당뇨병환자에서항혈소판제사용 - 아스피린일차예방을중심으로 - 경희대학교강동경희대병원 황유철
말씀드릴내용 당뇨병및심혈관질환의역학 아스피린의심혈관질환 1차, 2차예방효과 아스피린부작용및용량에따른효과차이 당뇨병환자에서아스피린사용의적응증
사망원인순위, 2010 년 25.6% 통계청
심혈관질환에의한의료비추세 6 조 1400 억 국민건강보험공단, 2002-2009
Multidisciplinary approach for CVD prevention
Steno-2: Percentage of Patients at Treatment Goals at End of Study
Steno-2: Effect of Multifactorial Intervention on Various CV Events in Type 2 Diabetes
Steno-2: Effect of Multifactorial Intervention on CV Events in Type 2 Diabetes
Diabetes Care 2008;31:S27-8.
Aspirin for CVD secondary prevention
Aspirin s Use in Acute Myocardial Infarction Second International Study of Infarct Survival (ISIS-2) 17,187 patients randomized to aspirin, streptokinase, both, or placebo Aspirin showed a 23% RRR (ARR 2.5% NNT 40) in cardiovascular death Benefit was additive with streptokinase Lancet 1988; 2: 349-60
Aspirin for Secondary Prevention Antithrombotic Trialists Collaboration Meta-analysis of 65 trials using aspirin in over high-risk patients Over 140,000 patients total 22% odds reduction in all vascular events (2.5% absolute reduction) BMJ 2002; 324: 71-86
Aspirin for CVD primary prevention
Aspirin for primary Prevention Study /year Aspirin dose (mg) F/U (yr) No. Female (%) Age (yr) CHD RR (95% CI) control vs. aspirin Stroke RR (95% CI) aspirin vs. control PHS DM/1989 325 EOD 5.0 533 70 >40 0.59 (0.33-1.06) 1.50 (0.69-3.25) ETDRS/1992 650 5.0 3711 44 >18 0.85 (0.73-1.00) 1.18 (0.88-1.58) PPP DM/2003 100 3.7 1031 52 >50 0.49 (0.17-1.43) 0.90 (0.38-2.09) WHS DM/2005 100 EOD 10.1 1027 100 >45 1.34 (0.85-2.12) 0.45 (0.25-0.82) TPT DM/199 75 6.7 68 0 >45 0.90 (0.28-2.89) 0.67 (0.06-7.06) BMD/1988 500 5.6 101 0 >50 1.00 (0.42-2.40) 1.39 (0.15-12.86) HOT DM/1998 75 3.8 1501 47 >50 0.77 (0.44-1.36) 0.91 (0.52-1.61) Pignone M et al. JACC 2010;55:2878-86.
Two primary prevention trials The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) Trial
Efficacy of Low-Dose Aspirin Therapy for the Primary Prevention of Atherosclerotic Events in Type 2 Diabetic Patients: The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Design: Prospective, randomized, open-label, controlled trial low-dose aspirin group (81 or 100 mg/day) vs. non-aspirin group 163 institutions in Japan Inclusion Criteria: Type 2 diabetes between ages 30 and 85 years Exclusion Criteria: prior CVD, atrial fibrillation, history of severe gastric or duodenal ulcer, and use of antiplatelet or antithrombotic medication
Patient Flow and Outcomes 2567 Patients were screened 2539 Randomized 28 Excluded 6 Withdrew consent 10 History of atherosclerotic disease 10 Aged >85 years 1 No diabetes 1 Receiving warfarin 1262 Randomized to receive aspirin 1277 Randomized to nonaspirin group 1139 Received aspirin through completion of trial 123 Stopped taking aspirin 9 Received aspirin or other antiplatelet therapy 6 Received aspirin 3 Received other antiplatelet medication 1165 Followed up through end of study 97 Lost to follow-up 1181 Followed up through end of study 96 Lost to follow-up 1262 Included in efficacy and safety analyses 1277 Included in efficacy and safety analyses
Baseline Clinical Characteristics Characteristic Aspirin Group (n = 1262) Nonaspirin Group (n = 1277) Age (y)* 65 ± 10 64 ± 10 Male, n (%) 706 (56) 681 (53) Current smoker, n (%) 289 (23) 248 (19) Body mass index (kg/m 2 )* 24 ± 4 24 ± 4 Hypertension, n (%) 742 (59) 731 (57) Dyslipidemia, n (%) 680 (54) 665 (52) Duration of diabetes (y), median (IQR) 7.3 (2.8-12.3) 6.7 (3.0-12.5) Systolic blood pressure (mm Hg)* 136 ± 15 134 ± 15 Diastolic blood pressure (mm Hg)* 77 ± 9 76 ± 9 *Mean ± SD.
Primary End Point: Total Atherosclerotic Events According to the Treatment Groups 10 8 6 Log-Rank Test, P = 0.16 HR (95% CI): 0.80 (0.58 1.10) % 4 2 Aspirin Group Nonaspirin Group 0 0 1 2 3 4 5 Years Nonaspirin Group (n) Aspirin Group (n) 1277 1220 1165 1117 813 135 1262 1210 1159 1095 806 140
Fatal Coronary and Cerebrovascular Events According to the Treatment Groups 1.0 Log-Rank Test, P = 0.0037 HR (95% CI): 0.10 (0.01 0.79) 0.8 0.6 % 0.4 0.2 Aspirin Group Non-Aspirin Group Nonaspirin Group (n) Aspirin Group (n) 0 0 1 2 3 4 5 Years 1277 1220 1165 1117 813 135 1262 1210 1159 1095 806 140
Other End Points Aspirin Group n (%) Nonaspirin Group n (%) HR 95% CI P Value CHD events (fatal + nonfatal) 28 (2.2) 35 (2.7) 0.81 0.49 1.33 0.40 Fatal MI 0 (0) 5 (0.4) Nonfatal MI 12 (1.0) 9 (0.7) 1.34 0.57 3.19 0.50 Unstable angina 4 (0.3) 10 (0.8) 0.40 0.13 1.29 0.13 Stable angina 12 (1.0) 11 (0.9) 1.10 0.49 2.50 0.82 Stroke (fatal + nonfatal) 28 (2.2) 32 (2.5) 0.84 0.53 1.32 0.44 Fatal stroke 1 (0.08) 5 (0.4) 0.20 0.024 1.74 0.15 Nonfatal stroke (ischemic) 22 (1.7) 24 (1.9) 0.93 0.52 1.66 0.80 Nonfatal stroke (hemorrhagic) 5 (0.4) 3 (0.2) 1.68 0.40 7.04 0.48 Transient ischemic attack 5 (0.4) 8 (0.6) 0.63 0.21 1.93 0.42 Peripheral artery disease* 7 (0.6) 11 (0.9) 0.64 0.25 1.65 0.35 Total mortality 34 (2.7) 38 (3.0) 0.90 0.57 1.14 0.67 *Arteriosclerosis obliterans (5 in aspirin group and 8 in nonaspirin group); aortic dissection (2 fatal in the aspirin group and 1 nonfatal in the nonaspirin group); mesenteric artery thrombosis (1 in the nonaspirin group) and retinal artery thrombosis (1 in the nonaspirin group).
Age, y Aspirin Group Nonaspirin Group Hazard Ratio (95% CI) 65 45/719 59/644 0.68 (0.46 0.99) <65 23/543 27/633 1.0 (0.57 1.70) Gender Male 40/706 51/681 0.74 (0.49 1.12) Female 28/556 35/596 0.88 (0.53 1.44) Hypertensive Status Hypertensive 49/742 55/731 0.88 (0.60 1.30) Normotensive 19/520 31/546 0.64 (0.36 1.13) Lipid Status Dyslipidemia 38/680 43/665 0.88 (0.57 1.37) Normolipidemia 30/582 43/612 0.71 (0.45 1.14) Smoking Current or past smoker Subgroup Analysis Events, No./Total No. 36/565 42/494 0.73 (0.47 1.14) Nonsmoker 32/697 44/783 0.83 (0.53 1.31) Favors Aspirin Favors No Aspirin 0.3 1.0 Hazard Ratio (95% CI) 2.0
Total Atherosclerotic Events According to the Treatment Groups: Subgroup Aged 65 Years or Older 12 10 8 Log-Rank Test, P = 0.047 HR (95% CI): 0.68 (0.46-0.99) % 6 4 2 Aspirin Group Nonaspirin Group Nonaspirin Group (n) Aspirin Group (n) 0 0 1 2 3 4 5 Years 644 612 582 553 396 73 719 683 656 619 452 77
Adverse Events No difference between aspirin group (10 patients) and nonaspirin group (7 patients) for composite of hemorrhagic stroke and severe GI bleeding 4 cases of severe gastrointestinal (GI) bleeding that required transfusion in aspirin group 6 hemorrhagic strokes (1 fatal) in aspirin group and 7 hemorrhagic strokes (4 fatal) in nonaspirin group
Belch J et al. BMJ 2008;337:a1840.
Study design 40 year, ABI <0.99, CVD (-) 100mg daily Belch J et al. BMJ 2008;337:a1840.
Cardiovascular outcomes Belch J et al. BMJ 2008;337:a1840.
All cause mortality Belch J et al. BMJ 2008;337:a1840.
Primary and secondary end points
Meta-analysis of aspirin primary prevention trials ADA/AHA/ACCF
Meta-Analysis of Aspirin - CHD
Meta-Analysis of Aspirin Stroke
Aspirin dose - prospective trials Campbell CL et al. JAMA 2007;297:2018-24.
Aspirin dose - Retrospective observational study Campbell CL et al. JAMA 2007;297:2018-24.
Risk for hemorrhagic stroke Absolute risk increase of 12 events per 10,000 person during 37 months He J et al. JAMA 1998;280:1930-5.
Hemorrhagic stroke in subgroups He J et al. JAMA 1998;280:1930-5.
Risk for GI bleeding
Risk for GI bleeding by age, sex
Risk for GI bleeding Meta-analysis of the six primary prevention trials - RR 1.54 (95% CI 1.30 to 1.82). - absolute increase in risk : 3 in 10 000 per year in mainly middle-aged adults Higher CVD risk are also at higher risk for aspirin-related adverse effects. Diabetes taking aspirin experienced a 55% increased risk (RR 1.55, 95% CI 1.13 to 2.14) Pignone M, et al. Diabetes Care. 2010;33(6):1395-1402.
ADA/AHA/ACC: Recommendations for Use of Aspirin for Primary Prevention of CV Events in People With Diabetes Recommendation Low-dose (75 162 mg/d) aspirin use for prevention is reasonable for adults with diabetes and no previous history of vascular disease who are at increased CVD risk and who are not at increased risk for bleeding Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk potential adverse effects from bleeding outweigh potential benefits Low-dose (75 162 mg/d) aspirin use for prevention might be considered for those with diabetes at intermediate CVD risk until further research is available Definition of risk 10-yr risk of CVD events >10% Most men >50, women >60 yrs with smoking, HTN, dyslip, premature CVD fam hx, albuminuria 10-yr CVD risk <5% Men <50, women <60 yrs with no major add l CVD risk factors Younger patients with 1 risk factor Older pts with no risk factors Pts w/ 10-yr CVD risk 5 10% Pignone M, et al. Diabetes Care. 2010;33(6):1395-1402.
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