Effect of Atrial Fibrillation on Mortality, Stroke Risk, and Quality-of-Life Scores in Patients With Heart Failure (from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF])
2017; Elsevier BV; Volume: 119; Issue: 11 Linguagem: Inglês
10.1016/j.amjcard.2017.02.050
ISSN1879-1913
AutoresTharian S. Cherian, Peter Shrader, Gregg C. Fonarow, Larry A. Allen, Jonathan P. Piccini, Eric D. Peterson, Laine Thomas, Peter R. Kowey, Bernard J. Gersh, Kenneth W. Mahaffey,
Tópico(s)Cardiac Arrhythmias and Treatments
ResumoThe degree to which clinical outcomes are worsened in patients with atrial fibrillation (AF) with heart failure (HF) compared with those without HF is not well described. This study aimed to determine the impact of HF on clinical outcomes in patients with AF. We analyzed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, a national registry of 10,135 patients with AF to determine associations between HF and left ventricular ejection fraction (LVEF) and outcomes, including stroke, mortality, and hospitalization using Cox multivariable modeling. Atrial Fibrillation Effect on Quality-of-Life Questionnaire (AFEQT) scores between groups were also compared. Overall, 33% (n = 3,203) of patients had HF; of these 33% (n = 985) had LVEF ≤40%. Oral anticoagulation was prescribed more commonly in patients with HF (81% vs 74%). Compared with patients without HF, those with HF had similar rate of stroke (1.28 vs 0.88 per 100-patient years, hazard ratio [HR] 1.11, confidence interval [CI] 0.83 to 1.48, p = 0.47) but higher mortality (HR 1.69, CI 1.49 to 1.92, p <0.001) and hospitalization (HR 1.31, CI 1.23 to 1.39, p <0.0001). Patients with LVEF ≤40% had similar stroke risk (HR 1.06, CI 0.67 to 1.67) but higher mortality (HR 2.06, CI 1.74 to 2.44) and hospitalization (HR 1.38, CI 1.25 to 1.51). AFEQT overall score was significantly lower (76.9 vs 83.3, p <0.0001) in patients with HF. In conclusion, HF was associated with increased risk of death and hospitalization and worse quality of life, but similar rates of thromboembolism regardless of LVEF among patients with AF. These findings highlight the need to develop therapeutic strategies targeting functional status and survival for patients with HF and AF. The degree to which clinical outcomes are worsened in patients with atrial fibrillation (AF) with heart failure (HF) compared with those without HF is not well described. This study aimed to determine the impact of HF on clinical outcomes in patients with AF. We analyzed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, a national registry of 10,135 patients with AF to determine associations between HF and left ventricular ejection fraction (LVEF) and outcomes, including stroke, mortality, and hospitalization using Cox multivariable modeling. Atrial Fibrillation Effect on Quality-of-Life Questionnaire (AFEQT) scores between groups were also compared. Overall, 33% (n = 3,203) of patients had HF; of these 33% (n = 985) had LVEF ≤40%. Oral anticoagulation was prescribed more commonly in patients with HF (81% vs 74%). Compared with patients without HF, those with HF had similar rate of stroke (1.28 vs 0.88 per 100-patient years, hazard ratio [HR] 1.11, confidence interval [CI] 0.83 to 1.48, p = 0.47) but higher mortality (HR 1.69, CI 1.49 to 1.92, p <0.001) and hospitalization (HR 1.31, CI 1.23 to 1.39, p <0.0001). Patients with LVEF ≤40% had similar stroke risk (HR 1.06, CI 0.67 to 1.67) but higher mortality (HR 2.06, CI 1.74 to 2.44) and hospitalization (HR 1.38, CI 1.25 to 1.51). AFEQT overall score was significantly lower (76.9 vs 83.3, p <0.0001) in patients with HF. In conclusion, HF was associated with increased risk of death and hospitalization and worse quality of life, but similar rates of thromboembolism regardless of LVEF among patients with AF. These findings highlight the need to develop therapeutic strategies targeting functional status and survival for patients with HF and AF. Heart failure (HF) prevalence in the United States is roughly 5.7 million, whereas an estimated 2.7 to 6.1 million Americans have atrial fibrillation (AF).1Go A.S. Hylek E.M. Phillips K.A. Chang Y. Henault L.E. Selby J.V. Singer D.E. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.JAMA. 2001; 285: 2370-2375Crossref PubMed Scopus (5209) Google Scholar Approximately 40% of subjects with either HF or AF will develop the other condition.2Wang T.J. Larson M.G. Levy D. Vasan R.S. Leip E.P. Wolf P.A. D'Agostino R.B. Murabito J.M. Kannel W.B. Benjamin E.J. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study.Circulation. 2003; 107: 2920-2925Crossref PubMed Scopus (1484) Google Scholar Both conditions are increasing in prevalence3Colilla S. Crow A. Petkun W. Singer D.E. Simon T. Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population.Am J Cardiol. 2013; 112: 1142-1147Abstract Full Text Full Text PDF PubMed Scopus (791) Google Scholar, 4Heidenreich P.A. Albert N.M. Allen L.A. Bluemke D.A. Butler J. Fonarow J.C. Ikonomidis J.S. Khavjou O. Konstam M.A. Maddox T.M. Nichol G. Pham M. Pina I.L. Trogdon J.G. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association.Circ Heart Fail. 2013; 6: 606-619Crossref PubMed Scopus (1819) Google Scholar and are associated with a wide range of adverse health outcomes. HF is included in many stratification tools for thromboembolic risk in AF, including the well-accepted CHA2DS2VASc score. Despite this, several studies have not identified HF as an independent risk factor for thromboembolism in AF.5Stroke Risk in Atrial Fibrillation Working GroupIndependent predictors of stroke in patients with atrial fibrillation: a systematic review.Neurology. 2007; 69: 546-554Crossref PubMed Scopus (570) Google Scholar, 6Stroke Risk in Atrial Fibrillation Working GroupComparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation.Stroke. 2008; 39: 1901-1910Crossref PubMed Scopus (241) Google Scholar, 7Friberg L. Rosenqvist M. Lip G.Y. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation Cohort Study.Eur Heart J. 2012; 33: 1500-1510Crossref PubMed Scopus (830) Google Scholar Similarly, echocardiographic studies have been inconclusive—studies have shown reduced left ventricular ejection fraction (LVEF) to be a significant predictor of thromboembolic events in AF,8The Stroke Prevention in Atrial Fibrillation InvestigatorsPredictors of thromboembolism in atrial fibrillation: I. Clinical features of patients at risk.Ann Intern Med. 1992; 116: 1-5Crossref PubMed Scopus (514) Google Scholar, 9Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials.Arch Intern Med. 1998; 158: 1316-1320Crossref PubMed Scopus (335) Google Scholar, 10Providência R. Botelho A. Trigo J. Quintal N. Nascimento J. Mota P. Leitao-Marques A. Possible refinement of clinical thromboembolism assessment in patients with atrial fibrillation using echocardiographic parameters.Europace. 2012; 14: 36-45Crossref PubMed Scopus (56) Google Scholar but this association has not been consistent.11Olshansky B. Heller E.N. Mitchell L.B. Chandler M. Slater W. Green M. Brodsky M. Barrell P. Greene H.L. Are transthoracic echocardiographic parameters associated with atrial fibrillation recurrence or stroke? Results from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study.J Am Coll Cardiol. 2005; 45: 2026-2033Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Furthermore, the association between AF and HF mortality has been mixed. Analysis of the Framingham data showed that the development of AF in patients with HF was associated with increased mortality.2Wang T.J. Larson M.G. Levy D. Vasan R.S. Leip E.P. Wolf P.A. D'Agostino R.B. Murabito J.M. Kannel W.B. Benjamin E.J. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study.Circulation. 2003; 107: 2920-2925Crossref PubMed Scopus (1484) Google Scholar Among those with advanced systolic dysfunction, the presence of AF has been associated with increased risk for mortality,12Middlekauff H.R. Stevenson W.G. Stevenson L.W. Prognostic significance of atrial fibrillation in advanced heart failure: a study of 390 patients.Circulation. 1991; 84: 40-48Crossref PubMed Scopus (474) Google Scholar, 13Dries D.L. Exner D.V. Gersh B.J. Domanski M.J. Waclawiw M.A. Stevenson L.W. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction.J Am Coll Cardiol. 1998; 32: 695-703Abstract Full Text Full Text PDF PubMed Scopus (839) Google Scholar whereas this association was not significant among those with mild-to-moderate HF.14Carson P.E. Johnson G.R. Dunkman W.B. Fletcher R.D. Farrell L. Cohn J.N. The influence of atrial fibrillation on prognosis in mild to moderate heart failure: the V-He FT VA Cooperative Studies Group.Circulation. 1993; 87: VI102-VI110PubMed Google Scholar In addition, the impact of HF on quality of life in patients with AF has not been studied. We examined the relation between HF and AF using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). We compared baseline characteristics and outcomes in patients with and without HF in the ORBIT-AF registry, an US-based, prospective outpatient registry of AF conducted at 176 sites from June 29, 2010, to August 09, 2011. Details of registry design have been published previously.15Piccini J.P. Fraulo E.S. Ansell J.E. Fonarow G.C. Gersh B.J. Go A.S. Hylek E.M. Kowey P.R. Mahaffey K.W. Thomas L.E. Long M.H. Lopes R.D. Mills R.M. Peterson E.D. Outcomes registry for better informed treatment of atrial fibrillation: rationale and design of ORBIT-AF.Am Heart J. 2011; 162: 606-612Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar The Duke Clinical Research Institute was responsible for ORBIT-AF site selection and study management. Eligible patients were ≥18 years with electrocardiographically confirmed AF. Reasons for exclusion included anticipated life expectancy 40%, HF with reduced LVEF (HFrEF) was defined as clinical status of HF and EF ≤40%.17Yusuf S. Pfeffer M.A. Swedberg K. Granger C.B. Held P. McMurray J.J. Michelson E.L. Olofsson B. Ostergren J. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.Lancet. 2003; 362: 777-781Abstract Full Text Full Text PDF PubMed Scopus (2398) Google Scholar Stroke or non-CNS embolism, all-cause death, cardiovascular death, and all-cause hospitalization outcomes were analyzed in the patients with and without HF and those with HFrEF and HFpEF. Baseline characteristics were summarized using medians and quartiles for continuous variables and frequencies and percentages for categorical variables. Pearson chi-square tests were used to compare categorical variables and Wilcoxon rank-sum tests for continuous variables. Rates of outcomes are presented as rates per 100 patient-years of follow-up. Hazard ratios (HRs) comparing HF and patients without HF and those with HFrEF and HFpEF were derived from a Cox frailty model. We calculated a multivariable model adjusted for covariates previously identified using a backward selection process.18Steinberg B.A. Peterson E.D. Kim S. Thomas L. Gersh B.J. Fonarow G.C. Kowey P.R. Mahaffey K.W. Sherwood M.W. Chang P. Piccini J.P. Ansell J. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).Circulation. 2015; 131: 488-494Crossref PubMed Scopus (192) Google Scholar Stroke or non-CNS embolism was adjusted for peripheral vascular disease, race, rhythm control, AF type, atrioventricular node/His bundle ablation, hypertension, age, and history of stroke/TIA. All-cause mortality was adjusted for level of education, rhythm control, cognitive impairment/dementia, hyperlipidemia, linear spline for estimated glomerular filtration rate (eGFR) ≤80, linear spline for eGFR >80, LAD type, cancer, diastolic blood pressure truncated at 70, intraventricular conduction, frailty, height, heart rate, hematocrit, diabetes, smoking, linear spline for systolic blood pressure ≤120, chronic obstructive pulmonary disease (COPD), BMI truncated at 30, gender, age, and functional status. CV mortality was adjusted for diabetes, anemia, diastolic blood pressure, linear spline for systolic blood pressure ≤125, hyperlipidemia, atrioventricular node/His bundle ablation, COPD, significant valvular disease, height, gender, LVEF type, functional status, eGFR, and age. All-cause hospitalization was adjusted for linear spline for age ≤70, linear spline for age >70, BMI, weight, osteoporosis, height, percutaneous coronary intervention, cancer, obstructive sleep apnea, anemia, frailty, insurance status, history of coronary artery disease, principal investigator/site specialty, previous antiarrhythmic drug use, peripheral vascular disease, functional status, linear spline for heart rate >68, diabetes, hematocrit, linear spline for eGFR ≤80, COPD, diastolic blood pressure truncated at 70, and European Heart Rhythm Association score. All p values presented are 2 sided. All statistical analyses for this study were performed using SAS software (version 9.3; SAS, Cary, North Carolina). Written informed consent was obtained for all study participants. The Duke Institutional Review Board approved the ORBIT-AF registry, and all participating sites obtained approval from local institutional review boards before patient recruitment. A total of 10,135 patients had baseline data available, from which 392 patients (3.9%) with no follow-up were excluded. Of the included patients, 33% had HF and 67% did not have HF. Among patients with HF, 2,998 (94%) had quantitative data regarding LVEF, of which 67% had HFpEF and 33% had HFrEF. Baseline characteristics of patients with and without HF are listed in Table 1. Compared with patients without HF, those with HF were older, less likely to be women, and more likely to have diabetes and peripheral vascular disease. Other cardiovascular co-morbidities, including valvular disease and coronary artery disease, were also more prevalent in patients with HF. Patients with HF had significantly higher CHA2DS2VASC scores, with a median score of 5 among patients with HF and 3 among those without. Compared with patients without HF, those with HF were also significantly more likely to be on anticoagulation.Table 1Baseline characteristicsVariableNo HFn=6540HFn=3203HF-PEFn=2013HF-REFn=985Age (median, IQR)74 (66-81)76 (68-83)77 (69-83)74 (66-82)Female2850 (44%)1295 (40%)956 (47%)250 (25%)Systolic Blood Pressure (median, IQR), (mm Hg)127 (118-138)122 (110-134)124 (113-136)120 (110-130)Diastolic Blood Pressure (median, IQR), (mm Hg)74 (68-80)70 (62-80)70 (64-80)70 (62-78)Body Mass Index (median, IQR), (kg/m2 )29 (26-34)29 (25-35)30 (25-35)29 (25-33)Current Smoker357 (5%)198 (6%)104 (5%)84 (9%)Diabetes Mellitus1638 (25%)1235 (39%)773 (38%)382 (39%)Hypertension5301 (81%)2798 (87%)1796(89%)831 (84%)Hyperlipidemia4595 (70%)2445 (76%)1534(76%)767 (78%)Peripheral Vascular Disease691 (11%)615 (19%)400 (20%)188 (19%)Prior stroke or TIA901 (14%)578 (18%)364 (18%)181 (18%)Coronary Artery Disease1837 (28%)1695 (53%)975 (48%)621 (63%)Prior Myocardial Infarction671 (10%)890 (28%)457 (23%)383 (39%)Prior Percutaneous coronary intervention889 (14%)799 (25%)475 (24%)286 (29%)Prior Coronary Artery Bypass Graft657 (10%)785 (25%)397 (20%)341 (35%)Anemia905 (14%)896 (28%)605 (30%)247 (25%)Implanted Devices1239 (19%)1451 (45%)717 (36%)650 (66%) Pacemaker1091 (17%)718 (22%)493 (24%)180 (18%) BiVentricular Pacemaker29 (0.4%)61 (1.9%)33 (2%)25 (3%) Implantable cardioverter defibrillator97 (1%)384 (12%)121 (6%)243 (25%) BiVentricular Pacemaker/ICD30 (0.5%)342 (11%)82 (4%)241 (24%)History of Valvular Disease1295 (20%)1213 (38%)770 (38%)399 (41%) Mitral Regurgitation737 (11%)752 (23%)442 (22%)277 (28%) Mitral Stenosis62 (1%)75 (2.3%)53 (3%)18 (2%) Aortic Regurgitation129 (2%)160 (5%)112 (6%)41 (4%) Aortic Stenosis208 (3%)205 (6%)150 (7%)47 (5%) Tricuspid Regurgitation596 (9%)602 (19%)395 (20%)189 (19%)Type of Atrial Fibrillation New Onset352(5%)86 (3%)49 (2%)33 (3%) Paroxysmal3596 (55%)1342 (42%)823 (41%)437 (44%) Persistent1001 (15%)631 (20%)390 (19%)199(20%) Permanent1591 (24%)1144 (36%)751 (37%)316 (32%)Sinus Rhythm on most recent ECG2496 (38%)782 (24%)511(25%)227 (23%)Etiology of Cardiomyopathy Ischemic---1307 (41%)694 (35%)527 (54%) Non-ischemic---1878 (59%)1304 (65%)456 (46%)Current NYHA Class No CHF6540 (100%) I1017 (32%)728(36%)227 (23%) II1460 (46%)925 (46%)443 (45%) III649 (20%)321 (16%)280 (28%) IV62 (2%)26 (1%)34 (3%)LV Ejection Fraction (EF) (median, IQR)60% (55-65)50% (38-60)55% (50-60)30% (25-38)LV dysfunction class Normal (EF ≥ 50%)5211 (90%)1675 (56%)1675 (83%)0 (0%) Mild (EF < 50%, > 40%)269 (5%)338 (11%)338 (17%)0 (0%) Moderate (EF≥30%, < 40%)247 (4%)618 (21%)0 (0%)618 (63%) Severe (EF < 30%)45 (0.8%)367 (12%)0 (0%)367 (37%)CHA2DS2VASC Score (median, IQR)3 (2-4)5(4-6)5 (4-6)5 (4-6) 0212(3%)0 (0%)0 (0%)0 (0%) 1618(9%)41 (1%)23 (1%)13 (1%) 21026 (16%)148 (5%)76 (4%)64 (7%) ≥34684 (72%)3014 (94%)1914 (95%)908 (92%)Oral Anticoagulation (Warfarin or dabigatran)4861 (74%)2581 (81%)1607 (80%)811 (82%)Oral Anticoagulation among CHADS2=1 & no OAC contraindications1318 (75%)118 (88%)63 (85%)46(90%)Oral Anticoagulation among CHADS2>=2& no OAC contraindications3006 (87%)2330 (90%)1458 (89%)726 (91%)Medications Aldosterone Antagonist162 (2%)381 (12%)177 (9%)183 (19%) ACE Inhibitor2084 (32%)1380 (43%)766 (38%)525 (53%) ARB1169 (18%)566 (18%)368 (18%)166 (17%) Amiodarone550 (8%)417 (13%)224 (11%)165 (17%) Beta-Blocker3854 (59%)2412 (75%)1431 (71%)840 (85%) Aspirin2831 (43%)1486 (46%)901 (45%)504 (51%) Clopidogrel381 (6%)311 (10%)173 (9%)121 (12%) Digoxin1191 (18%)1104 (34%)585 (29%)454 (46%) Calcium channel blocker2183 (33%)781 (24%)595 (30%)144 (15%)Hypertension – Defined as either 1. Blood Pressure ≥ 140 mm Hg systolic or 90 mm/Hg diastolic on atleast two occasions OR 2. Chart reported HTN being treated with medication, diet, and exercise OR 3. Undergoing anti-hypertensive therapy.Hyperlipidemia – Defined as hypercholesterolemia or hypertriglyceridemia, regardless of therapy for either condition.Anemia – Defined as hemoglobin less than 12 g/dl in women and 13 g/dl in men. Open table in a new tab Hypertension – Defined as either 1. Blood Pressure ≥ 140 mm Hg systolic or 90 mm/Hg diastolic on atleast two occasions OR 2. Chart reported HTN being treated with medication, diet, and exercise OR 3. Undergoing anti-hypertensive therapy. Hyperlipidemia – Defined as hypercholesterolemia or hypertriglyceridemia, regardless of therapy for either condition. Anemia – Defined as hemoglobin less than 12 g/dl in women and 13 g/dl in men. The origin of HF was ischemic in 41% of patients. Compared with patients with HFrEF, those with HFpEF were older, almost twice as likely to be women, and had a higher prevalence of hypertension. Patients with HFrEF in contrast were more likely to have coronary artery disease and have implanted devices. Regarding medical therapy, patients with HFpEF and those without HF were twice as likely to be treated with calcium channel blockers compared with patients with HFrEF. Aldosterone antagonists were used significantly more often in patients with HFrEF. Unadjusted rate of stroke or non-CNS embolism was significantly higher in patients with HF (1.28 vs 0.88 per 100 patient-years, HR 1.42, 95% confidence interval 1.07 to 1.87, p = 0.01) compared with those without HF. Although patients with HFrEF had similar unadjusted risk for stroke or non-CNS embolism (1.12 vs 0.88 per 100 patient-years), those with HFpEF had a significantly higher unadjusted risk for stroke or non-CNS embolism (1.36 vs 0.88 per 100 patient-years) compared with those without HF. Unadjusted rates of all-cause death and cardiovascular death were significantly higher in patients with HF compared with those without HF. Patients with HFrEF had significantly higher rates of the aforementioned outcomes compared with those with HFpEF. Compared with patients without HF, those with HF had a significantly higher rate of all-cause hospitalization, and there were no significant difference in this outcome between the patients with HFpEF and HFrEF (Table 2).Table 2Unadjusted clinical outcomesOutcomesNo HFn=6540(67%)HFn = 3203(33%)HFpEFn = 2013(67%)HFrEFn = 985(33%)Rate∗Rate per 100 patient years.Rate∗Rate per 100 patient years.HR†Compared to no HF group. (95% CI)P ValueRate∗Rate per 100 patient years.HR†Compared to no HF group. (95% CI)P ValueRate∗Rate per 100 patient years.HR†Compared to no HF group. (95% CI)P ValueStroke or Non-CNS Embolism0.881.281.42 (1.07-1.87)0.011.361.50 (1.10-2.06)0.011.121.27 (0.81-1.99)0.29All Cause Mortality3.5210.192.88 (2.56-3.24)<0.00019.162.59 (2.26-2.96)<0.000112.253.57 (3.05-4.17)<0.0001Cardiovascular Mortality1.084.994.48 (3.69-5.44)<0.00013.803.38 (2.70-4.23)<0.00017.456.93 (5.51-8.73)<0.0001All-cause Hospitalization28.1548.971.64 (1.55-1.74)<0.000149.331.64 (1.52-1.75)<0.000150.451.72 (1.57-1.88)<0.0001Sudden Cardiac Death0.291.133.78(2.58-5.56)<0.00010.802.63(1.66-4.17)<0.00011.675.63(3.54-8.96)<0.0001∗ Rate per 100 patient years.† Compared to no HF group. Open table in a new tab The association between HF status and rate of stroke or non-CNS embolism was no longer significant after adjustment for multiple variables (Table 3), including adjustment for anticoagulation status (HR 1.12, 95% confidence interval 0.84 to 1.49, p = 0.45). Similarly, there was no significant difference in stroke or non-CNS embolism rate between the patients with HFpEF compared with those without HF after adjustment. Adjusted rates of all cause death, cardiovascular death, and hospitalizations were significantly higher in patients with HF. Within patients with HF, those with HFrEF had significantly higher rates of all-cause death and cardiovascular death compared with those with HFpEF, but no such difference was seen in rates of hospitalization (Table 4).Table 3Adjusted clinical outcomesOutcomesNo HFn=6540(67%)HFn = 3203(33%)HFpEFn = 2013(67%)HFrEFn = 985(33%)RateRate∗Rate per 100 patient years.HR†Compared to no HF group and adjusted for prespecified covariates. (95% CI)P ValueRate∗Rate per 100 patient years.HR†Compared to no HF group and adjusted for prespecified covariates. (95% CI)P ValueRate∗Rate per 100 patient years.HR†Compared to no HF group and adjusted for prespecified covariates. (95% CI)P ValueStroke or Non-CNS Embolism0.881.281.11 (0.83-1.48)0.471.361.15 (0.83-1.59)0.401.121.06 (0.67-1.67)0.82All Cause Mortality3.5210.191.69 (1.49-1.92)<0.00019.161.51 (1.31-1.74)<0.000112.252.06 (1.74-2.44)<0.0001Cardiovascular Mortality1.084.992.12 (1.70-2.63)<0.00013.801.93 (1.53-2.45)<0.00017.454.09 (3.19-5.23)<0.0001All-cause Hospitalization28.1548.971.31 (1.23-1.39)<0.000149.331.29 (1.20-1.39)<0.000150.451.38 (1.25-1.51)<0.0001Sudden Cardiac Death0.291.131.78(1.15-2.75)0.010.801.50(0.91-2.47)0.111.672.06 (0.71-5.94)0.18∗ Rate per 100 patient years.† Compared to no HF group and adjusted for prespecified covariates. Open table in a new tab Table 4Adjusted clinical outcomes among heart failure patients by left ventricular ejection fractionOutcomesHFpEFn=2013 (67%)HFrEFn = 985(33%)Rate∗Rate per 100 patient years.Rate∗Rate per 100 patient years.HR†Compared to HFpEF group and adjusted for prespecified covariates. (95% CI)P ValueStroke or Non-CNS Embolism1.361.120.91 (0.56-1.49)0.72All Cause Mortality9.1612.251.32 (1.11-1.57)0.002Cardiovascular Mortality3.807.452.01 (1.59-2.56)<0.0001All-cause Hospitalization49.3350.451.04 (0.94-1.16)0.41∗ Rate per 100 patient years.† Compared to HFpEF group and adjusted for prespecified covariates. Open table in a new tab Patients with HF had a significantly lower AFEQT overall score compared with those without HF. There was a significant difference in the daily activities subscale between these 2 groups of patients. There were no significant differences in the symptoms, treatment concern, or treatment satisfaction subscales. There were no significant differences between patients with HFrEF and HFpEF with regard to the overall score or the symptoms, daily activities, treatment concern, or treatment satisfaction subscales (Table 5).Table 5Quality of life, atrial fibrillation effect on quality-of-life (AFEQT) scoresOutcomesNo HFHFHFPEFHFREFP Value∗Testing global association across categories.AFEQT Overall Score (median, IQR)83.3 (68.5-93.5)76.9 (61.1-90.7)76.9 (62.0 - 90.7)75.0 (57.4-88.0)<0.0001AFEQT Symptoms Subscale (median, IQR)91.7 (75.0-100.0)91.7 (79.2-100.0)91.7 (79.2-100.0)91.7 (75.0-100.0)0.96AFEQT Daily Activities Subscale81.0 (58.3-95.8)66.7 (41.7-87.5)68.8 (41.7-87.5)62.5 (37.5-83.3)<0.0001AFEQT Treatment Concern Subscale88.9 (72.2-100.0)88.9 (69.4-100.0)88.9 (69.4-100.0)86.1 (66.7-100.0)0.36AFEQT Treatment Satisfaction Subscale83.3 (75.0-100.0)83.3 (75.0-100.0)83.3 (75.0-100.0)83.3 (75.0-100.0)0.92∗ Testing global association across categories. Open table in a new tab Among this large cohort of patients with AF, majority of whom were on anticoagulation, we found that HF was not associated with higher risk of stroke or non-CNS embolism after adjustment for traditionally recognized risk factors for thromboembolism, including age, diabetes, hypertension, previous stroke/TIA, and peripheral vascular disease. In contrast, patients with HF regardless of LVEF were at higher risk for all-cause death, cardiovascular death, and hospitalization, findings that persisted after multivariable adjustment. A recent meta-analysis of clinical trials comparing novel oral anticoagulants to warfarin in patients with AF by Savarese et al similarly found that although rates of stroke and systemic embolism were comparable in patients with and without HF, those with HF had increased rates of all-cause and cardiovascular mortality.19Sevarese G. Giugliano R.P. Rosano G.M. McMurray J. Magnani G. Filippatos G. Dellegrottaglie S. Lund L.H. Trimarco B. Perrone-Filardi P. Efficacy and safety of oral anticoagulants in patients with atrial fibrillation and heart failure: a meta-analysis.JACC Heart Fail. 2015; 4: 870-880Crossref Scopus (55) Google Scholar We also report that health-related quality-of-life scores, particularly domains related to daily activities, were reduced in patients with AF and HF. Our findings are consistent with a meta-analysis by the Stroke Risk in Atrial Fibrillation working group, which found inconclusive evidence for HF as an independent risk factor for stroke when previous stroke/TIA, advancing age, diabetes, and hypertension were included in the model.5Stroke Risk in Atrial Fibrillation Working GroupIndependent predictors of stroke in patients with atrial fibrillation: a systematic review.Neurology. 2007; 69: 546-554Crossref PubMed Scopus (570) Google Scholar In our study, even after adjustment for anticoagulation, there was no significant difference in stroke or non-CNS embolism rates between patients with HF and the HFrEF subgroup compared with those without HF. One of the reasons for this surprising finding may be the lower than expected stroke rate in our cohort—the stroke rate in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, for instance, was 1.27% per year in the apixaban group and 1.60% per year in the warfarin group,20Granger C.B. Alexander J.H. McMurray J.J. Lopes R.D. Hylek E.M. Hann M. Al-Khalidi H.R. Ansell J. Atar D. Avezum A. Bahit M.C. Diaz R. Easton J.D. Ezekowitz J.A. Flaker G. Garcia D. Geraldes M. Gersh B.J. Golitsyn S. Goto S. Hermosillo A.G. Honloser S.H. Horowitz J. Mohan P. Jansky P. Lewis B.S. Lopez-Sendon J.L. Pais P. Parkhomenko A. Verheugt F.W. Zhu J. Wallentin L. Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (6709) Google Scholar compared with 0.88% and 1.28% in no-HF and HF groups in our study. Given that a majority of patients in our cohort was on anticoagulation (81% in patients with HF vs 74% in those without HF) and the lower than expected stroke rate, our sample size may not have been large enough to detect a difference between groups. Within the group of patients with HF in our cohort, there was no significant difference in rate of stroke or non-CNS embolism between patients with HFrEF and those without HF. A post hoc analysis of the ARISTOTLE trial similarly found that reduced LVEF was not associated with higher risk of stroke or systemic embolism.21McMurray J.J. Ezekowitz J.A. Lewis B.S. Gersh B.J. van Diepen S. Amerena J. Bartunek J. Commerford P. Oh B.H. Harjola V.P. Al-Khatib S.M. Hanna M. Alexander J.H. Lopes R.D. Wojdyla D.M. Wallentin L. Granger C.B. ARISTOTLE Committees and InvestigatorsLeft ventricular systolic dysfunction, heart failure, and the risk of stroke and systemic embolism in patients with atrial fibrillation: insights from the ARISTOTLE trial.Circ Heart Fail. 2013; 6: 451-460Crossref PubMed Scopus (116) Google Scholar Interestingly, patients with HFpEF, who were older and more likely to have hypertension, had a significantly higher unadjusted stroke risk compared with those without HF. That this association was no longer significant after adjustment for the aforementioned risk factors suggests that these risk factors are more significant predictors of stroke risk compared with HF and reduced EF in a cohort where majority of patients are on anticoagulation. HF is a significant cause of mortality and hospitalizations in the elderly in the United States.22Jessup M. Brozena S. Medical progress. Heart failure.N Engl J Med. 2003; 348: 2007-2018Crossref PubMed Scopus (1622) Google Scholar Thus, not surprisingly, our analysis showed that HF in AF was associated with significantly higher adjusted rates of cardiovascular mortality and all-cause mortality. A significant first step to improving mortality in patients with AF and HF is optimal medical management of HF. Unfortunately, we found that among patients with HFrEF in this AF cohort, 70% were receiving angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy, 85% were receiving β blockers, and only 19% of patients were on aldosterone antagonists. In addition, only 25% of the patients with HFrEF, who had an overall mortality of 12.25% per 100 patient-years and cardiovascular mortality of 7.45% per 100 patient-years, had ICDs implanted. Assuming that this apparent underuse of guideline-directed medical therapies was not due to appropriate contraindications, stricter adherence to such HF therapies may reduce mortality and hospitalization in this high-risk group. In addition to the expected increases in mortality and hospitalization for HF in AF, patients with HF had lower AFEQT overall score compared with those without HF, which was driven by lower scores in daily activities subscale. Compared with patients with HFpEF, HFrEF was not associated with worse AFEQT scores. Even in patients with AF without HF, the daily activities subscale had the lowest average subscale score. This suggests that encouraging therapies that might improve daily activities performance for patients with AF and HF may improve quality of life in this high-risk group. Our data would generally support the recent coverage decision by Medicare to include cardiac rehabilitation for patients with HF.23Center for Medicare and Medicaid ServicesDecision memo for cardiac rehabilitation (CR) programs—chronic heart failure.http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=270Google Scholar Our study has a number of limitations. First, this is an observational study of the ORBIT-AF registry and, therefore, is susceptible to enrollment, sampling, and reporting biases. Data on LVEF were not documented in 6% of patients with HF. Because HF status and LVEF were not randomly assigned, causative relation between these variables and outcomes cannot be established. Furthermore, despite detailed prospective data capture and statistical methods aimed at adjusting for baseline differences in the population, some degree of unmeasured confounding affects the results. Follow-up was a median 27 months, and with longer-term follow-up additional differences in event risk may emerge. Dr Fonarow receives consultant/advisory board support from Janssen Pharmaceuticals, Beerse, Belgium. Dr Allen is a member of the steering committee for Janssen Pharmaceuticals. Dr Piccini receives research support from ARCA Biopharma, Westminster, Colorado, Boston Scientific, Natick, Massachusetts, GE Healthcare, Chicago, Illinois, Johnson & Johnson, New Brunswick, New Jersey, and Janssen Scientific Affairs and consultancies from Forest Laboratories, New York, New York, Janssen Scientific Affairs, Pfizer/Bristol-Myers Squibb, New York, New York, Spectranetics, Colorado Springs, Colorado, and Medtronic, Minneapolis, Minnesota. Dr Peterson receives research support from Janssen Pharmaceuticals and Eli Lilly, Indianapolis, Indiana and consultancy support from Janssen Pharmaceuticals and Boehringer Ingelheim, Ingelheim, Germany. Dr Thomas participates in research with Novartis, Basel, Switzerland, Boston Scientific, Gilead Sciences, Inc, London, United Kingdom, and Janssen Scientific. Peter Kowey receives consultancy support from Johnson & Johnson, Daiich-Sankyo, Tokyo, Japan, Bristol-Myers Squibb, Boehringer Ingelheim. Dr Gersh is a member of Data Safety Monitoring Board for – Mount Sinai St. Lukes, New York, New York, Boston Scientific Corporation, Teva Pharmaceutical Industries, Petah Tikva, Israel, St. Jude Medical, Stratford-on-Avon, United Kingdom, Janssen Research & Development, Baxter Healthcare Corporation, Deerfield, Illinois, and Cardiovascular Research Foundation, New York, New York. He also receives consultation support from Janssen Scientific Affairs, Cipla Limited, Mumbai, India, and Armetheon Inc, Sunnyvale, California. He is also on an advisory board for Medtronic. Dr Mahaffey receives research support from Afferent, San Mateo, California, Amgen, Thousand Oaks, California, AstraZeneca, London, United Kingdom, Daiichi, Ferring, Saint-Prex, Switzerland, Google, Mountain View, California, Johnson & Johnson, Medtronic, Merck, Kenilworth, New Jersey, Novartis and St. Jude and consultancy support from Ablynx, Ghent, Belgium, AstraZeneca, BAROnova, Galeto, California, Bio2 Medical, London, United Kingdom, Boehringer Ingelheim, Bristol Myers Squibb, Cardiometabolic Health Congress, Boca Raton, Florida, Cubist, Lexington, Massachusetts, Ali Lilly, Elsevier, Amsterdam, The Netherlands, Epson, Tokyo, Japan, Glaxo Smith Kline, Brentford, United Kingdom, Johnson & Johnson, Merck, Mt. Sinai, Myokardia, San Francisco, California, Novartis, Oculeve, San Francisco, California, Portola, San Francisco, California, Radiomeer, San Francisco, California, Springer Publishing, New York, New York, The Medicines Company, Parsippany, New Jersey, Theravance, San Francisco, California, Vindico, Philadelphia, Pennsylvania, and WebMD, New York, New York. All other authors have no conflicts of interest to disclose.
Referência(s)