EURO PEAN SO CIETY O F CARDIOLOGY ®
Original scientific paper
Peripheral artery disease is a coronary heart disease risk equivalent among both men and women: results from a nationwide study
European Journal of Preventive Cardiology 2015, Vol. 22(3) 317–325 ! The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487313519344 ejpc.sagepub.com
Sumeet Subherwal1, Manesh R Patel1, Lars Kober2, Eric D Peterson1, Deepak L Bhatt3, Gunnar H Gislason4, Anne-Marie Schjerning Olsen4, William S Jones1, Christian Torp-Pedersen4 and Emil L Fosbol1,4
Abstract Aims: Lower extremity peripheral artery disease (PAD) has been proposed as a ‘coronary heart disease (CHD) risk equivalent’. We aimed to examine whether PAD confers similar risk for mortality as incident myocardial infarction (MI) and whether risk differs by gender. Methods: Using nationwide Danish administrative registries (2000–2008), we identified patients aged 40 years with incident PAD (PAD only, n ¼ 35,628), incident PAD with a history of MI (PAD þ MI, n ¼ 7029), and incident MI alone (MI alone, n ¼ 71,115). Results: Patients with PAD only tended to be younger, female, and have less comorbidity than the other groups. During follow up (median 1051 d, IQR 384–1938), we found that MI-alone patients had greater risk of adverse outcomes in the acute setting (first 90 d); however, the PAD-only and PAD þ MI groups had higher long-term mortality at 7 years than those with MI alone (47.8 and 60.4 vs. 36.4%, respectively; p < 0.0001). After adjustment, the PAD-only and PAD þ MI groups had a higher long-term risk for mortality [hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.44–1.51; and HR 1.65, 95% CI 1.58–1.72, respectively], cardiovascular mortality (HR 1.30, 95% CI 1.26–1.34; and HR 1.71, 95% CI 1.62– 1.80, respectively), and composite of death, MI, and ischaemic stroke, 95% CI HR, 1.38, 95% CI 1.36–1.42; and HR 1.68, 95% CI 1.61–1.75, respectively). The greater long-term risks of PAD were seen for both women and men. Conclusions: Both women and men with incident PAD have greater long-term risks of total and cardiovascular mortality vs. those with incident MI. PAD should be considered a CHD risk equivalent, warranting aggressive secondary prevention.
Keywords Coronary heart disease, myocardial infarction, peripheral artery disease Received 20 May 2013; accepted 15 December 2013
Introduction Lower extremity peripheral artery disease (PAD) is associated with increased cardiovascular morbidity and mortality.1–3 Indeed, the recent European Society of Cardiology (ESC) Guidelines for the Management of Dyslipidemias, the ESC Guidelines on Cardiovascular Disease Prevention in Clinical Practice, and the National Cholesterol Educational Program Adult Treatment Panel (ATP III) guidelines classify PAD as a coronary heart disease (CHD) risk equivalent,
1
Duke University Medical Center, Durham, NC, USA The Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark 3 Harvard Medical School, Boston, MA, USA 4 Copenhagen University Hospital Gentofte, Copenhagen, Denmark 2
Corresponding author: Sumeet Subherwal, Duke Clinical Research Institute, 2400 Pratt Street, Room 0311, Terrace Level, Durham, NC 27705, USA. Email: [email protected]
318 suggesting that PAD confers a long-term risk to patients similar to established heart disease. Consequently, these guidelines recommend more intense risk factor management of patients with PAD beyond that of the general population.4–6 Although population studies have demonstrated increased CHD risk among patients with PAD,2,3,7–9 no study has specifically addressed the question of whether patients with PAD share a similar long-term risk for mortality and cardiovascular mortality as those with an incident myocardial infarction (MI). Such an analysis would help justify or refute guideline recommendations on secondary prevention; importantly, it would also clarify the need for programmes to improve and promote risk factor modification in this population. Similarly, there has been a paucity of epidemiological data investigating whether the CHD risk of PAD compared with MI is similar in women and men.10,11 This prompted the American Heart Association (AHA) recently to call to action clinicians and the scientific community to increase research and awareness of outcomes in women with PAD.12 Using Danish nationwide administrative registries, we sought to determine (1) whether patients with an incident diagnosis of PAD, both with and without history of MI, share a similar long-term cardiovascular risk as patients with incident MI alone, and (2) whether outcomes differed by gender.
Methods
European Journal of Preventive Cardiology 22(3) diagnosis of MI but no prior PAD diagnosis (back to 1994). The index date used was the time-of-incident diagnosis of PAD (time of second visit for the outpatient PAD group or hospital discharge date for PAD patients) for the first two groups and time of incident diagnosis of MI for the third group (date of discharge). Groups were exclusive, and we did not update group status during follow up for our primary analysis.
Covariates Comorbidity was measured using the Charlson index by assessing hospitalizations 1 year before diagnosis, as described by Deyo et al.15,16 This includes important covariates such as prior stroke and history of atrial fibrillation. Patients were categorized as diabetic if they had a recorded diagnosis of diabetes 1 year prior to index or filled a prescription for a glucose-lowering drug within 6 months of the index date. Average 5-year family income prior to the index date was calculated and summarized in quartiles. Data for smoking were not available, although diagnosis of chronic obstructive pulmonary disease was captured.
Outcomes The primary endpoints were all-cause mortality, cardiovascular mortality (using ICD-10 I00-I99 codes as primary or secondary codes), and a composite of all-cause mortality, MI, or ischaemic stroke (using ICD-10 codes I61–I64).
Population and data sources This study was a population-based cohort study of Danish residents aged 40 years, using nationwide administrative registries for 2000–2008. Information on diagnoses and comorbidity was obtained from the Danish National Patient Registry, which holds data on all admissions and outpatient visits to Danish hospitals and specialty clinics since 1978.13 Since 1994, all admissions and visits have been registered by one primary diagnosis and, if appropriate, one or more secondary diagnoses according to the International Classification of Diseases, Tenth Revision (ICD-10). For this study, patients with PAD were identified using the ICD-10 codes (listed in the Supplementary Material online), while those with MI were identified using ICD-10 codes I21 and I22, as done previously with high validity.14 Patients were categorized into three groups: (1) PAD only: those with incident diagnosis of PAD (first-time hospitalization or at least two consecutive outpatient visits for PAD) without history of MI; (2) PAD þ MI: those with incident PAD and a history of MI (assessed back to 1978); or (3) MI alone: those with incident
Statistical analysis We used the Kruskal–Wallis test for continuous variables and chi-square test for categorical variables to test for differences between groups. For unadjusted rates of all-cause mortality and the composite endpoint, we compared the groups using Kaplan–Meier curves and performed the log rank test for statistical differences between groups. For cardiovascular death, unadjusted rates were shown using cumulative incidence curves because of the possibility of competing risks of mortality. Using the MI-alone group as the reference, we performed multivariable Cox proportional hazards analysis to assess relative hazard of all-cause mortality and the composite outcome, adjusting for age, sex, calendar year, family income, Charlson comorbidity index, and baseline medications (antiplatelet, betablocker, statin, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, or vitamin K antagonist). Patients were censored at the end of the follow-up period (31 December 2009) if the patient did not experience an event. For models performed for cardiovascular death, patients were also censored at
Subherwal et al. time of death from other causes (cause-specific hazard model). For all models, the proportional hazard assumption was violated; subsequently, we performed landmark analysis to differentiate an earlier time point with acute phase-related rates after incident diagnosis vs. a later time point when patients were in a more stable condition. Outcomes were assessed in two time frames of follow up: 0–90 d after the index date and >90 d to 7 years, according to when the slope of the outcomes curves changed. Given that the acute phase post-MI setting may represent higher risk and a less stable population than the PAD population at incident diagnosis, we performed a sensitivity analysis in which we compared the outcomes for MI patients surviving 14 d post discharge to both PAD groups. In addition, given the possible different risks associated with an outpatient vs. in-hospital diagnosis of PAD, we performed a sensitivity analysis investigating the relative risk of MI alone compared with an outpatient and an inhospital diagnosis of PAD. We tested important interactions in the models (age and diabetes). Prespecified subgroup analyses by gender were planned regardless of results derived from statistical interaction testing between gender and group assignment. Groups in our study were exclusive, but patients could potentially transition from one group to another during follow up. To account for this, we performed a sensitivity analysis in which patients were censored at time of transition from one group to another. All analyses used SAS version 9.2 (SAS Institute, Cary, NC, USA), and the level of statistical significance was set at p 0.05 (two-sided). The Danish Data Protection Agency approved the study (no. 200758-0015, ref. no. GEH-2010-001).
Results After selection criteria were applied, 113,772 patients were included in our cohort study: 35,628 with PAD only, 7029 with PAD þ MI, and 71,115 with MI alone. Overall, 49.9% of PAD patients were diagnosed in the outpatient setting, whereas all MI patients were diagnosed in hospital. Patients with PAD only tended to be younger, more often female, and have less comorbidity than the other two groups (Table 1). Meanwhile, patients with PAD þ MI were older, most likely male, and had the highest overall level of comorbidity. Both PAD groups had greater rates of diabetes mellitus than MI alone. Overall, use of cardioprotective medication was modest after incident diagnosis of either PAD or MI alone (Table 1); patients with MI alone were treated most aggressively within 3 months of incident diagnosis with any antiplatelet, beta-blocker, or statin therapy.
319 The PAD-only group had the lowest use of cardioprotective medications after incident diagnosis.
Unadjusted and adjusted all-cause mortality The proportional hazard assumption was violated in all models, meaning that the groups had different shortterm (90 d) and long-term (>90 d) outcome rates (p-values for interaction with time in all models were 90-d mortality
0.50 (0.48–0.52) 0.60 (0.57–0.64)
1.47 (1.44–1.51) 1.65 (1.58–1.72)
0.42 (0.41–0.44) 0.57 (0.53–0.61)
1.30 (1.26–1.34) 1.71 (1.62–1.80)
0.38 (0.37–0.40) 0.56 (0.53–0.59)
1.38 (1.36–1.42) 1.68 (1.61–1.75)
Values are hazard ratio (95% confidence interval). Adjusted for age, sex, year, subsequent MI or percutaneous coronary intervention, lower extremity revascularization, quartile of income, Charlson comorbidity index, and baseline medications (antiplatelet, beta-blocker, statin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, or vitamin K antagonist). Composite outcome, all-cause mortality, MI, or ischaemic stroke; MI, myocardial infarction; PAD, peripheral artery disease.
risk of cardiac outcomes and death. Furthermore, this greater risk remained regardless of whether PAD was inhospital or outpatient diagnosed. In addition, the overall difference between PAD and MI alone was not modified by the presence of diabetes, and therefore the association between PAD and long-term mortality can be considered independent of diabetes. Part of the greater long-term risk associated with PAD may be explained by more systemic atherosclerosis among patients with PAD.17 Prior analyses have demonstrated that PAD is an important predictor of subsequent CHD and is associated with increased risk for cardiovascular morbidity.3,7,18–21 Although PAD is assumed to be a CHD risk equivalent, no prior study, to the best of our knowledge, has been designed to examine this hypothesis. The Reduction of Atherothrombosis for Continued Health (REACH) registry has demonstrated that patients with symptomatic PAD had slightly higher 3year cardiovascular event rates than patients with coronary artery disease.22 However, the REACH registry design only examined prevalent disease and was unable to determine timing of incident diagnosis of PAD.2,8 The present analysis is unique in that the Danish administrative registries capture time of incident diagnosis of PAD as well as incident MI, and our study is therefore better designed to test whether patients seeking care for PAD share similar mortality as patients with MI alone. Furthermore, the Danish registries capture the entire population seeking care in the national healthcare system, which allows our findings to be generalized more broadly to real-world patients. A recent study by Achterberg et al.23 showed similar results in terms of a higher risk associated with PAD relative to
Table 3. Outcomes stratified by gender using the MI-alone group as reference Women Group All-cause mortality PAD only PAD þ MI Cardiovascular mortality PAD only PAD þ MI Composite outcome PAD only PAD þ MI
Men
0–90 d mortality
>90 d mortality
0–90 d mortality
>90 d mortality
0.49 (0.47–0.52) 0.63 (0.57–0.70)
1.25 (1.20–1.29) 1.32 (1.32–1.52)
0.47 (0.44–0.49) 0.56 (0.51–0.60)
1.52 (1.47–1.57) 1.60 (1.52–1.69)
0.43 (0.41–0.46) 0.58 (0.52–0.65)
1.12 (1.06–1.17) 1.46 (1.34–1.59)
0.38 (0.36–0.41) 0.52 (0.47–0.57)
1.31 (1.25–1.37) 1.64 (1.54–1.75)
0.40 (0.39–0.42) 0.61 (0.56–0.67)
1.16 (1.12–1.20) 1.45 (1.35–1.55)
0.35 (0.33–0.36) 0.50 (0.47–0.54)
1.43 (1.38–1.48) 1.63 (1.55–1.72)
Values are hazard ratio (95% confidence interval). Irrespective of gender, adjusted risk of adverse outcomes was greater among both PAD groups relative to the MI-alone group in the long-term. Adjusted for age, sex, year, subsequent MI or percutaneous coronary intervention, lower extremity revascularization, quartile of income, Charlson comorbidity index, and baseline medications (antiplatelet, beta-blocker, statin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, or vitamin K antagonist). Composite outcome, all-cause mortality, MI, or ischaemic stroke; MI, myocardial infarction; PAD, peripheral artery disease.
Subherwal et al. coronary artery disease; this study was in Holland and constitutes a similar health system as the Danish system. Other studies have also shown that PAD and MI often coexist and that they also constitute an additive risk for the patients.24 Despite our and others’ findings demonstrating increased risk associated with PAD, a lack of awareness of PAD continues among the public and primary care physicians.25,26 Although the magnitude of coronary disease risk in women has been highlighted in the past decade,10,11 major gaps in knowledge still exist regarding risks associated with PAD among women.12 Consequently, the AHA has recently highlighted the lack of public awareness of cardiovascular risks associated with PAD and the need for educational programmes designed specifically to address risk among women.12 Our findings underscore the need to better educate the public about adverse outcomes associated with PAD in both men and women. We hope our findings spur debate about the role of increased efforts at earlier screening and promote adherence to secondary prevention. We found similar rates of mortality, cardiovascular mortality, and the composite endpoint in men and women in the short term, but male gender was associated with higher hazard ratios of all endpoints in the long term. This is an important finding as women have been suspected to be associated with worse outcomes than men. These findings were consistent after adjusting for age, and we found no effect of modification of age as shown in a previous study.27 Clinicians, who are well aware that diabetes is a cardiac risk equivalent by conferring a 10-year risk for recurrent CHD events of >20%,4,28,29 have aggressively managed cardiovascular risk factors among patients with diabetes; combined with use of secondary prevention strategies, this has been shown to improve outcomes among these patients.30 Interestingly, in our study, although the use of cardioprotective medications by 3 months after incident diagnosis was suboptimal among all three groups, the use of cardioprotective medications was lowest among the PAD-only group. Over one-half of the PAD-only group members were not on any antiplatelet therapy by 3 months after diagnosis, and nearly two-thirds were not on any statin, despite demonstrated benefits of these therapies among the symptomatic PAD population.31–34 Although we did notice an improvement in use of cardioprotective medication over time, as evidenced by greater rates of adherence in the final study period, the use of cardioprotective medication among those with PAD still remained modest overall and lower compared with those with MI. Greater adherence rates and strict treatment goals have potential to improve outcomes among patients with PAD as well, although further research is needed to demonstrate this.
323 The limitations of this study is that the analysis used administrative data and therefore captured only those patients who sought treatment for PAD. The extent and severity of PAD could not be determined using noninvasive studies (i.e. vascular ultrasound, ankle/brachial index, pulse volume recording, computed tomography, or magnetic resonance imaging) given the study design. We limited our ICD-10 codes to lower extremity PAD, and these codes have previously been used as part of a broader definition of PAD with good validity.35 The majority of the cohort was, however, composed of patients with a nonspecific code for lower extremity PAD, meaning that information regarding the severity of the disease was unobtainable in these patients. However, given that the patients were identified in inpatient or outpatient specialty clinics, the cohort likely reflects a greater proportion of symptomatic patients with advanced PAD. Prior studies of symptomatic PAD that share similarly high mortality rates3 enrolled patients in the 1990s; it is noteworthy that in our study, the mortality remained strikingly high among a more contemporary population seeking treatment for PAD. Our analysis excluded patients with carotid, aneurysmal, renal, and mesenteric artery disease; therefore, our findings pertain to the lower extremity atherosclerotic PAD population. Our findings represent all patients in Denmark, but findings may differ in other parts of the world. Inference regarding causality should be made cautiously given the observational nature of our study. We could not adjust for smoking status but did adjust for chronic obstructive pulmonary disease. Our study supports greater use of secondary prevention strategies among PAD patients but cannot firmly establish whether aggressive secondary prevention will reduce the long-term risks of PAD. Further studies are needed to define the optimal goals for secondary prevention in this high-risk population. In conclusion, patients seeking medical care for lower extremity PAD are at greater long-term risks for total and cardiovascular mortality as well as a composite endpoint of mortality, MI, and ischaemic stroke than patients with incident MI alone. Therefore, lower extremity PAD may be considered a CHD risk equivalent. Women as well as men with PAD remain at higher risk of long-term adverse outcomes relative to patients with MI alone, yet those with both PAD and MI remain at the highest risk level. Increased awareness of the prognostic importance of PAD by clinicians and the public is warranted. Funding This work was supported in part internally by the Duke Clinical Research Institute. ELF is supported by an award from the American Heart Association–Pharmaceutical Roundtable and David and Stevie Spina (grant number 087142N).
324 Conflict of interest Disclosure information for MRP and EDP is available at https://www.dcri.org/about-us/conflict-of-interest. DLB has served on the advisory board for Medscape Cardiology, has received honoraria from the American College of Cardiology, Duke Clinical Research Institute, Slack Publications, and WebMD, has received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, and The Medicines Company, and has performed unfunded research for PLx Pharma and Takeda. GHG has received research grants from BristolMyers Squibb and Takeda and has received honoraria from AstraZeneca. All other authors declare no conflict of interest.
References 1. Leng GC, Lee AJ, Fowkes FG, et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996; 25: 1172–1181. 2. Steg PG, Bhatt DL, Wilson PW, et al. REACH Registry Investigators. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007; 297: 1197–1206. 3. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326: 381–386. 4. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, et al.; ESC Committee for Practice Guidelines. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32: 1769–1818. 5. Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012; 33: 1635–1701. 6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497. 7. Vogt MT, Cauley JA, Newman AB, et al. Decreased ankle/arm blood pressure index and mortality in elderly women. JAMA 1993; 270: 465–469. 8. Bhatt DL, Eagle KA, Ohman EM, et al. REACH Registry Investigators. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010; 304: 1350–1357. 9. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 1317–1324.
European Journal of Preventive Cardiology 22(3) 10. Mosca L, Mochari H, Christian A, et al. National study of women’s awareness, preventive action, and barriers to cardiovascular health. Circulation 2006; 113: 525–534. 11. Mosca L, Mochari-Greenberger H, Dolor RJ, et al. Twelve-year follow-up of American women’s awareness of cardiovascular disease risk and barriers to heart health. Circ Cardiovasc Qual Outcomes 2010; 3: 120–127. 12. Hirsch AT, Allison MA, Gomes AS, et al. American Heart Association Council on Peripheral Vascular Disease; Council on Cardiovascular Nursing; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology; Council on Epidemiology and Prevention. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation 2012; 125: 1449–1472. 13. Andersen TF, Madsen M, Jørgensen J, et al. The Danish National Hospital Register. a valuable source of data for modern health sciences. Dan Med Bull 1999; 46: 263–268. 14. Madsen M, Davidsen M, Rasmussen S, et al. The validity of the diagnosis of acute myocardial infarction in routine statistics: a comparison of mortality and hospital discharge data with the Danish MONICA registry. J Clin Epidemiol 2003; 56: 124–130. 15. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373–383. 16. Deyo RA, Cherkin DC and Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992; 45: 613–619. 17. Diehm C, Schuster A, Allenberg JR, et al. High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study. Atherosclerosis 2004; 172: 95–105. 18. Bhatt D, Peterson ED, Harrington RA, et al. CRUSADE Investigators. Prior polyvascular disease: risk factor for adverse ischaemic outcomes in acute coronary syndromes. Eur Heart J 2009; 30: 1195–1202. 19. Mukherjee D, Eagle KA, Kline-Rogers E, et al. GRACE Investigators. Impact of prior peripheral arterial disease and stroke on outcomes of acute coronary syndromes and effect of evidence-based therapies (from the Global Registry of Acute Coronary Events). Am J Cardiol 2007; 100: 1–6. 20. Roe MT, Chen AY, Thomas L, et al. Predicting longterm mortality in older patients after non–ST-segment elevation myocardial infarction: the CRUSADE longterm mortality model and risk score. Am Heart J 2011; 162: 875–883.e1. 21. Brilakis ES, Hernandez AF, Dai D, et al. Quality of care for acute coronary syndrome patients with known atherosclerotic disease: results from the Get With the Guidelines program. Circulation 2009; 120: 560–567. 22. Alberts MJ, Bhatt DL, Mas JL, et al. REduction of Atherothrombosis for Continued Health Registry Investigators. Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry. Eur Heart J 2009; 30: 2318–2326.
Subherwal et al. 23. Achterberg S, Cramer MJ, Kappelle LJ, et al. SMART Study Group. Patients with coronary, cerebrovascular or peripheral arterial obstructive disease differ in risk for new vascular events and mortality: the SMART study. Eur J Cardiovasc Prev Rehabil 2010; 17: 424–430. 24. Vaartjes I, van Dis I, Grobbee DE, et al. The dynamics of mortality in follow-up time after an acute MI, lower extremity arterial disease and ischemic stroke. BMC Cardiovasc Disorders 2010; 10: 57. 25. Hirsch AT, Murphy TP, Lovell MB, et al. Peripheral Arterial Disease Coalition. Gaps in public knowledge of peripheral arterial disease: the first national PAD public awareness survey. Circulation 2007; 116: 2086–2094. 26. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 1317–1324. 27. Wisman PP, Tangelder MJ, van Hattum ES, et al. Young women with PAD are at high risk of cardiovascular complications. Eur J Vasc Endovasc Surg 2012; 43: 441–445. 28. Haffner SM, Lehto S, Ro¨nnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229–234. 29. Schramm TK, Gislason GH, Køber L, et al. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation 2008; 117: 1945–1954.
325 30. Gæde P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580–591. 31. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86. 32. Collins R, Armitage J, Parish S, et al. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361: 2005–2016. 33. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–1339. 34. Subherwal S, Patel MR, Kober L, et al. Missed opportunities: despite improvement in use of cardioprotective medications among patients with lower-extremity peripheral artery disease, underuse remains. Circulation 2012; 126: 1345–1354. 35. Thygesen S, Christiansen CF, Christensen S, et al. The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients. BMC Med Res Methodol 2011; 11: 83.
Original scientific paper
Peripheral artery disease is a coronary heart disease risk equivalent among both men and women: results from a nationwide study
European Journal of Preventive Cardiology 2015, Vol. 22(3) 317–325 ! The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487313519344 ejpc.sagepub.com
Sumeet Subherwal1, Manesh R Patel1, Lars Kober2, Eric D Peterson1, Deepak L Bhatt3, Gunnar H Gislason4, Anne-Marie Schjerning Olsen4, William S Jones1, Christian Torp-Pedersen4 and Emil L Fosbol1,4
Abstract Aims: Lower extremity peripheral artery disease (PAD) has been proposed as a ‘coronary heart disease (CHD) risk equivalent’. We aimed to examine whether PAD confers similar risk for mortality as incident myocardial infarction (MI) and whether risk differs by gender. Methods: Using nationwide Danish administrative registries (2000–2008), we identified patients aged 40 years with incident PAD (PAD only, n ¼ 35,628), incident PAD with a history of MI (PAD þ MI, n ¼ 7029), and incident MI alone (MI alone, n ¼ 71,115). Results: Patients with PAD only tended to be younger, female, and have less comorbidity than the other groups. During follow up (median 1051 d, IQR 384–1938), we found that MI-alone patients had greater risk of adverse outcomes in the acute setting (first 90 d); however, the PAD-only and PAD þ MI groups had higher long-term mortality at 7 years than those with MI alone (47.8 and 60.4 vs. 36.4%, respectively; p < 0.0001). After adjustment, the PAD-only and PAD þ MI groups had a higher long-term risk for mortality [hazard ratio (HR) 1.47, 95% confidence interval (CI) 1.44–1.51; and HR 1.65, 95% CI 1.58–1.72, respectively], cardiovascular mortality (HR 1.30, 95% CI 1.26–1.34; and HR 1.71, 95% CI 1.62– 1.80, respectively), and composite of death, MI, and ischaemic stroke, 95% CI HR, 1.38, 95% CI 1.36–1.42; and HR 1.68, 95% CI 1.61–1.75, respectively). The greater long-term risks of PAD were seen for both women and men. Conclusions: Both women and men with incident PAD have greater long-term risks of total and cardiovascular mortality vs. those with incident MI. PAD should be considered a CHD risk equivalent, warranting aggressive secondary prevention.
Keywords Coronary heart disease, myocardial infarction, peripheral artery disease Received 20 May 2013; accepted 15 December 2013
Introduction Lower extremity peripheral artery disease (PAD) is associated with increased cardiovascular morbidity and mortality.1–3 Indeed, the recent European Society of Cardiology (ESC) Guidelines for the Management of Dyslipidemias, the ESC Guidelines on Cardiovascular Disease Prevention in Clinical Practice, and the National Cholesterol Educational Program Adult Treatment Panel (ATP III) guidelines classify PAD as a coronary heart disease (CHD) risk equivalent,
1
Duke University Medical Center, Durham, NC, USA The Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark 3 Harvard Medical School, Boston, MA, USA 4 Copenhagen University Hospital Gentofte, Copenhagen, Denmark 2
Corresponding author: Sumeet Subherwal, Duke Clinical Research Institute, 2400 Pratt Street, Room 0311, Terrace Level, Durham, NC 27705, USA. Email: [email protected]
318 suggesting that PAD confers a long-term risk to patients similar to established heart disease. Consequently, these guidelines recommend more intense risk factor management of patients with PAD beyond that of the general population.4–6 Although population studies have demonstrated increased CHD risk among patients with PAD,2,3,7–9 no study has specifically addressed the question of whether patients with PAD share a similar long-term risk for mortality and cardiovascular mortality as those with an incident myocardial infarction (MI). Such an analysis would help justify or refute guideline recommendations on secondary prevention; importantly, it would also clarify the need for programmes to improve and promote risk factor modification in this population. Similarly, there has been a paucity of epidemiological data investigating whether the CHD risk of PAD compared with MI is similar in women and men.10,11 This prompted the American Heart Association (AHA) recently to call to action clinicians and the scientific community to increase research and awareness of outcomes in women with PAD.12 Using Danish nationwide administrative registries, we sought to determine (1) whether patients with an incident diagnosis of PAD, both with and without history of MI, share a similar long-term cardiovascular risk as patients with incident MI alone, and (2) whether outcomes differed by gender.
Methods
European Journal of Preventive Cardiology 22(3) diagnosis of MI but no prior PAD diagnosis (back to 1994). The index date used was the time-of-incident diagnosis of PAD (time of second visit for the outpatient PAD group or hospital discharge date for PAD patients) for the first two groups and time of incident diagnosis of MI for the third group (date of discharge). Groups were exclusive, and we did not update group status during follow up for our primary analysis.
Covariates Comorbidity was measured using the Charlson index by assessing hospitalizations 1 year before diagnosis, as described by Deyo et al.15,16 This includes important covariates such as prior stroke and history of atrial fibrillation. Patients were categorized as diabetic if they had a recorded diagnosis of diabetes 1 year prior to index or filled a prescription for a glucose-lowering drug within 6 months of the index date. Average 5-year family income prior to the index date was calculated and summarized in quartiles. Data for smoking were not available, although diagnosis of chronic obstructive pulmonary disease was captured.
Outcomes The primary endpoints were all-cause mortality, cardiovascular mortality (using ICD-10 I00-I99 codes as primary or secondary codes), and a composite of all-cause mortality, MI, or ischaemic stroke (using ICD-10 codes I61–I64).
Population and data sources This study was a population-based cohort study of Danish residents aged 40 years, using nationwide administrative registries for 2000–2008. Information on diagnoses and comorbidity was obtained from the Danish National Patient Registry, which holds data on all admissions and outpatient visits to Danish hospitals and specialty clinics since 1978.13 Since 1994, all admissions and visits have been registered by one primary diagnosis and, if appropriate, one or more secondary diagnoses according to the International Classification of Diseases, Tenth Revision (ICD-10). For this study, patients with PAD were identified using the ICD-10 codes (listed in the Supplementary Material online), while those with MI were identified using ICD-10 codes I21 and I22, as done previously with high validity.14 Patients were categorized into three groups: (1) PAD only: those with incident diagnosis of PAD (first-time hospitalization or at least two consecutive outpatient visits for PAD) without history of MI; (2) PAD þ MI: those with incident PAD and a history of MI (assessed back to 1978); or (3) MI alone: those with incident
Statistical analysis We used the Kruskal–Wallis test for continuous variables and chi-square test for categorical variables to test for differences between groups. For unadjusted rates of all-cause mortality and the composite endpoint, we compared the groups using Kaplan–Meier curves and performed the log rank test for statistical differences between groups. For cardiovascular death, unadjusted rates were shown using cumulative incidence curves because of the possibility of competing risks of mortality. Using the MI-alone group as the reference, we performed multivariable Cox proportional hazards analysis to assess relative hazard of all-cause mortality and the composite outcome, adjusting for age, sex, calendar year, family income, Charlson comorbidity index, and baseline medications (antiplatelet, betablocker, statin, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, or vitamin K antagonist). Patients were censored at the end of the follow-up period (31 December 2009) if the patient did not experience an event. For models performed for cardiovascular death, patients were also censored at
Subherwal et al. time of death from other causes (cause-specific hazard model). For all models, the proportional hazard assumption was violated; subsequently, we performed landmark analysis to differentiate an earlier time point with acute phase-related rates after incident diagnosis vs. a later time point when patients were in a more stable condition. Outcomes were assessed in two time frames of follow up: 0–90 d after the index date and >90 d to 7 years, according to when the slope of the outcomes curves changed. Given that the acute phase post-MI setting may represent higher risk and a less stable population than the PAD population at incident diagnosis, we performed a sensitivity analysis in which we compared the outcomes for MI patients surviving 14 d post discharge to both PAD groups. In addition, given the possible different risks associated with an outpatient vs. in-hospital diagnosis of PAD, we performed a sensitivity analysis investigating the relative risk of MI alone compared with an outpatient and an inhospital diagnosis of PAD. We tested important interactions in the models (age and diabetes). Prespecified subgroup analyses by gender were planned regardless of results derived from statistical interaction testing between gender and group assignment. Groups in our study were exclusive, but patients could potentially transition from one group to another during follow up. To account for this, we performed a sensitivity analysis in which patients were censored at time of transition from one group to another. All analyses used SAS version 9.2 (SAS Institute, Cary, NC, USA), and the level of statistical significance was set at p 0.05 (two-sided). The Danish Data Protection Agency approved the study (no. 200758-0015, ref. no. GEH-2010-001).
Results After selection criteria were applied, 113,772 patients were included in our cohort study: 35,628 with PAD only, 7029 with PAD þ MI, and 71,115 with MI alone. Overall, 49.9% of PAD patients were diagnosed in the outpatient setting, whereas all MI patients were diagnosed in hospital. Patients with PAD only tended to be younger, more often female, and have less comorbidity than the other two groups (Table 1). Meanwhile, patients with PAD þ MI were older, most likely male, and had the highest overall level of comorbidity. Both PAD groups had greater rates of diabetes mellitus than MI alone. Overall, use of cardioprotective medication was modest after incident diagnosis of either PAD or MI alone (Table 1); patients with MI alone were treated most aggressively within 3 months of incident diagnosis with any antiplatelet, beta-blocker, or statin therapy.
319 The PAD-only group had the lowest use of cardioprotective medications after incident diagnosis.
Unadjusted and adjusted all-cause mortality The proportional hazard assumption was violated in all models, meaning that the groups had different shortterm (90 d) and long-term (>90 d) outcome rates (p-values for interaction with time in all models were 90-d mortality
0.50 (0.48–0.52) 0.60 (0.57–0.64)
1.47 (1.44–1.51) 1.65 (1.58–1.72)
0.42 (0.41–0.44) 0.57 (0.53–0.61)
1.30 (1.26–1.34) 1.71 (1.62–1.80)
0.38 (0.37–0.40) 0.56 (0.53–0.59)
1.38 (1.36–1.42) 1.68 (1.61–1.75)
Values are hazard ratio (95% confidence interval). Adjusted for age, sex, year, subsequent MI or percutaneous coronary intervention, lower extremity revascularization, quartile of income, Charlson comorbidity index, and baseline medications (antiplatelet, beta-blocker, statin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, or vitamin K antagonist). Composite outcome, all-cause mortality, MI, or ischaemic stroke; MI, myocardial infarction; PAD, peripheral artery disease.
risk of cardiac outcomes and death. Furthermore, this greater risk remained regardless of whether PAD was inhospital or outpatient diagnosed. In addition, the overall difference between PAD and MI alone was not modified by the presence of diabetes, and therefore the association between PAD and long-term mortality can be considered independent of diabetes. Part of the greater long-term risk associated with PAD may be explained by more systemic atherosclerosis among patients with PAD.17 Prior analyses have demonstrated that PAD is an important predictor of subsequent CHD and is associated with increased risk for cardiovascular morbidity.3,7,18–21 Although PAD is assumed to be a CHD risk equivalent, no prior study, to the best of our knowledge, has been designed to examine this hypothesis. The Reduction of Atherothrombosis for Continued Health (REACH) registry has demonstrated that patients with symptomatic PAD had slightly higher 3year cardiovascular event rates than patients with coronary artery disease.22 However, the REACH registry design only examined prevalent disease and was unable to determine timing of incident diagnosis of PAD.2,8 The present analysis is unique in that the Danish administrative registries capture time of incident diagnosis of PAD as well as incident MI, and our study is therefore better designed to test whether patients seeking care for PAD share similar mortality as patients with MI alone. Furthermore, the Danish registries capture the entire population seeking care in the national healthcare system, which allows our findings to be generalized more broadly to real-world patients. A recent study by Achterberg et al.23 showed similar results in terms of a higher risk associated with PAD relative to
Table 3. Outcomes stratified by gender using the MI-alone group as reference Women Group All-cause mortality PAD only PAD þ MI Cardiovascular mortality PAD only PAD þ MI Composite outcome PAD only PAD þ MI
Men
0–90 d mortality
>90 d mortality
0–90 d mortality
>90 d mortality
0.49 (0.47–0.52) 0.63 (0.57–0.70)
1.25 (1.20–1.29) 1.32 (1.32–1.52)
0.47 (0.44–0.49) 0.56 (0.51–0.60)
1.52 (1.47–1.57) 1.60 (1.52–1.69)
0.43 (0.41–0.46) 0.58 (0.52–0.65)
1.12 (1.06–1.17) 1.46 (1.34–1.59)
0.38 (0.36–0.41) 0.52 (0.47–0.57)
1.31 (1.25–1.37) 1.64 (1.54–1.75)
0.40 (0.39–0.42) 0.61 (0.56–0.67)
1.16 (1.12–1.20) 1.45 (1.35–1.55)
0.35 (0.33–0.36) 0.50 (0.47–0.54)
1.43 (1.38–1.48) 1.63 (1.55–1.72)
Values are hazard ratio (95% confidence interval). Irrespective of gender, adjusted risk of adverse outcomes was greater among both PAD groups relative to the MI-alone group in the long-term. Adjusted for age, sex, year, subsequent MI or percutaneous coronary intervention, lower extremity revascularization, quartile of income, Charlson comorbidity index, and baseline medications (antiplatelet, beta-blocker, statin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, or vitamin K antagonist). Composite outcome, all-cause mortality, MI, or ischaemic stroke; MI, myocardial infarction; PAD, peripheral artery disease.
Subherwal et al. coronary artery disease; this study was in Holland and constitutes a similar health system as the Danish system. Other studies have also shown that PAD and MI often coexist and that they also constitute an additive risk for the patients.24 Despite our and others’ findings demonstrating increased risk associated with PAD, a lack of awareness of PAD continues among the public and primary care physicians.25,26 Although the magnitude of coronary disease risk in women has been highlighted in the past decade,10,11 major gaps in knowledge still exist regarding risks associated with PAD among women.12 Consequently, the AHA has recently highlighted the lack of public awareness of cardiovascular risks associated with PAD and the need for educational programmes designed specifically to address risk among women.12 Our findings underscore the need to better educate the public about adverse outcomes associated with PAD in both men and women. We hope our findings spur debate about the role of increased efforts at earlier screening and promote adherence to secondary prevention. We found similar rates of mortality, cardiovascular mortality, and the composite endpoint in men and women in the short term, but male gender was associated with higher hazard ratios of all endpoints in the long term. This is an important finding as women have been suspected to be associated with worse outcomes than men. These findings were consistent after adjusting for age, and we found no effect of modification of age as shown in a previous study.27 Clinicians, who are well aware that diabetes is a cardiac risk equivalent by conferring a 10-year risk for recurrent CHD events of >20%,4,28,29 have aggressively managed cardiovascular risk factors among patients with diabetes; combined with use of secondary prevention strategies, this has been shown to improve outcomes among these patients.30 Interestingly, in our study, although the use of cardioprotective medications by 3 months after incident diagnosis was suboptimal among all three groups, the use of cardioprotective medications was lowest among the PAD-only group. Over one-half of the PAD-only group members were not on any antiplatelet therapy by 3 months after diagnosis, and nearly two-thirds were not on any statin, despite demonstrated benefits of these therapies among the symptomatic PAD population.31–34 Although we did notice an improvement in use of cardioprotective medication over time, as evidenced by greater rates of adherence in the final study period, the use of cardioprotective medication among those with PAD still remained modest overall and lower compared with those with MI. Greater adherence rates and strict treatment goals have potential to improve outcomes among patients with PAD as well, although further research is needed to demonstrate this.
323 The limitations of this study is that the analysis used administrative data and therefore captured only those patients who sought treatment for PAD. The extent and severity of PAD could not be determined using noninvasive studies (i.e. vascular ultrasound, ankle/brachial index, pulse volume recording, computed tomography, or magnetic resonance imaging) given the study design. We limited our ICD-10 codes to lower extremity PAD, and these codes have previously been used as part of a broader definition of PAD with good validity.35 The majority of the cohort was, however, composed of patients with a nonspecific code for lower extremity PAD, meaning that information regarding the severity of the disease was unobtainable in these patients. However, given that the patients were identified in inpatient or outpatient specialty clinics, the cohort likely reflects a greater proportion of symptomatic patients with advanced PAD. Prior studies of symptomatic PAD that share similarly high mortality rates3 enrolled patients in the 1990s; it is noteworthy that in our study, the mortality remained strikingly high among a more contemporary population seeking treatment for PAD. Our analysis excluded patients with carotid, aneurysmal, renal, and mesenteric artery disease; therefore, our findings pertain to the lower extremity atherosclerotic PAD population. Our findings represent all patients in Denmark, but findings may differ in other parts of the world. Inference regarding causality should be made cautiously given the observational nature of our study. We could not adjust for smoking status but did adjust for chronic obstructive pulmonary disease. Our study supports greater use of secondary prevention strategies among PAD patients but cannot firmly establish whether aggressive secondary prevention will reduce the long-term risks of PAD. Further studies are needed to define the optimal goals for secondary prevention in this high-risk population. In conclusion, patients seeking medical care for lower extremity PAD are at greater long-term risks for total and cardiovascular mortality as well as a composite endpoint of mortality, MI, and ischaemic stroke than patients with incident MI alone. Therefore, lower extremity PAD may be considered a CHD risk equivalent. Women as well as men with PAD remain at higher risk of long-term adverse outcomes relative to patients with MI alone, yet those with both PAD and MI remain at the highest risk level. Increased awareness of the prognostic importance of PAD by clinicians and the public is warranted. Funding This work was supported in part internally by the Duke Clinical Research Institute. ELF is supported by an award from the American Heart Association–Pharmaceutical Roundtable and David and Stevie Spina (grant number 087142N).
324 Conflict of interest Disclosure information for MRP and EDP is available at https://www.dcri.org/about-us/conflict-of-interest. DLB has served on the advisory board for Medscape Cardiology, has received honoraria from the American College of Cardiology, Duke Clinical Research Institute, Slack Publications, and WebMD, has received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, and The Medicines Company, and has performed unfunded research for PLx Pharma and Takeda. GHG has received research grants from BristolMyers Squibb and Takeda and has received honoraria from AstraZeneca. All other authors declare no conflict of interest.
References 1. Leng GC, Lee AJ, Fowkes FG, et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996; 25: 1172–1181. 2. Steg PG, Bhatt DL, Wilson PW, et al. REACH Registry Investigators. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007; 297: 1197–1206. 3. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326: 381–386. 4. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, et al.; ESC Committee for Practice Guidelines. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32: 1769–1818. 5. Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012; 33: 1635–1701. 6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497. 7. Vogt MT, Cauley JA, Newman AB, et al. Decreased ankle/arm blood pressure index and mortality in elderly women. JAMA 1993; 270: 465–469. 8. Bhatt DL, Eagle KA, Ohman EM, et al. REACH Registry Investigators. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010; 304: 1350–1357. 9. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 1317–1324.
European Journal of Preventive Cardiology 22(3) 10. Mosca L, Mochari H, Christian A, et al. National study of women’s awareness, preventive action, and barriers to cardiovascular health. Circulation 2006; 113: 525–534. 11. Mosca L, Mochari-Greenberger H, Dolor RJ, et al. Twelve-year follow-up of American women’s awareness of cardiovascular disease risk and barriers to heart health. Circ Cardiovasc Qual Outcomes 2010; 3: 120–127. 12. Hirsch AT, Allison MA, Gomes AS, et al. American Heart Association Council on Peripheral Vascular Disease; Council on Cardiovascular Nursing; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology; Council on Epidemiology and Prevention. A call to action: women and peripheral artery disease: a scientific statement from the American Heart Association. Circulation 2012; 125: 1449–1472. 13. Andersen TF, Madsen M, Jørgensen J, et al. The Danish National Hospital Register. a valuable source of data for modern health sciences. Dan Med Bull 1999; 46: 263–268. 14. Madsen M, Davidsen M, Rasmussen S, et al. The validity of the diagnosis of acute myocardial infarction in routine statistics: a comparison of mortality and hospital discharge data with the Danish MONICA registry. J Clin Epidemiol 2003; 56: 124–130. 15. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373–383. 16. Deyo RA, Cherkin DC and Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992; 45: 613–619. 17. Diehm C, Schuster A, Allenberg JR, et al. High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study. Atherosclerosis 2004; 172: 95–105. 18. Bhatt D, Peterson ED, Harrington RA, et al. CRUSADE Investigators. Prior polyvascular disease: risk factor for adverse ischaemic outcomes in acute coronary syndromes. Eur Heart J 2009; 30: 1195–1202. 19. Mukherjee D, Eagle KA, Kline-Rogers E, et al. GRACE Investigators. Impact of prior peripheral arterial disease and stroke on outcomes of acute coronary syndromes and effect of evidence-based therapies (from the Global Registry of Acute Coronary Events). Am J Cardiol 2007; 100: 1–6. 20. Roe MT, Chen AY, Thomas L, et al. Predicting longterm mortality in older patients after non–ST-segment elevation myocardial infarction: the CRUSADE longterm mortality model and risk score. Am Heart J 2011; 162: 875–883.e1. 21. Brilakis ES, Hernandez AF, Dai D, et al. Quality of care for acute coronary syndrome patients with known atherosclerotic disease: results from the Get With the Guidelines program. Circulation 2009; 120: 560–567. 22. Alberts MJ, Bhatt DL, Mas JL, et al. REduction of Atherothrombosis for Continued Health Registry Investigators. Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry. Eur Heart J 2009; 30: 2318–2326.
Subherwal et al. 23. Achterberg S, Cramer MJ, Kappelle LJ, et al. SMART Study Group. Patients with coronary, cerebrovascular or peripheral arterial obstructive disease differ in risk for new vascular events and mortality: the SMART study. Eur J Cardiovasc Prev Rehabil 2010; 17: 424–430. 24. Vaartjes I, van Dis I, Grobbee DE, et al. The dynamics of mortality in follow-up time after an acute MI, lower extremity arterial disease and ischemic stroke. BMC Cardiovasc Disorders 2010; 10: 57. 25. Hirsch AT, Murphy TP, Lovell MB, et al. Peripheral Arterial Disease Coalition. Gaps in public knowledge of peripheral arterial disease: the first national PAD public awareness survey. Circulation 2007; 116: 2086–2094. 26. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 1317–1324. 27. Wisman PP, Tangelder MJ, van Hattum ES, et al. Young women with PAD are at high risk of cardiovascular complications. Eur J Vasc Endovasc Surg 2012; 43: 441–445. 28. Haffner SM, Lehto S, Ro¨nnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998; 339: 229–234. 29. Schramm TK, Gislason GH, Køber L, et al. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation 2008; 117: 1945–1954.
325 30. Gæde P, Lund-Andersen H, Parving HH, et al. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358: 580–591. 31. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86. 32. Collins R, Armitage J, Parish S, et al. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361: 2005–2016. 33. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329–1339. 34. Subherwal S, Patel MR, Kober L, et al. Missed opportunities: despite improvement in use of cardioprotective medications among patients with lower-extremity peripheral artery disease, underuse remains. Circulation 2012; 126: 1345–1354. 35. Thygesen S, Christiansen CF, Christensen S, et al. The predictive value of ICD-10 diagnostic coding used to assess Charlson comorbidity index conditions in the population-based Danish National Registry of Patients. BMC Med Res Methodol 2011; 11: 83.
