The American College of Cardiology (ACC) 66th Annual Scientific Sessions took place on March 17-19 in Washington, D.C. Below is a compilation of clinical news highlights from the meeting.
New Study Adds to Concerns about Heightened Risk of Death for AF Patients Taking Digoxin
Patients with atrial fibrillation (AF) who are given digoxin to control their symptoms have an increased risk of death, whether or not they have a diagnosis of heart failure, compared with patients not taking the drug, and this risk increases with higher levels of digoxin in the bloodstream, according to research presented at the American College of Cardiology's 66th Annual Scientific Session.
An increased risk of death from any cause — the study's primary endpoint — was found in both patients with and without heart failure who started on digoxin. Researchers report the study is one of the largest and most comprehensive analyses of the risk of digoxin use in patients with AF performed to date.
"Based on our study, digoxin should be avoided in patients with AF, particularly if symptoms can be alleviated with other treatments," said Renato Lopes, MD, PhD, professor of medicine in the division of cardiology at Duke University Medical Center and lead author of the study. "We showed that starting digoxin was associated with increased risk of death and sudden death, regardless of the presence of heart failure. Thus, based on our findings, avoiding digoxin in patients with AF — irrespective of the presence of heart failure — seems to be the right approach."
AF affects about 9 percent of people over 65 years old in the U.S. Around 30 percent of patients with the condition worldwide take digoxin, Lopes said. The drug is one of the oldest medications used in cardiology and is very inexpensive. However, its safety for patients with AF has come under scrutiny, he said.
"A number of recent publications have questioned the safety of this drug, and different analyses looking at different questions have shown conflicting results. There are no randomized data assessing the efficacy and safety of digoxin in patients with AF," Lopes said.
To get a more definitive answer about digoxin's safety, Lopes and his colleagues analyzed data collected in the ARISTOTLE trial, which compared apixaban with warfarin for the prevention of blood clots, strokes, and death in patients with AF. Of the 18,201 patients enrolled in ARISTOTLE, 17,897 had data available on heart failure status and digoxin use during the trial. Of those patients, 5,824 were on digoxin at the start of the trial; 4,434 of these participants had their blood levels of digoxin measured at baseline. A total of 6,693 patients had heart failure at the time of trial enrollment.
To try to compensate for patients not being randomly assigned to digoxin use, the researchers performed a propensity score analysis — a statistical technique that attempts to estimate the effect of a treatment by accounting for the factors, or covariates, that differ between treated and untreated patients. In this case, those factors included patients' demographic characteristics; medical history; measurements of organ function; other medications used, including antiarrhythmic agents; region of the world; clinical setting, where digoxin was initiated; heart failure status; and biomarkers in the blood that can help predict the risk of death. Each patient taking digoxin was compared with three matched control patients from ARISTOTLE who were not taking the drug.
The researchers found that in patients already receiving digoxin and, therefore more likely to tolerate it, the overall relationship between digoxin use and death was non-significant. However, even in this cohort, the risk of death was related to digoxin concentration in the blood: for every 0.5 ng/ml increase in the blood level of digoxin, the risk of death rose by 19 percent. Among patients whose digoxin levels were greater than 1.2 ng/ml, the death rate increased by a highly significant 56 percent.
The risk of death was even higher for patients who were not taking digoxin before the trial but were started on the drug over the course of ARISTOTLE. These patients had a 78 percent increase in the risk of death from any cause and a four-fold increased risk of sudden death after starting digoxin use.
"Most sudden deaths occurred within six months after digoxin was started," Lopes said.
This hints at cause and effect, he said, though the fact that patients were not randomized to digoxin prevents a definitive determination of causality.
The lack of randomization and the potential for unmeasured confounding factors are the main limitations of the study, he said. In addition, for patients who were on digoxin at study entry, researchers did not know how long they had taken the drug before entering the study. Despite these limitations, the study is one of the most comprehensive in the field to date, incorporating clinical variables, biomarker adjustments and blood digoxin levels, Lopes said.
"To definitively determine the efficacy and safety of digoxin in AF patients would require a large and well-powered randomized trial," he said. "Until then, our finding that digoxin may be causing more harm than good in patients with AF is important, and may help guide physicians in their clinical decisions when managing these patients."
In the main ARISTOTLE trial, apixaban was found to be statistically significantly superior to warfarin for preventing blood clots, strokes, major bleeding events and death, whether or not patients were taking digoxin at the time of study entry. Therefore, Lopes said that for stroke prevention in AF patients, apixaban is a better option than warfarin, irrespective of digoxin use.
The digoxin safety study was funded by the Bristol-Myers Squibb and Pfizer Alliance in conjunction with the Duke Clinical Research Institute.
Genetically Guided Warfarin Dosing Lowers Risk of Some Adverse Events
Using genetic testing to help personalize doses of warfarin therapy given to patients undergoing elective orthopedic surgery appears to lower the risk of combined adverse events compared with clinically guided dosing, according to research presented at the American College of Cardiology's 66th Annual Scientific Session. Researchers said these findings could have implications for a broad population of patients starting warfarin therapy.
Warfarin is widely prescribed to prevent clots that can cause stroke, deep vein thrombosis (DVT), or pulmonary embolism (PE). The challenge with warfarin, however, is finding the right dose: too much can cause dangerous bleeding, too little may leave people at risk for blood clots. As a result, people taking warfarin for a variety of indications, such as atrial fibrillation, orthopedic surgery, or mechanical heart valves need regular blood testing to monitor how quickly their blood clots, called their international normalized ratio (INR). An INR of four or higher denotes a high risk of serious bleeding. In addition, certain medications, alcohol, and foods can affect the way warfarin works, as can variants in certain genes now known to influence warfarin sensitivity and metabolism.
The Genetic InFormatics Trial (GIFT) of Warfarin Therapy to Prevent DVT — the first trial to quantify the benefit of pharmacogenetic dosing of warfarin on clinical events — found that genotype-guided dosing was associated with a 27 percent reduction in the study's primary endpoint — a composite of death, confirmed venous thromboembolism, warfarin overdose (INR ≥4), and major bleeding — compared with those receiving clinically based dosing. Because there were no deaths during the trial, researchers were unable to assess whether genotype-guided dosing reduced mortality.
"The way we dose warfarin clinically is trial-and-error dosing. We often start patients on 5 mg daily and don't find out who is very sensitive to warfarin until their INR is four or more, indicating an overdose," said Brian F. Gage, MD, MSc, professor of medicine at Washington University School of Medicine in St. Louis, and the study's lead author. "Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events."
Gage said the clinical dosing used in this trial was likely better than standard dosing because it used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient's age, height, weight, interactions with other medications, and other clinical factors. The trial also showed a statistically significant improvement in INR control, the study's secondary endpoint, among patients whose warfarin dose was determined based on genetic information in addition to clinical factors. Previous studies had shown mixed results as to whether genotype-guided dosing improved INR control; however, Gage said compared with previous studies, the GIFT trial was considerably larger, added another gene (CYP4F2), and recruited older patients (65 years and older) at high risk of bleeding.
"Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin. What we didn't know is whether taking genotype into account improved outcomes," Gage said. "It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can't simply look at patients and predict their therapeutic warfarin dose."
This multicenter, randomized controlled trial followed 1,597 participants 65 years or older undergoing elective knee or hip replacement surgery (63.8 percent women, 91.1 percent Caucasian). Most of the patients were recruited at the Hospital for Special Surgery in New York City, Washington University in St. Louis, and the University of Utah and Intermountain Healthcare in Salt Lake City. Gage said orthopedic patients are at high risk of both bleeding and clotting and are routinely given an anticoagulant after hip or knee replacement, allowing researchers to determine whether genotype-guided dosing reduced post-operative adverse events. Participants were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).
Patients were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account) by the algorithms; they were also randomly assigned to a target INR of either 1.8 or 2.5. For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application (www.WarfarinDosing.org) that incorporated clinical factors in all patients and genotype in participants randomized to genotype-guided dosing. Most (94 percent) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose, or make adjustments. Patients were monitored using standard INR testing and most participants underwent screening with lower extremity Doppler ultrasound three to seven weeks after arthroplasty to check for clots. Researchers followed participants for 90 days and assessed the primary outcome through day 30 (DVTs and PEs detected through day 60 also were included in the primary outcome).
The rate of adverse events was 14.7 percent in the clinical arm and 10.8 percent in the genotype-guided arm, a 27 percent relative risk reduction. There was a significant reduction in INR values ≥4: from 9.8 percent in the clinical arm to 6.9 percent with genotype-guided dosing. However, in looking at events by themselves, there was no significant reduction in DVT/PE or major bleeds between the two groups. At 30 days follow-up, no participant died and one was lost to follow-up.
"The GIFT trial is an example of personalized medicine," Gage said. "If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right, from the get-go, we're less likely to have the patient overdose and can lower the risk of complications. This approach is especially important for older patients. Warfarin is the medication that is most likely to cause elderly patients to go to the emergency room."
Gage said that future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants. Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, there may be benefit of dosing algorithms tailored to ancestry.
Gage said he hopes that genetic and clinical dosing algorithms will be integrated within electronic medical records.
"The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose," he said.
The GIFT trial was funded by the National Heart, Lung, and Blood Institute; the Centers for Medicare and Medicaid Services paid for the genotyping and some of the Doppler ultrasounds.
Pacemaker Program Can Reduce Dangerous Fainting Episodes
Patients with recurrent fainting episodes who received a pacemaker delivering a pacing program designed to detect and stop the abnormal heart rhythms that precede syncope had a seven-fold reduction in fainting compared with patients in a placebo pacing group, according to research presented at the American College of Cardiology's 66th Annual Scientific Session.
The study — the first prospective double-blind placebo-controlled trial to show robustly positive results for the pacing program, known as Closed Loop Stimulation (DDD-CLS), in patients with recurrent syncope — met its primary endpoint of a significant reduction in fainting episodes with DDD-CLS compared to placebo pacing.
"Our study showed up to a seven-fold reduction in recurrences of syncope" in patients who used the DDD-CLS program, said Gonzalo Baron-Esquivias, MD, PhD, FESC, associate professor, chief of the clinical cardiology section and head of studies in the cardiology department at Virgen del Rocio University Hospital in Seville, Spain, and the study's lead author.
This study is important, he said, because of the lack of available treatments for recurrent syncope.
"Now a door is open and we have a new possible treatment for these patients," he said.
Syncope is triggered by a sudden drop in blood pressure and heart rate, which in turn reduces blood flow to the brain. While episodes of syncope are not fatal, they can be very dangerous due to loss of consciousness and can severely affect patients' quality of life. About half of all women and one-third of men will experience syncope in their lifetime. The real concern, Baron-Esquivias said, is that for many, these episodes will recur and they aren't predictable.
Pacemakers are widely used to treat other heart rhythm disorders, particularly bradycardia. In DDD-CLS pacing for recurrent syncope, the pacemaker detects contractions or spasms in the heart muscle that typically occur before an episode of syncope and releases an electrical signal that calms the heart down, preventing sudden dips in heart rate and blood pressure. Earlier small trials of DDD-CLS had shown mixed results in preventing fainting episodes.
In the SPAIN trial, Baron-Esquivias and his colleagues recruited 54 patients aged 40 or older from 12 medical centers in Spain and Canada. All had experienced more than five episodes of syncope in their lifetimes, with more than two in the past year. To be eligible, participants had to have normal results on an electrocardiogram, echocardiogram, 24-hour Holter test, carotid sinus massage and orthostatic test. They also had to show a drop in blood pressure and heart rate on a test in which the head rapidly changes position.
All participants were implanted with a pacemaker. The researchers randomly assigned half to receive DDD-CLS pacing for 12 months and the other half to a pacing program called DDI, which does not respond to the contractions in the heart that precede syncope and, therefore, functioned in the SPAIN trial as a placebo program. After 12 months, the two programs were switched so that the patients who had received DDD-CLS during the first year received DDI for the next 12 months, and vice versa. If a patient in either group had more than three episodes of syncope in one month, their pacing assignment was switched. Patients and their doctors were blinded at all times to their group assignment.
Forty-six patients completed the trial, which lasted two years. The patients' average age was 56, and 48 percent of them were men. During the trial, four patients experienced syncope while receiving DDD-CLS pacing, compared with 21 patients who fainted during DDI pacing, a statistically significant difference.
Among patients initially assigned to DDD-CLS, 72.2 percent saw a reduction of more than 50 percent in syncope episodes within the first year, but fainting recurred after they crossed over to the DDI group. Patients who crossed over to DDD-CLS after a year of placebo pacing saw a reduction of more than 50 percent in syncope episodes during the second year. Nine patients who initially received DDI pacing met the criterion for early crossover to DDD-CLS during the first year. The estimated time to a first fainting episode was longer among patients receiving DDD-CLS — 29 months compared with just over nine months for patients receiving DDI, a statistically significant difference.
Limitations of the study are its small size and short duration of follow-up (two years), Baron-Esquivias said.
Baron-Esquivias, who currently uses DDD-CLS pacing to treat patients with recurrent syncope in his own practice, said that if these findings are confirmed by larger, ongoing studies, such as the ongoing BioSync CLS trial sponsored by BIOTRONIK, he expects that international guidelines will be changed to recommend DDD-CLS pacing in these patients.
The trial was funded by the Investigation Agency of the Spanish Society of Cardiology, which received an unrestricted grant from BIOTRONIK Spain. BIOTRONIK is the developer of the DDD-CLS program.
Closing Left Atrial Appendage Reduces Stroke Risk from AF
For patients with atrial fibrillation (AF), closing the area of the heart known as the left atrial appendage as an add-on procedure during cardiac surgery was associated with a 40 percent reduction in the risk of thromboembolism, according to an observational study presented at the American College of Cardiology's 66th Annual Scientific Session.
Reducing stroke risk is paramount in patients with AF, who are five times more likely to experience a stroke compared to the general population. The study, which is the largest to assess the effects of closing the left atrial appendage, suggests the approach may be a good option, particularly for people with AF who are at high risk for stroke but cannot take or tolerate anticoagulant medications, according to researchers.
"There's currently a wide variation in the use of this procedure at the time of cardiac surgery, largely due to the fact that there's not good data on the safety or the efficacy of the procedure," said Daniel J. Friedman, MD, a cardiology fellow at Duke Clinical Research Institute in Durham, North Carolina, and the study's lead author. "While our study was not a randomized trial, it does demonstrate strong support for the benefits of closing the left atrial appendage at the time of cardiac surgery in patients with atrial fibrillation."
AF affects between 2.7 million and 6.1 million Americans, according to estimates from the Centers for Disease Control and Prevention. When the heart beats irregularly, it may not squeeze blood out of a small outgrowth of the left atrium known as the left atrial appendage as fully as it should, allowing blood to pool. This pooled blood can form a clot, which can then travel through the bloodstream causing a blockage, or thromboembolism. Anticoagulant medications are often used to prevent the formation of blood clots in patients with AF; however, some patients cannot tolerate these medications because of their side effects or cannot take them due to other medical conditions. Research suggests that about 50 percent of patients with AF who are eligible for anticoagulation therapy actually take anticoagulants.
About 90 percent of strokes in people with AF result from clots that form in the left atrial appendage. Some cardiac surgeons attempt to reduce the risk of stroke by closing the left atrial appendage, either by placing a small clip over it or by amputating it and then sewing the atrial wall closed. Because its benefits have been largely unknown and open-heart surgery carries significant risks, surgical left atrial appendage occlusion is typically performed as an add-on procedure in patients who are undergoing other types of cardiac surgery, such as bypass grafting or valve replacement surgery. The left atrial appendage can also be closed using a procedure performed through a catheter inserted in a vein, rather than through open-heart surgery, but this trial investigated only surgical occlusion.
To assess the safety and efficacy of closing the left atrial appendage, the researchers analyzed the health records of 10,524 patients in The Society of Thoracic Surgeons Adult Cardiac Surgery Database, a nationally-representative data set that includes 90 percent of cardiac surgery centers in the United States. They extracted data for Medicare patients with AF who underwent coronary artery bypass grafting, aortic valve surgery or mitral valve surgery in 2011 or 2012.
About 37 percent of the patients had their left atrial appendage closed during their surgery. Of these, 1.6 percent were hospitalized for thromboembolism within 12 months (the study's primary endpoint), significantly fewer than the 2.5 percent of patients experiencing thromboembolism who did not have their left atrial appendage closed. This translates to a 40 percent reduction in risk over 12 months, Friedman said, noting that this reduction would likely grow more impactful as it accumulates over time.
In addition, closing the left atrial appendage was associated with a 15 percent reduction in the rate of death and a 21 percent reduction in a composite of thromboembolism, hemorrhagic stroke and death. There was no significant difference in the rate of hemorrhagic stroke, a type of stroke caused when a blood vessel in the brain ruptures.
Friedman said the results suggest closing the left atrial appendage is safe and effective for AF patients undergoing cardiac surgery.
"Intuitively, surgical left atrial appendage occlusion should work; however, there have been concerns that incomplete occlusion actually could lead to increased risk for thromboembolism because it could result in small communications between the appendage and the left atrium," Friedman said. "The fact that we saw such a dramatic association between the procedure and a reduction in thromboembolism was reassuring that, at least in a more contemporary cohort of patients, left atrial appendage occlusion is able to be done in a much more effective way than initial reports had suggested may be the case."
Further analysis revealed the greatest reduction in thromboembolism after left atrial appendage occlusion among patients who were not taking anticoagulant medications at discharge. There was no difference in thromboembolism rates for those who were taking anticoagulants at discharge. Whether left atrial appendage occlusion is effective enough to allow patients to safely stop taking anticoagulants is one potential area for future investigation, Friedman said.
The study is limited by the fact that it is an observational analysis. A prospective, randomized controlled trial would provide more robust evidence to support clinical decision making. The study also was not able to compare different techniques used to close the left atrial appendage, another aspect that could be investigated in future studies, Friedman said.
The study was funded by grants from the Burroughs Wellcome Fund and the U.S. Food and Drug Administration. Friedman receives funding from the National Institutes of Health T 32 training grant HL069749.
Rivaroxaban Reduces VTE Recurrence Compared with Aspirin
In patients at elevated risk for a recurrence of potentially life-threatening blood clots, a low dose of the oral blood-thinning medication rivaroxaban reduced recurrences more than three-fold compared with aspirin, with no significant increase in bleeding side effects, according to research presented at the American College of Cardiology's 66th Annual Scientific Session.
"We have shown that practitioners can safely prescribe rivaroxaban for patients at risk for a recurrent venous thromboembolism (VTE) without being concerned that doing so will increase risk for bleeding side effects," said Philip S. Wells, MD, chief of the department of medicine at the University of Ottawa and Ottawa Hospital in Canada and a co-investigator on the study.
A VTE may occur as a blood clot in a deep vein, usually in a leg (deep vein thrombosis) or as a clot that travels from elsewhere in the body to the lungs (pulmonary embolism). Patients who have had a VTE generally are treated with a blood-thinning medication, or anticoagulant, for six to 12 months after the event. However, some patients remain at elevated risk for another blood clot, as well as for a heart attack or stroke, if anticoagulant therapy is stopped, Wells said. The most common risk factors for VTE are cancer and immobility due to surgery or illness, he said. In addition, some patients develop what are known as "unprovoked" VTEs — that is, VTEs that occur in the absence of known risk factors.
Previous studies have suggested that extended treatment with an anticoagulant such as warfarin or rivaroxaban reduced risk for a recurrent VTE, while other studies have shown that aspirin also reduced risk for a recurrent VTE and might present a lower risk for bleeding side effects than extended treatment with an anticoagulant. This study was the first to directly compare the safety and effectiveness of rivaroxaban and aspirin in patients at risk for a recurrent VTE, Wells said.
The international multicenter study enrolled 3,396 patients who had completed six to 12 months of anticoagulant therapy for a VTE. Patients' average age was 59, and 55 percent were men. Patients were 77 percent Caucasian, 14 percent Asian and 4 percent African-American. Patients were randomly assigned to receive 10 mg of rivaroxaban, 20 mg of rivaroxaban or 100 mg of aspirin once daily for up to 12 months.
The study's primary efficacy endpoint was recurrence of VTE. Secondary efficacy endpoints were deaths due to VTE and unexplained deaths for which VTE could not be excluded as a cause. The primary safety endpoint was major bleeding. The secondary safety endpoint was non-major bleeding that caused an interruption in treatment, a minor medical intervention, physician visit or disruption to daily quality of life.
After a median follow-up of 351 days, 1.2 percent of patients receiving 10 mg of rivaroxaban and 1.5 percent of those receiving 20 mg of rivaroxaban had had a recurrence of VTE, compared with 4.4 percent of patients receiving aspirin. The difference was statistically significant for both rivaroxaban groups compared with aspirin. There were no statistically significant differences on the secondary efficacy endpoints.
Major bleeding occurred in 0.3 percent of patients receiving aspirin, 0.4 percent of those receiving 10 mg of rivaroxaban, and 0.5 percent of those receiving 20 mg of rivaroxaban — differences that were not statistically significant. There were no statistically significant differences on the secondary safety endpoint.
"Rivaroxaban had significantly greater efficacy in preventing VTE recurrence without significantly increasing risk for major bleeding," Wells said. "Our findings show that it's [a safe option] and appears to be highly protective against potentially life-threatening recurrent VTE."
A limitation of the study is that the results may not be generalizable to other patients at risk for recurrent VTE, Wells said. For example, study participants were younger than the typical patient with a VTE. The investigators plan to conduct a follow-up study to examine whether low-dose rivaroxaban is equally effective in other patient populations, he said.
The study was funded by the German pharmaceutical company Bayer AG.
The study was simultaneously published online in the New England Journal of Medicine at the time of presentation.
For Atrial Fibrillation Ablation, Newer Anticoagulant Reduces Major Bleeds
Uninterrupted treatment with dabigatran, a non-vitamin K antagonist oral anticoagulant (NOACs), before, during and after ablation to treat atrial fibrillation significantly reduced the incidence of major bleeding events compared with uninterrupted use of the more established anticoagulant warfarin, according to research presented at the American College of Cardiology's 66th Annual Scientific Session.
The findings offer evidence that dabigatran is a safe and effective alternative to warfarin in the context of atrial fibrillation ablation. The trial showed a 5.3 percent reduction in its primary endpoint, major bleeding events during ablation or in the first two months after the procedure, with major bleeds occurring in 1.6 percent of study participants who received dabigatran and 6.9 percent of patients receiving warfarin.
"I think it's great news for the field," said Hugh Calkins, MD, professor of cardiology at Johns Hopkins Medicine and the study's lead author. "There have been very few randomized studies focused on doing ablation procedures in fully anticoagulated patients, and the use of NOACs has been increasing dramatically. I expect these findings will encourage clinicians to quickly shift to doing this procedure with uninterrupted use of NOACs."
Atrial fibrillation affects between 2.7 and 6.1 million Americans, according to estimates from the Centers for Disease Control and Prevention. People with atrial fibrillation are five times more likely to experience a stroke compared with the general population, and many patients take anticoagulants, or anti-clotting medications, to reduce this risk. However, taking anticoagulants during any kind of surgery can increase the risk of uncontrolled bleeding, raising concerns over how to appropriately weigh the risks and benefits of anticoagulants during ablation.
"Anticoagulation management at the time of atrial fibrillation ablation is critically important because stroke and bleeding are both major complications of the procedure," Calkins said.
Most physicians advise patients to use warfarin continuously before, during and after ablation to reduce the risk of stroke. However, warfarin has some downsides; for example, it requires dietary changes and frequent monitoring of blood coagulation markers, and ablation procedures must be canceled at the last minute if a patient's blood coagulation levels are off-target, creating logistical challenges. In addition, following this guidance can require patients who normally use NOACs to switch temporarily to warfarin around the time of ablation and then switch back, which is cumbersome and sometimes impractical.
The trial is the largest to compare the uninterrupted use of NOACs to uninterrupted use of warfarin in the context of ablation. The researchers prospectively enrolled 704 patients scheduled for atrial fibrillation ablation at 104 sites in 11 countries and randomly assigned patients to receive either dabigatran or warfarin. Patients started anticoagulant therapy four to eight weeks before ablation and used it continuously for up to eight weeks after the procedure.
After excluding patients who did not go through with ablation or failed to meet the study protocol for other reasons, the researchers analyzed outcomes from 317 patients receiving dabigatran (marketed as Pradaxa) and 318 patients receiving warfarin. Dabigatran showed significant improvement over warfarin for the study's primary endpoint, major bleeding events, and equaled warfarin with regard to secondary safety and efficacy endpoints, which included minor bleeding events, stroke, a composite of major bleeding and stroke, and a composite of all serious adverse events. Only one stroke occurred during the study, and it occurred in a patient assigned to receive warfarin.
Calkins noted that there is an approved reversal agent for dabigatran, which gives clinicians an additional tool to control major bleeding if it should occur during a procedure.
The findings confirm and enhance the results of previous, smaller studies suggesting NOACs present a lower risk of major bleeding events compared with warfarin, though this study contradicts the findings of one previous, smaller study comparing Pradaxa to warfarin.
The Uninterrupted Dabigatran Etexilate in Comparison to Uninterrupted Warfarin in Pulmonary Vein Ablation (RE-CIRCUIT) trial was funded by Boehringer Ingelheim, the German pharmaceutical company that markets Pradaxa.
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