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ONLINE APPENDIXExclusion criteria for participation in WOSCOPS History of treated myocardial infarction with documented ECG or enzyme changesAngina pectoris requiring hospitalization for treatment or investigation within the previous twelve months. Other individuals with positive Rose Questionnaire will not be excludedECG evidence of disease. Minnesota codes l-l, l-2, l-3, 4-1, 5-1, 6-4-1, 7-l-l or 9-6. Atria1 fibrillation (8-3-1), atrial flutter (8-3-2), frequent (> 1 in 5) ventricular premature beats, second (6-2) or third degree atrioventricular block (6-l) as well as A-V dissociation (8-6)Hypertension exceeding; systolic BP > 180mmHg or diastolic BP > 110 mmHg, despite treatmentHistory of rheumatic heart diseaseCongenital heart diseasePulmonary heart disease, chronic bronchitis, emphysema or kyphoscoliosis associated with ECG changes codes 2-2, 3-2, 7-2 or 7-3Cardiomegaly, congestive cardiac failure, significant valvular heart diseaseOther suspected serious physical illness.Psychiatric illness (reported by GP)Current lipid lowering therapyLaboratory exclusionsSupplemental Table 1. Baseline characteristics of study participants and the full cohort in the West of Scotland Coronary Prevention Study?StudyFull cohortn=3,318n=6,595Age, years55.1 (5.5)55.2 (5.5)Body-mass index, kgm225.9 (3.2)26.0 (3.2)Employed2,346 (71%)4,654 (71%)Smoking and alcohol statusCurrent smoker1,393 (42%)2,907 (44%)Alcohol intake, ≥21 units/week546 (17%)1,148 (17%)Blood pressure and heart rateSystolic, mmHg136 (17)136 (17)Diastolic, mmHg84 (11)84 (11)Heart rate, bpm65 (11)66 (11)Past medical historyHypertension544 (16%)1,037 (16%)Diabetes mellitus36 (1%)76 (1%)Angina a168 (5%)338 (5%)Intermittent claudication82 (3%)193 (3%)Minor ECG abnormalities a271 (8%)534 (8%)Family history of CHD191 (6%)376 (6%)MedicationNitrate74 (2%)139 (2%)Beta-blocker241 (7%)474 (7%)ACE inhibitor36 (1%)77 (1%)Lipid levelsTotal cholesterol, mg/dL270 (23)270 (23)LDL cholesterol, mg/dL191 (17)192 (19)HDL cholesterol, mg/dL44 (9)44 (8)Triglycerides, mg/dL154 (136)152 (133)Treatment allocationPlacebo1,647 (50%)3,293 (50%)Pravastatin 40 mg1,671 (50%)3,302 (50%)Continuous variables are mean (SD); categorical variable are n (%); ACE = angiotensin converting enzyme, CHD = coronary heart disease, ECG = electrocardiogram, HDL = high-density lipoprotein, LDL = low-density lipoprotein. a Symptoms consistent with angina on Rose questionnaire and minor ST-segment or T-wave abnormalities on the resting 12-lead electrocardiogram defined by Minnesota codes (4-2, 4-3, 5-2, 5-3).Supplemental Table 2. Stepwise linear regression model for determinants of baseline troponin I concentration after log transformation as a continuous variableBeta coefficientP-valueAge, 5 years1.0250.013Heart rate, 10 bpm0.950<0.001Angina1.1360.003Minor ECG abnormality1.179<0.001Hypertension 1.0670.020Systolic blood pressure, 10 mmHg1.027<0.001LDL cholesterol, 39 mg/dL1.083<0.001ACE-inhibitor0.7940.016Unemployment 1.135<0.001Retired1.0930.013 ACE = angiotensin converting enzyme, ECG = electrocardiogram, LDL = low-density lipoproteinSupplemental Table 3. Hazard ratios for the primary outcome (non-fatal myocardial infarction or death from coronary heart disease) and other outcomes at 5 years (trial end) and at 15 years for each quartile of troponin concentration at baselineHazard ratio (95%CI) by quarter of troponin I aQ1Q2Q3Q4P trendOutcome at 5 years Number of eventsNon-fatal MI/CHD death1591.001.13 (0.67-1.89)1.06 (0.62-1.87)2.27 (1.42-3.65)<0.001Non-fatal MI1371.001.08 (0.61-1.91)1.25 (0.70-2.22)2.36 (1.41-3.95)<0.001CHD death251.001.21 (0.35-4.19)0.39 (0.07-2.14)1.98 (0.61-6.41)0.161Outcome at 15 yearsNon-fatal MI/CHD death4131.000.97 (0.72-1.31)1.01 (0.74-1.37)1.54 (1.16-2.05)<0.001CHD death/admission7281.001.17 (0.94-1.46)1.11 (0.89-1.40)1.42 (1.14-1.77)0.011Fatal/non-fatal stroke2131.000.97 (0.64-1.46)0.86 (0.56-1.32)1.30 (0.87-1.94)0.144Heart failure admission611.001.00 (0.43-2.31)1.45 (0.64-3.28)1.98 (0.91-4.30)0.171All-cause death6101.001.02 (0.80-1.30)0.97 (0.76-1.25)1.34 (1.05-1.70)0.012CVD death2511.001.06 (0.71-1.60)0.97 (0.64-1.48)1.74 (1.19-2.55)<0.001Non-CVD death3591.001.01 (0.74-1.37)0.99 (0.72-1.35)1.10 (0.80-1.50)0.890a Adjusted for treatment allocation (pravastatin or placebo), age, BMI, heart rate, systolic blood pressure, diastolic blood pressure, HDL and LDL cholesterol level, history of angina, diabetes, hypertension, family history of premature coronary heart disease death, minor ECG abnormalities, nitrate use and smoking status. b All analyses based on rounding up values below 1.2 to 1.2 ng/L and excluding all values >500 ng/LAbbreviations: CHD = coronary heart disease; CVD = cardiovascular disease; MI = myocardial infarction; Q = quarterSupplemental Table 4. Number of events and hazards ratio for the primary endpoint of non-fatal myocardial infarction or coronary heart disease death by treatment allocationEvents by quartile of baseline troponin I concentrationQ1Q2Q3Q4TotalOutcome at 5 yearsNumber of events - placebo17271847109Number of events - pravastatin88112350Hazard ratio within quartile(CI) a0.46(0.20-1.10)0.32(0.14-0.70)0.45(0.21-0.97)0.48(0.29-0.79)0.45(0.32-0.65)P value by quartile0.0800.0040.0420.004<0.001Absolute risk reduction, %2.24.02.25.9P for interaction (quartile of troponin x treatment)0.67Outcome at 15 yearsNumber of events - placebo46564990241Number of events - pravastatin34414354172Hazard ratio within quartile(CI) a0.78(0.50-1.21)0.74(0.49-1.11)0.72(0.47-1.09)0.55(0.39-0.78)0.68(0.56-0.83)P value by quartile0.270.150.12<0.001<0.001Absolute risk reduction, %2.62.83.09.0P for interaction (quartile of troponin x treatment)0.19a Adjusted for age, BMI, heart rate, systolic blood pressure, diastolic blood pressure, HDL and LDL cholesterol level, history of angina, diabetes, hypertension, family history of premature coronary heart disease death, minor ECG abnormalities, nitrate use and smoking status. Supplemental Figure 1. Cumulative incidence plot for primary outcome of non-fatal myocardial infarction or coronary heart disease death in those without prevalent cardiovascular disease at baseline 6648455905500148590055245Quarter 1 ≤ 3.1 ng/LQuarter 2 3.1-3.9 ng/LQuarter 3 4.0-5.1 ng/LQuarter 4 ≥ 5.2 ng/L00Quarter 1 ≤ 3.1 ng/LQuarter 2 3.1-3.9 ng/LQuarter 3 4.0-5.1 ng/LQuarter 4 ≥ 5.2 ng/LOf the 3,318 study participants 436 had prevalent coronary heart disease defined as symptoms suggestive of angina on the Rose questionnaire, minor ECG abnormality, or nitrate consumption, and were excluded from this analysis. Adjusted hazard ratios compared to quarter 1 as reference (using quarter values from the primary analysis) for Q2 were 0.99 (95%CI 0.72 to 1.36), for Q3 were 0.91 (95%CI 0.65 to 1.27), and for Q4 were 1.43 (95%CI 1.05 to 1.95) (P-value for trend= 0.015).194310045720000Supplemental Figure 2. Cumulative incidence plot for non-fatal myocardial infarction or death from coronary heart disease in the top quartile (baseline troponin concentration ≥5.2 ng/L) and lower three quartiles (baseline troponin concentration <5.2 ng/L) by treatment allocation at 15 years 5995035863602.8%9.0%ARRARR02.8%9.0%ARRARR7077710108760Placebo Placebo 7045511310064Quarter 4 (>5.2 ng/L)Quarter 4 (>5.2 ng/L)7045511173098Quarters 1-3Quarters 1-366303413127926630341135865705929585900Pravastatin0Pravastatin7057697271824Quarter 4 (>5.2 ng/L)0Quarter 4 (>5.2 ng/L)66516252552706651625781057045066145415Quarters 1-3Quarters 1-3Event rate in top quarter (solid line) versus bottom three quarters (dotted line) of baseline troponin distribution on pravastatin (blue) and placebo (red). At 15 years the hazard ratio for pravastatin compared to placebo in the top quarter is 0.55 (P<0.001) and 0.75 in the lower 3 quarters (P=0.019) (P-value for interaction=0.16). ARR=absolute risk reduction.Supplemental Figure 3. Non-fatal myocardial infarction or death from coronary heart disease at 5 years in patients stratified into quarters by change in troponin I concentration and change in LDL concentration at one year on pravastatin2129790788035P=0.002 for trend00P=0.002 for trend5709285788035P=0.823 for trend00P=0.823 for trend In those on pravastatin, the greatest reduction in cardiovascular events was observed in those with the greatest reduction in troponin (P=0.002 for trend). Using the placebo group as a referent, the primary endpoint reduction with pravastatin was 4-fold greater in those with the highest reduction in troponin concentration (HR 0.21 [95%CI, 0.08 to 0.52]) compared to those in whom troponin concentration did not change (HR 0.82 [95%CI, 0.51 to 1.32], P=0.001 for trend) at 5 years, whereas primary endpoint reduction was similar across quarters of change in LDL cholesterol (P=0.823). Hazard ratios were adjusted for baseline troponin, baseline HDL and LDL cholesterol, age, BMI, heart rate, systolic blood pressure, diastolic blood pressure, symptoms of angina, diabetes, hypertension, family history of premature CAD, minor ECG abnormalities, nitrate use and smoking status. ................
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