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New Horizons in Atrial Fibrillation

Payal Kohli, MD TIMI Study Group, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts A REPORT FROM THE 2011 SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION © 2012 Direct One Communications, Inc. All rights reserved. 1

Disease Burden of Atrial Fibrillation

 With an overall prevalence of 0.4%–1%, atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice.

1,2   AF also accounts for one third of hospitalizations for cardiac rhythm disturbances.

2 Despite major advances in the diagnosis, risk stratification, and management of AF over the past two decades, mortality due to AF remains unchanged.

1  Over the same period, the aging US population has experienced a 66% increase in hospitalizations for treatment of AF.

Disease Burden of Atrial Fibrillation

 It is anticipated that 12–15 million patients worldwide will be diagnosed with AF by the year 2050.

2  The global epidemic in the incidence of AF affects various populations and ethnic groups and carries a high risk of stroke, all-cause mortality, heart failure, and associated hospitalizations.

 In Chinese patients of the Guangzhou Biobank Cohort, obesity (as defined by waist circumference or body mass index) was independently associated with a substantial risk of developing AF.

3  The annual cost to treat AF is $3,600 per patient.

Disease Burden of Atrial Fibrillation

  In a community-based study of 4,618 residents of Olmstead County, Minnesota, who were diagnosed with AF between 1980 and 2000, there was no evidence of improvement in overall mortality, early or late mortality, or mortality among patients with no preexisting cardiovascular conditions.

1 The reasons for these results are complex and may be a combination of: » The increased prevalence of AF, which, in turn, has increased the overall incidence of stroke.

» The introduction of potent antiplatelet therapies, which physicians use in place of anticoagulants.

Etiology of Atrial Fibrillation

 Atrial fibrillation results from increased ectopic activity in the atria, which can trigger susceptible substrates and lead to reentrant arrhythmia.   These triggers and substrates can result from a variety of causes, including environmental and genetic factors (eg, ischemic heart disease, hypertension, alcohol consumption, obstructive sleep apnea).

The most common risk factors are patient age and a history of myocardial infarction.

Etiology of Atrial Fibrillation

Biologic Factors

 Age appears to be the strongest risk factor for the development of AF.

4  Both acute and chronic coronary atherosclerotic disease confers risk. Observational data from a large cohort (n = 3,983) demonstrated a 3.6-fold increase in the risk of AF following a myocardial infarction.

4  Myocardial ischemia appears to produce both the trigger and the substrate for ectopic activity. In a canine model of coronary artery disease affecting the atria, sustained atrial ischemia/infarction following ligation of coronary vessels led to persistent ectopic activity, as well as substrates for reentry.

Genetic Factors

 Genetic factors may confer significant risk of AF by altering thresholds for triggers and by altering substrates.  Mendelian mutations are rare, but their presence suggests that this mode of inheritance plays a dominant role in the genetic predisposition for AF.  A mutation on chromosome 4q25 changes the function of PITX2, a gene involved in cardiac development, that doubles the risk of developing AF.

 Transgenic mice with Pitx2 mutations experience a loss of myocardial pacemaker cells, increasing their susceptibility to atrial arrhythmia.

Electrophysiologic Mechanisms

  Atrial fibrillation results from four principal electrophysiologic aberrations: 1. Increased arrhythmogenicity related to the pulmonary vein and other thoracic veins 2. Autonomic dysregulation 3. Fixed and functional reentry substrates, especially anisotropic high-frequency reentrant sources (“rotors”) throughout the atria 4. Electroanatomical remodeling of myocardial structures. One or more mechanisms may be responsible simultaneously for the generation of AF, making catheter ablation a more challenging option if the etiology is multifactorial.

Electrophysiologic Mechanisms

Atrial fibrillation is a heterogeneous arrhythmia that can result from a variety of electrophysiologic and electroanatomical mechanisms.

Adapted from a presentation by Hakan Oral, MD, at the 2011 Scientific Sessions of the American Heart Association.

Catheter Ablation

   Most commonly, pulmonary vein arrhythmogenicity triggers AF. For this reason, ablation efforts focus on targeting pulmonary vein tissue and the myocardial tissue cuff adjacent to the pulmonary vein.

Rotors, ganglionated plexi, and other triggers for AF also may be present. Techniques such as complex fractionated atrial electrography and isoproterenol infusions may be used to identify these triggers; however, their use may trigger passive activation of foci not responsible for generation and propagation of AF, resulting in false-positive results. These diagnostic procedures also may initiate an arrhythmia or induce contractile dysfunction.

Catheter Ablation

  Isolation of the pulmonary veins followed by isolation of the superior vena cava and the coronary sinus and subsequent linear ablation remains the most commonly used technique for catheter-based ablation.

Although surgical ablation is an option, the invasive nature of this procedure makes it less preferable.

 Ablation may result in embolic stroke, pulmonary vein stenosis, atrioesophageal fistula, atrial flutter, complete heart block, or recurrent arrhythmia.  Risk-prediction tools (eg, the CHADS 2 score) may be used to predict the thromboembolic risk of ablation.

Catheter Ablation

Schematic representation of pulmonary vein isolation and linear ablation, the most common catheter based technique for treating atrial fibrillation. Yellow connecting lines represent the trajectory for ablation.

Adapted from a presentation by Hakan Oral, MD, at the 2011 Scientific Sessions of the American Heart Association.

Indications for Ablation

ACC/AHA/HRS indications for ablation:  Symptomatic AF with Wolff-Parkinson-White syndrome  Symptomatic AF in the presence of persistent symptoms and failure of antiarrhythmic medications  Atrial fibrillation in the presence of heart failure or a decrease in ejection fraction ACR = American College of Cardiology; AHA = American Heart Association; HRS = Heart Rhythm Society © 2012 Direct One Communications, Inc. All rights reserved. 14

Indications for Ablation

Special consideration for ablation should be given to:  Young patients, who have a high likelihood of needing antiarrhythmic agents and anticoagulants for the rest of their lives  Patients with tachycardia-mediated cardiomyopathy   Patients with liver or renal disease that may complicate medical therapy Patients with structural heart disease © 2012 Direct One Communications, Inc. All rights reserved. 15

Rate vs Rhythm Control

 Physicians who choose not to use ablation for managing their patients with AF may need to consider the relative effectiveness of rate control versus rhythm control.

 The choice of whether to control rate or rhythm should be individualized for each patient and depends upon the: » » » » Patient’s age Type of symptoms Duration of disease Presence of additional comorbidities and stroke risk factors © 2012 Direct One Communications, Inc. All rights reserved. 16

Rate vs Rhythm Control

   Results of the AFFIRM study, in which 4,060 patients with AF were randomized to undergo rate control or rhythm control, suggested that rhythm control offered no survival benefit but was linked to a higher incidence of drug-related side effects.

8 The findings of a number of other studies (RACE, PIAF, HOT CAFE, AF-CHF, and J-RHYTHM) also demonstrated no benefit of rhythm control over rate control.

9–13 Data from the AF-CHF study even suggested an increase in hospitalizations due to bradyarrhythmia in the rhythm-control arm.

Rate vs Rhythm Control

 Data from the RACE-II trial suggested that rate control does not need to be as strict as previously thought necessary and that lenient rate control (heart rate < 110 beats/min, resting and exercise) is as effective as strict rate control (resting heart rate < 80 beats/min; exercise heart rate < 110 beats/min) and easier to achieve.

14  Therefore, rate control likely is the most effective strategy, especially for elderly patients who have minimal symptoms.

When to Use Rhythm Control

  In some situations, rhythm control is preferable.

For example, some patients who are especially susceptible to the long-term adverse effects of electroanatomical remodeling of the atria may benefit from maintenance of sinus rhythm. Sinus rhythm is, indeed, a marker for improved survival.

15  For this group, ablation (preferably catheter-based pulmonary-vein isolation), with or without the use of adjunctive antiarrhythmic drugs, is recommended.

 Because such remodeling is time dependent, this strategy should be employed early, after the decision to use rhythm control has been made.

Anticoagulation Therapy

 In addition to providing rate or rhythm control, anticoagulation is central to the management of AF.   Use of the CHADS 2 score to determine which patients with AF are appropriate candidates for anticoagulation therapy has been well established.

7 Nevertheless, Waldo et al with warfarin.

Underutilization of Warfarin

   Explanations for the underuse of warfarin in patients with AF most commonly include advanced age, which is highly correlated with increased intracranial hemorrhage, and the presence of preexisting bleeding diathesis (eg, gastrointestinal bleeding).

However, the most likely explanation relates to the complex dosing, intensive laboratory monitoring, and multiple dietary and pharmacologic interactions associated with warfarin therapy. For these reasons, great effort has been devoted to the study of novel oral anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban to treat patients with AF.

Novel Oral Anticoagulants

 The results of multiple clinical trials have emphasized the delicate balance between effective anticoagulation and the risk of hemorrhagic and thrombotic complications.

 Based on the results of the RE-LY study, 17 the FDA recently approved the use of dabigatran to prevent stroke in patients with nonvalvular AF, when given at a dose of 150 mg bid for patients with a creatinine clearance (CrCl) > 30 mL/min and at a dose of 75 mg bid for those with a CrCl = 15–30 mL/min.

Novel Oral Anticoagulants

 Likewise, the FDA recently approved the use of rivaroxaban to reduce the risk of stroke in patients with AF, based on the results of the ROCKET-AF trial.

18   The recommended dose for this purpose is 20 mg once daily for patients with a CrCl > 50 mL/min and 10 mg once daily for those with a CrCl = 30–50 mL/min. In addition, the FDA is giving priority review to the use of 5 mg of apixaban given twice daily based on positive results from the phase III AVERROES and ARISTOTLE trials.

Novel Oral Anticoagulants vs Warfarin

Novel Oral Anticoagulants

   These studies have provided a wealth of data that demonstrate the efficacy of oral anticoagulation therapy with minimal INR monitoring in patients with AF and low, medium, and high CHADS 2 scores. Postmarketing surveillance of dabigatran is ongoing. The FDA has issued warnings about increased bleeding related to the use of the drug in patients older than 75 years of age and the risk of rebound thromboses in patients who are transitioning from rivaroxaban to warfarin. Overall, however, dabigatran and other novel oral anticoagulants appear to be well tolerated.

Novel Oral Anticoagulants

 Concerns persist regarding the usefulness and cost effectiveness of novel anticoagulants in the setting of excellent control of the INR.

2  Potential drug interactions between both dabigatran and rivaroxaban with P-glycoprotein inhibitors (eg, dronedarone, ketoconazole) are of concern.

 Finally, many questions remain unanswered regarding the ability to reverse the anticoagulant effects of these drugs, patient monitoring, and the risks/benefits of using these agents against a background of potent antiplatelet therapy and in patients with AF and acute coronary syndromes.

Conclusion

 The transition of a new class of drugs from the clinical trial arena into clinical practice is often fraught with regulatory and logistic concerns.

   Often, safety warnings are issued after FDA approval.

Further, the addition of a new drug to other drugs a patient is already taking may compromise compliance.

Overall, however, the newer oral anticoagulants provide growing options within the medical arsenal, which will improve patient care and outcomes.

References

Miyasaka Y, Barnes ME, Bailey KR, et al. Mortality trends in patients diagnosed with first atrial fibrillation: a 21-year community-based study. J Am Coll Cardiol. 2007;49:986–992.

2. Fuster V, Ryden LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57:e101–e198.

3. Long MJ, Jiang CQ, Lam TH, et al. Atrial fibrillation and obesity among older Chinese: the Guangzhou Biobank Cohort Study. Int J Cardiol. 2011;148:48–52.

4. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med. 1995;98:476–484.

5. Nishida K, Qi XY, Wakili R, et al. Mechanisms of atrial tachyarrhythmias associated with coronary artery occlusion in a chronic canine model. Circulation. 2011;123:137–146.

6. Wang J, Klysik E, Sood S, Johnson RL, Wehrens XH, Martin JF. Pitx2 prevents susceptibility to atrial arrhythmias by inhibiting left-sided pacemaker specification. Proc Natl Acad Sci U S A. 2010;107:9753–9758.

7. Puwanant S, Varr BC, Shrestha K, et al. Role of the CHADS2 score in the evaluation of thromboembolic risk in patients with atrial fibrillation undergoing transesophageal echocardiography before pulmonary vein isolation. J Am Coll Cardiol. 2009;54:2032–2039.

8. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825–1833.

9. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347:1834–1840.

10. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial fibrillation—Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet. 2000;356:1789–1794.

References

11. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008;358:2667–2677.

12. Ogawa S, Yamashita T, Yamazaki T, et al. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM study. Circ J. 2009;73:242–248.

13. Opolski G, Torbicki A, Kosior DA, et al. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) study. Chest. 2004;126:476–486.

14. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010;362:1363–1373.

15. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109:1509–1513.

16. Waldo AL, Becker RC, Tapson VF, Colgan KJ. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J Am Coll Cardiol. 2005;46:1729–1736.

17. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151.

18. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–891.

19. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–992.

20. Mega JL. A new era for anticoagulation in atrial fibrillation. N Engl J Med. 2011;365:1052–1054.

21. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome.

N Engl J Med. 2012;366:9–19.