative treatment. This is similar to the situation with drug eluting stents which require an entire year’s worth of Plavix and ASA (maybe longer, the jury is still out). If these agents are withdrawn pre-operatively and the individual has a re-occlusion of the stent (particularly intra-operatively) the only option is a fast trip to an interventional cath lab which of course is not available in most areas of this province (fibrinolytics are not an option, we are doing surgery, right?). Typically, the cardiovascular drug industry and the cardiologists that push these items have paid no attention to these very common issues. Come spend a night on call in most operating rooms in this province.
Thank you for your fantastic overview of this new drug, along with the other supporting citations and research. The “dirty” aspects of warfarin prescribing and management are what makes dabigatran so much more attractive, despite the costs. I don’t know how many hours I’ve spent over the years contacting patients with INR results, or worse, the anxious efforts to contact patients with critically high INRs, always late on Friday afternoons, it seems. Or the late night ER visits treating warfarin nose or GI bleeds. It is these ‘real-world’ unintentional warfarin overdoses (caused by alcohol, NSAIDs, diet) that I find so hard about prescribing warfarin. The ordinary people who live outside the contexts of clinical trials, who don’t read the safety literature about diet and drug interactions, are those who will benefit most from a simplified, cleaner drug. This drug does deserve to get Pharmacare coverage. It is not a ‘me too’ drug with marginal or questionable benefit over presently available, cheaper options.
And no, I don’t hold stock or have received financial support from the company. Just a rural GP.
The M.I. results of RE-LY were 0.53%, 0.72% and 0.74% for placebo, Dabigatran 110 mgs and 150 mgs respectively. This seems like a potential problem over an extended period of time. The Medical Letter called this a “slightly higher risk”.
As usual, a thorough and useful review by Dr. Wong.
I too am very skeptical when it comes to new drugs. However, there are many drugs (PPIs come to mind) that are relatively expensive and yet commonly used.
I take this study to show me that it’s ever so slightly better than warfarin, for bleeding and for stroke prevention.
Is it worth the cost to move to a new drug? Well, I hate seeing patients with high INRs told to come to the ED; bleeding events from an INR gone haywire; and I can’t imagine patients are too happy to get poked, chase blood test results, and watch their diets. If this drug makes the big time, then I won’t fight the ‘too expensive’ fight. I am too happy to see warfarin go away.
Many problems arise with the handling of anesthesia, or the surgical procedure us is right, I as cardiologist who must handle DEBIGRATAN a supervised manner, as can not be controlled by 100 percent, have not by example in Nicaragua where I live of on this product, remember that the damage is irreversible, as in the case of the management of warfarins, patients have many relapses mainly adult, some believe in full management of aspirin, I think more well the PLAVIX is better, handles emergency and many hip fractures, bowel problems, ie we must handle extreme operating room planning, we must be very clear about this drug I personally prefer to read a bit more and handle much observation, I have a bad experience at least in america center with sales representatives in our countries usually give many gifts, with one ide drive your product, where the ethics of such damages would not recommend an emergency with fibrinolytic in areas with small hospitals
Martin Casco Vargas MD PhD