Peripheral arterial disease is associated with an increased risk of atrial fibrillation in the elderly

Transcription

1 Europace (2016) 18, doi: /europace/euv369 CLINICAL RESEARCH Atrial fibrillation Peripheral arterial disease is associated with an increased risk of atrial fibrillation in the elderly William F. Griffin 1, Taufiq Salahuddin 2, Wesley T. O Neal 2 *, and Elsayed Z. Soliman 3,4 1 Department of Internal Medicine, Medical University of South Carolina, Charleston, SC, USA; 2 Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA; 3 Department of Internal Medicine, Section on Cardiology, Wake Forest School of Medicine, Winston-Salem, NC, USA; and 4 Department of Epidemiology and Prevention, Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, NC, USA Received 28 August 2015; accepted after revision 9 October 2015; online publish-ahead-of-print 20 November 2015 Aims To examine the relationship between peripheral arterial disease (PAD) and atrial fibrillation (AF) in a population-based cohort study of older adults.... Methods We examined the relationship between PAD and AF in 5143 participants (85% white, 43% male) in the Cardiovascular and results Health Study (CHS), a longitudinal, observational study of adults aged 65 years and older. Peripheral arterial disease was defined by abnormal ankle-brachial index (ABI) values (,1.0 or.1.4). Incident AF events were ascertained by self-reported history, study electrocardiograms, and hospitalization discharge records. Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between PAD and AF. Over a median follow-up of 11.7 years, a total of 1521 participants developed AF. The incidence rate (per 1000 person-years) of AF was higher in those with PAD (incidence rate ¼ 32.9, 95% CI ¼ 29.5, 36.7) than those without PAD (incidence rate ¼ 23.3, 95% CI ¼ 22.0, 24.6). In a multivariate Cox regression analysis, PAD was associated with an increased risk for AF (HR ¼ 1.52, 95% CI ¼ 1.34, 1.72). Each 0.1 decrease in the ABI was associated with a 6% increase in the risk for AF (HR ¼ 1.06, 95% CI ¼ 1.02, 1.10). The associations of high (.1.4) and low (,1.0) ABI values with AF were examined separately and were in the same direction as the main result for PAD (ABI, 1.0: HR ¼ 1.24, 95% CI ¼ 1.08, 1.42; ABI. 1.4: HR ¼ 1.33, 95% CI ¼ 0.95, 1.86).... Conclusion The presence of PAD should alert practitioners to the increased risk of AF. Elderly patients with PAD possibly will benefit from routine electrocardiographic screening to identify AF events Keywords Peripheral arterial disease Atrial fibrillation Risk factors Introduction Atrial fibrillation (AF) commonly affects adults older than 65 years and is associated with annual stroke events. 1 3 Peripheral arterial disease (PAD) is associated with similar increases in morbidity and mortality, and the prevalence of this condition increases with aging. 4 Both conditions share many common risk factors, including diabetes and smoking. 4 6 Recently, data from the Women s Health Initiative (WHI) study and the Multi-Ethnic Study of Atherosclerosis (MESA) have shown that PAD is an independent risk factor for AF. 7,8 However, these reports were limited to women, 7 and among persons between 45 and 84 years of age. 8 The association between PAD and incident AF has not been examined in a population limited to the elderly. Due to the expected increase in the number of adults older than 65 years, 9 the identification of new AF risk factors is of paramount importance for public health officials with aims to reduce the burden of AF on the health-care system, including cost. Therefore, the purpose of this study was to examine the association between PAD and AF in the Cardiovascular Health Study (CHS), a population-based cohort study of the elderly. Methods Study population Details of CHS have been previously described. 10 Briefly, CHS is a prospective population-based cohort study of risk factors for coronary heart disease and stroke in individuals aged 65 years and older. A total * Corresponding author. Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA Tel: ; fax: address: woneal@wakehealth.edu Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 Peripheral arterial disease and atrial fibrillation 795 What s new? The relationship between peripheral arterial disease (PAD) and atrial fibrillation (AF) remains unclear in older adults. In this study from the Cardiovascular Health Study, a population-based cohort of adults aged 65 years and older, PAD was associated with an increased risk for AF. The risk increased with decreasing ankle-brachial index (ABI) values, demonstrating a potential utility of this tool to identify older adults who are at risk for developing AF. Routine ABI measurements potentially identify elderly persons who are at risk for AF before symptoms of PAD are evident. Elderly patients with PAD possibly will benefit from routine electrocardiographic screening to identify AF events. of 5888 participants with Medicare eligibility in the USA were recruited from 4 field centres located in the following locations: Forsyth County, NC; Sacramento County, CA; Washington County, MD; and Pittsburgh, PA. Subjects were followed with semi-annual contacts, alternating between telephone calls and surveillance clinic visits. Cardiovascular Health Study clinic exams ended in the June of 1999, and since that time 2 yearly phone calls to participants have been used to identify events and collect data. The institutional review board at each site approved the study, and written informed consent was obtained from participants at enrolment. In this analysis, a longitudinal cohort study was used to examine the association between PAD and incident AF. Participants were excluded if they had baseline AF, baseline covariate data were missing, or follow-up data were missing. Peripheral arterial disease Baseline ankle-brachial index (ABI) measurements were used to define PAD. Systolic blood pressures were measured in both the right and left brachial, posterior tibial, and dorsalis pedis arteries with Doppler instruments. The average of the measurements was used to calculate the ABI for each side. Consistent with guidelines regarding PAD diagnosis, a value of,1.0 or.1.4 defined PAD. 11 Atrial fibrillation In this analysis, AF events included paroxysmal, persistent, and permanent cases. Baseline AF cases were identified from the initial study electrocardiogram or by self-reported history of a physician diagnosis. Atrial fibrillation cases also were identified during the annual study electrocardiograms that were performed annually until Additionally, hospitalization discharge data were used to identify AF events using International Classification of Diseases codes and Hospital diagnosis codes for AF ascertainment have been shown to have a positive predictive value of 98.6%. 12 Covariates Participant characteristics were collected during the initial CHS interview and questionnaire. Age, sex, race, income, and education were selfreported. Annual income was dichotomized at $25 000, and education was dichotomized at high school or less. Smoking was defined as ever (e.g. current or former) or never smoker. Participants blood samples were obtained after a 12 h fast at a local field centre. Measurements of total cholesterol, high-density lipoprotein (HDL) cholesterol, and plasma glucose were used in this analysis. Diabetes was defined by selfreported history of a physician diagnosis, a fasting glucose value of 126 mg/dl, or by the current use of insulin or oral hypoglycaemic medications. Blood pressure was measured for each participant in the seated position, and systolic measurements were used in this analysis. The use of aspirin, statins, and antihypertensive medications was selfreported. Body mass index was computed as the weight in kilograms divided by the square of the height in metres. Baseline coronary heart disease was determined by self-reported history or by medical record adjudication of the following diagnoses: myocardial infarction, angina pectoris without myocardial infarction, or coronary revascularization procedures (angioplasty and coronary artery bypass graft surgery). 13 Baseline cases of stroke and heart failure were identified by selfreported history of a physician diagnosis followed by review of medical records. Statistical analysis Categorical variables were reported as frequency and percentage, while continuous variables were recorded as mean + standard deviation. Statistical significance for categorical variables was tested using the x 2 method and Student s t-test for continuous variables. Follow-up time was defined as the time between the initial study visit until one of the following: AF development, death, loss to follow-up, or end of follow-up (31 December 2010). Kaplan Meier estimates were used to compute the cumulative incidence of AF by PAD, and the difference in estimates was compared using the log-rank procedure. 14 Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between PAD and incident AF. Multivariate models were constructed as follows: Model 1 adjusted for age, sex, race, education, and income; Model 2 adjusted for Model 1 covariates plus smoking, systolic blood pressure, diabetes, body mass index, total cholesterol, HDL cholesterol, aspirin, antihypertensive medications, coronary heart disease, stroke, and heart failure. We tested for interactions between our main effect variable and age (dichotomized at 75 years), sex, and race (white vs. black). In a secondary analysis, we examined the association of low (,1.0) and high (.1.4) ABI values (referent group: 1.0 ABI 1.4) separately with AF. Additionally, the association of the ABI as a continuous variable (per 0.1 decrease) with AF was examined after excluding participants with ABI values.1.4. We also constructed a restricted cubic spline model to examine the graphical dose response relationship between ABI values and incident AF at the 5th, 50th, and 95th percentiles. 15 Statistical significance for our main effect models and interaction terms was defined as P, SAS Version 9.3 (Cary, NC) was used for all analyses. Results A total of 5143 participants (85% white; 43% male) with complete data were used in this analysis. Baseline characteristics stratified by PAD are shown in Table 1. Over a median follow-up of 11.7 years, a total of 1521 AF participants developed AF. The cumulative incidence rate (per 1000 person-years) of AF was higher for those with PAD (incidence rate ¼ 32.9, 95% CI ¼ 29.5, 36.7) compared with those without PAD (incidence rate ¼ 23.3, 95% CI ¼ 22.0, 24.6). The cumulative incidence curves of AF by PAD are shown in Figure 1 (log-rank P, ). In an unadjusted Cox regression model, PAD was associated with an increased risk for AF (HR ¼ 1.52, 95% CI ¼ 1.34, 1.72). The association remained significant with further adjustment in Models

3 796 W.F. Griffin et al. Table 1 Baseline characteristics (N ) Characteristic PAD No PAD P-value a (n ) (n )... Age (years) (%) 322 (30) 1909 (47), (%) 231 (22) 1004 (25) (%) 301 (29) 874 (21).80 (%) 202 (19) 300 (7.3) Male (%) 460 (44) 1730 (42) 0.47 White (%) 841 (80) 3537 (87), High school or less (%) 675 (64) 2269 (56), Annual income,$ (%) 778 (74) 2489 (61), Ever smoker (%) 632 (60) 2141 (52), Diabetes (%) 242 (23) 552 (14), Body mass index, mean (SD), 26 (4.1) 27 (4.0), kg/m 2 Systolic blood pressure, 147 (23) 138 (19), mean (SD), mm Hg Total cholesterol, mean (SD), 215 (41) 211 (38) mg/dl HDL cholesterol, mean (SD), 54 (17) 55 (15) mg/dl Antihypertensive medication 591 (56) 1762 (43), use (%) Aspirin use (%) 382 (36) 1335 (33) Coronary heart disease (%) 266 (25) 687 (17), Stroke (%) 75 (7.1) 118 (2.9), Heart failure (%) 65 (6.2) 122 (3.0), HDL, high-density lipoprotein; PAD, peripheral arterial disease; SD, standard deviation. a Statistical significance for continuous data was tested using Student s t-test, and categorical data were tested using the x 2 test. 1 and 2(Table 2). Additionally, the results were consistent across subgroups stratified by age, sex, and race (Table 2). The associations of high (.1.4) and low (,1.0) ABI values with AF were examined separately and were in the same direction as the main result for PAD (ABI, 1.0: adjusted HR ¼ 1.24, 95% CI ¼ 1.08, 1.42; ABI. 1.4: adjusted HR ¼ 1.33, 95% CI ¼ 0.95, 1.86). The result was not significant for high ABI values due to the small number of participants in this group (n ¼ 97). The HR for the risk of AF associated with the ABI as a continuous variable (per 0.1 decrease) was 1.06 (95% CI ¼ 1.02, 1.10) after excluding participants with ABI values.1.4. Figure 2 depicts the risk of AF across ABI values using a restricted cubic spline model. As shown, the risk for AF increased with decreasing ABI values. A similar trend was observed for increasing ABI values. Discussion In this analysis from CHS, we have shown that PAD is associated with an increased risk of AF. The association remained similar when stratified by age, sex, and race. Additionally, we observed that the risk of AF increased with decreasing ABI values, Figure 1 Cumulative incidence of Atrial Fibrillation*. *Incidence curves are statistically different (log-rank P, ). PAD, peripheral arterial disease. demonstrating the potential utility of the ABI to identify elderly persons who are at risk for developing AF. A recent analysis from WHI, a study of postmenopausal women, has shown that self-reported PAD is independently associated with an increased risk for AF (HR ¼ 1.53, 95% CI ¼ 1.37, 1.72). 7 Data from MESA also have shown that PAD is associated with an increased risk for AF (HR ¼ 1.5, 95% CI ¼ 1.1, 2.0). 8 Similar to prior findings, we observed an increased risk of AF with PAD. We also observed an increased risk for AF with decreasing ABI values. In MESA, a similar relationship of increased AF risk with decreasing ABI values was found. 8 Both studies demonstrate that the ABI is a useful tool to assess AF risk. Additionally, our findings extend prior work by showing that an increased risk of AF exists in elderly adults with PAD. Although not significant, a trend for increased AF risk was observed with ABI values.1.4. High ABI values are thought to represent medial arterial calcification rather than the intima-media thickening associated with atherosclerotic disease and low ABI values. 16 This finding also is in agreement with results from MESA. 8 The association between PAD and AF is not completely understood. It is known that both conditions share many risk factors and are associated with increased levels of pro-inflammatory markers and platelet-mediated thrombosis. 4 6,17,18 Potentially, PAD increases the risk of developing AF through shared risk factors that reflect a poor cardiovascular risk profile in which AF likely develops. Additionally, the dysfunctional regulation of inflammation and platelet-mediated thrombosis observed with PAD possibly increases atrial ectopy near the pulmonary vein ostia, the origin of AF. Although we offer several plausible explanations for the association between PAD and AF, further research is needed to determine the underlying mechanisms that link both conditions. Due to the high burden of AF among individuals older than 65 years and the subsequent increase in morbidity and mortality, 1 3 the presence of PAD should alert practitioners to the likelihood of developing AF. Elderly patients with PAD possibly will benefit from routine electrocardiographic screening to identify AF events.

4 Peripheral arterial disease and atrial fibrillation 797 Table 2 Risk of Atrial Fibrillation (N ) Cases/no. at risk Model 1 a P-value Model 2 b P-value P-interaction c HR (95%CI) HR (95% CI)... PAD 1521/ (1.21, 1.56), (1.10, 1.42) Age,75 years 981/ (1.09, 1.56) (1.01, 1.44) years 540/ (1.28, 1.85), (1.13, 1.67) Sex Female 803/ (1.09, 1.55) (1.02, 1.46) Male 718/ (1.20, 1.74) (1.05, 1.55) Race Black 158/ (0.72, 1.51) (0.75, 1.63) White 1363/ (1.24, 1.63), (1.11, 1.47) CI, confidence interval; HDL, high-density lipoprotein; HR, hazard ratio; PAD, peripheral arterial disease. a Adjusted for age, sex, race, education, and income. b Adjusted for Model 1 covariates plus smoking, systolic blood pressure, diabetes, body mass index, total cholesterol, HDL cholesterol, aspirin, antihypertensive medications, coronary heart disease, stroke, and heart failure. c Interactions tested using Model 2. Figure 2 Risk of Atrial Fibrillation across ABI*. *Each HR was computed with the median ABI value of 1.11 as the reference and was adjusted for age, sex, race, education, income, smoking, systolic blood pressure, diabetes, body mass index, total cholesterol, HDL cholesterol, aspirin, antihypertensive medications, coronary heart disease, stroke, and heart failure. ABI, ankle-brachial index; HDL, high-density lipoprotein. Additionally, due to the paroxysmal nature of certain cases, patients should be educated on the signs of the arrhythmia (e.g. palpitations) and instructed to seek medical attention if they experience such symptoms. Similarly, routine ABI measurements may identify those at risk for AF before symptoms of PAD are evident. These strategies likely will identify AF events earlier and allow for the initiation of anticoagulation therapies to prevent devastating stroke events. Due to the expected increase in persons above 65 years of age, 9 better methods are needed to detect AF in older populations to reduce the mortality associated with this arrhythmia. However, further studies are needed to determine the feasibility, cost, and potential benefit of using routine ABI measurements to identify those who are at risk for AF. Similar studies are needed to determine the role of routine electrocardiographic tracings in patients with PAD for AF detection. Several limitations in this study should be considered. Atrial fibrillation cases were ascertained by self-reported history, study electrocardiograms, and hospital discharge data, which possibly resulted in the misclassification of AF events. Additionally, paroxysmal cases potentially were missed. However, the resulting bias would make the relationship observed in the present study a more conservative estimate as missed cases would have been classified in the non-af group. Self-reported AF also is highly predictive of future stroke events, and self-reported cases are able to be used interchangeably in stroke risk prediction models, suggesting that self-reported AF is able to reliably detect the arrhythmia. 19 Similarly, hospitalization discharge data have been shown to adequately detect AF events. 20 Despite standardization of ABI measurements, 21 different definitions of PAD (e.g.,0.9) exist, and it is possible that our results vary with other definitions. However, PAD was defined by abnormal ABI values

5 798 W.F. Griffin et al. (e.g.,1.0 and.1.4) according to current guidelines. 11 Although we included several covariates in our multivariate models, other unmeasured factors that likely influenced the relationship between PAD and AF were unable to be accounted for due to the observational nature of this study. Finally, the study population was predominately white and located in specific geographical regions of the USA. Therefore, the generalizability of this study to other populations is uncertain. Conclusion In summary, we have shown that PAD, as defined by abnormal ABI values, is associated with an increased risk of AF in adults aged 65 years and older. The present study extends previous literature by demonstrating that the increased risk of AF associated with PAD also is found in elderly populations. Due to the increased morbidity and mortality associated with AF, further studies are needed to explore the utility of routine electrocardiographic screening for AF in elderly patients with abnormal ABI values. Acknowledgements This manuscript was prepared using CHS Research Materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of the CHS or the NHLBI. Conflict of interest: none declared. References 1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV et al. 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: Wolf PA, Mitchell JB, Baker CS, Kannel WB, D Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med 1998;158: Benjamin EJ, Wolf PA, D Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998; 98: Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, Circulation 2004;110: Benjamin EJ, Levy D, Vaziri SM, D Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 1994;271: Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82:2N 9N. 7. Perez MV, Wang PJ, Larson JC, Soliman EZ, Limacher M, Rodriguez B et al. Risk factors for atrial fibrillation and their population burden in postmenopausal women: the Women s Health Initiative Observational Study. Heart 2013;99: O Neal WT, Efird JT, Nazarian S, Alonso A, Heckbert SR, Soliman EZ. Peripheral arterial disease and risk of atrial fibrillation and stroke: the multi-ethnic study of atherosclerosis. J Am Heart Assoc 2014;3:e Odden MC, Coxson PG, Moran A, Lightwood JM, Goldman L, Bibbins-Domingo K. The impact of the aging population on coronary heart disease in the United States. Am J Med 2011;124: Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol 1991;1: Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;127: Psaty BM, Manolio TA, Kuller LH, Kronmal RA, Cushman M, Fried LP et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96: Psaty BM, Kuller LH, Bild D, Burke GL, Kittner SJ, Mittelmark M et al. Methods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study. Ann Epidemiol 1995;5: Gray RJ, Tsiatis AA. A linear rank test for use when the main interest is in differences in cure rates. Biometrics 1989;45: Marrie RA, Dawson NV, Garland A. Quantile regression and restricted cubic splines are useful for exploring relationships between continuous variables. J Clin Epidemiol 2009;62: Suominen V, Rantanen T, Venermo M, Saarinen J, Salenius J. Prevalence and risk factors of PAD among patients with elevated ABI. Eur J Vasc Endovasc Surg 2008; 35: Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ. Atherothrombosis and highrisk plaque: Part I: evolving concepts. J Am Coll Cardiol 2005;46: Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow s triad revisited. Lancet 2009;373: Soliman EZ, Howard G, Meschia JF, Cushman M, Muntner P, Pullicino PM et al. Self-reported atrial fibrillation and risk of stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Stroke 2011;42: Jensen PN, Johnson K, Floyd J, Heckbert SR, Carnahan R, Dublin S. A systematic review of validated methods for identifying atrial fibrillation using administrative data. Pharmacoepidemiol Drug Saf 2012;21(Suppl. 1): Jeelani NU, Braithwaite BD, Tomlin C, MacSweeney ST. Variation of method for measurement of brachial artery pressure significantly affects ankle-brachial pressure index values. Eur J Vasc Endovasc Surg 2000;20:25 8.