Evaluation of Medical Treatment for Peripheral Arterial Disease in Chinese High-Risk Patients

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1 Circ J 2007; 71: Evaluation of Medical Treatment for Peripheral Arterial Disease in Chinese High-Risk Patients Buaijiaer Hasimu, MD, PhD*,, ; Jue Li, MD, PhD*; Jinming Yu, MD, PhD*; Yitong Ma, MD, PhD ; Mingzhong Zhao, MD, PhD*; Tomohiro Nakayama, MD, PhD ; Wenlin Ma*; Jingang Yang, MD, PhD**; Liqiang Zheng, MD*; Xiankai Li, MD*; Yingyi Luo, MD*; Yuanxi Xu, MD*; Lihua Zhang, MD*; Lilin Zou, MD*; Weilin Xiao*; Yalei Han, MD**; Dayi Hu, MD* Background Peripheral arterial disease (PAD) is an important manifestation of systemic atherosclerosis and is associated with elevated cardiovascular morbidity and mortality. The aim of the present study was to evaluate the use of antiplatelet agents, statins and angiotensin-converting enzyme inhibitors (ACEI) in Chinese high-risk cardiovascular (CV) patients with PAD, with an emphasis on the need for aggressive medical management of all atherosclerotic manifestations. Methods and Results Medical records from 5,263 Chinese patients at high risk of CV were evaluated for the use of antiplatelet agents, statins and ACEI in patients with and without PAD. PAD was defined as an ankle brachial index (ABI) <0.9 in either leg. Multivariable logistic regression analyses were performed to compare medication use in the 2 groups. A total of 5,254 patients were analyzed (52.9% male, mean age 67.3 years). The prevalence of PAD in the total patient group was 25.4%; 22.5% of them had PAD only. Overall, 5.7% had PAD only, 19.6% had PAD and coronary heart disease (CHD) or stroke or diabetes, 7.7% had CHD only, 12.6% had stroke only, and 13.6% had diabetes only. The 28.9% subjects having none of PAD, CHD, stroke or diabetes were used as the reference group. Only 65%, 37% and 47% of all patients received antiplatelet agents, statins and ACEI, respectively. Antiplatelets, statins, ACEI and all 3 medications were used less frequently in PAD only patients (58.1%, 35.9, 53.5% and 21.6%) vs CHD only (90.9%, 74.5%, 70.6% and 55.9%, p<0.001). All 3 proven efficacious therapies were prescribed for only 56% of patients with CHD only, 8% with stroke only, 13% with diabetes only and 21% with PAD only. Conclusion PAD is prevalent in Chinese high-risk CV patients, equivalent to CHD, but these patients receive less intensive treatment than those with CHD. Programs to improve CV risk reduction in these high-risk patients are needed. (Circ J 2007; 71: 95 99) Key Words: Atherosclerosis; Medications; Peripheral artery disease Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis and the ankle branchial index (ABI) can be used as a non-invasive method of assessment. 1 9 Patients with PAD are at triple the risk of all-cause mortality and at more than 6-fold the risk of death from coronary heart disease (CHD) as those without the disease, 1 yet PAD is probably the most under diagnosed and least aggressively managed atherosclerotic disease. The PARTNERS program revealed that PAD patients received less intensive treatment and were prescribed antiplatelet therapy less frequently than were patients with cardiovascular disease (CVD). 7 A published survey suggested that clinicians were less likely to prescribe antiplatelet therapy (Received June 5, 2006; revised manuscript received October 16, 2006; accepted November 1, 2006) *Heart, Lung and Blood Vessel Center, Tongji University, Shanghai, **Heart Center, Beijing Tongren Hospital, Capital Medical University, Beijing, School of Economics and Management, Tongji University, Shanghai, Heart Center, The First Hospital, Xinjiang Medical University, Urumqi, China and Division of Molecular Diagnostics, Advanced Medical Research Center, Nihon University School of Medicine, Tokyo, Japan Mailing address: Dayi Hu, MD, Heart, Lung and Blood Vessel Center, Tongji University, Shanghai , PR China. for patients with PAD than for patients with coronary artery disease (CAD). 8 A recent publication by the Prevention of Atherothrombotic Disease Network 9 highlighted the need for improving detection and treatment of PAD as a largely under-diagnosed and under-treated deleterious disease. Prior to this study, PAD medication has not investigated in China, so the aim of the present study was to evaluate medical treatment of PAD in Chinese patients at high risk for generalized atherosclerosis. We investigated the use of antiplatelet agents, statins and angiotensin-converting enzyme inhibitors (ACEI) in Chinese high-risk cardiovascular (CV) patients with PAD, CHD, diabetes mellitus (DM) or stroke, with an emphasis on the need for aggressive medical management of all atherosclerotic manifestations Methods Study Population This is a large-scale epidemiological study in China with both cross-sectional and longitudinal studies. The methods and design have been described elsewhere in greater detail. 10 The study group comprised 5,646 Chinese hospitalized

2 96 HASIMU B et al. Table 1 Baseline Characteristics of the Patients at High-Risk for Cardiovascular Disease ABI Age SBP DBP TC TG HDL-C LDL-C (years) (mmhg) (mmhg) (mmol/l) (mmol/l) (mmol/l) (mmol/l) PAD only 0.73±0.18** 71.44±12.46** ±25.07* 80.1± ± ± ± ±0.81 CHD only 1.09± ± ±22.67** 78.08±12.66** 4.45± ± ±0. 29** 2.71±0.78 Stroke only 1.08±0.10* 68.17±10.55** ±22.66** 83.65±12.54** 4.65±1.06* 1.54± ± ±0.78* DM only 1.08±0.10* 64.22± ± ± ±1.11** 1.68±0.95* 1.19± ±0.84* Reference 1.09± ± ± ± ± ± ± ±0.82 All 0.98± ± ± ± ± ± ± ±0.82 ABI, ankle branchial index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; PAD, peripheral arterial disease; CHD, coronary heart disease; DM, diabetes mellitus. *p<0.05, **p<0.01. patients over 50 years old with 2 or more CV risk factors who were investigated using ABI measurement and clinical data collected cross-sectionally from medical records. Risk factors included obesity, smoking, DM, hypertension, lipid disorders, and history of CAD, stroke or PAD. Clinical Subgroups The cohort was divided into 5 clinical subgroups: (1) reference group; (2) CHD only; (3) stroke only; (4) DM only and (5) PAD and CHD or stroke or DM. The reference group referred to those without clinically recognized atherosclerosis in any vascular bed (no CHD, no stroke, no DM, no PAD). The presence of underlying CHD was defined as a history of a physician-diagnosed heart attack, evidence of prior myocardial infarction by ECG or self-reporting of a prior coronary revascularization procedure (coronary artery intervention, PCI or coronary artery bypass surgery). Stroke was defined as a history of incident stroke or stroke and transient ischemic attack together. Type 2 DM was defined as: (1) fasting plasma glucose concentration of >7.0 mmol/l in the absence of treatment; (2) plasma glucose concentration of 11.0mmol/L 2h after a 75-g oral glucose load; or (3) being treated with glucoselowering drugs. All subjects selected had no history of ketoacidosis. Hypertension was defined as systolic blood pressure (SBP) of 140 mmhg, diastolic blood pressure (DBP) of 90 mmhg or the current use of antihypertensive drugs to control hypertension. Lipid disorder was defined as total cholesterol (TC) >5.7 mmol/l, triglycerides (TG) >1.7 mmol/l, low-density lipoprotein-cholesterol (LDL-C) >3.6 mmol/l, high-density lipoprotein-cholesterol (HDL-C) <0.9 mmol/l or treatment with antihyperlipidemic agents. ACEIs included captopril, enalapril, lisinopril, ramipril, cilazapril and perindopril; statins included simvastatin, pravastatin, fluvastatin, and lovastatin; antiplatelet agents included aspirin and clopidogrel. ABI Measurement All patients had ankle and arm blood pressures recorded using a blood pressure cuff and a Nicolet handheld Doppler, from which the ABI (ratio of highest ankle/highest brachial systolic pressure) was calculated. The lowest ABI of the legs was the index leg used. PAD was defined as an ABI <0.9 in at least 1 leg. 7 We examined utilization rates for antiplatelet agents, statins and ACEI within the entire subject group, as well as among patients with evidence of CHD, stroke, DM or PAD. Statistical Analyses We used multivariate logistic regression analyses to compare the use of antiplatelet agents, statins and ACEI between patients with and without PAD. Continuous variables were given as the mean ± standard deviation (SD). Statistical significance was accepted at the 0.05 level. Statistical analysis was performed using SSCP version Results Clinical Characteristics Of the 5,646 patients included in the study, those with an ABI >1.4 (n=192) were excluded because of the possibility that rigidity and calcium in the peripheral arteries could falsely elevate the ABI in the elderly, and 200 patient were missing data, so 5,254 were included in the statistical analyses, 47.1% were women, mean age was 67.3±11.7 years. According to the study definition (ABI <0.90), 1,334 (25.4%) of patients had PAD, and of these 301 (22.5%) had PAD only. Overall, 5.7% had PAD only, 1,033 (19.6%) had PAD and CHD or stroke or DM, 408 (7.7%) had CHD only, 661 (12.6%) had stroke only, 716 (13.6%) had DM only, and 1,517 (28.9%) had none of PAD, CHD, stroke or DM (the reference group). Table 1 shows the ages, lipids and blood pressure profiles of patients with PAD only (n=301), CHD only (n= 408), stroke only (n=661), DM only (n=716), reference (n=1,517) and all patients (n=5,254). Compared with the reference group, mean ABI values were significantly lower in the PAD only, stroke only and DM only groups; patients were significantly older in the PAD only and stroke only groups; SBP was significantly high in PAD only, CHD only and stroke only groups; DBP was significantly higher in CHD only and stroke only groups; TC and LDL-C were significantly higher in stroke only and DM only groups; TG was significantly higher in DM only group; HDL-C was significantly lower in the CHD only group. Treatments Table 2 shows the use of medication in high-risk CV patients. The use of all 3 types of agents proven to reduce CV risk was low in all high-risk patients (22.8%). As compared with the reference group (patients without CHD, stroke, DM, or PAD), PAD only patients were more likely to be receiving ACEI (53.5% vs 41.5% p<0.001), but there was no significant difference in the use of antiplatelet agents (58.1% vs 54.6 % p=0.266), statins (35.9% vs 30.4% p=0.061) or all 3 medications (21.6% vs 17.5%, p=0.095); CHD only patients were significantly more likely to be receiving antiplatelet agents (90.9% vs 54.6% p<0.001),

3 PAD and Chinese Cardiovascular Risk Patients 97 Table 2 Medication in High-Risk Cardiovascular Patients Antiplatelet agent Statins ACEI All 3 medications All patients (n=5,254) 65.5% 37.0% 47.0% 22.8% Reference (n=1,517) 54.6% 30.4% 41.5% 17.5% CHD only (n=408) 90.9%** 74.5%** 70.6%** 55.9%** 8.32 ( )** 6.70 ( )** 3.39 ( )** 5.96 ( )** Stroke only (n=661) 69.4%** 20.4%** 31.9%** 8.0%** 1.89 ( )** 0.59 ( )** 0.66 ( )** 0.41 ( )** DM only (n=716) 50.4% 27.7% 39.1% 13.0%** 0.84 ( ) 0.88 ( ) 0.91 ( ) ( )** PAD only (n=301) 58.1% 35.9% 53.5%** 21.6% ( ) 1.28 ( ) 1.62 ( )** 1.30 ( ) PAD+ (CHD or stroke or DM) 72.4%** 41.9%** 53.7%** 27.4%** ( )** 1.65 ( )** 1.64 ( )** 1.78 ( )** n=1,033. ACEI, angiotensin-converting enzyme-inhibitor. Other abbreviations see in Table 1. *p<0.05, **p<0.01. Table 3 Medication in Patients With or Without LD or HT Antiplatelet agents (%) Statins (%) ACEI (%) All 3 medications (%) Diagnosed PAD (n=76) Undiagnosed PAD (n=1,258) PAD with HT (n=1,137) PAD without HT (n=197) * 22.8 CHD with HT (n=881) CHD without HT (n=218) * 46.8* PAD with LD (n=948) PAD without LD (n=386) 52.3* 0.0* 43.5* 0.0* CHD with LD (n=960) CHD without LD (n=139) 74.8* 0.0* 48.9* 0.0* LD, lipid disorder; HT, hypertension. Other abbreviations see in Table1. *p<0.05. statins (74.5% vs 30.4% p<0.001), ACEI (70.6% vs 41.5% p<0.001), or all 3 medications (55.9% vs 17.5%, p<0.001); stroke only patients were significantly more likely to be receiving antiplatelet agents (69.4% vs 54.6% p<0.001), but less likely to be receiving statins (20.4% vs 30.4% p<0.001), ACEI (31.9% vs 41.5% p<0.001), or all 3 medications (8.0% vs 17.5%, p<0.001); DM only patients had no significant differences in receiving antiplatelet agents (50.4% vs 54.6% p=0.068), statins (27.7% vs 30.4% p=0.186) or ACEI (39.1% vs 41.5% p=0.290), but were less likely to be receiving all 3 medications (13.0% vs 17.5%, p=0.006); PAD patients with CHD or stroke or DM were significantly more likely than the reference patients to be receiving antiplatelet agents (72.4% vs 54.6% p<0.001), statins (41.9% vs 30.4% p<0.001) and ACEI (53.7% vs 41.5% p<0.001), or all 3 medications (27.4% vs 17.5% p<0.001). Table 3 shows the medications used in patients with or without lipid disorder or hypertension. There were no significant differences between diagnosed PAD patients and undiagnosed PAD patients in receiving antiplatelet agents, statins, ACEI or all 3 medications. PAD or CHD patients with hypertension were significantly more likely than those without hypertension to be receiving ACEI (56.9% vs 35.0%; 61.9% vs 72.6%, p<0.05); but there was no significant difference in the use of antiplatelet agents, statins or all 3 medications. PAD or CHD patients without lipid disorders were significantly less likely than those with lipid disorders to be receiving antiplatelet agents (52.3% vs 76.1%; 91.6% vs 74.8%; p<0.05), statins (0.0% vs 57.1%; 0.0% vs 80.4%, p<0.05) ACEI (43.5% vs 57.8%; 43.5% vs 73.6%, p<0.05), or all 3 medications (0.0% vs 36.7%; 0.0% vs 60.6%; p<0.05). Discussion This is the first large-scale research to study the medications given to Chinese high-risk CV patients. We found that the 3 medication types proven to reduce CV risk and mortality (antiplatelet agents, 12 statins 13 and ACEI 15 ) were systematically underused for patients at high risk for CV, even among those with stroke. Lipid-lowering therapy has benefit in patients with PAD, who often have coexisting coronary and cerebral arterial disease. 13,14,17 19 The beneficial effects may be related to plaque stabilization, reductions in inflammatory cell activity, platelet activation, thrombus formation, and improvement in endothelial function. The current recommendation 11 for patients with PAD is to achieve a serum LDL-C concentration of less than 100 mg/dl. The use of ACEI in patients with PAD may confer protection against cardiovascular events beyond that expected from blood-pressure lowering. In the Heart Outcomes Prevention Evaluation Study, 4,051 of the 9,297 patients had evidence of PAD. 15 In the entire study population, the primary endpoint of death from vascular causes, nonfatal myocardial infarction, or stroke occurred in 17.7% of the placebo group, as compared with 14.1% of the ramipril group. The efficacy of ramipril did not differ significantly between patients with PAD and those without it. That study s findings not only underscore the importance of including patients with PAD in trials of the secondary

4 98 HASIMU B et al. prevention of CVD, but also suggests that ACEI reduce the risk of ischemic events in these patients. Patients with PAD have systemic atherosclerosis and are at high risk for CVD and death. Aspirin should be considered the primary antiplatelet drug for preventing ischemic events in patients with PAD. Aspirin is also effective in maintaining vascular-graft patency and may prevent thrombotic complications of PAD. The American College of Chest Physicians recommends aspirin at doses of mg/day for patients with PAD. 16 Despite these recommendations, only 58.1%, 35.9%, and 53.5% of PAD only patients in our study received antiplatelet agents, statins or ACEI treatment, respectively. There were no significant differences between diagnosed PAD patients and undiagnosed PAD patients in receiving antiplatelet, statin, ACEI or all 3 medications. PAD or CHD patients with hypertension were significantly more likely than those without hypertension to be receiving ACEI; but there was no significant difference in the use of antiplatelet agents, statins or all 3 medications. PAD or CHD patients without lipid disorders were significantly less likely than those with lipid disorders to be receiving antiplatelet agents, statins, ACEI, or all 3 medications. Regarding PAD, stroke and DM, which are CHD risk equivalents, medications proven to decrease the risk of CVD should be used extensively in these patients; however, in the present study patients with PAD only were less intensively managed than were patients with CHD only. More strikingly, ACEI and statin prescriptions in stroke only patients were even lower, and DM only patients were also under treated. PAD coexisting with CHD or stroke or DM is very high risk condition and deserves intensive treatment, but we found that the medication usage was still suboptimal. The use of all 3 types of agents proven to reduce CV risk was low in all high-risk patients in the present study. Only 65.4%, 36.9% and 46.9% of high-risk patients and 69.1%, 40.5%, and 53.6% of PAD patients were receiving antiplatelet, statin or ACEI treatment, respectively, and only 5.7% of PAD patients had been diagnosed; 17.9% of the PAD patients were symptomatic, and 60% of these patients were unaware of their condition despite being symptomatic, confirming that in China PAD is also an under-recognized and under-treated condition, as observed in other countries. 7,20 24 Study Limitations We did not investigate the dosages of the 3 types of medications, especially aspirin, which can be bought over-thecounter. Most of Chinese patients tend to take mg lower than the recommended dosage. The numbers of patients with CVD has been increasing in China because of recent changes in diet and lifestyle. Atherosclerotic risk factors, such as DM, hypercholestrolemia, and hypertension, can and should be treated adequately, and smoking should be strongly advised against. In conclusion, PAD is prevalent in Chinese high-risk CV patients, and they receive less intensive treatment than patients with CHD. Patient and physician education are needed to improve the identification of patients with symptomatic PAD and increase the awareness of its consequences. Such a policy will contribute to improving the prognosis of a group of patients at elevated CV risk. Acknowledgment This study was supported by Sanofi-Synthelabo Company. References 1. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326: Diehm C, Schuster A, Allenberg JR, Darius H, Haberl R, Lange S, et al. 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