Doctor's Review: Medicine on the Move

October 20, 2017

© 2013 Kevin C. Rose / Atlantaphotos.com

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Conference Proceedings: 2012 Annual Meeting of the ASH

A bloody business

The American Society of Hematology (ASH) meeting has always been two conferences in one. There’s the oncologists' ASH, focussing on leukemia, myeloma and lymphoma. And there's the non-cancer ASH, covering a smorgasbord of conditions such as erythropoiesis, iron metabolism, thalassemia and sickle cell disease, granulocytes, HIV and immunodeficiency, vascular biology, transfusion, thrombosis, fibrinolysis and, of course, anticoagulation.

Much of the attention at last December’s annual meeting in Atlanta was focused on advances in the treatment of leukemias and myelomas. But the news most relevant to everyday practice concerned anticoagulation. It’s a key area at any time given how many of our lives and deaths hinge upon it, and the field is especially busy right now with several new therapies jostling to replace warfarin. Canadian research is very strong and when anticoagulants were being discussed, the Atlanta podium seemed to be Canadian-occupied territory.

Dabigatran definitely safer

Few new drugs have excited as much interest or raised as many questions from practitioners as the direct oral thrombin inhibitor dabigatran (Pradaxa). There have been concerns about the lack of a reversal agent that can be applied in the event of bleeding.

But research presented at ASH found that 30-day outcomes after major bleeding while on dabigatran are actually somewhat better than in bleeds which occur while taking warfarin.1 Led by Dr Sam Schulman of McMaster University, the study examined severity and outcomes among 27,419 patients, most from the landmark RE-LY study, which had already demonstrated a lower frequency of bleeding on dabigatran than on warfarin.

After a first major bleed, 30-day mortality was 9% among dabigatran patients and 13 % among warfarin patients. Patients in the warfarin group were more likely to be treated with surgery (14% versus 10.7%) and spent more time on average in intensive care (3.2 versus 1.9 days).

Dabigatran has a much shorter half-life than warfarin, Dr Schulman noted, reducing the need for an antidote. "If the drug is stopped and the blood is replaced, bleeding on dabigatran seems to be manageable... doctors need to see these data to be reassured that this drug is not dangerous."

But he still believes an antidote is desirable, particularly for dabigatran overdose, or for very elevated serum concentrations following sudden renal failure. Dabigatran's maker, Boehringer Ingelheim, currently has a monoclonal antibody reversal agent in phase I trials.

Dr Schulman also presented an extended follow-up of the RE-SONATE study at the last ASH. RE-SONATE compared dabigatran to placebo as extended maintenance therapy to prevent recurrences of venous thromboembolism in patients who had already taken 6 to 18 months of a vitamin K antagonist such as warfarin. The follow-up data showed how patients fared in the 12 months following discontinuation of dabigatran (or placebo). The new anticoagulant's huge advantage over placebo during treatment (hazard ratio for symptomatic VTE or death 0.08, P = < 0.0001) began to slowly fade upon discontinuation. At 40 days post-discontinuation, cumulative cases of death or symptomatic VTE were 2% on dabigatran and 5.7% on placebo (p=0.0005). At one year, the cumulative rate was 7.8% in the dabigatran group vs 11.6% in the placebo group (p=0.02). Given the relatively high risk even in the dabigatran group a year after discontinuation, the authors argue that these results really show a need for a longer duration of anticoagulant therapy after a first VTE.

The lawyers step in

The new data may be of legal use to the drug's manufacturer. Boehringer Ingelheim is facing over 160 US lawsuits over bleeding complications. In its first two years, dabigatran has racked up $1.5 billion in sales, but has been linked to at least 542 US bleeding deaths. Of course, nobody expects such an anticoagulant to be perfectly safe, merely to have a good risk-benefit ratio, and Boehringer says it will vigorously defend its product on those grounds.

Dabigatran's major selling point has been that it avoids the need for continual monitoring of International Normalized Ratio (INR), a burden to patient and provider alike. So it came as little surprise that the new anticoagulant seems to achieve more lasting treatment compliance. A study of US military patients presented at ASH found that treatment-naive patients were more likely to stick with dabigatran than with warfarin at six months (64% vs 41%) and at one year (50% vs 24%).2 Twice as many patients switched from warfarin to dabigatran as went the other way.

New challengers

So far so good for dabigatran. But the new anticoagulant is starting to face stiffer competition than that offered by warfarin, a 58-year-old drug that most experts agree would never win approval in today's regulatory environment. The FXa (activated Factor X) inhibitors rivaroxaban (Xarelto) and the just-approved apixaban (Eliquis) have also demonstrated greater safety than warfarin.

The international AMPLIFY-EXT study3, presented by Dr Giancarlo Agnelli of the University of Perugia, showed that apixaban given for one year sharply reduced recurrent VTE and pulmonary embolism risk. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 8.8% of the placebo arm, and 1.7% of the 2.5 mg apixaban arm. The researchers concluded, apixaban is “effective, safe, and simple to use.” The number needed to treat (NNT) to prevent one VTE recurrence was 14. The NNT to cause one major or clinically-relevant bleed was 200.

Meanwhile, rivaroxaban clearly outperformed low-molecular-weight heparin (LMWH) in preventing VTE after major orthopedic surgery, said Dr Alexander Turpie, Emeritus Professor at McMaster University, who presented two international studies, the phase III RECORD and the phase IV XAMOS.

RECORD evaluated rivaroxaban in over 12,000 patients undergoing hip and knee replacement surgery. “Rivaroxaban, compared with (the LMWH) enoxaparin, reduced the risk of VTE by about 50%. This was a very large reduction without a significant increase in major bleeding complication rates,” said Dr Turpie.

XAMOS compared rivaroxaban to “standard of care” in 17,701 patients at 252 different centres in 37 countries.4 “The data show that the results from the RECORD study can be applied to routine clinical practice,” said Dr Turpie. Other studies presented at ASH showed how both rivaroxaban outperformed enoxaparin and warfarin in acute VTE and PE.5

Rivaroxaban had a good conference in many ways. This was partly because its original phase III trial, in atrial fibrillation, was in a population so burdened with comorbidities that its benefit was somewhat masked. This generated lower expectations that are now routinely being surpassed in post-marketing trials.

Attendees also heard mostly enthusiastic reports from European doctors who have longer experience with rivaroxaban. "Patients in real-world major orthopedic surgery benefit from VTE prophylaxis with rivaroxaban even more than was expected from phase III trial results," Dr Jan Beyer-Westendorf of Dresden University Hospital told the conference. Post-surgical VTEs at his hospital fell to 2.4% after rivaroxaban became their gold standard compared to 5.5% with fondaparinux and 3.9% with LMWH. Major bleeds were seen in 7.4% of patients during the rivaroxaban period, compared to 11.1% with fondaparinux and 14.9% with LMWH. Time to discharge was also cut.

From hair to feet

Dresden now has a Novel Anticoagulants Registry to track the real-world performance of dabigatran and rivaroxaban. This has already brought to light one uncommon side effect of these therapies: hair loss. Both dabigatran and rivaroxaban appear to cause new-onset hair loss in about 1% of patients.6 Apixaban was not being used, but it would hardly be surprising if it did the same — warfarin and heparin are already associated with hair loss.

Finally, the humble compression stocking took a beating at ASH in yet another Canadian-led study. Dr Susan R. Kahn from McGill University led a study that mailed truly compressive and “placebo” stockings to 806 patients after a first episode of proximal deep vein thrombosis (DVT). After 2 years of frequent wear, the rate of post-thrombotic syndrome (PTS) was no better with the real stockings (14.8%) than with the fakes (12.3%).7

This contradicts previous research, but does so with stronger data. "The benefits of ECS to prevent PTS reported in two previous smaller, single-centre studies could be due, at least in part, to bias from their open-label design," Dr Kahn told ASH 2012. But she added that stockings may still have a role in managing venous symptoms such as leg swelling and heaviness after DVT.

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