Managing A-Fib: Expanding the Armamentarium of Therapies
Sinus rhythm vs. rate controlApproximately 2.2 million people in the U.S. have AF, with about 160,000 new cases are diagnosed annually. After age 65, between 3 and 5 percent of people have AF, according to the Heart Rhythm Society (HRS). The condition costs approximately $6.65 billion annually in the U.S., largely due to increased hospitalization.
Traditionally, there are two approaches to the treatment of AF. One is cardioversion and anti-arrhythmic drugs to maintain sinus rhythm, and the other is the use of rate-controlling drugs, allowing AF to persist.
“Currently, we do not have a standard way to know the health-related quality of life [HrQol] of the patients,” says Valentin Fuster, MD, PhD, director of the Heart Center at Mount Sinai Medical Center in New York City. “Therefore, when we discern about the value of rate versus rhythm control, we haven’t clearly defined the patient from a symptomatic point of view.”
Fuster is calling for an international standardization of HrQol symptoms because choosing a strategy is highly influenced by how the patient feels.
Currently, clinicians tend to use generic HrQol questionnaires—most commonly the Short-Form health survey of 36 items—which “might not detect subtle, but important, HrQol changes in patients with AF,” wrote Fuster in a March editorial (Nature Rev 2010;7:115-116). Instead, he recommends using a disease-specific questionnaire or scale.
“To ensure that the debate progresses on whether rate or rhythm control is the better therapeutic strategy for patients with AF, and to enable us to make well-informed clinical decisions for individual patients with AF, the international AF community must agree on a standard, easy-to-use, AF-specific HrQol questionnaire,” Fuster wrote.
AFFIRM confusesThe AFFIRM trial has been most influential in informing physicians’ choices between sinus rhythm and rate control. The investigators concluded that the management of AF with the sinus rhythm control strategy offers no survival advantage over the rate control strategy, and there are “potential advantages,” such as a lower risk of adverse drug effects, with the rate control strategy (N Engl J Med 2002;347(23):1825-1833).
Eric N. Prystowsky, MD, director of the electrophysiology lab at St. Vincent Hospital in Indianapolis, says AFFIRM resulted in a “big misunderstanding” for the daily management of AF patients. He notes that AFFIRM was one of the many studies to assess the different strategies. “These studies focused on an elderly population, who could symptomatically be enrolled in either treatment strategy,” says Prystowsky, suggesting that the same strategy shouldn’t be applied to all AF patients. Almost 45 percent of the eligible patients in AFFIRM, according to the entry criteria, were excluded, largely because of physician and patient choice.
“Due to its exclusionary criteria, AFFIRM doesn’t really inform practitioners how to manage symptomatic AF patients,” says Robert C. Kowal, MD, PhD, a cardiac electrophysiologist at Baylor Heart and Vascular Hospital in Houston.
Rate control is easier to maintain compared with trying to keep a patient in sinus rhythm, so many practitioners default to this strategy, says Prystowsky. “Also,” he adds, “the trial did not find that rate control is superior to rhythm control, but rather that the two strategies were neutral.”
However, Prystowsky points out that the percentage of patients who are non-responsive to rate control decreases as they age. “If patients are more sedentary, they tend to respond better to a rate control strategy,” he says. “However, younger patients with paroxysmal AF—typically younger than 65 years—often desire a better strategy.”
Kowal concurs that sinus rhythm is “generally superior to rate control, but the problem is how physicians achieve sinus rhythm. If we had better modalities or therapies than anti-arrhythmic drugs to establish sinus rhythm with a high frequency and a high durability, then sinus rhythm would begin to show superiority to rate control in trials.”
|Watchman vs. drugs | Jury’s Still Out|
“PROTECT-AF informed practitioners that to eliminate the LAA in patients with AF reduced stroke to a similar rate or even better than with warfarin. This was the hypothesis that the Watchman LAA closure device [from Atritech] validated in the trial,” Holmes says.
In 707 randomized patients, the researchers found there were three efficacy events per 100 patient-years in the Watchman group, compared with 4.9 in the warfarin (Coumadin, Bristol-Myers Squibb) group—a relative reduction of 38 percent. However, serious safety events were more common in the device group (7.4 events), compared with the warfarin group (4.4), most of which were related to the procedural implant.
Holmes adds that 50 percent of AF patients at risk for stroke are not prescribed warfarin, either because of its black-box warning or other concerns, including bleeding. For this group, aspirin and clopidogrel (Plavix, Bristol-Myers Squibb and Sanofi Aventis) are administered, which, according to Holmes, “is not nearly as effective.” For these patients, Watchman was found to be non-inferior to warfarin for the prevention of the composite of all-cause mortality and stroke.
Bradley Knight, MD, director of cardiac electrophysiology at Northwestern Memorial Hospital in Chicago, an investigator in PROTECT-AF, says that if Watchman receives FDA approval, it could have a “strong role” in clinical practice. “As a non-pharmacologic option for patients who have contraindications or do not wish to take medicine, it will experience relatively high adoption rates,” he says. However, he doesn’t see Watchman as a “cure-all because some patients will still develop thrombus who clot and stroke.”
While Robert C. Kowal, MD, PhD, a cardiac electrophysiologist at Baylor Heart and Vascular Hospital in Houston, calls the Watchman device “intriguing,” he questions the small size of PROTECT AF, and also questions the possibility that not all strokes originate in the LAA. He asks: “Will the device only be used in patients who can’t take Coumadin or will it have a more widespread indication?”
In March, the FDA requested Atritech perform a confirmatory study to further prove the safety and effectiveness of the Watchman LAA closure device. The study would test the safety of the device in patients with AF who are at increased risk of stroke and are eligible for anticoagulation therapy.
Eric N. Prystowsky, MD, director of the electrophysiology lab at St. Vincent Hospital in Indianapolis, is “respectfully disappointed” with the FDA’s decision to prolong their assessment of Watchman. He explains that the trial was “incredibly difficult” to conduct, as the patients were forewarned about all the potential complications, and therefore many chose not to enroll.
However, Valentin Fuster, MD, PhD, director of the Heart Center at Mount Sinai Medical Center in New York City, agrees with the FDA’s decision that the Watchman device needs more safety data before it joins the armamentarium for AF, especially with respect to perforations and pericardial complications. “While longer follow-up safety data are needed, if approved, the device could provide a significant advance in preventing thromboembolism, particularly in elderly patients in whom practitioners are hesitant to administer anticoagulants,” he says.
Knight points out that if the newer oral anticoagulants become available, the current landscape of risk/benefit ratio with oral anticoagulation will change, and the “potential high adoption rate of Watchman could fade.”
“For anti-thrombotic therapy, we will soon have oral agents that will not require constant blood monitoring, like with warfarin,” says Fuster, who is encouraged by the results of the RE-LY trial. “These results open the door for better management of these patients, particularly the elderly, with less significant bleeding and without the need to check the lab anticoagulation, leading to a significant advance in the field.”
However, Holmes questions the promise of the new oral anticoagulant therapies. “They are not going to completely eliminate bleeding risks. Dabigatran [Pradaxa, Boehringer Ingelheim] in the RE-LY trial still had substantial major bleeding, which increased out to 2.5 years, and there isn’t any indication that it will decrease after that period of time,” he says.
Prystowsky sees the Watchman as a potential “wave of the future” within the therapeutic armamentarium. “The device won’t be appropriate for every patient, but new technologies are needed for patients who cannot take or are unresponsive to anticoagulant drugs,” he says. “Even if it’s restricted to special cases, it would be a wonderful tool.”
RF ablation: Earlier, more often?“If we maintain normal sinus rhythm with ablation, it is very likely that the incidence of thromboembolism will decrease,” says Fuster. “The current retrospective data indicate that if an experienced operator performs ablation, we might be able to succeed in not having to administer anticoagulants to our patients.”
Two recent studies support Fuster’s perspective. First, among patients with paroxysmal AF who had been unresponsive to at least one anti-arrhythmic drug, ablation compared with anti-arrhythmic drug therapy resulted in a longer time to treatment failure during the nine-month follow-up period (JAMA 2010;303(4):333-340). Related to the risk of thromboembolism, the risk–benefit ratio favored the suspension of oral anticoagulation therapy after successful AF ablation even in patients at moderate- to high-risk of thromboembolic events (J Am Coll Cardiol 2010;55:735-743).
Therefore, Fuster sees the landscape of RF ablation changing in the “near future,” suggesting that experienced operators will begin intervening earlier with ablation because success rates appear superior in patients with paroxysmal AF. Secondly, he says physicians will intervene earlier with ablation because the procedure becomes more difficult to achieve success as the patient ages, due to the diastolic dysfunction of the left ventricle, which can lead to worse symptoms, including shortness of breath.
“Finally, if this procedure is performed earlier in the patient care cycle, there is less recurrence of the rhythm, and we may see less thromboembolism, as the JACC study indicates,” says Fuster. While he’s unsure if the guidelines will change, he is convinced clinical practice will trend toward intervening earlier and more often.
“We, on the guideline committee, made a consorted decision to recommend a safer therapy first, which unfortunately manifested as a negative reputation for ablation,” says Prystowsky, who stresses: “Second-line therapy doesn’t mean second rate—ablation is first rate. The trials of ablation versus anti-arrhythmic drugs thus far have shown ablation superior to drugs.”
“There is no doubt that ablation, when pitted against drugs, is more effective,” Prystowsky states. “Despite its effectiveness, we recommended ablation as a second-line therapy because it can be riskier than drugs.” Yet, in his opinion, ablation is less risky than long-term use of amiodarone (Cordarone, Wyeth/Pfizer).
Prystowsky also says that ablation is a “perfectly legitimate” first-line therapy choice for those patients who, when informed of the risks and benefits, choose not to take drugs. He also says that patients with a slow heart rate, who will require a pacemaker, should receive ablation as a first-line therapy.
Kowal concurs that for patients with paroxysmal AF, who have relatively few other risk factors, ablation may be a better first-line therapy to drugs.
However, not all electrophysiologists are jumping on the bandwagon. “While it’s a very good treatment, AF ablation should be reserved for those patients who fail anti-arrhythmic drug therapy, as the HRS guidelines suggest,” says Bradley Knight, MD, director of cardiac electrophysiology at Northwestern Memorial Hospital in Chicago. He recommends ablation for only about half of the patients referred to him.
Also, Kowal cautions against employing ablation for patients with paroxysmal AF who have obstructive sleep apnea or a higher volume in the left atrium.
As expected, patients with more complex diseases present with more complex problems. “We still need a better understanding of how to intervene on more difficult cases, including those patients with persistent AF, or other complications including diabetes, sleep apnea, hypertension or long-term AF,” Kowal says. Among this “tougher patient population,” we can impact their outcomes, but the percentage is smaller and they may need repeat procedures, he states.
While the guidelines are dictating much of clinical practice, more data are still needed, as no large trial has yet assessed major endpoints, such as stroke and mortality, with drugs versus ablation. For those unanswered clinical questions, many will await results from the CABANA trial, which showed promise in its pilot for ablation at ACC.10. This pivotal trial of first-line therapies compares catheter ablation with either rate control or rhythm control drugs for reducing total mortality in patients with untreated or incompletely treated AF, and its results are emerging in late 2015 or 2016. Cost effectiveness and HrQol also will be evaluated.
Ablation cost considerationsFor any disease state that is associated with frequent hospitalization, the therapy will need to prove its cost effectiveness, and with ablation, it will need to reduce readmissions, Knight explains. “AF ablation is considered an expensive procedure relative to medical therapy, but if a single procedure reduces the future incidence of hospitalizations and emergency room visits, it’s probably worth it,” he says.
Using a decision-analytic model, Chan et al found that the use of left atrial catheter ablation “may be costeffective in low-risk patients,” compared with amiodarone and rate control therapy in patients with AF (J Am Coll Cardiol 2006;47:2513-2520).
However, cost effectiveness is difficult to assess with AF patients because the therapies do not prolong life, according to Knight, but instead improve symptoms. “We often discuss the cost of saving one year of life. However, we don’t often discuss the cost of significantly improving quality of life. Yet, for this condition with AF ablation, you can make a strong case with just keeping patients out of repeat readmission,” he says.
Cryoablation’s role“The point-by-point AF ablation approach to isolate the pulmonary veins is tedious and time consuming,” says Knight, adding that newer therapies would allow electrophysiologists to deliver circumferential lesions anatomically, as with a balloon.
Kowal, a STOP-AF investigator, also points out that AF ablation can be “technically challenging and time consuming because of this point-by-point set of lesions around the pulmonary vein or dragging the catheter around the vein, requiring constant vigilance throughout the case.” He says that balloons were designed to attain the same results through a controlled circumferential lesion around these veins with a particular energy source.
Presented at ACC.10, STOP-AF found that nearly 70 percent of patients with intermittent or paroxysmal AF who were treated with the cryoablation catheter system (Arctic Front, Medtronic) remained free of AF after one year, as compared with just over 7 percent of patients assigned to drug therapy, based on 245 patients in 24 centers. Less than 1 percent of patients treated with cryoablation were hospitalized for the recurrence of AF, as compared with 6 percent in the anti-arrhythmic drug group.
According to Kowal, the STOP-AF results benefitted from the fact that the operators all were experienced with AF ablation procedures. He adds that European clinical practice indicates that after 30 to 40 cases, “the success rates increase, and complication rates decrease.”
Prystowsky, who is “encouraged” by the STOP-AF study, thinks that cryoablation will be useful in non-complex disease states. “Cryoablation will have its place in clinical practice, but we’re not exactly sure what that place is right now,” he says, adding that the larger balloon appears to have more efficacy. He adds that with cryoablation, “substantial, potential complications remain, including phrenic nerve damage.”
However, Kowal contends that at Baylor’s lab, they would use cryoablation as the “predominant strategy” for paroxysmal AF, if it received FDA approval.
Prystowsky agrees that the approval of cryoablation for patients with paroxysmal AF, which is FDA pending, could expand the field of electrophysiology. “It’s great to have choices as an electrophysiologist. There are physicians who were trained in AF ablation, but have chosen not to perform ablation in practice due to its technical and arduous nature. These physicians might find a niche with cryoablation because it requires less technical skills,” he says.
“Within the electrophysiology community, we are excited about newer therapies on the horizon, as we’ve been performing AF ablations in the same manner for the last 10 to 12 years,” Knight says.