September is Atrial Fibrillation (AF) Awareness Month, which reminds us that even in the midst of the pandemic, cardiovascular and other diseases progress unabated. As a result, we welcome this opportunity to review some of the important approved developments in AF therapeutics and assess their validity when subjected to scientific scrutiny.
Atrial fibrillation is a pandemic in its own right. With five million afflicted Americans and 34 million patients worldwide, this arrhythmia has become a frequent diagnosis in cardiology clinics, primary care offices and emergency rooms. More concerning is an expected >60 percent increase in cases by 2050 attributed to the aging of the population and to a rise in the prevalence of other risk factors such as obesity, heart failure, hypertension, obstructive sleep apnea and pulmonary diseases.
Some of the most recognized complications of AF are arterial thromboemboli (TE), the most catastrophic of which are strokes. Atrial fibrillation accounts for 20 percent of all ischemic strokes or the equivalent of 125,000 cases annually in the US. Atrial fibrillation-related strokes tend to be severe and lead to an estimated median survival of only one year.
Until recently, Warfarin was the only approved therapy for TE prevention in AF patients. In fact, Warfarin, despite some serious negative press, remains one of the most effective pharmacotherapies in cardiovascular medicine. A meta-analysis of multiple RCTs conducted in the US, Europe and Canada showed a relative risk reduction of 62 percent in ischemic strokes/TEs compared to placebo.
More recently, driven by the narrow therapeutic window of Warfarin, its propensity to interact with other medications/diet, and its challenging pharmacokinetics, oral anticoagulants that directly inhibit factors IIa and Xa were developed. These medications known as direct oral anticoagulants (DOACs) include Dabigatran, Rivaroxaban, Apixaban and Edoxaban. They were tested individually against Warfarin in large RCTs that enrolled thousands of patients. The studies were designed as non-inferiority trials that would at least preserve 50 percent of the relative benefit of Warfarin compared to placebo. Although the different drugs varied in their pharmacology, overall, they were found to be at least as efficacious as Warfarin at reducing all strokes and systemic emboli. One of their remarkable impacts was the significant reduction in the most feared bleeding complication: intracranial hemorrhage.
Despite these impressive results, it is important to note that DOACs cannot substitute for Warfarin for all of the latter indications. In fact, these new agents are not approved for use in patients with valvular AF (namely mitral stenosis) or those with mechanical heart valves, and may not be advisable in patients with left ventricular thrombi.
With a yearly rate of major bleeding ranging from 2.1 to 3.6 percent, oral anticoagulants (OAC) are only recommended for patients with a high enough likelihood of stroke/TE to offset that risk. As such, an evaluation for an OAC prescription is advised for patients with a CHADSVASC score≥2. Unfortunately, despite new anticoagulants and clear streamlined recommendations by the HRS/ACC/AHA, multiple studies have shown that these drugs are underused because of patient, physician and economic factors. Moreover, patients at higher risk for embolic events tend to be at increased bleeding risk, further limiting their eligibility for long-term anticoagulation.
Left atrial appendage (LAA) occlusion was pioneered by our surgical colleagues based on data suggesting that >90 percent of all clots in AF patients form in that appendage. Percutaneous LAA occluders (LAAOs) were introduced in clinical trials in the 1990s but only one device is currently FDA approved. The Watchman device won FDA approval after completion of two RCTs: ProtecT AF and PREVAIL. Although similar to the DOACs trials in their non-inferiority design, these studies were criticized for relatively small sample sizes and a broader statistical definition of non-inferiority. Moreover the results were mixed and more challenging to interpret. A subsequent meta-analysis combining these RCTs and their registries showed a reduction in hemorrhagic strokes and nonprocedural bleeding in the Watchman arm, and an equivalent nonprocedural ischemic stroke rate compared to Warfarin.
Subsequently, an observational study of over 13,000 Medicare patients who received a Watchman implant (2015-2017) showed a lower hospitalization rate for ischemic strokes compared to expected rates across all strata of the CHADSVASC score. The safety data derived from the NCDR database looking at 38,000 patients have also been reassuring with even lower complication rate compared to the original RCTs.
An improved, second generation Watchman device recently gained FDA approval, while other LAAOs are in clinical trials. Also, randomization against DOACs, less aggressive post procedural anticoagulation protocols, and expanded use to a broader patient population are under evaluation. These may lead to a drop in device cost, an improved safety profile and near elimination of patient compliance issues.
Ultimately percutaneous LAA occlusion may become first choice therapy for most if not all patients with AF at significant risk for stroke/TEs. Could DOACs become some of the most impressive, yet unnecessary, developments in AF stroke prevention? Only rigorous science can answer the question.
An important issue central to AF management is the choice of rate vs. rhythm control. Symptomatic patients are typically advised a strategy that restores and maintains sinus rhythm (SR). On the other hand, recommendations to asymptomatic AF patients are more nuanced and have evolved significantly over the past decade. As new data have accumulated pointing to mortality, hospitalization and stroke reduction benefits with rhythm management, we have been more aggressive pursuing this strategy early in the course of the disease even in the absence of disabling symptoms. These findings from CABANA, EAST-AFNET4 and CASTLE-AF stand in stark contrast to those of the earlier studies such as AFFIRM, RACE and AF-CHF possibly because of deployment of AF ablation for rhythm management as opposed to the sole use of AADs in the earlier studies.
Possibly one of the most impactful recent developments in AF therapeutics was the advent of catheter ablation. Multiple studies have shown its superiority over AADs in achieving SR maintenance, and unlike AADs, the advances in that field have been remarkable. Unfortunately, these have failed to produce a cure for the arrhythmia, and the success rate of AF ablations has not changed significantly over the past two decades, despite all the hype around new technologies. The AF-free rates remain stubbornly stuck around 65-75 percent, and possibly lower on longer-term follow up.
On the other hand, the procedural safety has benefited tremendously from the technological leaps and rendered the intervention less complex and more accessible to patients by expanding its adoption by the Electrophysiology community. In light of the above, it is perhaps best to recalibrate our expectations and those of our patients. While complete, long-term elimination of AF remains elusive, a reduction in arrhythmia burden is definitely achievable. Despite being less rewarding, the latter retains beneficial clinical implications on mortality and hospitalizations. As an example, CASTLE AF showed a significant clinical benefit from ablation in CHF patients by achieving a reduction in AF burden to 10-20 percent.
As new ablation technologies continue to push the boundaries of scientific knowledge, we should approach the new comers with a hopeful spirit and a critical mind. Deploying unnecessary tools increases the cost of delivering care, and may lead us astray by shifting our focus from the outcome to the process itself.
The difference between hope and hype is a respect for science devoid of political, emotional and financial interference. Let’s proudly raise that flag.
Ibrahim Hanna, MD is the Medical Director of Cardiac Electrophysiology at Princeton Baptist Medical Center.
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