Introduction

Atrial fibrillation (AF) is a serious and growing problem in the United States. It is projected to affect 5.6 million adults by the year 2050. Complications, including stroke, may result from AF. As health care professionals, we seek to identify patients at highest risk for adverse events in an attempt to provide meaningful interventions to decrease the risk. The last few years have changed the way we reduce stroke risk in patients with AF with the introduction of non-vitamin K antagonist oral anticoagulants(NOACs).

When it comes to AF, thoughtfully considering which patients may benefit from anticoagulation is critical. Yet, given our historical choices for anticoagulation, uncertainties remain, largely revolving around the perceived risk of life-threatening bleeding; as such, warfarin has been underutilized. This chapter focuses on the risk of stroke in AF and the balance between the benefits and risks of anticoagulation, as well as new anticoagulants that may offer specific advantages over warfarin and the use of vitamin K and non-vitamin K antagonists (NOACs).

Assessing Stroke Risk in Atrial Fibrillation

Data from the Framingham study support that the presence of AF increases the risk of stroke nearly five-fold, a risk greater than that associated with hypertension, coronary disease, or heart failure. But the presence of other risk factors appears additive and the risk has been shown to be increased in the presence of congestive heart failure, hypertension, age greater than or equal to 75 years, diabetes, and history of previous stroke or transient ischemic attack (TIA).

These risk factors provide the basis for the CHADS2 scoring scheme, (Table I), which has been used to estimate the annual risk of stroke for an individual patient with AF. One point each is assigned for the presence of congestive heart failure, hypertension, age greater than or equal to 75 years, and diabetes; two points are assigned if a patient has had a previous stroke or transient ischemic attack.

A new scoring system, the CHA2DS2-VASc score, has largely replaced the CHADS2 scoring system. The CHA2DS2-VASc score has been validated to be a better risk predictor of stroke and is the scoring system recommended by the current guidelines.

The components of this scoring scheme are similar to those of the CHADS2 scoring system with one point assigned for congestive heart failure, hypertension, and diabetes. However, age 65-74 years is assigned a point, as is female gender. The presence of vascular disease, including a history of MI or peripheral artery disease, is assigned a point. If a patient is older than 75 years of age, two points are assigned. (Table I).

Which patients should receive oral anticoagulation and what is the goal?

Not all patients with AF will derive similar benefit from anticoagulation and the risk of bleeding may be increased in certain subgroups of patients. Current U.S. guidelines (AHA/ACC/HRS) and from Europe (ESC) suggest the use of the CHA2DS2-VASc as an effective scoring tool to determine if anticoagulation is warranted.

The current guidelines by the AHA/ACC/HRS and the ESC recommend anticoagulation with a NOAC or a VKA for patients with a CHA2DS2-VASc score > or =2. For the ESC the NOACs are preferred to vitamin K antagonists in these patients. For the AHA/ACC/HRS either NOACs or vitamin K antagonists are recommended.

For the patient with a CHA2DS2-VASc score of 1, the ESC recommends anticoagulation therapy. The US guidelines maintain that the clinicians can consider NOACs, vitamin K antagonists, or aspirin. Data from the Danish national registry and a national registry from Taiwan have shown that a CHA2DS2-VASc score of 1 in males and 2 in females is associated with increased stroke risk and mortality if not on anticoagulation. These data may increase the use of anticoagulation in lower risk patients.

Overall however, the guidelines place less value on aspirin use for stroke prevention in AF, particularly in higher risk patients.

Role of warfarin

Numerous randomized trials conducted in the 1990s have shown that anticoagulation with warfarin decreases the risk of stroke in patients with AF. A pooled analysis of these trials showed a relative risk reduction of 62%.

Based on pooled analyses of the data, but no randomized trials, the goal for anticoagulation with warfarin is an international normalized ratio (INR) of 2-3. This is on the basis that an INR of 2-3 decreases the risk of stroke and is associated with an acceptably low risk of intracranial hemorrhage. An INR >3 is associated with a greater risk of bleeding but little additional benefit in terms of stroke reduction.

Maintaining the INR within the therapeutic range is difficult. However, if the time in therapeutic range (TTR) is >65%, the risk of stroke is significantly reduced with vitamin K antagonists than with the combination of aspirin plus clopidogrel.

The role of non-vitamin K antagonist anticoagulants: a paradigm shift

While previous studies have shown the benefits of warfarin in reducing the risk of stroke in patients with AF, there are challenges with vitamin K antagonists, which result in underutilization. Warfarin use requires regular monitoring and is associated with drug-drug and drug-food interactions. To overcome these problems NOACs were developed.

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial randomized 18,113 patients with AF who were at risk for stroke to receive either dabigatran (110 mg orally or 150 mg orally twice daily), a direct thrombin inhibitor, or warfarin with a goal INR of 2-3. After a median 2-year follow-up, stroke and embolism rates (SSE) were significantly lower in the dabigatran 150 mg group compared with the warfarin group (1.11%/yr. vs 1.69%/yr. p<0.001). With regards to the risk of major bleeding, there was no significant difference between dabigatran 150 mg or warfarin (3.11%/yr. vs 3.36%/yr. p = .31), but there were fewer bleeding events in the dabigatran 110 mg twice daily group compared with warfarin (2.71%/yr. vs 3.36%/yr. p = .003). The 110 mg dose was non-inferior to warfarin with respect to stroke and systemic embolism and was superior to warfarin for the endpoint of major bleeding.

Nonetheless, after careful review, the FDA in the United States approved only the dabigatran 150 mg twice daily dose and, based on pharmacokinetic data, approved a dose of 75 mg twice daily for patients with renal insufficiency, although this dose was not included in clinical trials. In other countries, dabigatran 110 mg twice daily is available.

The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) randomized 14,264 patients with AF with the risk for stroke to receive rivaroxaban 20 mg once daily or warfarin. Rivaroxaban was shown to be non-inferior to warfarin in an on-treatment and intention-to-treat analysis (both P <.001) but was not shown to be superior to warfarin (P = .12). The primary endpoint of stroke or systemic embolism was significantly lower in the rivaroxaban group compared with warfarin (2.1/100 patient-yr. compared with 2.4/100 patient-yr.). There was no difference in major and non-major clinically relevant bleeding (14.9/100 patient-yr. in rivaraxaban group vs 14.5/100 patient-yr. in warfarin group P = 0.44) but there was a lower risk of intracranial hemorrhage in the rivaroxaban group (0.5/100 patient yr. vs 0.7 /100 patient-yr. P = .003).

Rivaroxaban approved by the FDA for prevention of stroke in non-valvular AF

The Apixaban for Reduction In STroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18,201 patients with AF at risk for stroke (at least CHADS2 of 1) to apixaban or warfarin. Apixaban was superior to warfarin in preventing stroke or systemic embolism (event rates 1.3%/yr. vs 1.6%/yr. P=0.01 for superiority). Apixaban was also associated with less bleeding (2.1%/yr. vs 3.1%/yr. P<0.001) and also lowered mortality (3.5%/yr. vs 3.9%/yr. P=0.047) compared with warfarin. Apixaban has been approved by FDA for prevention of stroke in patients with non-valvular AF.

The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial randomized 21,105 patients with AF and a CHADS2 score of >or = 2 to warfarin, edoxaban 30mg, or edoxaban 60mg once daily dosing. By modified intention to treat analysis, the rates of stroke or systemic embolism were 1.18%/yr. in the edoxaban 60mg, 1.6%/yr. in edoxaban 30mg and 1.5% in the warfarin arms. Both regimens were non-inferior to warfarin in preventing stroke or systemic embolism. Both edoxaban arms had significantly lower rates of bleeding (2.75%/yr. in edoxaban 60mg, 1.6%/yr. in edoxaban 30mg, 3.4%/yr. in warfarin arm P<0.001) and significantly lower cardiovascular deaths. Edoxaban has been approved by the FDA for stroke prevention in non-valvular AF. However, because of reduced efficacy in patients with a creatinine clearance >95ml/m², edoxaban is not recommended in these patients.

The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or are Unsuitable for Vitamin K Antagonist Treatment: A Randomized Double Blind Study (AVERROES) trial randomized 5,599 patients with AF at risk for stroke (CHADS2 score was ≥1) and who were deemed unsuitable to VKA therapy to aspirin or apixaban. Apixaban reduced the risk of stroke or systemic embolism (1.6%/yr. vs 3.7%/yr. P<0.001) with no increase in the risk of major bleeding or intracranial hemorrhage (1.4%/yr. vs 1.2%/yr. P 0.57) compared to aspirin.

The NOACs, compared with warfarin, have fewer drug-drug and drug-food interactions, may not require bridging anticoagulation, and do not require frequent dose adjustments. It is recommended that creatinine clearance be monitored at least annually and dosing needs to be adjusted for creatinine clearance.

For 50 or so years clinicians did not have an alternative anticoagulant to warfarin. Large, well-powered, randomized, controlled trials (RCT) with NOACs mentioned above have led to a paradigm shift away from warfarin use. NOAC use has gained rapid clinical acceptance. Recent data from the US and Europe have shown a trend towards increasing use of NOACs since their approval. Simultaneously the use of warfarin has also declined.

Unlike warfarin, tests to assess the anticoagulation effect of NOACs are not currently readily available. These tests have not been standardized and few of them are commercially available. There may be instances where measurement of the anticoagulant effect of a NOAC may be beneficial. These include: as a means to monitor compliance, in patients prior to selected procedures including cardioversion, in patients with possible drug interaction, or in patients who experience major bleeding. The value of these measurements in selected patients still needs to be defined. The lack of reversal agent was considered a disadvantage of NOACs. Now, with the development of reversal agents for both dabigatran and factor Xa inhibitors, this might not be an issue.

Undesirable effects

Are there ways to assess the risk of bleeding?

Weighing the risks and benefits of anticoagulation is important for each patient, but this is especially the case in elderly patients who may have a greater risk of falls or significant bleeding with oral anticoagulation. The Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial, sought to determine the safety and efficacy of warfarin anticoagulation versus aspirin in an elderly AF population. The trial showed that warfarin anticoagulation was still beneficial compared with aspirin. The group randomized to aspirin had more bleeding events than those receiving warfarin.

Nonetheless, scoring schemes have been developed to help determine which patients are at greatest risk of bleeding in the presence of oral anticoagulation. In the HAS BLED scoring scheme, patients with a score greater than or equal to 3, are at high risk for bleeding (Table II). Unfortunately, many of the parameters which predict bleeding also predict stroke.

Another bleeding risAnother bleeding risk stratification scheme derived from tk stratification scheme derived from the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study assigns three points to the presence of anemia or severe renal disease (glomerular filtration rate <30 ml/min or dialysis dependence), two points for an age greater than or equal to 75 years, and one point for a history of prior hemorrhage or diagnosed hypertension.

If the cumulative score is 0-3, the patient is considered to be at low risk for hemorrhage related to warfarin use with an annualized hemorrhage rate of 0.76%. If the cumulative score is 4, the patient is considered to be at intermediate risk (with an annualized rate of hemorrhage 2.62%). If the score is between 5-10, the patient is at high risk for hemorrhage with an annualized rate of 5.76%.

The ACC/AHA/HRS do not advise the formal use of bleeding scores. There is concern that certain high-risk patients would be deprived of stroke reducing anticoagulation therapy. The ESC guidelines recommend the use of a HAS-BLED score to assess the risk of bleeding. The scores may be helpful in identifying patients who require extra surveillance.

Choice of anticoagulant

Although the clinician has a choice of NOAC and VKA for patients with non-valvular AF, VKAs are the choice for patients with valvular AF.

There still exists a degree of uncertainty regarding what constitutes valvular AF. Valvular AF is defined as AF associated with mechanical or bioprosthetic valves, rheumatic mitral stenosis, and mitral valve repair. AF associated with non-rheumatic valvular disorders, including aortic valve pathology and mitral regurgitation, can be treated with NOAC or VKA. There was significant heterogeneity in the exclusion criteria and definition of valvular AF among the RCTs involving NOACs. Both ACC/AHA and ESC guidelines agree that mechanical heart valves and rheumatic heart disease are a subset that should be on VKA therapy. A few patients with bioprosthetic valves were enrolled in ENGAGE AF TIMI and ARISTOTLE trials. A well-powered RCT of NOACs compared with VKAs in patients with bioprosthetic valves and mitral repair is needed to identify the anticoagulant of choice.

Trials with NOACs have excluded patients with advanced kidney disease. Hence warfarin is recommended for patients with chronic kidney disease and GFR <15 ml/min. Apixaban is dosed at 5 mg twice a day and the dose is adjusted to 2.5mg twice daily if 2 of 3 criteria are met (age >80 years, creatinine >1.5 mg/dl, body weight <60 kg). Although no direct comparisons are available between NOACs, dabigatran is often used in very high-risk patients for stroke since the risk reduction compared with warfarin was very high for ischemic stroke. Rivaroxaban and edoxaban are once daily dosing and may be beneficial for patients with compliance issues or memory loss. For patients at risk of bleeding, apixaban has a lower bleeding rate, including lower GI bleeding compared with warfarin.

Special situation

Silent atrial fibrillation

The incidence of silent AF is uncertain. Between 12-20% of patients with known AF do not have symptoms.

Available data support the notion that stroke and TIA occur similarly in patients with paroxysmal, persistent, or permanent AF. Data from the AFFIRM study showed that mortality and major events were similar in symptomatic and asymptomatic AF.

Patients with atrial-based pacemakers provide an additional perspective on patients with AF. These devices are capable of continuously monitoring atrial activity and can detect and determine the duration of episodes of AF, many of which are not symptomatic.

In the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial, the burden and risk of subclinical atrial tachyarrhythmias using atrial high-rate event data from patients with pacemakers with no prior diagnosis of AF was studied. Subclinical atrial tachyarrhythmia was defined as atrial rate >190 bpm for a duration >6 min. The study showed that the risk of stroke was increased in patients with subclinical arrhythmias (event rates of stroke/systemic embolism 1.7%/yr. vs 0.7%/yr. P=0.007). An interesting aspect of this study was the fact that only half of the patients with a stroke had evidence of subclinical AF. However, many of these patients did not have AF detected prior to the stroke.

Device detected AF can also detect atrial arrhythmias in patients who have had a stroke with no known cause. In the Cryptogenic Stroke and Underlying Atrial Fibrillation (CRYSTAL AF) study, the use of implantable cardiac monitors (ICM) was shown to be superior to conventional monitoring (clinical follow-up and short-term ECG monitoring) for detecting AF. At 12 months, AF detection rates were 12.4% in the ICM arm versus 2% in the conventional arm (p<0.001). Whether anticoagulation therapy reduces stroke in these patients remains to be determined.

In summary, the direct link between AF and stroke remains elusive. It may be that AF is a marker for stroke risk and simply reflects other structural heart disease including fibrosis, hypertrophy, or valvular disease. Whether or not oral anticoagulation reduces stroke in subclinical AF is the subject of clinical trials.

Direct current cardioversion

Direct current cardioversion (DCCV) is performed to restore sinus rhythm in patients with AF and atrial flutter. For patients undergoing DCCV, thromboembolic stroke is a concern, especially if the AF has been ongoing for ≥48 hours or unknown duration or there is structural or functional cardiac disease. If the patient is hemodynamically unstable, then DCCV should be performed and heparin anticoagulation started concurrently.

If the patient is stable however, one option would be to give oral anticoagulation with VKA and then perform DCCV. A therapeutic INR of 2-3 is recommended for 3 consecutive weeks before DCCV is performed.

Another option would be to perform a transesophageal echocardiogram (TEE) to evaluate for thrombus. If negative, perform DCCV with initiating anticoagulation with heparin or low molecular weight heparin. If thrombus is present, anticoagulation with an INR of 2-3 on warfarin should be initiated for at least 3 weeks prior and 4 weeks after cardioversion. Patients with a high CHA2DS2-VASc score might be continued on therapy indefinitely.

It is advisable to continue anticoagulation for at least 4 weeks after cardioversion because mechanical remodeling may lag behind electrical remodeling, putting the patient at risk for stroke despite the presence of sinus rhythm.

NOACs can be used as alternative to warfarin for anticoagulation prior to cardioversion. The data regarding safety and efficacy of NOACs at the time of cardioversion comes from post-hoc analysis of patients from the large RCTs discussed above.

Patients in the RELY study who underwent electrical cardioversion with or without TEE showed low and comparable rates of stroke/systemic embolism (SSE) with dabigatran compared to warfarin (0.77%, 0.30%, and 0.60% in D110, D150, and warfarin, respectively). The rates of major bleeding were also low across all the groups. (1.7%, 0.6%, and 0.6% in D110, D150, and warfarin, respectively). The presence of left atrial thrombus was low with either warfarin or dabigatran (1.1%, 1.8%, and 1.2% in D110, D150, and warfarin groups respectively) when TEE imaging was performed. The rates of SSE were similar in patients who underwent TEE vs those who did not undergo TEE.

Rivaroxaban use in patients undergoing electrical cardioversion was evaluated in a prospective randomized trial entitled the eXplore the efficacy and safety of once-daily oral riVaroxaban for the prevention of caRdiovascular events in patients with non-valvular aTrial fibrillation scheduled for cardioversion (X-VeRT). The trial showed similar rates of adverse events between rivaroxaban and VKA arms (stroke rate 0.5% vs 1%). However, the rivaroxaban treated arm had significantly shorter time to cardioversion compared to VKA (mean duration 25 days vs 34 days). Post-hoc analysis from the ARISTOTLE trial in patients undergoing cardioversion showed rare and comparable event rates of SSE (0 in both arms), major bleeding (0.3% vs 0.2%), and death (0.6% vs 0.5%) between apixaban and warfarin.

In summary, NOACs appear to be as effective as warfarin in the prevention of stroke related to cardioversion. The time to cardioversion is shorter with NOACs.

Risk of stroke after ablation

It is generally accepted that patients receive anticoagulation for some period of time after ablation, but there is debate regarding the duration of anticoagulation thereafter. A non-randomized study suggested that patients without recurrence of AF may stop anticoagulation after 3-6 months and have a risk of stroke not different from those patients continuing warfarin (0.07% vs 0.45% P=0.06). In another study by Saad et al., discontinuation of anticoagulation after ablation in patients with a CHADS2 score ≤3 was not associated with significant thromboembolic risk during a follow-up period of 4 years. The patients were maintained on antiplatelet therapy indefinitely. Observational studies have shown a lower incidence of embolic events in patients undergoing AF ablation compared to the general AF population (0.6 vs. 1.71 per 100 patient-years in patients with CHA2DS2VASc ≥ 2).

The incidence of AF recurrence in a patient who has undergone ablation is unpredictable and the patient may be asymptomatic. The practitioner should fully evaluate the risk of stroke for each patient undergoing AF ablation using the CHA₂DS₂-VASc score; if he or she is at risk for stroke, even after ablation, anticoagulation therapy should be continued, sometimes indefinitely until we have more evidence.

Interruption of anticoagulation

Anticoagulation therapy may need to be interrupted for certain surgical procedures or invasive procedures. Parenteral anticoagulants are often used to prevent thromboembolic events. However, the safety and efficacy of this bridging anticoagulation has been questioned. A meta-analysis in patients receiving vitamin K antagonists has failed to demonstrate a reduction in thromboembolic events and has reported excess major bleeding with bridging anticoagulation. A prospective, randomized trial in patients at moderate risk for thromboembolic events (CHADs score 2.3) found a low rate of thromboembolic events, not significantly different between placebo and dalteparin (0.4% vs 0.3% P=0.01 for non-inferiority), and significantly higher rates of major bleeding with parenteral anticoagulation (3.2% vs 1.3% P=0.005 for superiority). Consequently, the use of parenteral anticoagulation when vitamin K antagonists are interrupted for surgery or an invasive procedure in patients at lower risk of thromboembolic rates is discouraged. The value of bridging in patients at higher risk of thromboembolic rates and for patients with longer duration of interruption of anticoagulation is being defined.

NOACs have a shorter duration of action compared to VKAs. Depending on the risk of bleeding associated with the procedure (low risk vs high risk) and the degree of renal impairment, NOACs are generally stopped 24-72 hours prior to the procedure. All NOACs carry a black box warning for increased risk of stroke when these agents are stopped which will be a concern for the patient as well as the physician. The use of parenteral anticoagulants in conjunction with NOACs is still being defined. Many procedures at lower risk for bleeding are being performed with no or brief interruption of anticoagulation therapy.

Anticoagulation in patients with coronary stents

Patients with AF may have acute coronary syndrome and undergo coronary stent implantation. This adds aspirin and P2Y12 inhibitor (clopidogrel, ticagrelor, prasugrel) to the drug regimen which may include NOACs or warfarin. Therapy with aspirin/P2Y12 inhibitor (DAPT; dual antiplatelet therapy) and warfarin (triple therapy) is associated with an increased risk of bleeding. Results from the ACTION (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines) registry has shown higher rates of major bleeding in patients receiving triple therapy (17.6% vs 11% p < 0.0001) without significant difference in composite of MI, death, or stroke (32.6% vs 32.7% p=0.99) compared to DAPT.

Registry data have shown that the use of P2Y12 inhibitor/warfarin combination is associated with similar adverse cardiac events and non-significant but lower risk of bleeding compared to triple therapy. A small, underpowered RCT – WOEST (What is the Optimal antiplatElet & Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary StenTing) – investigated the safety and efficacy of clopidogrel+anticoagulation (dual therapy) versus aspirin+clopidogrel+anticoagulation (triple therapy). Dual therapy was associated with a non-significant decrease in bleeding risk (11% vs 14.3% per 100 patient-yrs.) and no increase in thromboembolic events (1.2% vs 2.5% per 100 patient-yrs.). RCTs are ongoing to help aid clinical decision-making in this subset. A consensus recommendation from ESC/HRS suggests proton pump inhibitor use in patients on triple therapy. However, there is no evidence from RCTs to support this recommendation.

The optimal stent choice and the optimal combination of antiplatelet and anticoagulants that provides clinical benefit with acceptable bleeding risk remains to be determined. Evidence from RCTs is awaited to answer these dilemmas that clinicians face in day-to-day practice.

Conclusion

AF is a serious and growing health problem in the United States and the global community. The presence of AF increases the risk of stroke, which in turn has its own problems and impact. Data have shown that the use of warfarin reduces the risk of stroke in patients with AF, yet this drug has been historically underutilized due to challenges with its use.

NOACs are easier to use, have a lower risk of major bleeding, and have been shown to be non-inferior, and in some cases, superior to warfarin. NOACs have started to replace warfarin as first choice anticoagulant in clinical practice. Optimal strategies to reduce stroke and risk of major bleeding in subsets of AF patients undergoing PCI and ablation will continue to evolve. As we evaluate our patients with AF, we must carefully address the risk of stroke and give recommendations regarding the use of anticoagulation to reduce the risk.

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