Abstract
Several key reports from the American Heart Association meeting, held in Orlando (FL, USA) in November 2011, are presented related to anti-thrombotic therapy in acute coronary syndrome and the use of dronedarone in permanent atrial fibrillation is discussed in this brief (and selective) overview of this meeting. A summary of the ATLAS-TIMI-51, TRACER and PALLAS trials is provided.
Even considering the great advances in the management of cardiovascular disorders, conditions associated with thrombosis or thromboembolism still represent a major challenge in modern clinical cardiology. The importance of improving this field is attributable to suboptimal efficacy of the available anticoagulants, considerable risk of often devastating complications (e.g., intracranial hemorrhage) and, ultimately, to the paramount significance of the thrombotic disorders to the public health. Indeed, acute coronary syndromes (ACS) are still the leading cause of mortality and one of the main reasons for hospital admissions in the developed nations Citation[1]. Similarly, atrial fibrillation (AF) poses an epidemic-like burden to the aging population Citation[2].
During the past two decades, antiplatelet therapy has been key for the management of ACS, with dual antiplatelet therapy (aspirin plus a thienopyridine) now being standard treatment Citation[3]. Despite this, and the introduction of new potent antiplatelets (prasugrel and ticagrelor), negative thrombosis-related outcomes remain common Citation[4,5]. Thus, the utility of novel anticoagulants as an addition to antiplatelet therapy in ACS was actively explored as a new management option.
Given the impressive results from the ATHENA trial Citation[6] with an impressive reduction in cardiovascular hospitalizations (a major burden on healthcare systems in the management of AF), there was some enthusiasm for a potential beneficial effect of the antiarrhythmic drug dronedarone when tested in patients with permanent AF Citation[7].
Several key reports from the American Heart Association (AHA) meeting related to anti-thrombotic therapy in ACS, and the use of dronedarone in permanent AF are discussed in this brief (and selective) overview.
Rivaroxaban in the ATLAS ACS 2–TIMI 51
The long awaited ATLAS ACS 2–TIMI 51 trial results attracted great attention at the AHA. The aim of this double-blind, placebo-controlled trial was to assess the effectiveness and safety of the novel Factor Xa inhibitor rivaroxaban in ACS patients. The study was focused on the high-risk ACS patients, with half of them having had an ST-segment elevation myocardial infarction (MI), although subjects with a previous stroke or transient ischemic attack were excluded due to a particularly high risk of intracranial hemorrhage in previous trials Citation[8,9]. The study participants received a standard dual antiplatelet therapy (i.e., low-dose aspirin and clopidogrel [93%]) and were then randomized to one of the two twice-daily doses of rivaroxaban (2.5 mg or 5 mg twice daily [b.i.d.]) or placebo. The primary end point of rate of death from cardiovascular causes, MI and stroke was significantly lower in both rivaroxaban arms compared with placebo. While the primary end point was 10.7% of the placebo group subjects, this was reduced to 9.1% (p = 0.02) and 8.8% (p = 0.03) for the lower and the higher doses of rivaroxaban, respectively. There was also a significant reduction in both cardiovascular causes and all-cause mortality rates with the 2.5-mg b.i.d. dose only.
However, the rate of major bleeding (defined according to Thrombolysis In Myocardial Infarction criteria) that was not related to cardiac surgery was 2.1% in the rivaroxaban groups and 0.6% with placebo (p < 0.001). A similar figure was seen for intracranial hemorrhage (0.6 vs 0.2%; p = 0.009), although 80% of patients with intracranial hemorrhage died in the placebo group compared with 30% of those on rivaroxaban. In the trial patients who developed stroke, rivaroxaban was associated with less disability than placebo. There was no significant difference between the study treatments in fatal bleeding (p = 0.66), and bleeding rates were lower in the 2.5 mg b.i.d. group compared with the 5.0 mg b.i.d. group.
In summary, the ATLAS ACS 2–TIMI 51 trial was the first trial to show a mortality reduction by the addition of an anticoagulant agent to the dual antiplatelet therapy. The benefits of that treatment appear to outweigh the risk of complications, especially with the lower dose. Indeed, the 2.5 mg b.i.d. dose of rivaroxaban had a better benefit-to-risk profile, showing a reduction in overall and cardiovascular mortality and a lower bleeding risk than the 5 mg b.i.d. regimen. Thus, the addition of very low-dose anticoagulation with rivaroxaban may represent a new treatment strategy in ACS patients Citation[9].
Vorapaxar in the TRACER trial
Another trial of a novel anti-thrombotic drug, the thrombin receptor antagonist vorapaxar, in ACS patients was also presented at the AHA sessions last year. The TRACER trial studied ACS patients without ST-segment elevation Citation[10]. Most patients have been already on dual-agent antiplatelet therapy. The primary efficacy end point was a composite of death from cardiovascular causes, MI, stroke, recurrent ischemia with rehospitalization or urgent coronary revascularization. Unlike rivaroxaban in the ATLAS ACS 2–TIMI 51 trial, vorapaxar failed to demonstrate any advantages for the primary end point, but also significantly increased the risk of major bleeding, including intracranial hemorrhage. There was a significant 12% reduction in MI and a trend towards lower ischemic stroke rates. There could be an interaction between vorapaxar and thienopyridine antiplatelet agents, as vorapaxar may have a lower hazard for bleeding and efficacy trend in patients not suitable for thienopyridine therapy.
These observations open speculation on the possible utility of vorapaxar in addition to only one standard antiplatelet agent. Also, the failure of the vorapaxar could partly be associated with the choice of the targeted patient population. For example, lower risk ACS patients were targeted in the TRACER study compared with those studied in the ATLAS ACS 2–TIMI 51 trial.
Thus, a new era of secondary prevention after an ACS may be evident, with increasing attention to the balance of thrombotic versus bleeding risks with multidrug anti-thrombotic therapy. Further advances in the field are likely to be based on selecting of optimal target patient groups, as well as the individual assessment of risks of complications and the selection of optimal therapy.
Dronedarone in the PALLAS trial
Dronedarone is an antiarrhythmic drug that is moderately effective in restoring sinus rhythm and, among paroxysmal AF patients, reduces hospitalization or death Citation[6]. Dronedarone also lowers heart rate and blood pressure, and has antiadrenergic and potential ventricular antiarrhythmic effects Citation[11]. The PALLAS trial tested the hypothesis that dronedarone would reduce major vascular events in high-risk permanent AF patients (defined as patients aged >65 years with risk factors for major vascular events). After the enrollment of 3236 patients, the study was stopped early, given that the first co-primary end point (stroke, MI, systemic embolism or death from cardiovascular causes) was 2.28-fold higher in dronedarone-treated patients, and mortality was increased 2.1-fold (including a 3.26-fold increase in arrhythmia deaths). Stroke was increased 2.32-fold, while hospitalization for heart failure increased 1.81-fold. Thus, the PALLAS trial concluded that dronedarone significantly increased the rates of heart failure, stroke and death from cardiovascular causes in patients with permanent AF, and should not be used in such patients. The results of this trial have informed new prescribing recommendations for dronedarone.
Apixaban in the ADOPT trial
Medically ill patients are at risk of venous thromboembolism. The double-blind, double-dummy, placebo-controlled ADOPT trial investigated the role of extended prophylaxis with apixaban compared with short-term prophylaxis with enoxaparin Citation[12].
In this trial, 6528 acutely ill hospitalized patients who had congestive heart failure or respiratory failure or other medical disorders and at least one additional risk factor for venous thromboembolism, were randomized to apixaban 2.5 mg b.i.d. for 30 days, or enoxaparin, 40 mg once daily subcutaneously for 6–14 days. The primary efficacy outcome (30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis or asymptomatic proximal leg deep-vein thrombosis) was not significantly reduced with apixaban (2.71% vs enoxaparin 3.06%; relative risk with apixaban: 0.87; 95% CI: 0.62–1.23; p = 0.44). Major bleeding occurred in 0.47% of the apixaban group, versus 0.19% of the enoxaparin group (relative risk: 2.58; 95% CI: 1.02–7.24; p = 0.04). Thus, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin, and apixaban was associated with more major bleeding events than enoxaparin.
Expert opinion
Thrombosis is currently the focus of major clinical trials in cardiovascular disease, with exciting developments in new oral anticoagulants, particularly for stroke prevention in AF and prophylaxis or treatment of venous thromboembolism Citation[13,14]. Nonetheless, the recent trials at AHA raise yet more questions. In ATLAS–TIMI 51, rivaroxaban was administered at a dose lower than the AF thromboprophylaxis regimen, and as a twice-daily regimen. The impact of rivaroxaban in ACS, where treatment was additive to aspirin plus clopidogrel, is uncertain, given that newer and more potent alternatives to clopidogrel, such as prasugrel and ticagrelor, may become the treatment of choice. Also, despite the impressive and safe results for apixaban in its trials of stroke prevention for AF, the data in ADOPT were less impressive, as were the results of APPRAISE-2, where apixaban 5 mg b.i.d. added to aspirin plus clopidogrel (as ‘triple therapy’) did not show benefit but potentially caused harm Citation[15]. This is highly relevant since some patients with AF may present with an ACS, necessitating a period of triple therapy, prior to an anticoagulant plus a single antiplatelet drug, followed by oral anticoagulant monotherapy in patients with stable vascular disease Citation[16–18].
Financial & competing interests disclosure
GYH Lip has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, sanofi-aventis, BMS/Pfizer, Daiichi-Sankyo, Biotronik, Portola and Boehringer Ingelheim, and has been on the speakers bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim and sanofi-aventis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
- Lloyd-Jones D, Adams RJ, Brown TM et al. American Heart Association statistics committee and stroke statistics subcommittee. Executive summary: heart disease and stroke statistics – 2010 update: a report from the American Heart Association. Circulation121, 948–954 (2010).
- Lip GY, Tse HF. Management of atrial fibrillation. Lancet370, 604–618 (2007).
- Roe MT, Messenger JC, Weintraub WS et al. Treatments, trends, and outcomes of acute myocardial infarction and percutaneous coronary intervention. J. Am. Coll. Cardiol.56, 254–263 (2010).
- Wiviott SD, Braunwald E, McCabe CH et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med.357, 2001–2015 (2007).
- Wallentin L, Becker RC, Budaj A et al. PLATO investigator. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med.361, 1045–1057 (2009).
- Hohnloser SH, Crijns HJ, van Eickels M et al. ATHENA investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N. Engl. J. Med.360, 668–678 (2009).
- Connolly SJ, Camm AJ, Halperin JL et al. The PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N. Engl. J. Med.365(24), 2268–2276 (2011).
- Diener HC, Bogousslavsky J, Brass LM et al. MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet364, 331–337 (2004).
- Mega JL, Braunwald E, Wiviott SD et al. The ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med.366(1), 9–19 (2012).
- Tricoci P, Huang Z, Held C et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N. Engl. J. Med.366(1), 20–33 (2012).
- Kozlowski D, Budrejko S, Lip GYH et al. Dronedarone: an overview. Ann. Med. doi:10.3109/07853890.2011.594808 (2011) (Epub ahead of print).
- Goldhaber S, Leizorovicz, A, Kakkar AK et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N. Engl. J. Med.365(23), 2167–2177 (2011).
- Ahrens I, Lip GY, Peter K. New oral anticoagulant drugs in cardiovasculardisease. Thromb. Haemost.104, 49–60 (2010).
- Pengo V, Crippa L, Falanga A et al. Questions and answers on the use of dabigatran and perpectives on the use of other new oral anticoagulants in patients with atrial fibrillation. A consensus document of the Italian Federation of Thrombosis Centers (FCSA). Thromb. Haemost.106, 868–876 (2011).
- Alexande J, Lopes RD, James S et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N. Engl. J. Med.365(8), 699–708 (2011).
- Lip GY, Huber K, Andreotti F et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Thromb. Haemost.103, 13–28 (2010).
- Faxon DP, Eikelboom JW, Berger PB et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. Thromb. Haemost.106, 572–584 (2011).
- Huber K, Airaksinen KJ, Cuisset T, Marín F, Rubboli A, Lip GY. Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: similarities and dissimilarities between North America and Europe. Thromb. Haemost.106(4), 569–571 (2011).