The mediKOL brief – will dabigatran replace warfarin?

Simon Smyth

mediKOL

Nobody likes warfarin – the unmet need is high

Warfarin is used to prevent strokes in patients with atrial fibrillation. It is the most effective medication approved for this indication, however, for many well documented reasons, patients do not like taking it and physicians do not like prescribing it. Reasons include:

• Multiple drug and dietary interactions,

• The risk of haemorrhage,

• Inconvenience of monitoring the international normalised ratio (INR),

• Large inter and intra-patient variability,

• Concerns about real-world effectiveness.

As such, it is estimated that warfarin is only prescribed to approximately two thirds of appropriate candidates, a significant proportion of whom are unhappy or unstable on it. The remaining patients are offered the much more convenient, but much less efficacious, aspirin.

"Patients do not like taking warfarin and physicians do not like prescribing it"

In addition to patients and physicians, payors also have issues with warfarin – it may be cheap to buy, but the associated monitoring requirements are very inconvenient and demand a costly infrastructure. The need for a safer, better tolerated and more convenient anticoagulant therefore is abundantly clear. 

Many products are vying to replace warfarin

With such a high unmet need it is no surprise that a large number of compounds are in development for this indication (fig 1). Of the emerging oral anticoagulants, Boehringer Ingelheim’s direct thrombin inhibitor dabigatran is leading the way.

While it is already available in many countries, including the EU and Canada, for preventing venous thromboembolism (VTE) in patients undergoing total hip replacement or total knee replacement surgery, replacing warfarin as the treatment of choice for stroke prevention in atrial fibrillation (SPAF) is the most sought after indication.

"A large number of compounds are in development all seeking to replace warfarin"

Prevention of VTE is an acute indication where patients are treated for between 10 and 30 days, in contrast, prevention of stroke in AF patients requires life-long, chronic therapy.

Dabigatran likely to be first

Dabigatran has the potential to become the first new treatment approved for stroke prevention in atrial fibrillation patients for decades. Very positive results from the phase III RE-LY trial, recently presented at the European Society of Cardiology conference, should help it achieve that goal.

Deservedly, much has been written about this trial and what it means, and most cardiologists are of the opinion that the drug’s performance exceeded all expectations – the phrases ‘breakthrough’, ‘paradigm shift’ and ‘revolutionary’ have been widely used.

While a full discussion of the results is beyond the scope of this short article, the main efficacy / safety results can be summarised as follows:

• Compared to dose-adjusted warfarin, dabigatran given at a dose of 150 mg twice daily prevented more strokes, and dabigatran at a dose of 110 mg twice daily caused fewer haemorrhages. As such, the 150-mg dose appears to be more efficacious than warfarin and the 110-mg dose appears to be safer.

• The rate of myocardial infarction (MI) was significantly higher with both dabigatran doses compared to warfarin. Rates of dyspepsia (including abdominal pain) were also significantly higher with both doses of dabigatran.

"Dabigatran has exceeded expectations - results of the REL-Y trial mean it is likely to become the first new treatment approved for stroke prevention in atrial fibrillation patients for decades"

From an efficacy perspective, dabigatran has established a new benchmark that any competing product will have to match. Having said that, the GI side-effects and the propensity to increase the risk of MI over warfarin are real issues and they are likely to be seized upon by its competitors. Its twice daily dosing profile and the open label design of the RE-LY trial are further areas of weakness (table 1).

The price of dabigatran is also likely to be a significant and complicated issue. The different pricing scenarios are discussed at length in an accompanying issue of The mediKOL Brief – How will dabigatran be priced for chronic use.

What patients will dabigatran target?

The RE-LY trial enrolled patients with atrial fibrillation and one other risk factor i.e. AF patients classified as having a moderate or high risk of stroke (patients with a CHADS₂ score greater than 1). This represents approximately two thirds of all diagnosed AF patients – a significant target market.

However, certain patient populations were excluded from the trial and it is unlikely that dabigatran will be approved for these patients based on the current data. For instance, 15% of the AF patients for whom dabigatran is under consideration have severe renal failure, yet patients with severe renal failure were excluded from the RE-LY trial. KOLs have also indicated that the increased rate of MI might also restrict use to patients without coronary artery disease or a history of MI, thus further reducing the target population.

Table 2, below,  segments the diagnosed AF population into four patient sub-groups (untreated, aspirin treated, warfarin unstable/unhappy and warfarin stable), and the three standard categories of risk of stroke (low, medium and high). The number of diagnosed patients classified as medium and high risk is also indicated for the US market.

As with most pharmaceutical products, dabigatran will take time to penetrate into the market. KOLS have indicated that, alongside newly diagnosed and untreated patients, dabigatran was most likely to be used first in eligible medium and high risk patients treated with aspirin – i.e. the sub-optimally treated patients. Eligible patients unhappy with warfarin or patients badly controlled on it would be considered next.

Opinion was divided over whether or not to switch any patient stable on warfarin. Some KOLs argued that it might be unethical to restrict the use of any treatment that reduces the risk of stroke better than warfarin given the consequences of a stroke. Others wanted more data arguing that they would not switch a stable patient based on the results of only one trial.

"Dabigatran will not replace warfarin overnight, however, in certain patient segments adoption is likely to be swift"

Conclusions

The SPAF market is large and poorly served. Any product with the potential to replace warfarin will be a clinical and commercial success and the RE-LY trial has put dabigatran on that path. While it will not replace warfarin overnight, it is likely to penetrate into some segments of the market relatively quickly and benefit many patients. Potential first to market status strengthens its position further. Warfarin is a tough comparator, but the challenge for competitor products is now even tougher.

About the author:

Simon Smyth is Commercial Director at mediKOL. To contact the author about this article please email Simon at simon.smyth@medikol.co.uk

mediKOL Insight: Where next for thrombosis? Perspectives from a panel of KOLs, is now available. It provides:

• An in-depth and insightful appraisal of the current and future thrombosis market, driven principally by the opinions of the leading KOLs, who mediKOL actively challenged on the key issues in the field.

• Three future market scenarios illustrating how the thrombosis market might evolve based on future clinical and regulatory events, and underpinned by our KOL discussions.

• Individual product and market forecasts compared and contrasted with ‘consensus’ forecasts supplied under licence from EvaluatePharma®.

• The views and opinions from the leading specialists in the thrombosis field on the current and future clinical environment, distilled, analysed and presented in clear and concise commercial terms.

• A discussion of the key commercial issues relevant to the development of anti-coagulants for thromboembolic indications.

For more information on mediKOL or the mediKOL Insight series of reports please contact Andy Hagan at andy.hagan@mediKOL.co.uk or +44 7890175263.

About mediKOL – mediKOL was established in 2008 as the research arm of the consulting company groupH. mediKOL’s principal product is mediKOL Insight – a series of key opinion leader (KOL) based reports that provide high quality, ‘off-the-shelf’ commercial analysis on a range of indications. Each mediKOL report is focused on one indication and features a scenario-based analysis on the future of that indication. This is underpinned by the views and opinions of some of the world’s most respected KOLs and allied experts. Our reports are supported by market data and consensus forecasts supplied under license from EvaluatePharma®.

About groupH – groupH is a global healthcare consulting company established in 2004 with a strong track record of successfully completed commercial consulting engagements. It provides direction to companies developing or marketing innovative healthcare products. Solutions are tailored around the key challenges that organisations face when growing their business by entering new markets, launching new products or engaging in transactions that may encompass acquisition or licensing. The scope of its work is global and covers all disease areas. For further information on groupH please email info@grouph.co.uk or visit the website www.groupH.co.uk