Atrial fibrillation. Causative factors of AF. Untreated/inadequately treated hypertension

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1 Earn 3 CPD Points online Atrial fibrillation 30 years on Review of atrial fibrillation and the lessons of 30 years Professor Paul Dorian Division of Cardiology and Division of Clinical Pharmacology University of Toronto Toronto, Canada Stroke prevention is the single most effective and achievable treatment in AF and is safer than generally believed This article was made possible by an unrestricted educational grant from Boehringer Ingelheim. At the outset of this review, Professor Paul Dorian from the University of Toronto points out that atrial fibrillation (AF) is not one disease; it is a rhythm disorder that has numerous causes and manifestations. The best strategy is to treat the patient, not the arrhythmia, while remaining extremely aware of the fact that AF not only shortens lifespan but adversely affects the patient s quality of life. The primary problem is that this rhythm disorder seriously affects the patient s quality of life, beyond the underlying causative condition, Professor Dorian stressed. Personally, I am not convinced that AF is a direct cause of increased mortality, except for its role in stroke. However, there is no question that AF is associated with increased mortality, but that is primarily because of the disease causing the rhythm disorder, whether it be heart failure, coronary artery disease, hypertension or diabetes. Professor Dorian noted that the issue of whether to use rhythm or rate control, debated over a number of years, is not helpful, as most patients require both interventions. It also diverts attention from what should be the real focus, which is reducing the risk of stroke and getting patients to feel better, however that is achieved. Contemporary treatment goals in AF were summarised by Professor Dorian Causative factors of AF Untreated/inadequately treated hypertension I find it helpful to think of AF as endorgan damage derived from inadequate treatment of long-standing hypertension in the majority of patients seen in Westernised societies. With regard to hypertension in AF patients, there is some evidence, as yet incomplete but persuasive, which suggests (Table1). Symptom control should be directed at improving the individual s quality of life, rather than emphasising the restoration of sinus rhythm in the belief that this prolongs life. Table 1. Treatment goals in AF Reduction of cardiovascular morbidity and mortality Thromboembolism prevention Symptom control Therapy to reduce major morbid events (CHF, ischaemic events, hospitalisations) More consistent use of anticoagulants Individualised treatment patient-specific therapeutic contract Anti-arrhythmic drugs may be effective in restoring normal rhythm, but may also shorten life by causing pro-arrhythmias and other toxicity. AF ablation can be effective in restoring sinus rhythm. Causative and contributing factors to the development of non-valvular AF can and should be better controlled. Undiagnosed/inadequately treated hypertension and obesity/sleep apnoea are the chief targets. Lifestyle contributions, such as excessive lifelong competitive exercise and episodic alcohol excess, should also be the focus in at-risk patients. that the office-based blood pressure target for these patients should be 135/85mmHg. Current research is ongoing in this area, Professor Dorian noted. Very useful evidence of the importance of hypertension in AF was presented in a poster at the 2014 American College of Cardiology meeting using data drawn from the ARISTOTLE trial of apixaban versus warfarin (Figure 1). 1 Two 1

2 Stroke or systemic embolism HR 1.53, 95% CI Death from any cause HR 0.99, 95% CI Cardiovascular death HR 1.06, 95% CI Myocardial infarction HR 1.38, 95% CI ISTH major bleeding HR 1.12, 95% CI Major or clinically relevant non-major bleeding HR 1.14, 95% CI Any bleeding HR 1.11, 95% CI Uncontrolled blood pressure worse *Poorly controlled blood pressure is defined as SBP > 140 mmhg and/or DBP > 90 mmhg at any point during the trial using the average of 2 most recent blood pressure measurements for each time point. Stroke or systemic embolism endpoint adjusted by age, region, weight, diabetes, moderate valvular disease, prior stroke/tia/systemic embolism, type of atrial fibrillation and prior VKA use. Death from any cause, cardiovascular death, and myocardial infarction adjusted for by age, sex, region, weight, moderate valvular disease, left bundle branch block, history of myocardial infarction, prior stroke/tia/systemic embolism, anemia, smoking status, prior VKA use, NYHA class, CHADS2 score and renal function. Bleeding safety outcomes were adjusted by age, sex, region, coronary artery disease, prior myocardial infarcion, history of bleeding, anemia, CHADS2 score, and renal function. Figure 1. Adjusted hazard ratios and 95% CI for the association between poorly controlled blood pressure and efficacy and safety endpoints We need to redouble our efforts to control hypertension measured episodes of poorly controlled hypertension (>140/90mmHg) were associated with a 50% increase in the risk of stroke (adjusted by age, geographical region, weight, diabetes, moderate valvular disease, prior stroke/tia, systemic embolism, type of AF and prior vitamin K use) and a 40% increase in the risk of myocardial infarction. Obesity and sleep apnoea In a large North American survey of patients with AF under the age of 75 years, 50% of patients had undiagnosed sleep apnoea, frequently associated with obesity. Treating sleep apnoea reduces the episodes of AF, Professor Dorian noted. Weight reduction and cardiometabolic risk factor modification have been shown in a randomised clinical trial to reduce the burden of AF and improve quality of life (Table 2). 2 Exercise and fitness in AF Exercise plays a positive role in the prevention of the advent of AF, although extremes of exercise (ultra-marathon) fall outside this. A very recent study among the general population in Finland highlights the relationship between cardiorespiratory fitness and AF. 3 The authors warn that more than 50% of sedentary patients will develop AF by the age of 75 years. Increasing levels of fitness are, however, associated with a substantial reduction in the 25-year risk of developing AF. Table 2. Weight reduction and risk factor modification reduce AF burden and improve quality of life. 2 Mean Intervention Control Variable Baseline (n = 75) Follow-up a (n = 42) Baseline (n = 75) Follow-up a (n = 39) p Value b Atrial fibrillation detected by 7-d continuous ambulatory rhythm recording n = 75 n = 57 n = 75 n = 52 1 episode, No. (%) 49 (65) 9 (21) 43 (57) 22 (56) <.001 No. of episodes 3.3 (1.6 to 4.9) 0.62 (0.19 to 1.0) 2.8 (1.7 to 4.0) 2.0 (1.1 to 3.0) <.001 Total duration, min 1176 (720 to 1632) 491 (159 to 822) 1394 (795 to 1994) 1546 (782 to 2308) <.001 2

3 Proportion of cases Moderate exercise reduces risk Total endurance training (hours) Figure 2. Moderate endurance training decreases the risk for lone AF Baseline risk in sedentary person Vigorous exercise eg. approx 1 hr. 3 /wk for 20 years increases risk Regression analysis associated height (OR 1.06 p = 0.03), waist circumference (OR 1.06 [95% CI ], p < 0.01), OSA (OR 5.04 p = 0.01), and cumulative heavy sport activity of more than 2000h with an increased risk of AF (OR 4.52 [95% CI ], p < 0.001). The NOACs offer a better alternative to warfarin for AF patients At the extremes of competitive exercise, there is a signal of an increased risk of developing incident AF. 4 Although moderate exercise reduces the risk of Stroke prevention in AF It is important to realise that it is the presence of AF, not the burden of symptoms of AF, that increases the risk of stroke. One of the most important studies used to rate the risk factors for predicting stroke and thromboembolism in patients with AF was a nationwide Danish study. 5 It included patients admitted to hospital with AF who were not being treated with an oral anticoagulant (at that stage, , being treated with a vitamin K antagonist). They were then followed for 10 years and had their stroke or thromboembolism events recorded (Table 3). Table 3. Stroke/systemic embolism rates/ 100 patient years (no oral anticoagulants) ALL pts. Are CHADS 0 or 1 Score and covariates 10 years follow-up CHA 2 DS 2 -VASc score= (0.57 to 0.76) CHA 2 DS 2 -VASc score=1 Heart failure 1.78 (0.99 to 3.21) Hypertension 1.49 (1.21 to 1.84) Diabetes mellitus 2.02 (1.29 to 3.16) Vascular disease 1.47 (1.01 to 2.12) Age (1.83 to 2.38) Female sex 0.82 (0.68 to 1.00) developing AF, extremely intensive exercise may increase the risk, as in the case of competitive exercise (Figure 2). It is clear from this study that age contributed the most to the risk of developing a stroke/systemic embolism. This study included patients at low and moderate risk for AF and thus excluded patients with prior stroke who are already known to have a very high stroke risk. In this study, just being aged with AF, without any other risk factors, resulted in a 2% absolute risk per year of experiencing a stroke in the next 10 years. This translates into a 10-year risk of experiencing a stroke of 18-20% in these patients. It is recommended that all of these patients be on anticoagulants. Warfarin is a very effective anticoagulant, but there are problems with both the usage and management of patients on warfarin, Professor Dorian said (Table 4). Table 4. What is the problem? Initiation of warfarin is associated with an early increased risk of major haemorrhage Initiation of warfarin in patients newly diagnosed with AF increases stroke rates in the short run (2-4 weeks) Doctors still ( ) don t like to use warfarin More than 50% of patients stop warfarin within a year 3

4 Warfarin is a very hard medication to continue for life All the novel oral anticoagulants (NOACs), i.e. non-vitamin K antagonists (VKAs), have been shown to be as or more effective than warfarin in stroke prevention in AF in both warfarin-naïve and warfarin-experienced patients. A very important consideration in dealing with well-controlled warfarin-treated AF patients is that past good control is not a predictor of future optimal benefit. Among very large randomised trials, a UK study of chronic AF patients being treated in general practice underscores the difficulties of using warfarin to prevent strokes in AF. 6 In this study, those patients at greatest risk (age 70 and older) were less likely to be put on VKA treatment and four years after initiation of therapy (in those receiving therapy) 50% would discontinue their therapy contributing to a large pool of unprotected patients. The worldwide appropriate use of oral anticoagulation in AF remains low and INR control is sub-optimal (data drawn from the RE-LY AF Registry which includes Africa). 7 On average, only 30-40% of AF patients are adequately controlled on their warfarin therapy. Patient-centred care is a vital part of today s medical practice and in the context of AF it is important to understand what patients think about bleeding and stroke, as well as what their attending physicians think about these conditions. From a well-conducted study 8 undertaken a number of years ago, it is clear that patients are much more invested in avoiding strokes than avoiding bleeds, while their physicians are comparatively more concerned about bleeding. This study ensured that patients understood the consequences of major bleeds and stroke; despite this, the majority of patients were willing to experience 22 bleeds in order to avoid one stroke, while their physicians would only tolerate 2-4 bleeds to avoid one stroke in their patients. The NOACs offer advantages to physicians and patients in this regard, as they are more effective (or non-inferior) in reducing stroke (or systemic embolic events) than warfarin with a reduction (or non-inferiority) in respect of major bleeds (Figure 3). 9 The absolute number of life-threatening bleeds is less with dabigatran than with warfarin. 10 Rivaroxaban therapy leads to a higher overall rate of transfusion requirement for haemoglobin drop than warfarin, but reduces the number of life-threatening severe bleeds, 11 Professor Dorian pointed out. An objection that has been raised to the use of NOACs includes the non-availability of a reversal agent for these anticoagulants. While much can be said about this, a recent study 12 has shown that if a patient has a major bleed with warfarin (which has an antidote), the likelihood of dying is 13% over the ensuing 30 days, while the risk of dying following a major bleed on dabigatran, currently without a reversal agent, is only 8% (Figure 4). In summary, stroke is the single most important and preventable cause of death and disability in AF. Any stroke risk factor, or age over 65 years, warrants the use of oral anticoagulants. All NOACs are better than warfarin in some respect. The most important benefit is prevention of stroke and the most important risk is a disabling or fatal bleed. RR (95% CI) P Dabigatran 150 mg b.i.d ( ) Rivaroxaban 20 mg o.d ( ) 0.12 Apixaban 5 mg b.i.d 0.80 ( ) Edoxaban 60 mg o.d ( ) 0.10 Combined 0.81 ( ) < Favours NOAC Favours warfarin Note: Important differences between the treatments, patient demographics and trial characteristics that might affect study outcomes were not accounted for in the meta-analysis. Ruff CT, et al. Lancet 2013 Dec 3; doi: /S (13) Figure 3. NOACs in patients with AF: a meta-analysis of phase III trials comparing warfarin to a directacting anticoagulant 4

5 Mortality rate (%) Warfarin Dabigatran 13.0% p = % Time (days) Thirty-day mortality rate after a major bleeding event. n = 1034 with 1121 major bleeds in 5 phase III trials comparing dabigatran with warfarin in patients Major bleeds with dabigatran treated more frequently with blood transfusions (61% vs. 42%), less frequently with plasma (20% vs. 31%) Patients who experienced a bleed had a shorter ICU stay if previously treated with dabigatran vs. warfarin (mean 1.6 vs. 2.7 nights, p = 0.01) Figure 4. Outcomes after major bleeding: Dabigatran vs Warfarin Disclosures Honoraria and research support from Bayer, Boehringer Ingelheim, BMS, Pfizer and Servier. References 1. Rao M, Halvorsen S, Wojdyla D, et al. Poorly controlled blood pressure is independently associated with a 50% higher risk of stroke or systemic embolism in patients with atrial fibrillation: results from the ARISTOTLE trial. Presented at: American College of Cardiology/i2 Scientific Session; March 29, 2014; Washington, DC. 2. Abed HS, Wittert GA, Leong DP, et al. Effect of weight reduction and cardiometabolic risk factor management on symptom burden and severity in patients with AF: a randomised clinical trial. JAMA 2013; 310(19): Khan H, Kella D, Rauramma R, et al. Cardiorespiratory fitness and atrial fibrillation: A population-based follow-up study. Heart Rhythm 2015; pii: S (15) [Epub ahead of print]. 4. Calvo N, Brugada J, Sitges M, et al. Atrial fibrillation and atrial flutter in athletes. Br J Sports Med 2012; 46 (Suppl 1): Olesen JB, Lip GYH, Hansen ML, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011; 342: d124. Doi /bmj.d Gallagher AM, Rietbrock S, Plumb J, Van Staa TP. Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis? J Thromb Haemost 2008; 6(9): Oldgren J, Healey JS, Ezekowitz M, et al. Variations in etiology and management of AF in a prospective registry of emerging department patients in 46 countries: the RE-LY AF Registry. Circulation 2014; 129(15): Devreaux PJ, Anderson DR, Gardner MJ, et al. Differences between perspectives of physicians and patients on anticoagulation in patients with AF: observational study. BMJ 2001; 323 (7323): Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet 2013; 383(9921): Doi.10:1016/S (13) Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361(12): Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365(10): Majeed A, Hwang HG, Connolly SJ, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 2013; 128(21): Earn CPD points online Visit Click on Accredited CPD/CEU programmes. Log in or register and start earning CPD points today. Certificates will be ed to you. Disclaimer The views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities. Published by 70 Arlington Street, Everglen, Cape Town, 7550 Tel: (021) I info@denovomedica.com 5