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Optimal Blood Pressure in Patients With Atrial Fibrillation (from the AFFIRM Trial)

2014; Elsevier BV; Volume: 114; Issue: 5 Linguagem: Inglês

10.1016/j.amjcard.2014.06.002

ISSN

1879-1913

Autores

Apurva O. Badheka, Nileshkumar Patel, Peeyush Grover, Neeraj Shah, Nilay Patel, Vikas Singh, Abhishek Deshmukh, Kathan Mehta, Ankit Chothani, Ghanshyambhai T. Savani, Shilpkumar Arora, Ankit Rathod, George R. Marzouka, James Lafferty, Jawahar L. Mehta, Raul D. Mitrani,

Tópico(s)

Cardiac Arrhythmias and Treatments

Resumo

Many medications used to treat atrial fibrillation (AF) also reduce blood pressure (BP). The relation between BP and mortality is unclear in patients with AF. We performed a post hoc analysis of 3,947 participants from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management trial. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at baseline and follow-up were categorized by 10-mm Hg increments. The end points were all-cause mortality (ACM) and secondary outcome (combination of ACM, ventricular tachycardia and/or fibrillation, pulseless electrical activity, significant bradycardia, stroke, major bleeding, myocardial infarction, and pulmonary embolism). SBP and DBP followed a "U-shaped" curve with respect to primary and secondary outcomes after multivariate analysis. A nonlinear Cox proportional hazards model showed that the incidence of ACM was lowest at 140/78 mm Hg. Subgroup analyses revealed similar U-shaped curves. There was an increased ACM observed with BP <110/60 mm Hg (hazard ratio 2.4, p <0.01, respectively, for SBP and DBP). In conclusion, in patients with AF, U-shaped relation existed between BP and ACM. These data suggest that the optimal BP target in patients with AF may be greater than the general population and that pharmacologic therapy to treat AF may be associated with ACM or adverse events if BP is reduced to <110/60 mm Hg. Many medications used to treat atrial fibrillation (AF) also reduce blood pressure (BP). The relation between BP and mortality is unclear in patients with AF. We performed a post hoc analysis of 3,947 participants from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management trial. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) at baseline and follow-up were categorized by 10-mm Hg increments. The end points were all-cause mortality (ACM) and secondary outcome (combination of ACM, ventricular tachycardia and/or fibrillation, pulseless electrical activity, significant bradycardia, stroke, major bleeding, myocardial infarction, and pulmonary embolism). SBP and DBP followed a "U-shaped" curve with respect to primary and secondary outcomes after multivariate analysis. A nonlinear Cox proportional hazards model showed that the incidence of ACM was lowest at 140/78 mm Hg. Subgroup analyses revealed similar U-shaped curves. There was an increased ACM observed with BP <110/60 mm Hg (hazard ratio 2.4, p <0.01, respectively, for SBP and DBP). In conclusion, in patients with AF, U-shaped relation existed between BP and ACM. These data suggest that the optimal BP target in patients with AF may be greater than the general population and that pharmacologic therapy to treat AF may be associated with ACM or adverse events if BP is reduced to <110/60 mm Hg. The seventh report of the Joint National Committee considers a blood pressure (BP) of 115/75 mm Hg in the elderly. This report also outlines a linear relation of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with cardiovascular mortality.1Chobanian A.V. Bakris G.L. Black H.R. Cushman W.C. Green L.A. Izzo Jr., J.L. Jones D.W. Materson B.J. Oparil S. Wright Jr., J.T. Roccella E.J. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.Hypertension. 2003; 42: 1206-1252Crossref PubMed Scopus (10821) Google Scholar, 2Badheka A. Shenoy M. Rathod A. Tuliani T. Afonso L. Long-term mortality and role of troponin elevation in hypertensive emergencies.Am J Cardiol. 2012; 109: 600Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar However, in certain populations such as the elderly and in patients with acute coronary syndrome, a "J-shaped" relation between BP and outcomes has been observed.3Boutitie F. Gueyffier F. Pocock S. Fagard R. Boissel J.P. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data.Ann Intern Med. 2002; 136: 438-448Crossref PubMed Scopus (274) Google Scholar, 4Bangalore S. Qin J. Sloan S. Murphy S.A. Cannon C.P. What is the optimal blood pressure in patients after acute coronary syndromes?: Relationship of blood pressure and cardiovascular events in the PRavastatin OR atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial.Circulation. 2010; 122: 2142-2151Crossref PubMed Scopus (189) Google Scholar Low BP (<110/70 mm Hg) has been shown to be associated with an increase in adverse events, with the lowest mortality demonstrable in the BP range 130 to 140/80 to 90 mm Hg.4Bangalore S. Qin J. Sloan S. Murphy S.A. Cannon C.P. What is the optimal blood pressure in patients after acute coronary syndromes?: Relationship of blood pressure and cardiovascular events in the PRavastatin OR atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial.Circulation. 2010; 122: 2142-2151Crossref PubMed Scopus (189) Google Scholar Similar findings have also been demonstrated with chronic coronary artery disease (CAD), hypertension, and stroke.4Bangalore S. Qin J. Sloan S. Murphy S.A. Cannon C.P. What is the optimal blood pressure in patients after acute coronary syndromes?: Relationship of blood pressure and cardiovascular events in the PRavastatin OR atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial.Circulation. 2010; 122: 2142-2151Crossref PubMed Scopus (189) Google Scholar, 5Lee T.T. Chen J. Cohen D.J. Tsao L. The association between blood pressure and mortality in patients with heart failure.Am Heart J. 2006; 151: 76-83Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 6Vokó Z. Bots M.L. Hofman A. Koudstaal P.J. Witteman J.C. Breteler M.M. J-shaped relation between blood pressure and stroke in treated hypertensives.Hypertension. 1999; 34: 1181-1185Crossref PubMed Scopus (156) Google Scholar, 7Witteman J.C. Grobbee D.E. Valkenburg H.A. van Hemert A.M. Stijnen T. Burger H. Hofman A. J-shaped relation between change in diastolic blood pressure and progression of aortic atherosclerosis.Lancet. 1994; 343: 504-507Abstract PubMed Scopus (223) Google Scholar, 8Vagaonescu T.D. Wilson A.C. Kostis J.B. Atrial fibrillation and isolated systolic hypertension: the systolic hypertension in the elderly program and systolic hypertension in the elderly program-extension study.Hypertension. 2008; 51: 1552-1556Crossref PubMed Scopus (43) Google Scholar, 9Badheka A.O. Rathod A. Kizilbash M.A. Garg N. Mohamad T. Afonso L. Jacob S. Influence of obesity on outcomes in atrial fibrillation: yet another obesity paradox.Am J Med. 2010; 123: 646-651Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 10Badheka A.O. Rathod A. Kizilbash M.A. Bhardwaj A. Ali O. Afonso L. Jacob S. Comparison of mortality and morbidity in patients with atrial fibrillation and heart failure with preserved versus decreased left ventricular ejection fraction.Am J Cardiol. 2011; 108: 1283-1288Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 11Leonardi-Bee J. Bath P.M. Phillips S.J. Sandercock P.A. Blood pressure and clinical outcomes in the International Stroke Trial.Stroke. 2002; 33: 1315-1320Crossref PubMed Scopus (810) Google Scholar, 12Samuelsson O.G. Wilhelmsen L.W. Pennert K.M. Wedel H. Berglund G.L. The J-shaped relationship between coronary heart disease and achieved blood pressure level in treated hypertension: further analyses of 12 years of follow-up of treated hypertensives in the Primary Prevention Trial in Gothenburg, Sweden.J Hypertens. 1990; 8: 547-555Crossref PubMed Scopus (80) Google Scholar However, the "optimal" or "goal" BP in atrial fibrillation (AF) has never been studied in the past and had not been addressed in the Joint National Committee-8 guidelines.13James P.A. Oparil S. Carter B.L. Cushman W.C. Dennison-Himmelfarb C. Handler J. Lackland D.T. LeFevre M.L. MacKenzie T.D. Ogedegbe O. Smith Jr., S.C. Svetkey L.P. Taler S.J. Townsend R.R. Wright Jr., J.T. Narva A.S. Ortiz E. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).JAMA. 2014; 311: 507-520Crossref PubMed Scopus (6174) Google Scholar Given the loss of atrial contractility, the optimal BP in patients with AF may differ from the general population. Additionally, most medications used to treat AF, for either rhythm or rate control, result in decreased BPs. Therefore, it would be critical to define not only optimal BP but thresholds in BP below which adverse events may increase. Using patients enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial,14Wyse D.G. Waldo A.L. DiMarco J.P. Domanski M.J. Rosenberg Y. Schron E.B. Kellen J.C. Greene H.L. Mickel M.C. Dalquist J.E. Corley S.D. A comparison of rate control and rhythm control in patients with atrial fibrillation.N Engl J Med. 2002; 347: 1825-1833Crossref PubMed Scopus (3781) Google Scholar, 15Corley S.D. Epstein A.E. DiMarco J.P. Domanski M.J. Geller N. Greene H.L. Josephson R.A. Kellen J.C. Klein R.C. Krahn A.D. Mickel M. Mitchell L.B. Nelson J.D. Rosenberg Y. Schron E. Shemanski L. Waldo A.L. Wyse D.G. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.Circulation. 2004; 109: 1509-1513Crossref PubMed Scopus (1055) Google Scholar we hypothesized that patients with AF have a U-shaped relation between BP and outcomes. Furthermore, the goal of this study was to determine the optimal BP in patients with AF and also define lower boundaries of BP control at which mortality and/or adverse events increase. We performed a post hoc analysis of patients enrolled in the AFFIRM trial.14Wyse D.G. Waldo A.L. DiMarco J.P. Domanski M.J. Rosenberg Y. Schron E.B. Kellen J.C. Greene H.L. Mickel M.C. Dalquist J.E. Corley S.D. A comparison of rate control and rhythm control in patients with atrial fibrillation.N Engl J Med. 2002; 347: 1825-1833Crossref PubMed Scopus (3781) Google Scholar, 15Corley S.D. Epstein A.E. DiMarco J.P. Domanski M.J. Geller N. Greene H.L. Josephson R.A. Kellen J.C. Klein R.C. Krahn A.D. Mickel M. Mitchell L.B. Nelson J.D. Rosenberg Y. Schron E. Shemanski L. Waldo A.L. Wyse D.G. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.Circulation. 2004; 109: 1509-1513Crossref PubMed Scopus (1055) Google Scholar The details of AFFIRM trial have been described previously.9Badheka A.O. Rathod A. Kizilbash M.A. Garg N. Mohamad T. Afonso L. Jacob S. Influence of obesity on outcomes in atrial fibrillation: yet another obesity paradox.Am J Med. 2010; 123: 646-651Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 14Wyse D.G. Waldo A.L. DiMarco J.P. Domanski M.J. Rosenberg Y. Schron E.B. Kellen J.C. Greene H.L. Mickel M.C. Dalquist J.E. Corley S.D. A comparison of rate control and rhythm control in patients with atrial fibrillation.N Engl J Med. 2002; 347: 1825-1833Crossref PubMed Scopus (3781) Google Scholar, 15Corley S.D. Epstein A.E. DiMarco J.P. Domanski M.J. Geller N. Greene H.L. Josephson R.A. Kellen J.C. Klein R.C. Krahn A.D. Mickel M. Mitchell L.B. Nelson J.D. Rosenberg Y. Schron E. Shemanski L. Waldo A.L. Wyse D.G. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.Circulation. 2004; 109: 1509-1513Crossref PubMed Scopus (1055) Google Scholar, 16Mehta K. Grover P.M. Shah N. Patel N.J. Chothani A. Singh V. Savani G.T. Deshmukh A. Rathod A. Patel N. Panaich S.S. Arora S. Nalluri N. Khalpada D. Bhalaria V. Parmar N.G. Badheka A.O. Viles-Gonzalez J.F. Mitrani R.D. Non-influence of lipid lowering therapy in atrial fibrillation recurrence.Int J Cardiol. 2013; 168: 5006-5007Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 17Patel N.J. Hoosien M. Deshmukh A. Badheka A.O. Grover P.M. Shah N. Singh V. Mehta K. Chothani A. Savani G.T. Arora S. Bhalara V. Patel N. Khalpada D. Rathod A. Vazzana T.J. Lafferty J. Viles-Gonzalez J.F. Mitrani R.D. Digoxin significantly improves all-cause mortality in atrial fibrillation patients with severely reduced left ventricular systolic function.Int J Cardiol. 2013; 169: e84-e86Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar In brief, AFFIRM was a prospective trial (n = 4,060) comparing survival in patients with AF and at least 1 risk factor for stroke randomized to a strategy of rate control (n = 2,027) versus a strategy of rhythm control (n = 2,033). Our inclusion criteria included subjects who had initial (baseline) BP recordings and at least 1 other BP recording during the first year of follow-up. There were 3,947 patients (with available BP data) who were included into our study sample. Patients with limited or no BP data were excluded (n = 113). BP measurements were consistent with the American Heart Association's scientific statement on human BP determination by sphygmomanometer.18Perloff D. Grim C. Flack J. Frohlich E.D. Hill M. McDonald M. Morgenstern B.Z. Human blood pressure determination by sphygmomanometry.Circulation. 1993; 88: 2460-2470Crossref PubMed Scopus (1289) Google Scholar, 19Atrial Fibrillation Follow-Up Investigation of Rhythm Management-Protocol. Version 2.2, August 10, 1998.Google Scholar Per study protocol, the BP was recorded in the preferred arm after the patient has been sitting quietly for at least 5 minutes.14Wyse D.G. Waldo A.L. DiMarco J.P. Domanski M.J. Rosenberg Y. Schron E.B. Kellen J.C. Greene H.L. Mickel M.C. Dalquist J.E. Corley S.D. A comparison of rate control and rhythm control in patients with atrial fibrillation.N Engl J Med. 2002; 347: 1825-1833Crossref PubMed Scopus (3781) Google Scholar, 15Corley S.D. Epstein A.E. DiMarco J.P. Domanski M.J. Geller N. Greene H.L. Josephson R.A. Kellen J.C. Klein R.C. Krahn A.D. Mickel M. Mitchell L.B. Nelson J.D. Rosenberg Y. Schron E. Shemanski L. Waldo A.L. Wyse D.G. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.Circulation. 2004; 109: 1509-1513Crossref PubMed Scopus (1055) Google Scholar, 18Perloff D. Grim C. Flack J. Frohlich E.D. Hill M. McDonald M. Morgenstern B.Z. Human blood pressure determination by sphygmomanometry.Circulation. 1993; 88: 2460-2470Crossref PubMed Scopus (1289) Google Scholar, 19Atrial Fibrillation Follow-Up Investigation of Rhythm Management-Protocol. Version 2.2, August 10, 1998.Google Scholar, 20Atrial fibrillation follow-up investigation of rhythm management—the AFFIRM study design. The Planning and Steering Committees of the AFFIRM study for the NHLBI AFFIRM investigators.Am J Cardiol. 1997; 79: 1198-1202Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar The average BP was defined as the average of all available BP measurements taken during each postbaseline visit. SBP and DBP were categorized into 10-mm Hg increments to study the association between BP and primary and secondary clinical outcomes. The primary end point of our analysis was all-cause mortality (ACM). The secondary outcome considered was a composite of ACM and events including sustained ventricular tachycardia, ventricular fibrillation, pulseless electrical activity, concurrent AF, bradycardia, stroke, major bleeding, myocardial infarction, and pulmonary embolism. Our definitions remained consistent with the original trial.14Wyse D.G. Waldo A.L. DiMarco J.P. Domanski M.J. Rosenberg Y. Schron E.B. Kellen J.C. Greene H.L. Mickel M.C. Dalquist J.E. Corley S.D. A comparison of rate control and rhythm control in patients with atrial fibrillation.N Engl J Med. 2002; 347: 1825-1833Crossref PubMed Scopus (3781) Google Scholar, 15Corley S.D. Epstein A.E. DiMarco J.P. Domanski M.J. Geller N. Greene H.L. Josephson R.A. Kellen J.C. Klein R.C. Krahn A.D. Mickel M. Mitchell L.B. Nelson J.D. Rosenberg Y. Schron E. Shemanski L. Waldo A.L. Wyse D.G. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study.Circulation. 2004; 109: 1509-1513Crossref PubMed Scopus (1055) Google Scholar Follow-up data were available at 2, 4, 8, and 12 months and then 3 visits per year until a period of 6 years or study termination. Baseline characteristics of the study population were compared across the SBP and DBP groups by the chi-square test for categorical variables and the 1-way analysis of variance or the Kruskal-Wallis test for continuous variables, depending on the distribution of the variable. We hypothesized that if a J- or U-shaped relation is discovered between BP and outcome, it is more likely to be seen with average on-treatment follow-up BP (which is closer to the patient's "actual" long-term BP) rather than a single baseline BP value.4Bangalore S. Qin J. Sloan S. Murphy S.A. Cannon C.P. What is the optimal blood pressure in patients after acute coronary syndromes?: Relationship of blood pressure and cardiovascular events in the PRavastatin OR atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial.Circulation. 2010; 122: 2142-2151Crossref PubMed Scopus (189) Google Scholar We also conducted formal tests of linearity for the relation between BP and outcomes. The R2 of the quadratic model of SBP was significantly better than that of the linear model of SBP (p <0.001). Thus, the model with SBP as a quadratic function gives a better fit. Similar results were obtained using DBP and for secondary outcome as well. Hence, we decided to define the relation between average on-treatment BP and outcomes as a quadratic nonlinear relation. A nadir BP was calculated with the delta method, which is equal to coefficient of the linear term divided by 2 times the coefficient of the quadratic (square) term.21Durazo-arvizu R. McGee D. Li Z. Cooper R. Establishing the nadir of the body mass index-mortality relationship: a case study.J Am Stat Assoc. 1997; 92: 312-319Crossref Scopus (43) Google Scholar The value of nadir BP was then used to determine the range of SBP and DBP at which the event rate would be the lowest, and this range of SBP (130–140 mmHg) and DBP (70–80 mmHg) was subsequently used as the referent group in the Cox proportional hazards models. We created 2 separate adjusted models using baseline BP and average on-treatment follow-up BP. The predictive value for each model was calculated using Harrell's concordance index (C index), and a comparison was drawn between them using bootstrapping. Because the predictive value of models with average on-treatment BP was significantly better than that of baseline BP models, all subsequent mention of BP relates to average follow-up BP and not to baseline BP. Univariate Cox proportional hazards analysis was performed to investigate individual variables significantly associated with primary and secondary outcomes. Variables with p <0.2 in the initial univariate screen and those believed to be clinically relevant were included in the multivariate model.22Robert B. Bendel A.A.A. Comparison of stopping rules in forward "stepwise" regression.J Am Stat Assoc. 1977; 72: 46-53Google Scholar Initially, we constructed multivariate Cox proportional hazards models incorporating all potential confounding variables. Subsequently, we created reduced models including only variables with p 10 signifying collinearity. No significant interactions or multicollinearity was observed. The variance inflation factor for all variables in the model was <10. To evaluate the relation between SBP (in a continuous manner) and HR of primary and secondary outcomes, we performed restricted cubic spline analysis for the Cox proportional hazards model using the covariates listed previously. Separate subgroup analyses were also performed in important subgroups. A p value of <0.05 was considered statistically significant. All analyses were performed using the Stata software, version 11.0 (StataCorp LP, College Station, Texas). The baseline characteristics of the study population, stratified by average SBP and DBP ranges, are listed in Tables 1 and 2. Participants with a lower mean SBP were likely to be younger, men, and have a lower body mass index, history of CAD, and history of myocardial infarction and/or CHF. Participants with a lower mean DBP were more likely to be older, leaner, and have a history of CAD, myocardial infarction, peripheral vascular disease, and diabetes. Lower SBP and DBP were significantly associated with a decreased left ventricular ejection fraction (LVEF; 50%). Use of angiotensin-converting enzyme inhibitors, diuretics, calcium channel blockers, and other antihypertensive drugs was associated with a higher SBP. Use of diuretics, other antihypertensive drugs, digoxin, and/or amiodarone was associated with lower DBP. The mean follow-up period was 42.4 ± 14.7 months.Table 1Demographic and baseline characteristics (complete cohort) by average systolic blood pressure categoriesVariableSystolic Blood Pressure (mm Hg)p Value≤110 (n = 143)>110 to ≤120 (n = 426)>120 to ≤130 (n = 849)>130 to ≤140 (n = 1107)>140 to ≤150 (n = 854)>150 to ≤160 (n = 383)>160 (n = 185)Age (years)68.6 ± 9.569.0 ± 8.469.3 ± 8.269.1 ± 8.169.9 ± 7.870.4 ± 7.970.7 ± 7.50.02Men108 (75.5%)289 (67.8%)555 (65.3%)673 (60.7%)478 (55.9%)206 (53.7%)93 (50.2%)<0.01Body mass index (kg/m2)26.3 ± 5.428.3 ± 5.728.7 ± 5.629.1 ± 6.229.5 ± 6.129.3 ± 6.529.0 ± 5.90.001Hypertension63 (44.0%)221 (51.8%)510 (60.0%)806 (72.8%)695 (81.3%)343 (89.5%)170 (91.8%)<0.01Coronary artery diseases78 (54.5%)190 (44.6%)336 (39.5%)396 (35.7%)295 (34.5%)138 (36.0%)72 (38.9%)<0.01Myocardial infarction51 (35.6%)104 (24.4%)161 (18.9%)169 (15.2%)117 (13.7%)62 (16.1%)25 (13.5%)<0.01Revascularization39 (27.2%)100 (23.4%)175 (20.6%)186 (16.8%)138 (16.1%)68 (17.7%)32 (17.3%)0.001Heart failure68 (47.5%)121 (28.4%)201 (23.6%)220 (19.8%)172 (20.1%)77 (20.1%)42 (22.7%)<0.01NYHA HF class<0.01 083 (58.0%)323 (75.8%)679 (79.9%)922 (83.2%)699 (81.8%)316 (82.5%)148 (80.4%) 124 (16.7%)48 (11.2%)88 (10.3%)108 (9.7%)98 (11.4%)38 (9.9%)23 (12.5%) 222 (15.3%)46 (10.8%)63 (7.4%)64 (5.7%)46 (5.3%)25 (6.5%)13 (7.0%) 314 (9.7%)9 (2.1%)19 (2.2%)13 (1.1%)11 (1.2%)4 (1.0%)0 (0%)Peripheral vascular disease10 (7%)33 (7.8%)50 (5.9%)72 (6.5%)52 (6.1%)39 (10.2%)11 (6%)0.14Prior stroke22 (15.4%)60 (14.1%)108 (12.7%)134 (12.1%)121 (14.2%)49 (12.8%)30 (16.2%)0.62Smoker26 (18.2%)66 (15.5%)101 (11.9%)134 (12.1%)90 (10.5%)43 (11.2%)21 (11.4%)0.07Diabetes mellitus26 (18.2%)69 (16.2%)149 (17.6%)199 (18%)192 (22.5%)105 (27.4%)51 (27.6%)<0.01Pacemaker17 (11.9%)31 (7.3%)56 (6.6%)67 (6.1%)49 (5.7%)17 (4.4%)8 (4.3%)0.05Aspirin39 (27.3%)123 (28.9%)216 (25.4%)284 (25.7%)214 (25.1%)109 (28.5%)52 (28.1%)0.68Warfarin124 (86.7%)372 (87.3%)712 (83.9%)962 (86.9%)715 (83.7%)317 (82.8%)151 (81.6%)0.11Lipid lowering drug33 (23.1%)102 (23.9%)200 (23.6%)269 (24.3%)175 (20.5%)76 (19.8%)39 (21.1%)0.34Beta blocker42 (35%)146 (41.6%)242 (36.5%)325 (37.9%)257 (38.1%)105 (36.6%)58 (40.6%)0.72ACE inhibitors67 (46.9%)153 (35.9%)287 (33.8%)405 (36.6%)343 (40.2%)181 (47.3%)106 (57.3%)<0.01Diuretics74 (51.8%)181 (42.5%)335 (39.5%)435 (39.3%)374 (43.8%)180 (47%)96 (51.9%)0.001Other antihypertensive48 (33.6%)132 (31%)236 (27.8%)355 (32.1%)278 (32.6%)139 (36.3%)69 (37.3%)0.04CCBs30 (25%)84 (23.9%)219 (33.1%)295 (34.4%)219 (32.4%)97 (33.9%)53 (37.3%)0.006Digoxin (%)87 (60.8%)227 (53.3%)446 (52.6%)593 (53.6%)434 (50.8%)216 (56.4%)89 (48.1%)0.18Amiodarone (%)29 (20.3%)83 (19.5%)136 (16%)208 (18.8%)150 (17.6%)78 (20.4%)37 (20%)0.46Sotalol (%)18 (12.6%)56 (13.2%)121 (14.3%)156 (14.1%)140 (16.4%)76 (19.8%)33 (17.8%)0.06Class 1 antiarrhythmic12 (8.4%)43 (10.1%)104 (12.3%)150 (13.6%)122 (14.3%)50 (13.1%)25 (13.5%)0.25Ejection fraction∗Echocardiographic data available for 2,948 patients (74.7% of entire study population). 50%37 (37.8%)193 (66.1%)490 (76.8%)632 (75.6%)519 (78.8%)209 (74.9%)114 (78.1%) 40%–49%15 (15.3%)33 (11.3%)73 (11.4%)120 (14.4%)71 (10.8%)45 (16.1%)22 (15.1%) 30%–39%21 (21.4%)32 (11%)41 (6.4%)59 (7.1%)50 (7.6%)19 (6.8%)8 (5.5%) <30%25 (25.5%)34 (11.6%)34 (5.3%)25 (3%)19 (2.9%)6 (2.2%)2 (1.4%)Ventricular septal thickness (mm)∗Echocardiographic data available for 2,948 patients (74.7% of entire study population).1.0 ± 0.21.0 ± 0.21.1 ± 0.21.1 ± 0.21.1 ± 0.21.1 ± 0.21.1 ± 0.2 60 to ≤70 (n = 804)>70 to ≤80 (n = 1986)>80 to ≤90 (n = 964)>90 (n = 103)Age (years)72.5 ± 8.271.8 ± 7.170.1 ± 7.666.8 ± 8.662.8 ± 9.00.0001Male gender52 (57.8%)491 (61.1%)1,178 (59.3%)605 (62.8%)76 (73.8%)0.03Body mass index (kg/m2)26.2 ± 6.028.0 ± 5.628.8 ± 6.030.1 ± 6.030.6 ± 6.50.0001Hypertension57 (63.3%)469 (58.3%)1,390 (70%)795 (82.5%)97 (94.2%)<0.01Coronary artery diseases57 (63.3%)397 (49.4%)722 (36.4%)300 (31.1%)29 (28.2%)<0.01Myocardial infarction34 (37.8%)206 (25.6%)316 (15.9%)121 (126%)12 (11.6%)<0.01Revascularization37 (41.1%)221 (27.5%)335 (16.9%)137 (14.2%)8 (7.8%)<0.01Heart failure52 (57.8%)243 (30.2%)417 (21%)167 (17.3%)22 (21.4%)<0.01NYHA HF class<0.01 048 (53.3%)585 (72.8%)1,624 (81.8%)826 (85.8%)87 (84.5%) 119 (21.1%)113 (14.1%)210 (10.6%)79 (8.2%)6 (5.8%) 217 (18.9%)79 (9.8%)122 (6.1%)53 (5.5%)8 (7.8%) 36 (6.7%)27 (3.4%)30 (1.5%)5 (0.5%)2 (1.9%)Peripheral vascular diseases10 (11.1%)77 (9.6%)128 (6.5%)47 (4.9%)5 (4.9%)0.001Prior stroke15 (16.7%)112 (13.9%)266 (13.4%)123 (12.8%)8 (7.8%)0.39Smoker12 (13.3%)101 (12.6%)225 (11.3%)120 (12.5%)23 (22.3%)0.02Diabetes mellitus27 (30%)196 (24.4%)390 (19.6%)164 (17%)14 (13.6%)<0.01Pacemaker11 (12.2%)55 (6.8%)121 (6.1%)53 (5.5%)5 (4.9%)0.12Aspirin31 (34.4%)228 (28.4%)524 (26.4%)235 (24.4%)19 (18.5%)0.04Warfarin75 (83.3%)675 (84%)1,680 (84.6%)836 (86.7%)87 (84.5%)0.5Lipid lowering drug21 (23.3%)214 (26.6%)443 (22.3%)202 (21%)14 (13.6%)0.008Beta blocker20 (26.7%)223 (34.4%)603 (38.6%)297 (40.5%)32 (41.6%)0.04ACE inhibitors42 (46.7%)308 (38.3%)723 (36.4%)408 (42.3%)61 (59.2%)<0.01Diuretics64 (71.1%)373 (46.4%)804 (40.5%)378 (39.2%)56 (54.4%)<0.01Other antihypertensive35 (38.9%)312 (38.8%)615 (31%)268 (27.8%)27 (26.2%)<0.01CCBs21 (28%)204 (31.5%)508 (32.5%)240 (32.8%)24 (31.6%)0.91Digoxin69 (76.7%)432 (53.8%)1,059 (53.4%)476 (49.4%)56 (54.4%)<0.01Amiodarone22 (24.4%)183 (22.8%)338 (17%)162 (16.8%)16 (15.5%)0.002Sotalol10 (11.1%)117 (14.6%)290 (14.6%)165 (17.1%)18 (17.5%)0.27Class 1 antiarrhythmic12 (13.3%)78 (9.7%)266 (13.4%)135 (14%)15 (14.6%)0.06Ejection fraction∗Echocardiographic data available for 2,948 patients (74.7% of entire study population). 50%31 (45.6%)414 (70.2%)1,122 (75.9%)567 (77.6%)60 (74.1%) 40%–49%13 (19.1%)77 (13.1%)187 (12.7%)89 (12.2%)13 (16.1%) 30%–39%10 (14.7%)49 (8.3%)114 (7.7%)52 (7.1%)5 (6.2%) <30%14 (20.6%)50 (8.5%)55 (3.7%)23 (3.2%)3 (3.7%)Ventricular septal thickness (mm)∗Echocardiographic data available for 2,948 patients (74.7% of entire study population).1.1 ± 0.21.1 ± 0.21.1 ± 0.21.2 ± 0.21.2 ± 0.20.0001LV posterior wall thickness (mm)∗Echocardiographic data available for 2,948 patients (74.7% of entire study population).1.0 ± 0.21.0 ± 0.21.0 ± 0.21.1 ± 0.21.1 ± 0.20.0005Left atrial diameters (mm)∗Echocardiographic data available for 2,948 patients (74.7% of entire study population).4.5 ± 0.64.3 ± 0.74.3 ± 0.64.3 ± 0.64.2 ± 0.70.08ACE inhibitors = angiotensin-converting enzyme inhibitors; CCBs = calcium channel blockers; NYHA HF class = New York Heart Association heart failure class.∗ Echocardiographic data available for 2,948 patients (74.7% of entire study population). 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