Did you miss the American College of Cardiology’s 59th annual scientific session? ACC.10 is the premier cardiovascular medical meeting, bringing together cardiologists and cardiovascular specialists to further advances in cardiovascular medicine. Included are highlights from this year’s meeting, which took place in Atlanta. Phase 2 Study Showed Investigational Factor Xa Inhibitor, Betrixaban, Reduced Incidence of Bleeding Compared to Warfarin in Patients with Atrial Fibrillation Portola Pharmaceuticals and Merck announced the results of EXPLORE-Xa, a Phase 2 exploratory, dose-finding study of betrixaban, an investigational oral direct Factor Xa inhibitor. Results showed that a once-daily dose of oral betrixaban, given to patients with non-valvular atrial fibrillation or atrial flutter and at least one risk factor for stroke, reduced the incidence of major and clinically relevant non-major (CRNM) bleeds* compared to dose-adjusted warfarin. The data were presented during a late-breaking clinical trials session at the American College of Cardiology 59th annual scientific session. "Given that bleeding can be a significant safety issue for patients who take warfarin, there is a critical unmet need for anticoagulant therapy options," said U.S. national coordinator in the study, Michael Ezekowitz, MB, ChB, DPhil, vice president of the Lankenau Institute for Medical Research and professor at Jefferson Medical College. "The EXPLORE-Xa study accomplished its objective of providing important information to guide the betrixaban dosing strategy for future investigational studies." In this multinational, dose-finding study of 508 patients with non-valvular atrial fibrillation or atrial flutter and at least one risk factor for stroke, a once daily dose of betrixaban 40 mg (n=127) demonstrated significantly less major and CRNM bleeding than open-label warfarin (n=127, p=0.035). The risk of major and CRNM bleeding for the 60 mg (n=127) and 80 mg (n=127) doses of betrixaban was similar to warfarin. The Phase 2b randomized, parallel group study examined three blinded doses of betrixaban compared with open-label, dose-adjusted warfarin in 508 patients with non-valvular atrial fibrillation or atrial flutter and at least one risk factor for stroke. Patients ranged from ages 46 to 91, and a total of 87 percent previously received a vitamin K antagonist. Participants were not excluded for severe renal impairment, except those on dialysis. One hundred and twenty-seven patients were randomized to each of four treatment groups: betrixaban 40, 60 or 80 mg or open-label warfarin (INR 2-3), the current standard of care. The study was conducted in 35 centers in the U.S., Canada and Germany with a minimum follow-up of three months and a maximum of 12 months. The goal of the study was to assess the safety and tolerability of betrixaban compared to warfarin to provide information to guide further clinical development. The primary study endpoint was the time to occurrence of major or CRNM bleeding. The incidence (crude rates) of major or CRNM bleeding was 0.8 percent, 3.9 percent, 3.9 percent and 5.5 percent for the betrixaban 40 mg, 60 mg, and 80 mg and warfarin groups, respectively. The secondary endpoints included the time to occurrence of any bleeding (major, CRNM, and minimal) and the time to occurrence of death, stroke (ischemic or hemorrhagic), myocardial infarction, or other systemic embolism. The incidence (crude rates) of any bleeding was significantly lower compared to warfarin (31.5 percent) for patients taking betrixaban 40 mg (17.3 percent, p=0.011) and 80 mg (18.9 percent, p=0.022); but not those taking betrixaban 60 mg (25.2 percent, p=0.309). The number of events in the secondary composite endpoint of death, stroke, myocardial infarction or other systemic embolism ranged from 0-1 in each of the four dosing groups, which was the expected stroke/embolic event rate for the warfarin control group. There was one stroke each in the betrixaban 60 mg and 80 mg groups, and one death each in the betrixaban 40 mg and warfarin groups. There were no myocardial infarctions or other systemic emboli in any of the four dosing groups. The most common adverse events in the betrixaban groups combined (n=381) were diarrhea (6 percent versus 0.8 percent on warfarin); nausea (5.5 percent versus 1.6 percent on warfarin); constipation (5.2 percent versus 2.4 percent on warfarin); headache (5.2 percent versus 2.4 percent on warfarin); and peripheral edema (6.8 percent versus 7.9 percent on warfarin). A numerically higher percentage of patient discontinuations occurred in each of the three betrixaban groups than in the open-label warfarin group (8.7-9.4 percent vs. 6.3 percent). * Major bleeding was defined as: a fall in hemoglobin of 2g/dL or more or a transfusion of 2 units of packed cells or whole blood or bleeding at a critical site such as intracranial bleeding. RACE II Study: Atrial Fibrillation Patients Stay Healthy Even Without Strict Control of Heart Rate Contrary to current guidelines, taking a lenient approach to controlling heart rate in patients with atrial fibrillation appears to be just as good as taking a strict approach and poses no greater risk of death or other serious complications, according to research presented at the American College of Cardiology’s 59th annual scientific session. The Rate Control Efficacy in Permanent Atrial Fibrillation (RACE II) study evaluated whether therapy aimed at achieving a resting heart rate of less than 110 beats per minute in patients with atrial fibrillation was “noninferior” to therapy targeted at a resting heart rate of less than 80 beats per minute. RACE II, the first randomized trial to investigate the best level of heart rate control in patients with atrial fibrillation, found that clinical outcomes were similar with the two approaches, but lenient control was easier and less time-consuming to achieve. “Guidelines, though not evidence-based, recommend strict rate control in patients with atrial fibrillation to reduce symptoms and the risk of heart failure, bleeding and stroke, and to improve quality of life, exercise tolerance and survival,” said Isabelle C. Van Gelder, MD, a cardiology professor at the University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, and the Interuniversity Cardiology Institute Netherlands, Utrecht, The Netherlands. “Our study suggests that lenient rate control is the first-choice strategy in patients with permanent atrial fibrillation.” According to the ACC, an estimated 2.3 million people in North America have atrial fibrillation, an irregular heart rhythm that increases the risk of stroke and heart failure. Previous studies have shown that patients fare just as well when medications are used to control the heart rate, rather than trying to force the heart back into a normal rhythm. But whether maintaining a near normal heart rate (strict rate control) is necessary to keep patients healthy over the long run has been unknown. The researchers recruited 614 patients with atrial fibrillation, randomly assigning them to lenient rate control, defined as a heart rate of less than 110 bpm at rest, or to strict rate control, defined as a heart rate of less than 80 bpm at rest and less than 110 bpm during moderate exercise. To achieve the target heart rate, patients were treated with beta blockers, calcium-channel blockers, and/or digoxin. During a follow-up that ranged from two to three years, 38 patients in the lenient-control group and 43 patients in the strict-control group either died of cardiovascular causes, were hospitalized for heart failure, or experienced a stroke, a blood clot, serious bleeding or a life-threatening arrhythmia. The estimated cumulative incidence of these events at 3 years was 12.9 percent in the lenient-control group and 14.9 percent in the strict-control group. This similarity was highly statistically significant for the “noninferiority” of the lenient-control strategy. Efforts to achieve the target heart rate were more successful with lenient control than with strict control (98 percent vs. 67 percent) and required fewer visits to the doctor (75 vs. 684, with a median of 0 and 2 visits, respectively). Symptoms were comparable in the two groups. “For both patients and health care providers, lenient rate control is more convenient,” Van Gelder said. Catheter Ablation is a More Effective Treatment for Atrial Fibrillation Than Drug Therapy Using a catheter-based technique to interrupt the abnormal electrical impulses in the heart appears to be more effective than drug therapy in treating AF, according to research presented at the American College of Cardiology’s 59th annual scientific session. The Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) pilot study — one of the first to evaluate the feasibility of catheter ablation in patients with more advanced AF and substantial underlying cardiovascular disease — was designed to lay the foundation for a large, randomized controlled trial. “This pilot study establishes the feasibility and importance of conducting an extended pivotal trial critical for establishing long-term outcomes, mortality, quality of life, and cost of ablation and drug therapy for atrial fibrillation,” said Douglas L. Packer, MD, a cardiologist at Mayo Clinic, Rochester, MN, and trial principal investigator. For the study, investigators recruited 60 patients with AF, more than two-thirds of whom had a persistent or long-standing persistent form of the arrhythmia. The study group tended to have multiple additional health problems: 80 percent of patients had high blood pressure, 18 percent had diabetes, 35 percent had coronary artery disease, and 36 percent had mild-to-moderate heart failure. Nearly half (48 percent) already had left atrial enlargement. Some 30 percent of patients had previously tried anti-arrhythmic drug therapy. Of the 60 patients in the study, 31 were randomly assigned to drug therapy, and were treated with either anti-arrhythmic drugs (87 percent) or medications to control the heart rate only without eliminating the arrhythmia (13 percent). The remaining 29 patients were randomly assigned to catheter ablation. In nearly all patients, radiofrequency energy was applied to tissue around the entrance of the pulmonary veins. In addition, in 13 out of 29 patients (45 percent) electrophysiologists chose to create additional linear lesions to block the spread of electrical impulses in problem areas. Investigators found that catheter ablation was more effective than drug therapy for preventing recurrent symptomatic AF. However, treatment success rates in these patients, some of whom had persistent and long-standing persistent atrial fibrillation, were lower than observed in other randomized clinical trials. Late recurrent AF may also diminish the overall effectiveness of ablation therapy, according to Dr. Packer. The CABANA pivotal trial, which will further examine these issues, is currently recruiting patients and is aiming for a total enrollment of 3,000. STOP-AF Study: Arrhythmia Recurrence About 10 Times Less Likely with Freezing Balloon In patients with an intermittent form of atrial fibrillation, use of a freezing balloon is nearly 10 times more effective and equally safe as conventional anti-arrhythmic drug therapy for eliminating the irregular heart rhythm, according to research presented at the American College of Cardiology’s 59th annual scientific session. The Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP-AF) study found that nearly 70 percent of patients with intermittent, or paroxysmal, atrial fibrillation who were treated with the Arctic Front® Cardiac CryoAblation Catheter System remained free of atrial fibrillation after one year, as compared with just over 7 percent of patients assigned to drug therapy. For the study, investigators from 26 medical centers in the United States and Canada recruited 245 patients with paroxysmal atrial fibrillation, a form of the arrhythmia characterized by intermittent episodes of an irregular or racing heart beat. All patients had already tried treatment with at least one anti-arrhythmic drug, but were unsuccessful. Patients were randomly assigned in a 2-to-1 ratio to cryoablation or treatment with an anti-arrhythmic medication that had not previously failed. During the next 90 days data collection was deferred, allowing each patient’s doctor to adjust drug therapy or repeat cryoablation, as needed. After that, patients were followed up in the clinic at 1, 3, 6, 9 and 12 months. They also sent heart rhythm tracings to their doctor over telephone lines every week and when experiencing symptoms. Researchers found that the cryoablation procedure was initially successful in about 98 percent of patients. After one year, nearly 70 percent of patients treated with cryoablation were free of atrial fibrillation and had not required use of a non-study drug or an interventional procedure to treat atrial fibrillation, as compared with just 7 percent of patients in the anti-arrhythmic drug group. Just over 3 percent of patients treated with cryoablation experienced a serious complication, specifically, narrowing of the pulmonary vein in seven out of 228 patients, one of whom required an interventional procedure to widen the vein. Phrenic nerve palsy (damage or irritation to the nerve that controls the diaphragm and therefore can affect breathing) was noted after 11 percent of cryoablation procedures, but none of the cases were considered serious, and approximately 98 percent resolved by the 12-month follow-up. Researchers also tracked complications related to AF itself. During the follow-up period, nearly 97 percent of patients in the cryoablation group and nearly 92 percent of patients in the drug-therapy group avoided cardiovascular death, heart attack, stroke, or hospitalization for recurrence or ablation of atrial fibrillation, ablation of atrial flutter, complications related to unwanted blood clots, heart failure, hemorrhage, or anti-arrhythmic drug treatment. Less than 1 percent of patients treated with cryoablation were hospitalized for the recurrence of atrial fibrillation, as compared with 6 percent in the anti-arrhythmic drug group. Dabigatran Etexilate Shows Greater Reductions Than Warfarin in Stroke in Patients with Atrial Fibrillation Across All Stroke Risk Groups Data presented at the 59th Annual Scientific Session of the American College of Cardiology have shown greater reductions in stroke in patients with atrial fibrillation for dabigatran etexilate* compared to the current standard of care, warfarin, irrespective of a patient’s risk profile for stroke.1 The new sub-group analysis from the RE-LY® study** assessed the rate of stroke and systemic embolism in patients defined as being at low (n=5,775), moderate (n=6,455) and high (n=5,882) risk of such events by the validated stroke risk stratification score, CHADS2.1,2 The RE-LY® sub-group analysis showed that dabigatran etexilate 150mg bid reduced the rate of stroke and systemic embolism compared with well-controlled warfarin, irrespective of a patient’s stroke risk. Dabigatran etexilate 110mg bid resulted in similar reductions as well-controlled warfarin. Both doses were associated with lower major bleeding rates in patients at low risk of stroke.1 In detail, the results showed:1 • Dabigatran etexilate 150mg bid reduced the rate of stroke and systemic embolism when compared with well-controlled warfarin across all stroke risk groups with the relative risk (RR) being 0.62 (0.38−1.02) in low, 0.61 (0.40−0.92) in moderate, and 0.70 (0.52−0.95) in high-risk patients • Dabigatran etexilate 110mg bid showed similar reductions in the rate of stroke and systemic embolism to well-controlled warfarin, with RR being 1.00 (0.65−1.55) in low, 1.04 (0.73−1.49) in moderate and 0.79 (0.59−1.06) in high-risk patients • Both doses of dabigatran etexilate were associated with lower rates of major bleeding compared to well-controlled warfarin in low risk patients (D110mg RR: 0.67 (0.49−0.90), D150mg RR: 0.73 (0.54−0.98)). • Consistent with the overall RE-LY® results, both doses of dabigatran were associated with substantial reductions in the rates of intracranial hemorrhage in all risk groups. Lead author Dr. Jonas Oldgren of Uppsala University Hospital, Sweden, said, “For healthcare professionals treating patients with atrial fibrillation at risk of stroke and systemic embolism, this sub-group analysis is very encouraging as it shows that dabigatran etexilate 150mg bid is the first treatment reducing strokes more than warfarin across the full spectrum of stroke risk in patients with AF.” Stroke risk stratification scores such as CHADS2 have been developed to guide appropriate use of anticoagulant therapy in patients with AF to maximize its benefit.2 For patients defined as being at high or moderate risk of stroke, the reduction in stroke risk with vitamin K antagonists (VKAs), such as warfarin, is likely to outweigh the risk of bleeding.3 For patients with a low risk CHADS2 score, the benefits of VKAs are not as clear. Therefore, currently many patients only receive aspirin, which is less effective than warfarin in reducing the risk of stroke, leaving patients insufficiently protected from the threat of severe and highly debilitating strokes.4-7 Dr. Jonas Oldgren continues, “Healthcare professionals and patients have long been waiting for a treatment that can provide stroke prevention across all levels of risk. We have shown that dabigatran etexilate provides greater benefits in stroke reduction across patients at low, medium and high risk, as well as reduced bleeding vs. warfarin in patients at low risk. This provides important evidence of the clear benefit that this novel oral anticoagulant can provide over current treatment with VKAs, such as warfarin.” Up to three million people worldwide suffer strokes related to AF each year,8-10 which tend to be especially severe and disabling,8 with half of people dying within one year.11 * Dabigatran etexilate (Pradaxa®) is being investigated for the prevention of stroke in patients with atrial fibrillation. ** Randomized Evaluation of Long-Term Anticoagulant Therapy 1 Oldgren J, et al. Dabigatran etexilate versus warfarin in atrial fibrillation patients with low, moderate and high CHADS2 score – a RE-LY® subgroup analysis. Presented at the 59th Annual Scientific Session of the American College of Cardiology, 15th March 2010. 2 Gage BF, et al. Validation of Clinical Classification Schemes for Predicting Stroke Results From the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-2870. 3 Fuster V, Rydn LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation – executive summary. Circulation 2006;114:700-752. 4 Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Arch Intern Med 1994;154:1449-1157. 5 Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492-501. 6 The European Atrial Fibrillation Trial Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342:1255-1262. 7 Laupacis A, Boysen G, Connolly S, et al. The efficacy of aspirin in patients with atrial fibrillation: analysis of pooled data from 3 randomized trials. Arch Intern Med 1997;157:1237-1240. 8 Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27:1760-4. 9 Atlas of Heart Disease and Stroke, World Health Organization, September 2004. Viewed July 2009 at http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf. 10 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-988. 11 Marini C, De Santis F, Sacco S, et al. Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study. Stroke 2005; 36:1115-1119. New Analysis Suggests Early Initiation of Multaq® (dronedarone) Feasible in AF Patients Following Discontinuation of Amiodarone Data from a post-hoc analysis presented at the 59th Annual Scientific Session of the American College of Cardiology in Atlanta, evaluated transition to Multaq® (dronedarone) in patients with atrial fibrillation (AF) or atrial flutter (AFL) following prior treatment with amiodarone. The data comes from a post-hoc analysis of pooled data from the EURIDIS and ADONIS sinus rhythm maintenance trials and assessed the impact of initiation of dronedarone therapy on safety and efficacy within two days after stopping amiodarone. The analysis included 223 patients previously treated with amiodarone, in which Multaq (dronedarone) or placebo was initiated in a subgroup of 154 patients (Multaq = 98, placebo = 56) within two days of discontinuing amiodarone. The subgroup represents 18 percent of the patients enrolled in the EURIDIS and ADONIS studies (7.9% treated with Multaq) and was compared with a group of patients who had no prior treatment with amiodarone (n=1014). Groups were compared on the primary study endpoint, time to first recurrence of AF/AFL as well as incidence of adverse events. In this subgroup, Multaq (dronedarone) decreased AF/AFL recurrence compared to placebo (HR=0.64 [95% CI 0.44-0.95], P=0.022), which is consistent with the overall study results in which dronedarone decreased the rate of AF recurrence by HR=0.75 [95% CI 0.65-0.87], P=0.001. The rate of serious adverse events was low and similar across groups with no episodes of torsades de pointes reported. There were more bradyarrhythmic events in patients treated with dronedarone (3.1%) compared to placebo (0%) and drug discontinuation due to QTc-prolongations (dronedarone = 7.9% versus placebo = 3.6% with QTc >500 msec) in the patients previously treated with amiodarone, as expected from the pharmacodynamic profile of the drugs.1 “The data presented suggest it may be possible to initiate Multaq following discontinuation of amiodarone in paroxysmal and persistent patients within two days, while maintaining efficacy at preventing AF recurrence. Caution should be given to heart rate and QTc intervals prior to consideration of early initiation of dronedarone,” said Peter Kowey, MD, FACC, Chief of the Division of Cardiovascular Diseases at the Main Line Health System, Wynnewood, Pennsylvania. “These results are hypothesis generating and indicate that a prospective trial is warranted which is currently being put in place sponsored by the manufacturers.” In the U.S., Multaq is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent AF or AFL, with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction [LVEF] 1 Kowey P. “Impact of Dronedarone Started Rapidly After Amiodarone Discontinuation” abstract. ACC 2010. 2 Multaq® U.S. Prescribing information http://www.multaq.com Feature Interview STOP AF Trial Results: Interview with Kevin Wheelan, MD Tell us about the success rates in STOP-AF. This trial randomized patients to antiarrhythmic drug treatment or cryoballoon ablation for pulmonary vein isolation to treat atrial fibrillation (AF). Results showed that at 1 year, only 7 percent of the patients in the drug treatment group had responded to medication, while 70 percent of the patients in the cryoablation group were free of AF. This ten-fold improvement is quite impressive. What antiarrhythmic drugs did patients initially try? The 3 drugs used were propafenone, sotalol, and flecainide. Amiodarone was not a permitted drug in the protocol. How long after antiarrhythmic drug failure was it safe to try cryoablation? Cryoablation was used after drug failure was documented. Patients were randomized to a different medication or ablation. During the study, 65 patients crossed over from the drug treatment arm to ablation. How often was repeat cryoablation needed? Cryoablation was repeated during the initial blanking period in 19% of patients. How did complications associated with cryoablation and antiarrhythmic therapy compare? On an intention-to-treat basis, i.e., starting out with the primary treatment strategy, there were more complications in the drug treatment group than in the cryoablation group. That’s not really an appropriate way to look at it because it’s very obvious that the type of complications between drugs and cryoablation are different. In the cryoablation group, approximately 11 percent of patients developed phrenic nerve palsy, and all but 2 percent of the patients recovered — only one patient had symptoms at the completion of the 1-year follow-up, and none required intervention. Three percent of patients developed narrowing in the pulmonary veins, of which 2 patients required further treatment. These are procedure-related complications; however, serious adverse events overall occurred at the same rate in both the ablation and drug treatment arms of the trial. How will this data about the Arctic Front revolutionize how EP labs manage AF? I think that the learning curve for cryoablation is shorter and easier than for radiofrequency (RF) ablation. Technically performing the RF ablation requires doing an individual point-by-point movement of the catheter in the atrium and zapping the abnormal tissue. The advantage of cryoablation is that one is able to apply the balloon to circumferentially isolate the whole vein in a series of freezes, and so the learning curve to acquire those skills is shorter. More electrophysiologists will be able to become proficient doing the freezing procedure. This will hopefully result in shorter procedure times. I think when you look at these results and the fact that this was the first time that a balloon-based technology has been used in the U.S., it is really amazing. I believe that with the published success rates from Europe and now the U.S. data that cryoablation could become used in 50 percent of patients with AF, cryo could become the primary procedure of choice. It will take time to analyze the data and for physicians to move in that direction, but trials continue to show that drugs don’t work that well and that ablation is becoming better and safer. You may have seen the preliminary results of the CABANA trial, which show that ablation was better than drug treatment in preventing complications from AF. I believe we’re going to see the paradigm begin to shift more toward the use of this technology in EP labs across the country.