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Effective Event Reduction in the Era of New Oral Anticoagulants: Pursuing Options

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PRIORITY PRESS - 65th Annual Meeting of the Canadian Cardiovascular Society

Toronto, Ontario / October 27-31, 2012

Toronto - After 50 years of warfarin use for stroke prevention in atrial fibrillation (AF), there are now 3 new oral anticoagulants equal to, or better than warfarin for stroke prevention. Importantly, they are safer than warfarin in terms of major bleeding, especially intracranial hemorrhage, possibly the most feared side effect of anticoagulation. Speakers here summarized pivotal trial data for the 3 novel oral anticoagulants for stroke prevention in AF and addressed a potentially new use for one of these agents in acute coronary syndromes as the trial showed a mortality benefit when added to standard antiplatelet therapy.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

In a review of the new oral anticoagulant pivotal trials, Dr. Manesh Patel, Associate Professor of Medicine and Assistant Professor of Cardiology, Duke University, Durham, North Carolina, summarized key findings supporting the use of the new oral anticoagulants in the setting of non-valvular atrial fibrillation (AF) for stroke prevention.

Review of Landmark Anticoagulant Trials

The first trial reviewed was RE-LY (Randomised Evaluation of Long Term Anticoagulant Therapy), in which 2 doses of the direct thrombin inhibitor dabigatran were tested against warfarin in over 18,000 patients with AF and risk for stroke (N Engl J Med 2009;361:1139-51). The mean CHADS2 score in RE-LY was 2.1.

At a median duration of 2 years, the event of stroke or systemic embolism was 1.53% per year with dabigatran 110 mg b.i.d. and 1.69% in the warfarin arm, demonstrating non-inferiority of the direct thrombin inhibitor. At the150 mg b.i.d. dose, the primary end point was reduced to 1.11% per year compared to warfarin, having achieved statistical significance at P<0.001. Total and major bleeds were lower with the 110 mg dose but were comparable to warfarin at the 150 mg dose. Life-threatening and intracranial bleeds were lower with both doses of dabigatran.

The ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism trial in Atrial Fibrillation) compared the factor Xa inhibitor rivaroxaban 20 mg once daily vs. warfarin, in over 14,000 AF patients at moderate to high risk for stroke (N Engl J Med 2011;365:883-91). “The majority of patients (87%) had a CHADS score ≥3 and for those with a creatinine clearance of 30 to 49 mL/min, the rivaroxaban dose was reduced to 15 mg/day,” Dr. Patel observed. The primary end point was also stroke or non-CNS embolism.

On-treatment analysis showed statistically lower yearly rate of stroke and systemic embolism for rivaroxaban at 1.7% vs. 2.15% for warfarin. Rates of critical organ bleeding, fatal bleeding and ICH were lower with the factor Xa inhibitor than with warfarin, Dr. Patel reported. Investigators again concluded that in AF patients at high risk of stroke, rivaroxaban was non-inferior to warfarin at preventing stroke and systemic embolic events without increasing the risk of major bleeding.

Over half of patients in ROCKET-AF also had a prior stroke or transient ischemic attack (TIA). While the event rate was higher than those without a prior stroke or TIA, rivaroxaban effectively reduced the primary end point relative to warfarin, as Dr. Patel pointed out.

In a subgroup analysis, the overall event rate was relatively higher in patients with reduced renal function compared to those with preserved renal function. “Results with our 15 mg dose of rivaroxaban were similar to the overall trial results which gives us a measure of comfort as we randomize these patients to this dose,” Dr. Patel added. Similarly, 43% of the ROCKET-AF population was also ≥75 years of age; here again, events in the Xa inhibitor arm were reduced by at least the same order of magnitude as was seen across the entire cohort and bleeding risk was also similar.

In ARISTOTLE (Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation), over 18,000 patients with AF and at least 1 additional risk factor for stroke (similar to the RE-LY trial, with a mean CHADS2 score of 2.1) were randomized to apixaban 5 mg b.i.d., also a factor Xa inhibitor, or to warfarin (N Engl J Med 2011;365:981-92). The primary end point was also stroke or systemic embolism. At a median treatment duration of 1.8 years, the factor Xa inhibitor reduced the event rate to 1.27% per year compared to 1.60% per year for warfarin (P<0.001 on ITT analysis).

Total mortality rate for apixaban was 3.52% per year vs. 3.94% per year. Major bleeding rates were also significantly lower for the factor Xa inhibitor group at 2.13% per year compared with 3.09% per year for patients on warfarin (P<0.001). Rates of both hemorrhagic stroke and ICH were also significantly lower with apixaban than with warfarin. Investigators concluded that in AF patients at increased risk of stroke, this agent is superior to warfarin in preventing stroke or systemic embolism and caused less bleeding.

According to Dr. Patel, patients with AF are seen in cardiovascular (CV), primary care, as well as family practices, and up to 30% are not getting any anticoagulant therapy at all. “Once you decide to treat these patients, the novel oral anticoagulants have several advantages over warfarin in that they reduce ICH [and] fatal bleeds, and they are at least as good if not better than warfarin,” he remarked.

Acute Coronary Syndromes

As discussed by Dr. Robert Welsh, Associate Professor of Medicine, University of Alberta, Edmonton, the management of acute coronary syndromes (ACS) has improved significantly in recent years. The introduction of both percutaneous coronary intervention (PCI) and new potent antiplatelets including prasugrel and ticagrelor resulted in reductions in morbidity and mortality. Nevertheless, the risk of recurrent ischemic events is still high at 30 days post ACS.

New therapeutic and long-term strategies are being explored to further reduce recurrent ischemic events. For example, in the ATLAS ACS 2-TIMI 51 phase III study, investigators randomized over 15,000 patients with recent ACS to rivaroxaban 2.5 mg b.i.d., 5 mg b.i.d. or placebo on a background of ASA therapy and a thienopyridine (clopidogrel or ticlopidine)  (N Engl J Med 2012;366:9-19).

Overall, both doses of rivaroxaban reduced the 2-year composite end point of CV death, myocardial infarction (MI) or stroke to 8.9% compared with 10.7% for placebo (modified ITT P=0.008). “With the very-low dose of rivaroxaban (2.5 mg b.i.d.), you see a consistent benefit for each of the components of the combined end point as well,” Dr. Welsh noted.

Indeed, very low dose Xa inhibition significantly reduced CV death and all-cause mortality to 2.7% and 2.9% vs. 4.1% and 4.5% for placebo (mITT P=0.002 for both end points). Stent thrombosis was similarly reduced by both doses of the Xa inhibitor to 2.3% at 2 years from 2.9% for placebo (mITT P=0.02), Dr. Welsh observed.

The rivaroxaban 5 mg b.i.d. dose was associated with a slightly higher risk of fatal bleeds (0.4%) compared with placebo (0.2%) but was lower with the 2.5 mg b.i.d. dose (0.1%). ICH rates were 0.2%, 0.4% and 0.7% for placebo, 2.5 mg and the 5 mg b.i.d. doses respectively. Fatal ICH rates were the same for placebo and the 2.5 mg b.i.d. dose (0.1%) vs. 0.2% for the 5 mg b.i.d. dose. Rates of major bleeds and ICH were higher with rivaroxaban but without excess risk of fatal bleeds.

Treatment Option in the ACS Setting

As Dr. Welsh reminded delegates, prasugrel was approved in 2010 for the treatment of ACS patients scheduled for PCI based on results from TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38). In this study, prasugrel significantly reduced ischemic event rates compared with clopidogrel, although with an increased risk of major bleeding including fatal bleeding, without any difference in overall mortality between the 2 treatment arms (N Engl J Med 2007;357:2001-15).

Ticagrelor was similarly approved for the treatment of ACS in 2011, based on findings from PLATO (Platelet Inhibition and Patient Outcomes), where it was shown that ticagrelor was significantly superior to clopidogrel for the primary composite end point as well as a 16% relative risk reduction in all-cause mortality (N Engl J Med 2009;361:1045-57).

“I think that the very low dose of rivaroxaban is an attractive option because the mortality reduction in this group of patients,” Dr. Welsh told delegates. “We now need to ask ourselves if a program of systematic downtitration of antiplatelets (notably ASA) could sustain the benefits of very low dose rivaroxaban on mortality post-ACS but enhance safety outcomes.”   

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