- Email: [email protected]
Comparison of Lipid Management in Patients With Coronary Versus Peripheral Arterial Disease
Comparison of Lipid Management in Patients With Coronary Versus Peripheral Arterial Disease Suresh Sharma, MDa, Rashmi Thapa, MDa, Vinodh Jeevanantham, MD, MPHa, Taylor Myers, BSa, Casper Hu, BSa, Michael Brimacombe, PhDb, James L. Vacek, MD, MSca, Buddhadeb Dawn, MDa, and Kamal Gupta, MDa,* Peripheral arterial disease (PAD), similar to coronary artery disease (CAD), is a significant predictor of cardiovascular morbidity and mortality. Guidelines recommend a low-density lipoprotein (LDL) goal of <100 mg/dl for both groups. We assessed whether lipid control and statin use were as aggressively applied to PAD as to patients with CAD. This retrospective study of patients with the diagnosis of CAD, PAD, or both CAD and PAD compared lipid levels and statin use. For comparison of statins, we used a statin potency unit (1 potency unit [ 10 mg of simvastatin). Among 11,134 subjects (CAD 9,563, PAD 596, and both CAD and PAD 975), mean LDL in the PAD group was higher than the CAD (92 vs 83 mg/dl, respectively, p <0.001) and the combined CAD and PAD groups (92 vs 80 mg/dl, respectively, p <0.001). Fewer patients with PAD achieved a target LDL of <100 mg/dl compared with CAD (62% vs 78%, respectively, p <0.001) and the combined group (62% vs 79%, respectively, p <0.001). Similar differences were noted for a target LDL of <70 mg/dl. Compared with the CAD group, a lesser number of patients with PAD received statin therapy (76% vs 100%, respectively, p <0.001) with lower mean potency unit (5.3 vs 8.1, respectively, p <0.001). In conclusion, our study demonstrated lower use and less aggressive application of statins in patients with PAD compared with patients with CAD, ensuing lower mean LDL in the CAD and combined PAD and CAD groups. Our study suggests that physicians are more aggressive with lipid control in patients with CAD compared with patients with PAD alone. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:1320e1325)
There is paucity of published reports that compare the treatment goals achieved among patients with peripheral arterial disease (PAD) compared with coronary artery disease (CAD). Furthermore, little is known if the target lipid control and use of lipid-lowering therapy are similar in patients with diagnosis of PAD alone versus patient with associated diagnosis of CAD with PAD. We hypothesize that compared with patients with CAD, a greater proportion of PAD-only patients continue to receive less aggressive lipid-lowering treatment in current clinical practice. Therefore our study aims to (1) compare lipid control between PAD versus CAD groups and PAD versus combined CAD and PAD groups and (2) compare statin use between PAD versus CAD groups and PAD versus combined CAD and PAD groups. Methods This is a retrospective observational study conducted in a large academic healthcare system. The Institutional Research Board of the University of Kansas Medical Center, where this study was conducted, approved the study. a
Department of Internal Medicine, Division of Cardiovascular Diseases and bDepartment of Biostatistics, University of Kansas Medical Center and Hospital, Kansas City, Kansas. Manuscript received November 13, 2013; revised manuscript received and accepted January 8, 2014. See page 1324 for disclosure information. *Corresponding author: Tel: (913) 588-9601; fax: (913) 588-6010. E-mail address: [email protected] (K. Gupta). 0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.01.405
Electronic medical records from January 2009 to March 2012 were reviewed, and ambulatory patients who were 18 years of age or older and had International Classification of Disease codes for CAD, PAD, or both listed under the problem list were identified as the study population. Subjects were included in the study only if their lipid profile and medication lists were available in the electronic medical record system. Based on the diagnostic codes, patients were categorized into 3groups—CAD only, PAD only, or combined CAD and PAD. Demographic variables, last lipid profile available, co-morbidities, and statin therapy were compared among the 3 groups. The percentage of patients with low-density lipoprotein (LDL) levels <100 and <70 mg/dl was compared among the PAD, CAD, and combined CAD and PAD groups. Mean levels of total cholesterol, high-density lipoprotein cholesterol, LDL cholesterol, and triglycerides were also compared among the 3 groups. We identified the statins used and the mean doses utilized for each agent. To compare the various doses of statins used, we converted all statin doses to an equivalent potency unit, based on the comparative efficacy of the currently used statins on lipids levels,1e3 where 1 potency unit ¼ 10 mg of simvastatin. For ezetimibe/statin combinations, the potency unit conversion was based on the strength of the statin considering the uniform dose of 10 mg of ezetimibe. For niacin/statin combinations, the potency unit conversion was also based on the strength of statin. Statistical analysis was performed using the Statistical Program for Social Sciences (version 19.0; SPSS, Inc., www.ajconline.org
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Table 1 Baseline characteristics of CAD, PAD, and combined CAD and PAD groups Variables Age (yrs) Men White Black Others BMI (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Smoker Diabetes mellitus Hypertension Chronic kidney disease End-stage renal disease Cerebrovascular disease
CAD (n ¼ 9,563)
PAD (n ¼ 596)
p Value*
CAD and PAD (n ¼ 975)
p Value†
69 11 6,281 (66) 7,675 (80) 882 (9) 1,006 (11) 30 7 128 18 74 11 1,366 (14) 3,098 (32) 7,431 (78) 1,158 (12) 147 (1.5) 216 (2)
70 12 299 (51) 435 (73) 103 (17) 58 (10) 29 8 131 20 73 11 137 (23) 164 (28) 458 (77) 73 (12) 12 (2) 30 (5)
0.007 <0.001 <0.001
72 10 661 (68) 812 (83) 75 (8) 88 (9) 29 6 130 20 71 12 258 (26) 401 (41) 814 (84) 211 (22) 43 (4) 26 (3)
0.003 <0.001 <0.001
<0.001 <0.001 0.006 <0.001 0.013 0.63 0.92 0.36 <0.001
0.46 0.45 <0.001 0.12 <0.001 0.001 <0.001 0.012 0.014
Data are expressed as mean SD or as number (%). BMI ¼ body mass index. * p Value (CAD vs PAD). † p Value (PAD vs combined diagnosis of CAD and PAD).
Table 2 Comparison of lipid panel among CAD, PAD, and combined CAD and PAD groups Lipids (mg/dl)
CAD (n ¼ 9,563)
PAD (n ¼ 596)
p Value*
CAD and PAD (n ¼ 975)
p Value†
Total cholesterol LDL cholesterol LDL cholesterol <100 LDL cholesterol <70 HDL cholesterol Triglycerides
151 40 83 33 7,420 (78) 3,743 (39) 45 15 129 91
163 43 92 35 371 (62) 178 (30) 46 16 134 86
<0.001 <0.001 <0.001 <0.001 0.008 0.144
148 42 80 31 768 (79) 404 (41) 43 15 136 113
<0.001 <0.00 <0.001 <0.001 <0.001 0.78
Data are expressed as mean SD or as number (%). HDL ¼ high-density lipoprotein. * p Value (CAD vs PAD). † p Value (PAD vs combined diagnosis of CAD and PAD).
Chicago, Illinois). Data were plotted (e.g., histograms and spaghetti plots linking variables) to examine for potential outliers and for the necessity of transformation before analysis. Summary statistics (e.g., mean, SD, minimum, maximum, and proportions) were calculated for all variables. Continuous variables are expressed as mean SD. For categorical variables, we used proportions for overall and subgroups. Chi-square test was used to find association between categorical variables. Fisher’s exact test was used where appropriate. One-way analysis of variance was used to compare all 3 groups, and independent sample t tests were used to compare PAD versus CAD groups and PAD versus combined CAD and PAD groups. A p value of <0.05 was accepted as indicating statistical significance. Results A total of 27,473 subjects comprised the population from which the study patients were obtained. Based on the diagnostic codes, 11,134 study patients were identified and categorized into 3 groups—9,563 (85.9%) had the diagnosis of CAD alone, 596 (5.4%) had the diagnosis of PAD alone,
and 975 (8.7%) carried diagnoses of both CAD and PAD. A total of 1,571 patients had diagnosis of PAD (PAD only and combined CAD and PAD groups) with prevalence of 5.7%. The baseline characteristics of 3 different diagnostic groups are listed in Table 1. Patients in the PAD group were significantly older, had higher percentage of women and black patients, and had lower body mass index compared with CAD group. PAD group had significantly higher number of smokers compared with CAD group. Diabetes, hypertension, and chronic/end-stage renal disease were more prevalent in the group with both CAD and PAD compared with the PAD-only group. Cerebrovascular diseases were significantly higher in the PAD group. One-way analysis of variance showed that mean LDL level in the PAD group was significantly higher than the mean LDL level in the CAD and the combined CAD and PAD groups (92 vs 83 vs 80 mg/dl, respectively, p <0.001). The PAD group also had significantly higher mean total cholesterol compared with the other 2 groups (163 vs 151 vs 148 mg/dl, respectively, p <0.001) However, the mean high-density lipoprotein levels in PAD group were significantly higher than the other 2 groups (46 vs 45 vs 43 mg/dl,
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Figure 1. Comparative analysis of lipid control in various diagnostic groups. (A) Mean LDL (mg/dl). (B) Percentage of patients in various diagnostic groups achieving LDL <100 mg/dl. (C) Percentage of patients in various diagnostic groups achieving LDL <70 mg/dl. (D) Mean total cholesterol (mg/dl).
Table 3 Comparison of statin therapy among CAD, PAD, and combined CAD and PAD groups Variables (Statin Type) Simvastatin Atorvastatin Rosuvastatin Pravastatin Lovastatin Fluvastatin Ezetimibe/simvastatin Niacin/simvastatin Niacin/lovastatin Total
CAD (n ¼ 9,563) 3,604 2,080 2,412 807 300 22 292 43 3 9,563
(38) (22) (25) (8) (3) (0.2) (3) (0.4) (0.03) (100)
PAD (n ¼ 596) (34) (15) (13) (7) (4) (0.3) (2) (0.3) 453 (76)
p Value*
203 90 77 44 25 2 10 2
<0.001
CAD and PAD (n ¼ 975) 326 194 219 79 20 3 30 1 1 873
(33) (20) (23) (8) (2) (0.3) (3) (0.1) (0.1) (90)
p Value†
<0.001
Data are presented as n (%) and mean SD. * p Value (CAD vs PAD). † p Value (PAD vs combined diagnosis of CAD and PAD).
respectively, p <0.001), likely due to higher percentage of women in PAD group. Mean triglyceride levels were significantly different among 3 groups (134 vs 129 vs 136 mg/dl, respectively, p ¼ 0.034). Comparative analyses were performed between PAD and CAD groups and PAD versus combined PAD and CAD groups as listed in Table 2 and Figure 1. Significantly fewer number of patients with PAD achieved a target LDL of <100 mg/dl compared with CAD and the combined CAD and PAD groups. Similarly, significantly fewer patients in the PAD group achieved target LDL of <70 mg/dl (Table 2; Figure 1). In the CAD group, 100% of patients were on statin therapy compared with only 76% in the PAD group and 90% in the combined CAD and PAD groups (p <0.001). PAD group had significantly greater use of less potent statins (simvastatin, pravastatin, and lovastatin) and lesser use of high potent statins (rosuvastatin and atorvastatin). This
was not compensated for by a higher mean dose of the lower potency statins in the PAD group (Table 3). Patients with PAD were receiving significantly lower mean potency unit of statins compared with CAD and combined CAD and PAD groups (5.3 vs 8.1 vs 8.7, respectively, p <0.001). Comparative analysis confirmed these observations as listed in Table 4 and Figure 2. Discussion Our study, one of the largest cohort studies describing current clinical practice, shows that there are significant differences in lipid control and statin use in patients with CAD compared with those with PAD. There was significantly less use of statins with less optimal lipid control in patients with PAD, compared with patients with CAD. We also found that the associated diagnosis of CAD in addition
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Table 4 Comparison of statin therapy (mean dose) among CAD, PAD, and combined CAD and PAD groups Variables Mean Dose of Individual Statin (mg)
CAD (n ¼ 9,563)
PAD (n ¼ 596)
p Value*
CAD and PAD (n ¼ 975)
p Value†
Simvastatin Atorvastatin Rosuvastatin Pravastatin Lovastatin Fluvastatin Ezetimibe/simvastatin Niacin/simvastatin Niacin/lovastatin Mean potency unit
36 21 39 24 21 12 42 22 31 12 59 26 42 21 29 10 20 0 8.1 (8.2)
17 22 11 22 12 0 16 14 — 5.3 (5.8)
<0.001 <0.001 <0.001 0.22 0.22 0.29 0.73 0.85 — <0.001
37 22 44 25 22 13 45 25 31 12 67 23 47 23 20 0 20 0 8.7 (8.8)
<0.001 <0.001 <0.001 0.12 0.40 0.49 0.36 0.67 — <0.001
30 30 15 38 28 80 40 30
Data are expressed as mean SD or as number (%). * p Value (CAD vs PAD). † p Value (PAD vs combined diagnosis of CAD and PAD).
Figure 2. Comparative analysis of mean potency units of statin between various diagnostic groups.
to PAD resulted in better risk factor control compared with diagnosis of PAD alone, again suggesting a management bias toward more aggressive lipid management if the diagnosis of CAD is present in a given subject. There is a significant difference in mean LDL and mean total cholesterol levels achieved in patients with PAD compared with patients with CAD or patients with the combined diagnosis of CAD and PAD. There was a significantly better control of mean LDL associated with a diagnosis of CAD. Another interesting observation was that a significantly higher number of patients with CAD achieved the target goal of LDL <100 mg/dl as well as stricter LDL control with goal of <70 mg/dl. In concordance with our hypothesis, we noted that a significantly higher proportion of patients with PAD achieved target LDL control of <100 and <70 mg/dl, if they had an associated diagnosis of CAD compared with PAD alone. To further substantiate the finding of significantly different lipid control in the diagnostic groups, we assessed the use of lipid-lowering medications in the study population. We observed that a significantly smaller proportion of patients with PAD were prescribed statin therapy compared with patients with CAD or combined CAD and PAD. The higher use of statin in CAD group certainly represents increased awareness among physicians toward risk factor control but can have additional explanations including the use of mandatory reminders (flags) via the electronic medical record system for patients
with CAD but not patients with PAD. Apart from the lesser use of statin therapy, patients with PAD were using significantly lower mean potency unit of statins compared with patients with diagnosis of CAD. Fowkes et al4 recently shed light on soaring rates of PAD globally with the current estimates of 202 million cases worldwide (14.6 million in the Americas) with significant increase in PAD prevalence over last decade. Age-adjusted prevalence of PAD in our study is 5.7%, which is in accordance with the results of recent studies on national statistics.5,6 Patients with PAD, either symptomatic or asymptomatic, are at risk of declining functional status7e10 and worse cardiovascular outcomes.7,11e14 Optimal risk factor control for prevention of vascular events remains the primary goal of therapy for patients with PAD.15e18 Studies have shown temporal trends of improvement in adherence with guideline-recommended secondary prevention strategies in patients with CAD. The use of antiplatelet, antihypertension, and lipid-lowering medications is now incorporated in performance measures of CAD management. Given the recent emphasis on quality measures and improvement, studies have focused on the use of risk factor modification in CAD.19e22 This has been largely achieved by the implementation of stricter guidelines and programs to improve adherence with the recommended guidelines. Importantly, Get with the Guidelines for CAD and ACTION registry are examples of outcome-based, quality improvement programs developed by scientific committees that help healthcare institutions apply The American College of Cardiology/American Heart Association Clinical Guidelines recommendations in their facilities and provide invaluable tools to assist them in achieving their goal of quality improvement.23e25 Another initiative, which has helped patients with CAD, is recommendation of achieving stricter LDL goal of <70 mg/dl. By following the recommendation of “Lower is better,” the clinicians are able to achieve lower LDL goal by the use of lipid-lowering therapy with high potency statins as observed in our study. Although we noticed better risk factor control and target lipid level achieved in patients with PAD in the present study compared with historic patients with PAD,26e28
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significant percentage of patients with PAD was not prescribed lipid-lowering medications. The intensity of risk factor control was better in patients with PAD when they had associated diagnosis of CAD. This may represent greater emphasis of lipid control in the presence of CAD or superior clinician awareness of the greater systemic atherosclerosis in this group and resultant increased morbidity and mortality associated with polyvascular disease over the long-term follow-up. However, the awareness of aggressive risk factor control has significant room for improvement when it comes to secondary prevention measures in patients with PAD alone. Due to significant increase in cardiovascular morbidity and mortality, functional decline, and loss of mobility, alarming increase in prevalence of PAD represents significant public health burden. Hence, there is potential to improve the current practice and risk factor control in patients with PAD by increasing awareness in healthcare providers through developing outcome-based, quality improvement programs by scientific committees. Being retrospective in nature, our work is subject to the corresponding limitations, including bias related to the use of diagnostic code for diagnosis for data retrieval from electronic medical chart. Our study findings are consistent with relatively less awareness among physicians for risk factor control for secondary prevention of PAD compared with CAD. However, we did not evaluate the difference in care based on the primary care versus specialty care providers. Also, our analysis did not include the patients with carotid, aortic, renal, and mesenteric arterial disease; thus our findings are applicable to lower extremity PAD population only. Also, our study was completed before the release of 2013 The American College of Cardiology/American Heart Association Guidelines on the Treatment of Blood Cholesterol29 and thus used previously published recommendations as benchmark.
Disclosures
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The authors have no conflicts of interest to disclose. 18. 1. Roberts WC. The rule of 5 and the rule of 7 in lipid-lowering by statin drugs. Am J Cardiol 1997;80:106e107. 2. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81:582e587. 3. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000;101:207e213. 4. Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, Norman PE, Sampson UK, Williams LJ, Mensah GA, Criqui MH. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329e1340. 5. 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, 1999-2000. Circulation 2004;110: 738e743. 6. Allison MA, Ho E, Denenberg JO, Langer RD, Newman AB, Fabsitz RR, Criqui MH. Ethnic-specific prevalence of peripheral arterial disease in the United States. Am J Prev Med 2007;32:328e333. 7. McDermott MM, Greenland P, Liu K, Guralnik JM, Celic L, Criqui MH, Chan C, Martin GJ, Schneider J, Pearce WH, Taylor LM, Clark E. The ankle brachial index is associated with leg function and physical
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activity: the Walking and Leg Circulation Study. Ann Intern Med 2002;136:873e883. McDermott MM, Greenland P, Liu K, Guralnik JM, Criqui MH, Dolan NC, Chan C, Celic L, Pearce WH, Schneider JR, Sharma L, Clark E, Gibson D, Martin GJ. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. JAMA 2001;286:1599e1606. McDermott MM, Liu K, Greenland P, Guralnik JM, Criqui MH, Chan C, Pearce WH, Schneider JR, Ferrucci L, Celic L, Taylor LM, Vonesh E, Martin GJ, Clark E. Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms. JAMA 2004;292:453e461. McDermott MM, Guralnik JM, Tian L, Ferrucci L, Liu K, Liao Y, Criqui MH. Baseline functional performance predicts the rate of mobility loss in persons with peripheral arterial disease. J Am Coll Cardiol 2007;50:974e982. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, Browner D. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381e386. Vogt MT, Cauley JA, Newman AB, Kuller LH, Hulley SB. Decreased ankle/arm blood pressure index and mortality in elderly women. JAMA 1993;270:465e469. Diehm C, Lange S, Darius H, Pittrow D, von Stritzky B, Tepohl G, Haberl RL, Allenberg JR, Dasch B, Trampisch HJ. Association of low ankle brachial index with high mortality in primary care. Eur Heart J 2006;27:1743e1749. Fowkes FG, Murray GD, Butcher I, Heald CL, Lee RJ, Chambless LE, Folsom AR, Hirsch AT, Dramaix M, deBacker G, Wautrecht JC, Kornitzer M, Newman AB, Cushman M, Sutton-Tyrrell K, Fowkes FG, Lee AJ, Price JF, d’Agostino RB, Murabito JM, Norman PE, Jamrozik K, Curb JD, Masaki KH, Rodriguez BL, Dekker JM, Bouter LM, Heine RJ, Nijpels G, Stehouwer CD, Ferrucci L, McDermott MM, Stoffers HE, Hooi JD, Knottnerus JA, Ogren M, Hedblad B, Witteman JC, Breteler MM, Hunink MG, Hofman A, Criqui MH, Langer RD, Fronek A, Hiatt WR, Hamman R, Resnick HE, Guralnik J, McDermott MM. Ankle brachial index combined with Framingham risk score to predict cardiovascular events and mortality: a meta-analysis. JAMA 2008;300:197e208. Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360: 7e22. Collins R, Armitage J, Parish S, Sleight P, Peto R, Heart Protection Study Collaborative G. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363: 757e767. Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC. Lipid-lowering for peripheral arterial disease of the lower limb. Cochrane Database Syst Rev 2007:CD000123. Heart Protection Study Collaborative G. Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions. J Vasc Surg 2007;45:645e654; discussion 653-644. Ho PM, Spertus JA, Masoudi FA, Reid KJ, Peterson ED, Magid DJ, Krumholz HM, Rumsfeld JS. Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med 2006;166:1842e1847. Jackevicius CA, Li P, Tu JV. Prevalence, predictors, and outcomes of primary nonadherence after acute myocardial infarction. Circulation 2008;117:1028e1036. Baroletti S, Dell’Orfano H. Medication adherence in cardiovascular disease. Circulation 2010;121:1455e1458. Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, Gupta R, Kelishadi R, Iqbal R, Avezum A, Kruger A, Kutty R, Lanas F, Lisheng L, Wei L, Lopez-Jaramillo P, Oguz A, Rahman O, Swidan H, Yusoff K, Zatonski W, Rosengren A, Teo KK, Prospective Urban Rural Epidemiology Study I. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey. Lancet 2011;378:1231e1243. Lewis WR, Ellrodt AG, Peterson E, Hernandez AF, LaBresh KA, Cannon CP, Pan W, Fonarow GC. Trends in the use of evidence-based
Coronary Artery Disease/Lipid Control in Peripheral Arterial Disease treatments for coronary artery disease among women and the elderly: findings from the get with the guidelines quality-improvement program. Circ Cardiovasc Qual Outcomes 2009;2:633e641. 24. Birtcher KK, Pan W, Labresh KA, Cannon CP, Fonarow GC, Ellrodt G. Performance achievement award program for Get with the GuidelineseCoronary Artery Disease is associated with global and sustained improvement in cardiac care for patients hospitalized with an acute myocardial infarction. Crit Path Cardiol 2010;9:103e112. 25. Xian Y, Pan W, Peterson ED, Heidenreich PA, Cannon CP, Hernandez AF, Friedman B, Holloway RG, Fonarow GC, Committee GS, Hospitals. Are quality improvements associated with the Get with the GuidelinesCoronary Artery Disease (GWTG-CAD) program sustained over time? A longitudinal comparison of GWTG-CAD hospitals versus nonGWTG-CAD hospitals. Am Heart J 2010;159:207e214. 26. McDermott MM, Mehta S, Ahn H, Greenland P. Atherosclerotic risk factors are less intensively treated in patients with peripheral arterial
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disease than in patients with coronary artery disease. J Gen Intern Med 1997;12:209e215. 27. Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, Krook SH, Hunninghake DB, Comerota AJ, Walsh ME, McDermott MM, Hiatt WR. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001;286:1317e1324. 28. Rehring TF, Sandhoff BG, Stolcpart RS, Merenich JA, Hollis HW Jr. Atherosclerotic risk factor control in patients with peripheral arterial disease. J Vasc Surg 2005;41:816e822. 29. Stone NJ, Robinson J, Lichtenstein AH, Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013 (Epub ahead of print).
There is paucity of published reports that compare the treatment goals achieved among patients with peripheral arterial disease (PAD) compared with coronary artery disease (CAD). Furthermore, little is known if the target lipid control and use of lipid-lowering therapy are similar in patients with diagnosis of PAD alone versus patient with associated diagnosis of CAD with PAD. We hypothesize that compared with patients with CAD, a greater proportion of PAD-only patients continue to receive less aggressive lipid-lowering treatment in current clinical practice. Therefore our study aims to (1) compare lipid control between PAD versus CAD groups and PAD versus combined CAD and PAD groups and (2) compare statin use between PAD versus CAD groups and PAD versus combined CAD and PAD groups. Methods This is a retrospective observational study conducted in a large academic healthcare system. The Institutional Research Board of the University of Kansas Medical Center, where this study was conducted, approved the study. a
Department of Internal Medicine, Division of Cardiovascular Diseases and bDepartment of Biostatistics, University of Kansas Medical Center and Hospital, Kansas City, Kansas. Manuscript received November 13, 2013; revised manuscript received and accepted January 8, 2014. See page 1324 for disclosure information. *Corresponding author: Tel: (913) 588-9601; fax: (913) 588-6010. E-mail address: [email protected] (K. Gupta). 0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.01.405
Electronic medical records from January 2009 to March 2012 were reviewed, and ambulatory patients who were 18 years of age or older and had International Classification of Disease codes for CAD, PAD, or both listed under the problem list were identified as the study population. Subjects were included in the study only if their lipid profile and medication lists were available in the electronic medical record system. Based on the diagnostic codes, patients were categorized into 3groups—CAD only, PAD only, or combined CAD and PAD. Demographic variables, last lipid profile available, co-morbidities, and statin therapy were compared among the 3 groups. The percentage of patients with low-density lipoprotein (LDL) levels <100 and <70 mg/dl was compared among the PAD, CAD, and combined CAD and PAD groups. Mean levels of total cholesterol, high-density lipoprotein cholesterol, LDL cholesterol, and triglycerides were also compared among the 3 groups. We identified the statins used and the mean doses utilized for each agent. To compare the various doses of statins used, we converted all statin doses to an equivalent potency unit, based on the comparative efficacy of the currently used statins on lipids levels,1e3 where 1 potency unit ¼ 10 mg of simvastatin. For ezetimibe/statin combinations, the potency unit conversion was based on the strength of the statin considering the uniform dose of 10 mg of ezetimibe. For niacin/statin combinations, the potency unit conversion was also based on the strength of statin. Statistical analysis was performed using the Statistical Program for Social Sciences (version 19.0; SPSS, Inc., www.ajconline.org
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Table 1 Baseline characteristics of CAD, PAD, and combined CAD and PAD groups Variables Age (yrs) Men White Black Others BMI (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Smoker Diabetes mellitus Hypertension Chronic kidney disease End-stage renal disease Cerebrovascular disease
CAD (n ¼ 9,563)
PAD (n ¼ 596)
p Value*
CAD and PAD (n ¼ 975)
p Value†
69 11 6,281 (66) 7,675 (80) 882 (9) 1,006 (11) 30 7 128 18 74 11 1,366 (14) 3,098 (32) 7,431 (78) 1,158 (12) 147 (1.5) 216 (2)
70 12 299 (51) 435 (73) 103 (17) 58 (10) 29 8 131 20 73 11 137 (23) 164 (28) 458 (77) 73 (12) 12 (2) 30 (5)
0.007 <0.001 <0.001
72 10 661 (68) 812 (83) 75 (8) 88 (9) 29 6 130 20 71 12 258 (26) 401 (41) 814 (84) 211 (22) 43 (4) 26 (3)
0.003 <0.001 <0.001
<0.001 <0.001 0.006 <0.001 0.013 0.63 0.92 0.36 <0.001
0.46 0.45 <0.001 0.12 <0.001 0.001 <0.001 0.012 0.014
Data are expressed as mean SD or as number (%). BMI ¼ body mass index. * p Value (CAD vs PAD). † p Value (PAD vs combined diagnosis of CAD and PAD).
Table 2 Comparison of lipid panel among CAD, PAD, and combined CAD and PAD groups Lipids (mg/dl)
CAD (n ¼ 9,563)
PAD (n ¼ 596)
p Value*
CAD and PAD (n ¼ 975)
p Value†
Total cholesterol LDL cholesterol LDL cholesterol <100 LDL cholesterol <70 HDL cholesterol Triglycerides
151 40 83 33 7,420 (78) 3,743 (39) 45 15 129 91
163 43 92 35 371 (62) 178 (30) 46 16 134 86
<0.001 <0.001 <0.001 <0.001 0.008 0.144
148 42 80 31 768 (79) 404 (41) 43 15 136 113
<0.001 <0.00 <0.001 <0.001 <0.001 0.78
Data are expressed as mean SD or as number (%). HDL ¼ high-density lipoprotein. * p Value (CAD vs PAD). † p Value (PAD vs combined diagnosis of CAD and PAD).
Chicago, Illinois). Data were plotted (e.g., histograms and spaghetti plots linking variables) to examine for potential outliers and for the necessity of transformation before analysis. Summary statistics (e.g., mean, SD, minimum, maximum, and proportions) were calculated for all variables. Continuous variables are expressed as mean SD. For categorical variables, we used proportions for overall and subgroups. Chi-square test was used to find association between categorical variables. Fisher’s exact test was used where appropriate. One-way analysis of variance was used to compare all 3 groups, and independent sample t tests were used to compare PAD versus CAD groups and PAD versus combined CAD and PAD groups. A p value of <0.05 was accepted as indicating statistical significance. Results A total of 27,473 subjects comprised the population from which the study patients were obtained. Based on the diagnostic codes, 11,134 study patients were identified and categorized into 3 groups—9,563 (85.9%) had the diagnosis of CAD alone, 596 (5.4%) had the diagnosis of PAD alone,
and 975 (8.7%) carried diagnoses of both CAD and PAD. A total of 1,571 patients had diagnosis of PAD (PAD only and combined CAD and PAD groups) with prevalence of 5.7%. The baseline characteristics of 3 different diagnostic groups are listed in Table 1. Patients in the PAD group were significantly older, had higher percentage of women and black patients, and had lower body mass index compared with CAD group. PAD group had significantly higher number of smokers compared with CAD group. Diabetes, hypertension, and chronic/end-stage renal disease were more prevalent in the group with both CAD and PAD compared with the PAD-only group. Cerebrovascular diseases were significantly higher in the PAD group. One-way analysis of variance showed that mean LDL level in the PAD group was significantly higher than the mean LDL level in the CAD and the combined CAD and PAD groups (92 vs 83 vs 80 mg/dl, respectively, p <0.001). The PAD group also had significantly higher mean total cholesterol compared with the other 2 groups (163 vs 151 vs 148 mg/dl, respectively, p <0.001) However, the mean high-density lipoprotein levels in PAD group were significantly higher than the other 2 groups (46 vs 45 vs 43 mg/dl,
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Figure 1. Comparative analysis of lipid control in various diagnostic groups. (A) Mean LDL (mg/dl). (B) Percentage of patients in various diagnostic groups achieving LDL <100 mg/dl. (C) Percentage of patients in various diagnostic groups achieving LDL <70 mg/dl. (D) Mean total cholesterol (mg/dl).
Table 3 Comparison of statin therapy among CAD, PAD, and combined CAD and PAD groups Variables (Statin Type) Simvastatin Atorvastatin Rosuvastatin Pravastatin Lovastatin Fluvastatin Ezetimibe/simvastatin Niacin/simvastatin Niacin/lovastatin Total
CAD (n ¼ 9,563) 3,604 2,080 2,412 807 300 22 292 43 3 9,563
(38) (22) (25) (8) (3) (0.2) (3) (0.4) (0.03) (100)
PAD (n ¼ 596) (34) (15) (13) (7) (4) (0.3) (2) (0.3) 453 (76)
p Value*
203 90 77 44 25 2 10 2
<0.001
CAD and PAD (n ¼ 975) 326 194 219 79 20 3 30 1 1 873
(33) (20) (23) (8) (2) (0.3) (3) (0.1) (0.1) (90)
p Value†
<0.001
Data are presented as n (%) and mean SD. * p Value (CAD vs PAD). † p Value (PAD vs combined diagnosis of CAD and PAD).
respectively, p <0.001), likely due to higher percentage of women in PAD group. Mean triglyceride levels were significantly different among 3 groups (134 vs 129 vs 136 mg/dl, respectively, p ¼ 0.034). Comparative analyses were performed between PAD and CAD groups and PAD versus combined PAD and CAD groups as listed in Table 2 and Figure 1. Significantly fewer number of patients with PAD achieved a target LDL of <100 mg/dl compared with CAD and the combined CAD and PAD groups. Similarly, significantly fewer patients in the PAD group achieved target LDL of <70 mg/dl (Table 2; Figure 1). In the CAD group, 100% of patients were on statin therapy compared with only 76% in the PAD group and 90% in the combined CAD and PAD groups (p <0.001). PAD group had significantly greater use of less potent statins (simvastatin, pravastatin, and lovastatin) and lesser use of high potent statins (rosuvastatin and atorvastatin). This
was not compensated for by a higher mean dose of the lower potency statins in the PAD group (Table 3). Patients with PAD were receiving significantly lower mean potency unit of statins compared with CAD and combined CAD and PAD groups (5.3 vs 8.1 vs 8.7, respectively, p <0.001). Comparative analysis confirmed these observations as listed in Table 4 and Figure 2. Discussion Our study, one of the largest cohort studies describing current clinical practice, shows that there are significant differences in lipid control and statin use in patients with CAD compared with those with PAD. There was significantly less use of statins with less optimal lipid control in patients with PAD, compared with patients with CAD. We also found that the associated diagnosis of CAD in addition
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Table 4 Comparison of statin therapy (mean dose) among CAD, PAD, and combined CAD and PAD groups Variables Mean Dose of Individual Statin (mg)
CAD (n ¼ 9,563)
PAD (n ¼ 596)
p Value*
CAD and PAD (n ¼ 975)
p Value†
Simvastatin Atorvastatin Rosuvastatin Pravastatin Lovastatin Fluvastatin Ezetimibe/simvastatin Niacin/simvastatin Niacin/lovastatin Mean potency unit
36 21 39 24 21 12 42 22 31 12 59 26 42 21 29 10 20 0 8.1 (8.2)
17 22 11 22 12 0 16 14 — 5.3 (5.8)
<0.001 <0.001 <0.001 0.22 0.22 0.29 0.73 0.85 — <0.001
37 22 44 25 22 13 45 25 31 12 67 23 47 23 20 0 20 0 8.7 (8.8)
<0.001 <0.001 <0.001 0.12 0.40 0.49 0.36 0.67 — <0.001
30 30 15 38 28 80 40 30
Data are expressed as mean SD or as number (%). * p Value (CAD vs PAD). † p Value (PAD vs combined diagnosis of CAD and PAD).
Figure 2. Comparative analysis of mean potency units of statin between various diagnostic groups.
to PAD resulted in better risk factor control compared with diagnosis of PAD alone, again suggesting a management bias toward more aggressive lipid management if the diagnosis of CAD is present in a given subject. There is a significant difference in mean LDL and mean total cholesterol levels achieved in patients with PAD compared with patients with CAD or patients with the combined diagnosis of CAD and PAD. There was a significantly better control of mean LDL associated with a diagnosis of CAD. Another interesting observation was that a significantly higher number of patients with CAD achieved the target goal of LDL <100 mg/dl as well as stricter LDL control with goal of <70 mg/dl. In concordance with our hypothesis, we noted that a significantly higher proportion of patients with PAD achieved target LDL control of <100 and <70 mg/dl, if they had an associated diagnosis of CAD compared with PAD alone. To further substantiate the finding of significantly different lipid control in the diagnostic groups, we assessed the use of lipid-lowering medications in the study population. We observed that a significantly smaller proportion of patients with PAD were prescribed statin therapy compared with patients with CAD or combined CAD and PAD. The higher use of statin in CAD group certainly represents increased awareness among physicians toward risk factor control but can have additional explanations including the use of mandatory reminders (flags) via the electronic medical record system for patients
with CAD but not patients with PAD. Apart from the lesser use of statin therapy, patients with PAD were using significantly lower mean potency unit of statins compared with patients with diagnosis of CAD. Fowkes et al4 recently shed light on soaring rates of PAD globally with the current estimates of 202 million cases worldwide (14.6 million in the Americas) with significant increase in PAD prevalence over last decade. Age-adjusted prevalence of PAD in our study is 5.7%, which is in accordance with the results of recent studies on national statistics.5,6 Patients with PAD, either symptomatic or asymptomatic, are at risk of declining functional status7e10 and worse cardiovascular outcomes.7,11e14 Optimal risk factor control for prevention of vascular events remains the primary goal of therapy for patients with PAD.15e18 Studies have shown temporal trends of improvement in adherence with guideline-recommended secondary prevention strategies in patients with CAD. The use of antiplatelet, antihypertension, and lipid-lowering medications is now incorporated in performance measures of CAD management. Given the recent emphasis on quality measures and improvement, studies have focused on the use of risk factor modification in CAD.19e22 This has been largely achieved by the implementation of stricter guidelines and programs to improve adherence with the recommended guidelines. Importantly, Get with the Guidelines for CAD and ACTION registry are examples of outcome-based, quality improvement programs developed by scientific committees that help healthcare institutions apply The American College of Cardiology/American Heart Association Clinical Guidelines recommendations in their facilities and provide invaluable tools to assist them in achieving their goal of quality improvement.23e25 Another initiative, which has helped patients with CAD, is recommendation of achieving stricter LDL goal of <70 mg/dl. By following the recommendation of “Lower is better,” the clinicians are able to achieve lower LDL goal by the use of lipid-lowering therapy with high potency statins as observed in our study. Although we noticed better risk factor control and target lipid level achieved in patients with PAD in the present study compared with historic patients with PAD,26e28
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significant percentage of patients with PAD was not prescribed lipid-lowering medications. The intensity of risk factor control was better in patients with PAD when they had associated diagnosis of CAD. This may represent greater emphasis of lipid control in the presence of CAD or superior clinician awareness of the greater systemic atherosclerosis in this group and resultant increased morbidity and mortality associated with polyvascular disease over the long-term follow-up. However, the awareness of aggressive risk factor control has significant room for improvement when it comes to secondary prevention measures in patients with PAD alone. Due to significant increase in cardiovascular morbidity and mortality, functional decline, and loss of mobility, alarming increase in prevalence of PAD represents significant public health burden. Hence, there is potential to improve the current practice and risk factor control in patients with PAD by increasing awareness in healthcare providers through developing outcome-based, quality improvement programs by scientific committees. Being retrospective in nature, our work is subject to the corresponding limitations, including bias related to the use of diagnostic code for diagnosis for data retrieval from electronic medical chart. Our study findings are consistent with relatively less awareness among physicians for risk factor control for secondary prevention of PAD compared with CAD. However, we did not evaluate the difference in care based on the primary care versus specialty care providers. Also, our analysis did not include the patients with carotid, aortic, renal, and mesenteric arterial disease; thus our findings are applicable to lower extremity PAD population only. Also, our study was completed before the release of 2013 The American College of Cardiology/American Heart Association Guidelines on the Treatment of Blood Cholesterol29 and thus used previously published recommendations as benchmark.
Disclosures
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