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CardioNerds (Amit Goyal), Dr. Colin Blumenthal (CardioNerds Academy House Faculty Leader and FIT at the University of Pennsylvania), and Dr. Anjali Wagle (CardioNerds Ambassador and FIT at Johns Hopkins University), discuss the baseline assessment of stroke and bleeding risk in patients with atrial fibrillation (AF) with Dr. Elaine Hylek. Dr. Hylek is a professor of medicine at the Boston University School of Medicine and is the Director of the Thrombosis and Anticoagulation Service at Boston Medical Center. Stroke is a potentially devastating and preventable complication of AF. Understanding the balance between stroke and bleeding risk is crucial in determining who should be on anticoagulation. Join us to discuss this topic! In the next episode of the series, we will discuss situational risk assessment in the context of peri-cardioversion, peri-procedural status, triggered atrial fibrillation, and more. Audio editing by CardioNerds Academy Intern, Pace Wetstein.

This CardioNerds Atrial Fibrillation series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Kelly Arps and Dr. Colin Blumenthal.

This series is supported by an educational grant from the Bristol Myers Squibb and Pfizer Alliance. All CardioNerds content is planned, produced, and reviewed solely by CardioNerds.

We have collaborated with VCU Health to provide CME. Claim free CME here!

Disclosures: Dr. Hylek discloses grant and research support from Medtronic and Janssen, and honoraria and/or consulting fees from Boehringer Ingelheim, and Bayer.

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls and Quotes – Atrial Fibrillation: Assessment of Stroke & Bleeding Risk

1. The CHA₂DS₂-VASc should be used to determine stroke risk in all patients. It was updated from the CHADS₂ score to better separate patients into high and low risk and a score of 0 has a very low risk of a stroke.
2. Understanding a given model’s derivation is key to application for any risk model. Understanding who was and was not included when a risk score was derived helps determine how to clinically use it. For example, mechanical valves, hypertrophic cardiomyopathy, cardiac amyloidosis, and moderate to severe MS were all excluded or poorly represented and should receive AC in AF regardless of CV.
3. The HAS-BLED score should be used to identify modifiable risk factors for bleeding and address them. It is less useful to determine when we should stop AC. Factors that go into the score are dynamic and the intention was to alert the provider of potentially modifiable factors that could be addressed to lower bleeding risk (such as better BP control).
4. Fear the clot. Patients should be on AC unless there is a serious contraindication as embolic strokes can be devastating with a high mortality (~24% mortality at 30 days)
5. “What am I saying by not writing the prescription… I am saying that it’s OK to have an ischemic stroke.” Survey data shows that patients are willing to experience 3.5 GI bleeds on average before 1 stroke, so favoring AC is often a patient centered approach

Notes – Atrial Fibrillation: Assessment of Stroke & Bleeding Risk

Notes drafted by Dr. Anjali Wagle

1. Why do strokes happen in atrial fibrillation? Why is reducing stroke risk so important?

Atrial fibrillation is associated with a significantly increased risk of stroke. The mortality of strokes related to AF have been estimated to be around 25% at 30 days in early studies which included either persistent or permanent AF, though of note, these studied were biased towards larger strokes since the diagnosis was based on physical exam and not high resolution imaging.

AF promotes thrombogenesis through Virchow’s triad which includes:

1. Abnormal blood flow
2. Endothelial damage
3. Hypercoagulability

In atrial fibrillation, patients usually have a dilated left atrium and decreased blood flow through the atrial appendage which contribute to thrombogenesis.

Multiple risk scores have been derived (i.e., CHA₂DS₂VASc) for estimation of stroke risk in patient with AF to identify whom to treat with anticoagulation to reduce the stroke risk.

2. How were CHADS₂ and CHA₂DS₂VASc (CV) created and validated?

The CHADS₂ score was derived in 2001 by Gage et al from data including hospitalized patients with nonrheumatic AF who were not prescribed warfarin at hospitalized discharge. The CHADS₂ score assigns one point to congestive heart failure, hypertension, age ≥ 75 years, and diabetes mellitus and two points to a previous history of stroke or transient ischemic attack (TIA) for a total of 6 points. Stroke rate per 100 patient-years rose by a factor of 1.5 for each 1-point increase in the CHADS2 score.

However, it was found that there were several limitations associated with the CHADS₂ score including that more than half of the patients were classified as moderate risk, making it unclear if antiplatelet or anticoagulation should be used in this population. Additionally, there were other “minor” risk factors (female sex, CAD, age 65-74) that were not included in the score.

In 2010, Lip et al proposed the CHA₂DS₂VASc score that included these three additional factors: female gender, vascular events, and age 65-74. These additions to the original CHADS₂ score allowed the CHA₂DS₂VASc score to reclassify patients in the moderate risk group into either the high or low risk groups (CV <1 or >2), making the decision of when to start anticoagulation easier.

Some weaknesses of the CV score include that the individual factors are binary. For example, one point for diabetes does not discriminate risk based on if the patient’s A1c is 14 vs. 7. Similarly, the score is static and assumes the risk from each risk factor doesn’t change over time even though the endothelial dysfunction caused by a specific disease state isn’t fixed. Additionally, the C-statistic for the CV score is only 0.6 with newer scores that are more accurate including such as GARFIELD-AF (but these newer scores are less user friendly). That being said, the score still does a very good job of differentiating between high and low risk patients, which is the most important clinical question when deciding if someone needs anticoagulation.

3. Which populations were not studied in the validation of the CV score?

Many of these studies have woefully low enrollment of racially diverse populations. Additionally, patients with amyloidosis, moderate-severe MS, and HOCM have a baseline higher risk of stroke were excluded from these studies. Patients with bioprosthetic valves were also excluded from the original derivation though there is now limited data showing use of the CV is reasonable.

4. How does AF burden affect stroke risk? Is there a temporal association between AF and stroke?

Early trials did not find a temporal association between AF and stroke, though these trials often used physical exam definitions for stroke and current technology like implantable loop recorders (ILRs) didn’t exist to monitor 24/7. More modern studies like the TREND and KP-RHYTHM trials showed that stroke risk is related to AF burden. Longer episodes of AF seem to clearly be associated with stroke, but shorter episodes of AF aren’t as temporally related to stroke. In the LOOP trial use of ILRs to detect episodes of AF longer than 6 minutes led to a 3-fold increase in AF detection and initiation of AF, but did not reduce the number of strokes. This could indicate that there is some amount of AF that doesn’t require AC or that short runs of AF are associated with atrial myopathy that could be causing the strokes. It remains unclear what is the “chicken and egg” in this scenario.

5. How can we assess bleeding risk for patients with atrial fibrillation? How can we use these scores in our clinical practice?

Developed and published in 2010 by Pisters et al., the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly [age >65], medication predisposing to bleeding, excessive alcohol use) score aimed to create an easy to calculate and clinically meaningful score to estimate bleeding risk. It was validated using 3,978 patients from the Euro Heart Survey on AF and had good predictive accuracy (C-statistic 0.72). Of note, the score uses the less severe ISTH definition for a major hemorrhage, which doesn’t require as severe bleeding as the TIMI major bleeding definition.

Many of the factors that go into the score are dynamic (for example HTN is SBP > 160 and not a history of HTN). The intention was to alert the provider of potentially modifiable factors that could be addressed to lower bleeding risk (such as better BP control). This would reduce the patients HAS-BLED score and therefore their bleeding risk. There is no absolute cutoff where anticoagulation in AF would be considered prohibitive.

6. What is the approach for patients with borderline stroke risk with a CV of 1 in men or 2 in women?

Patients with a CV of 1 have between a 0.6% and a 0.9% risk of stroke/TIA/systemic embolism in a given year. That means even with a CV of 1 they have close to a 1/100 risk of an event in a given year. Given the high mortality and morbidity with embolic strokes and the lower incidence of major bleeding with modern DOACs, should have shared decision-making conversation with patients about starting AC at this risk level. One can consider other risk factors not in CV like LA function, appendage morphology, AF burden etc to help as tie breakers.

References – Atrial Fibrillation: Assessment of Stroke & Bleeding Risk

1. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010 Nov;138(5):1093-100.
2. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of Clinical Classification Schemes for Predicting Stroke: Results From the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864–2870.
3. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society. Journal of the American College of Cardiology. 2006;48(4):e149-e246. doi:10.1016/j.jacc.2006.07.018
4. Lip GY, Lim HS. Atrial fibrillation and stroke prevention. The Lancet Neurology. 2007;6(11):981-993. doi:10.1016/S1474-4422(07)70264-84.
5. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic Therapy to Prevent Stroke in Patients Who Have Nonvalvular Atrial Fibrillation. Ann Intern Med. 2007;146(12):857-867. doi:10.7326/0003-4819-146-12-200706190-00007
6. van Doorn S, Debray TPA, Kaasenbrood F, et al. Predictive performance of the CHA2DS2-VASc rule in atrial fibrillation: a systematic review and meta-analysis. Journal of Thrombosis and Haemostasis. 2017;15(6):1065-1077. doi:10.1111/jth.13690
7. Lip GYH, Nieuwlaat R, Pisters R, Lane DA, Crijns HJGM. Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using a Novel Risk Factor-Based Approach. Chest. 2010;137(2):263-272. doi:10.1378/chest.09-1584
8. Okumura K, Inoue H, Atarashi H, et al. Validation of CHA₂DS₂-VASc and HAS-BLED Scores in Japanese Patients With Nonvalvular Atrial Fibrillation: – An Analysis of the J-RHYTHM Registry –. Circ J. 2014;78(7):1593-1599. doi:10.1253/circj.CJ-14-0144