Hindsight is 20-20

1. February 28, 2003 Patricia K. Monge-Meberg MD Hindsight is 20-20 Stress Testing Asymptomatic Patients

2. The Case: New Patient to AD Williams cc: referred from Rheumatology Clinic for PCP 54 yo w/m h/o seronegative R.A. SHx: lives alone, works in renovations, quit tobacco >20 yrs ago (est. 15 py), rare beer, no hx of cocaine, marijuana, ivda FHx: F - died of �heart problems� in early 50�s M - died of breast cancer Younger sister - MS DM � maternal grandmother And surgically removed hip lipomaAnd surgically removed hip lipoma

3. Initial visit continued: Meds: occas. Aleve for arthritis pain rare aspirin for pain has tried glucosamine in past All: NKDA Exercise: active at work, some sporadic weight lifting, bicycling

4. Initial visit continued: ROS CV: no chest pain, pressure, palpitations, sob, pnd, le edema, claudication GI: heartburn when using regular Aleve or aspirin (improved with d/c drug) Endo: wt stable, no p/p/p, heat/cold intolerance MS: knees, ankles, lower back am stiffness, improves w/in 45 minutes and heat from shower, no c/o joint swelling

5. Initial visit continued: PE: ht 72� wt 220 BMI 28 116/71 hr 69 HEENT: fundi � disks sharp, no nicking or hemorrhage CV: PMI nondisplaced, regular rhythm, nl S1, S2, no m/r/g, no bruits � carotid, aortic, femoral, no LE edema MS: no joint swelling, FROM, nontender exam

6. Initial visit continued: A/P Rheum: referral to clinic, OTC NSAIDs as tolerated with OTC maalox or pepcid HM: encourage regular exercise baby aspirin qd colon cancer screening fasting lipid panel Colon cancer screening � pt preference of hemoccult cardsColon cancer screening � pt preference of hemoccult cards

7. Lab results: Cholesterol 204 (200-239 borderline) HDL 35 (<40 low) TG 185 (150-199 borderline high) LDL 127 (100-129 near optimal) Non-HDL cholesterol 169 Total 240+ high, <200 desirable HDL 60+ high LDL <100 optimal, 130-159 borderline high, 160-189 high, 190+ very highTotal 240+ high, <200 desirable HDL 60+ high LDL <100 optimal, 130-159 borderline high, 160-189 high, 190+ very high

8. ATP III Guidelines: 2. No presence of clinical atherosclerotic dz (clinical CHD, symptomatic carotid artery disease, peripheral artery disease, AAA 3. Other Major Risk Factors: Cigarette smoking, Hypertension Low HDL (<40) FHx of Premature CHD (first degree male relative < 55, female < 65) Age: men >= 45; women >= 55 ATP III Guidelines At-A-Glance Quick Desk Reference Step 1: determine lipoprotein levels after 9-12 hour fast ATP III Guidelines At-A-Glance Quick Desk Reference Step 1: determine lipoprotein levels after 9-12 hour fast

9. ATP III Guidelines: 4. Using the on-line calculator: www.nhlbi.nih.gov/guidelines/cholesterol/index.htm Risk Score: 7% Determine risk category: to establish LDL goal, need for TLC, level to adding Rx 2+ risk factors with a 10yr risk < 20% LDL goal <130 4. If 2+ risk factors (other than LDL) are present without CHD or a CHD risk equivalent, assess 10-year (short term) CHD risk (see Framingham tables)4. If 2+ risk factors (other than LDL) are present without CHD or a CHD risk equivalent, assess 10-year (short term) CHD risk (see Framingham tables)

10. ATP III Guidelines: (6 & 7 Tx of LDL, 8 Metabolic Syndrome) Treat elevated triglycerides once LDL goal met to reach non-HDL goal (which is 30 mg/dL higher than LDL goal) his goal <160 (tx plan: nicotinic acid or fibrate)

11. Next Visit:09/06/02 � MCV ER Presented to ER with Chest pain, SOB EKG with ST depression anterolateral leads, + cardiac enzymes Chol 164, HDL 23, TG 271, LDL 86 Cardiac Cath: one vessel dz to LAD CABG 9/13/02 without complications Discharge Rx: ec-asa 81mg, metoprolol 25 q12h, atorvastatin 10mg

12. Clinical Question: In a patient with low 10 year risk for CHD and no symptoms is cardiac stress testing indicated? And is one modality preferred if any?

13. Search for an answer: Up-To-Date ACC/AHA 2002 Guideline Update for Exercise Testing ( www.acc.org or www.americanheart.org ) �Exercise Thallium Tomography Predicts Future Clinically Manifest Coronary Artery Disease in a High-Risk Asymptomatic Population� Circulation. 1996; 93: 915-923 Blumenthal, Roger S. MD, Becker, Diane M. ScD, MPH Which referenced the 1997 ACC/AHA Guidelines Which had 2 sentences on stress imaging tests that referenced the articleWhich referenced the 1997 ACC/AHA Guidelines Which had 2 sentences on stress imaging tests that referenced the article

14. Reason to look: Lifetime risk from Framingham Heart Study: men age 40 ? 49% women age 40 ? 32% in people free of CHD at age 70 men ? 35% women ? 24% Up-To-Date Screening for coronary heart disease Lifetime risk estimate for CHD is an average value for the general population, but individuals may have higher or lower absolute lifetime risks depending on whether or not they smoke, have high blood pressure, high blood cholesterol, or diabetes, are sedentary or overweight. Lifetime risk estimate for CHD is an average value for the general population, but individuals may have higher or lower absolute lifetime risks depending on whether or not they smoke, have high blood pressure, high blood cholesterol, or diabetes, are sedentary or overweight.

15. Reason to look: First clinical symptom of CHD can be catastrophic Acute MI Unstable Angina Sudden Cardiac Death Initial manifestation in 18% of coronary events And of all sudden cardiac deaths >50% occur in people without a prior history of CHD

16. Reason to Look: It�s nice not to have a heart attack The chance that treatment during �subclinical� stage can decrease clinical and financial burden of chronic CHD Patients ask for it prior to starting an exercise program Anecdotes of sending for stress prior to prescribing Viagra

17. How to Look, What you�ll find: Resting EKG Exercise Stress Test Echocardiography Nuclear Imaging EBCT (electron beam computed tomography) Arterial Ultrasound Uptodate Resting EKG: 1/3-1/2 normal cardiac arteriogram have EKG abnormalities and approximately 30% with CHD proven by cath have a normal EKG Two studies sited with RR when abnl EKG for CHD 2.39 adjusted OR women 2.16, men 2.45Uptodate Resting EKG: 1/3-1/2 normal cardiac arteriogram have EKG abnormalities and approximately 30% with CHD proven by cath have a normal EKG Two studies sited with RR when abnl EKG for CHD 2.39 adjusted OR women 2.16, men 2.45

18. How to Look, What you�ll find: ACC/AHA 2002 Guidelines Level of evidence (LOE) A highest rank, derived from multiple randomized clinical trials that involved large numbers of pts B intermediate rank, derived from limited number of randomized trials that involved small numbers or pts or from careful analyses of nonrandomized studies or observational studies C lower rank, primary basis for recommendation was �expert consensus. ACC/AHA Task Force -The initial committee consisted of acknowledged experts in exercise testing, as well as general cardiologists, (a general internist, a family medicine physician), and cardiologists with expertise in the use of stress imaging modalities. (The committee included representatives of the American Academy of Family Physicians, the American College of Sports Medicine, and the American College of Physicians.) Both the academic and private practice sectors, as well as both adult and pediatric expertise, were represented. This document was reviewed by three (2) outside reviewers nominated by the ACC and three (2) outside reviewers nominated by the AHA, as well as by (ACC/AHA Task Force) outside reviewers nominated by the American Academy of Family Physicians, the American College of Physicians, the American College of Sports Medicine, the American Society of Echocardiography, and the American Society of Nuclear Cardiology. The UpDate did not include those in ()ACC/AHA Task Force -The initial committee consisted of acknowledged experts in exercise testing, as well as general cardiologists, (a general internist, a family medicine physician), and cardiologists with expertise in the use of stress imaging modalities. (The committee included representatives of the American Academy of Family Physicians, the American College of Sports Medicine, and the American College of Physicians.) Both the academic and private practice sectors, as well as both adult and pediatric expertise, were represented. This document was reviewed by three (2) outside reviewers nominated by the ACC and three (2) outside reviewers nominated by the AHA, as well as by (ACC/AHA Task Force) outside reviewers nominated by the American Academy of Family Physicians, the American College of Physicians, the American College of Sports Medicine, the American Society of Echocardiography, and the American Society of Nuclear Cardiology. The UpDate did not include those in ()

19. How to Look, What you�ll find: ACC/AHA 2002 Guidelines Classifications to summarize indications Class I evidence and/or general agreement that a given procedure or tx is useful and effective Class II conflicting evidence and/or divergence of opinion about usefulness/efficacy Ii a wt of evidence/opinion is in favor of usefulness/efficacy II b usefulness/efficacy is less well established by evidence/opinion Class III evidence and/or general agreement that the procedure/tx is not useful/effective and is some cases may be harmful

20. Exercise Testing in Asymptomatic Persons Without Known CAD Class I � none Class II a DM planning to start vigorous exercise (LOE: C) Class II b Mult. Risk factors to guide risk reduction therapy Evaluation of men>45, women>55 Planning to start vigorous exercise (esp. if sedentary) In occupations which may impact public safety at higher risk due to other dz (PVD, CRF) Class III Routine screening Vigorous aka moderate to high intensity , one place read if going to be doing more than walking 4 mph (4 METS); Sex 3.7-5.0 Vigorous aka moderate to high intensity , one place read if going to be doing more than walking 4 mph (4 METS); Sex 3.7-5.0

21. �Exercise Thallium Tomography Predicts Future Clinically Manifest Coronary Artery Disease in a High-Risk Asymptomatic Population� Study design: to determine the extent to which detection of reduced myocardial perfusion by thallium scintigraphy and/or exercise-induced ST-segment changes on maximal graded treadmill testing predicted future CHD events in asymptomatic, apparently healthy siblings of persons with clinically manifest CHD prior to 60 years of age. Study design: based on observation that premature CHD clusters in families citing that siblings of persons with CHD events prior to 60 have excess risk: twice as high in sisters, up to 12 times as high in brothers prior studies have observed high prevalence of known risk factors: htn, dyslipidemia, cigarette smoking In patients with clinically apparent CHD, a positive exercise ECG and/or thallium scintigram is associated with an increased likelihood of subsequent coronary events, but in most asymptomatic populations, noninvasive exercise testing results in a low predictive value due to a low prevalence of CHD.9 10 11 We hypothesized that the predictive value of stress testing and thallium scintigraphy would be increased in an asymptomatic group of individuals with a family history of premature CHD because of the known propensity of this population to develop premature CHD events and because of their high prevalence of predictive risk factors. < READ SLIDE > Study design: based on observation that premature CHD clusters in families citing that siblings of persons with CHD events prior to 60 have excess risk: twice as high in sisters, up to 12 times as high in brothers prior studies have observed high prevalence of known risk factors: htn, dyslipidemia, cigarette smoking In patients with clinically apparent CHD, a positive exercise ECG and/or thallium scintigram is associated with an increased likelihood of subsequent coronary events, but in most asymptomatic populations, noninvasive exercise testing results in a low predictive value due to a low prevalence of CHD.9 10 11 We hypothesized that the predictive value of stress testing and thallium scintigraphy would be increased in an asymptomatic group of individuals with a family history of premature CHD because of the known propensity of this population to develop premature CHD events and because of their high prevalence of predictive risk factors. < READ SLIDE >

22. Methods: Table 1. Coronary Heart Disease Events: Event Criteria 1. Sudden cardiac death Witnessed instantaneous death or unwitnessed death, accompanied by documented stenosis in 1 coronary vessel of 50% at autopsy 2. Acute myocardial infarction Chest pain with new pathological Q waves on ECG, and/or elevation of serum creatine kinase (CK) to 2 times upper limit of normal, and increase of the MB isoenzyme to 5% of total CK 3. Revascularization Coronary bypass surgery or percutaneous transluminal angioplasty for anginal symptoms or objective noninvasive evidence of increasing ischemia Table 1 describes criteria for index patient Exclusion Criteria for Index patients: coronary disease associated with calcific aortic stenosis, collagen vascular disease, cardiac transplantation, or chronic glucocorticosteroid therapy. Index patients were recruited during specified weeks, during which all eligible patients on the medical and surgical units of the Johns Hopkins Hospital were identified. Recruitment was distributed throughout the week, Monday through Friday, and by season. Table 1 describes criteria for index patient Exclusion Criteria for Index patients: coronary disease associated with calcific aortic stenosis, collagen vascular disease, cardiac transplantation, or chronic glucocorticosteroid therapy. Index patients were recruited during specified weeks, during which all eligible patients on the medical and surgical units of the Johns Hopkins Hospital were identified. Recruitment was distributed throughout the week, Monday through Friday, and by season.

23. Methods: Table 2. Eligible Sibling Characteristics No. of Participants 264 Sex (male) 181 (69%) Race (white) 257 (97%) Age, y 45.6�7.6 (37-59) Education, y 12.9�3 (5-23) Risk factor profile LDL cholesterol, mg/dL 148.3 (42-472) HDL cholesterol, mg/dL 51.2 (18-101) Hypertension 80 (30%) Current smoking 111 (42%) During hospitalization, index patients were asked for access to all siblings who did not have known coronary artery disease. Within a week of index patient discharge, eligible siblings were sent a description of the study and a refusal postcard to return if they preferred not to be contacted. Siblings were called within 2 weeks and asked to participate in screening that included a detailed cardiovascular history and physical examination, risk factor assessment, and a maximal graded treadmill test with thallium scintigraphy. A standardized health history questionnaire was administered via telephone to determine eligibility, and the absence of preexisting coronary disease was verified and validated with their primary physician. The health history was repeated by an attending cardiologist on the day of the screening and an anginal assessment and resting ECG were administered to again verify the absence of symptoms or a prior coronary disease event. After the screening, results were sent to the patient and his/her physician. Siblings were eligible if they were less than 60 years of age and had no known history of coronary artery disease. Siblings were excluded if they had functional status limitations that precluded exercise testing, if they were receiving chronic or recent glucocorticosteroid therapy, had a collagen vascular disease, or had any comorbidity for which life expectancy was judged to be 5 years or less (for example, cancer). Siblings less than 30 years of age were included only if the index patient had experienced an event prior to 35 years of age. From 1983 until 1987, both male and female siblings were recruited, while from 1987 until the end of recruitment in 1991, only male siblings were included. Hypertensive on screening (blood pressure >140/90 mm Hg). During hospitalization, index patients were asked for access to all siblings who did not have known coronary artery disease. Within a week of index patient discharge, eligible siblings were sent a description of the study and a refusal postcard to return if they preferred not to be contacted. Siblings were called within 2 weeks and asked to participate in screening that included a detailed cardiovascular history and physical examination, risk factor assessment, and a maximal graded treadmill test with thallium scintigraphy. A standardized health history questionnaire was administered via telephone to determine eligibility, and the absence of preexisting coronary disease was verified and validated with their primary physician. The health history was repeated by an attending cardiologist on the day of the screening and an anginal assessment and resting ECG were administered to again verify the absence of symptoms or a prior coronary disease event. After the screening, results were sent to the patient and his/her physician. Siblings were eligible if they were less than 60 years of age and had no known history of coronary artery disease. Siblings were excluded if they had functional status limitations that precluded exercise testing, if they were receiving chronic or recent glucocorticosteroid therapy, had a collagen vascular disease, or had any comorbidity for which life expectancy was judged to be 5 years or less (for example, cancer). Siblings less than 30 years of age were included only if the index patient had experienced an event prior to 35 years of age. From 1983 until 1987, both male and female siblings were recruited, while from 1987 until the end of recruitment in 1991, only male siblings were included. Hypertensive on screening (blood pressure >140/90 mm Hg).

24. Methods: Maximal Graded Exercise Testing Two board-certified cardiologists, who were blinded to the risk factor status of the individual, reached a consensus as to whether the exercise test was positive or negative for ischemia. Stress Thallium Scintigraphy Image interpretation was performed visually by an experienced nuclear cardiologist (L.C.B.) without knowledge of the subject's identity or exercise test results. Results were coded as positive or negative for reversible ischemia. Borderline reversible defects and mild to moderate fixed defects were recorded as negative. A severe fixed defect was also considered abnormal but did not occur in any of the subjects. In 16 siblings, only planar imaging was performed because of unavailability of the tomographic camera on the day of screening. 5 siblings (all women) declined thallium study & underwent only stress ECG . In men, a positive stress test was defined as horizontal or downsloping ST-segment depression of 1 mm over baseline at 0.06 seconds after the J-point in three or more consecutive beats at any time during the exercise test or during the first 3 minutes of recovery after exercise. To reduce the probability of a high rate of false-positive tests in women, an abnormal response was prospectively defined as 2.0-mm flat or downsloping ST-segment depression over baseline in leads II, III, or AVF or 1.5-mm ST depression in other leads. Two board-certified cardiologists, who were blinded to the risk factor status of the individual, reached a consensus as to whether the exercise test was positive or negative for ischemia. . In men, a positive stress test was defined as horizontal or downsloping ST-segment depression of 1 mm over baseline at 0.06 seconds after the J-point in three or more consecutive beats at any time during the exercise test or during the first 3 minutes of recovery after exercise. To reduce the probability of a high rate of false-positive tests in women, an abnormal response was prospectively defined as 2.0-mm flat or downsloping ST-segment depression over baseline in leads II, III, or AVF or 1.5-mm ST depression in other leads. Two board-certified cardiologists, who were blinded to the risk factor status of the individual, reached a consensus as to whether the exercise test was positive or negative for ischemia.

25. Results:Evaluation of CHD Events: Follow-up Questionnaire A health status and CHD events history questionnaire was administered by telephone in all siblings who were screened. any new CHD or related diagnosis Info on new diagnostic tests including repeat treadmill testing, thallium scintigraphy, or coronary arteriography or interventions including coronary angioplasty, atherectomy, or bypass surgery All outcomes were assessed in siblings 1 to 9 years after baseline screening. Info. was verified by obtaining physician office records, hospital records, death records, and original data on all diagnostic tests performed. All records were reviewed by two cardiologists to verify the presence or absence of a CHD event. Evaluation of CHD Events: Follow-up QuestionnaireA health status and CHD events history questionnaire was administered by telephone in all siblings who were screened. Information on any new CHD or related diagnosis was elicited by a trained interviewer using standardized questions. Information was requested on new diagnostic tests including repeat treadmill testing, thallium scintigraphy, or coronary arteriography. Questions elicited information about CHD interventions including coronary angioplasty, atherectomy, or bypass surgery. All outcomes were assessed in siblings 1 to 9 years after baseline screening. The information was verified by obtaining physician office records, hospital records, death records, and original data on all diagnostic tests performed. All records were reviewed by two cardiologists to verify the presence or absence of a CHD event. CHD events were prospectively defined according to the criteria in Table Evaluation of CHD Events: Follow-up QuestionnaireA health status and CHD events history questionnaire was administered by telephone in all siblings who were screened. Information on any new CHD or related diagnosis was elicited by a trained interviewer using standardized questions. Information was requested on new diagnostic tests including repeat treadmill testing, thallium scintigraphy, or coronary arteriography. Questions elicited information about CHD interventions including coronary angioplasty, atherectomy, or bypass surgery. All outcomes were assessed in siblings 1 to 9 years after baseline screening. The information was verified by obtaining physician office records, hospital records, death records, and original data on all diagnostic tests performed. All records were reviewed by two cardiologists to verify the presence or absence of a CHD event. CHD events were prospectively defined according to the criteria in Table

26. Results: Results of Exercise Testing and Thallium Scintigraphy Maximal symptom-limited treadmill exercise tests were performed in all siblings. Mean maximal heart rate was 173�16 beats per minute; 96% of siblings achieved >85% of the maximal predicted age-adjusted heart rate. The mean MET level attained was 11.6. No individual experienced typical anginal chest pain during the test. Ischemic-type ST-segment abnormalities were observed during and/or after exercise in 22 of the 181 male siblings (12.2%) and 4 of the 83 female siblings (4.8%). Marked ST-segment depression ( 3 mm) occurred in only 1 sibling; abnormalities first appeared at a heart rate of <120 beats per minute in only 2 male siblings; 1 male sibling had exercise-induced hypotension. An abnormal exercise thallium perfusion scan, characterized by one or more reversible exercise-induced perfusion defects, was observed in 52 of 181 male siblings (28.7%) and 7 of 78 female siblings (9.0%). Abnormal thallium scans were about twice as frequent as abnormal exercise ECGs. Most perfusion defects were single; multiple defects were observed in only 5 of the 52 men with abnormal scans and none of the 7 women. Forty-nine of the 64 total defects were graded as mild, 14 (22%) as moderate, and only 1 (2%) as severe. The exercise ECG and thallium results for male and female siblings are shown in Fig 1 . The exercise ECG and thallium scan were both abnormal in 12 men but no women. All 12 of these "double-positives" occurred in men who were more than 45 years of age at the time of screening. Abnormal exercise ECGs and/or thallium scans were much more common in male than female siblings and were more common in siblings 45 years of age among both sexes. In only 55% of men 45 years of age were the exercise test and thallium scan both normal. In comparison, 76% of men <45 years of age, 80% of women 45 years of age, and 96% of women <45 years of age had both tests normal. The addition of thallium imaging to the exercise tests resulted in substantially more individuals being identified as abnormal; 23% of men 45 years of age, 22% of men <45, 12% of women 45, and 4% of women <45 were identified as abnormal based on the thallium results. Results of Exercise Testing and Thallium Scintigraphy Maximal symptom-limited treadmill exercise tests were performed in all siblings. Mean maximal heart rate was 173�16 beats per minute; 96% of siblings achieved >85% of the maximal predicted age-adjusted heart rate. The mean MET level attained was 11.6. No individual experienced typical anginal chest pain during the test. Ischemic-type ST-segment abnormalities were observed during and/or after exercise in 22 of the 181 male siblings (12.2%) and 4 of the 83 female siblings (4.8%). Marked ST-segment depression ( 3 mm) occurred in only 1 sibling; abnormalities first appeared at a heart rate of <120 beats per minute in only 2 male siblings; 1 male sibling had exercise-induced hypotension. An abnormal exercise thallium perfusion scan, characterized by one or more reversible exercise-induced perfusion defects, was observed in 52 of 181 male siblings (28.7%) and 7 of 78 female siblings (9.0%). Abnormal thallium scans were about twice as frequent as abnormal exercise ECGs. Most perfusion defects were single; multiple defects were observed in only 5 of the 52 men with abnormal scans and none of the 7 women. Forty-nine of the 64 total defects were graded as mild, 14 (22%) as moderate, and only 1 (2%) as severe. The exercise ECG and thallium results for male and female siblings are shown in Fig 1 . The exercise ECG and thallium scan were both abnormal in 12 men but no women. All 12 of these "double-positives" occurred in men who were more than 45 years of age at the time of screening. Abnormal exercise ECGs and/or thallium scans were much more common in male than female siblings and were more common in siblings 45 years of age among both sexes. In only 55% of men 45 years of age were the exercise test and thallium scan both normal. In comparison, 76% of men <45 years of age, 80% of women 45 years of age, and 96% of women <45 years of age had both tests normal. The addition of thallium imaging to the exercise tests resulted in substantially more individuals being identified as abnormal; 23% of men 45 years of age, 22% of men <45, 12% of women 45, and 4% of women <45 were identified as abnormal based on the thallium results.

27. Results:Table 4. Association of Demographic Variables and Exercise Test Results With Coronary Disease Events Value Coronary Disease Event W/O Event p (n=19) N (%) (n=245) N (%) Age 45 y at screening 16 (84) 127 (52) .006 Male sex 17 (89) 164 (67) .042 Exercise test abnormal 7 (37) 19 (8) .0001 Thallium scan abnormal 12 (63) 47 (20) .0001 2x2 contingency tables analyzed by chi-squared statistic. Thallium scan was not obtained in 5 subjects. (all women) Coronary Heart Disease Events During an average follow-up period of 6.2 years (range, 1 to 9 years), 19 siblings who were asymptomatic and apparently healthy at the time of screening developed clinically manifest CHD (Table 3 ). One 47-year-old man experienced sudden death 10 months after screening. Although there was no history of angina or myocardial infarction, autopsy showed severe multivessel coronary artery disease and extensive posterior wall scarring. Table 3 (too difficult to add in) Incident Coronary Disease Events and Exercise Test Results Ten siblings had an acute myocardial infarction an average of 33.4 months after screening. All presented with chest pain and ST-segment elevation and 6 received thrombolytic therapy. One had ventricular fibrillation and was resuscitated. Seven siblings developed angina pectoris without infarction and underwent a coronary revascularization procedure (5 angioplasty, 2 bypass surgery). One additional sibling with worsening exercise test findings but no chest pain also underwent coronary bypass surgery. All of the siblings undergoing revascularization had severe coronary narrowings at catheterization, and 6 of the 8 had significant multivessel disease. In addition to these initial events, 2 siblings with a first infarct experienced a second one, both requiring bypass surgery; 2 siblings with an infarct subsequently underwent coronary angioplasty, 1 of these also resulted in emergency bypass surgery. Fifteen of 19 siblings developing clinical CHD were men 45 years old at the time of screening. Mean age at screening was 50 in siblings with CHD events compared with 45 in those without events (P<.05). The overall incidence of CHD events was 7.2%; among men 45 at screening, the incidence of events was 16.9%. Having an event was significantly associated with being 45 years old at screening, being male, having an abnormal exercise ECG, and having an abnormal thallium scan (Table 4 ). 2x2 contingency tables analyzed by chi-squared statistic. Thallium scan was not obtained in 5 subjects. (all women) Coronary Heart Disease Events During an average follow-up period of 6.2 years (range, 1 to 9 years), 19 siblings who were asymptomatic and apparently healthy at the time of screening developed clinically manifest CHD (Table 3 ). One 47-year-old man experienced sudden death 10 months after screening. Although there was no history of angina or myocardial infarction, autopsy showed severe multivessel coronary artery disease and extensive posterior wall scarring.

28. Results:Table 5. Prediction of First Coronary Events by Exercise ECG and Thallium Scan Group ECG Thal Mean N Crude 5-y Unadjustd Adjusted f/u m. Incidence Cum RR RR Inc A - - 75.9 186 3% 2.5�1.2% 1.0 1.0 B - + 65.2 47 13% 12�5.1% 4.5 3.6 (1.4-13.8) (1.1-11.4) C + - 72.2 14 7% 8 �7.4% 2.4 1.5 (0.3-19.9) (0.2-12.5) D + + 36.0 12 50% 64�16.3% 33.3 14.5 (10.6-105) (4.2-50.2) RR indicates relative risk. 1 Kaplan-Meier survival curves (�2 SE). 2 Cox proportional hazards analysis (95% confidence intervals). 3 Adjusted for age 45 years vs <45 (RR=3.62 [0.97-13.5], P=.06) and sex (RR=3.29 [0.70-15.5], P=.13). 4 P<.05, 5 P<.01, 6 P<.0001. Prediction of Individuals Developing Clinical Coronary Heart Disease Events Crude incidence rates for first coronary events in siblings with different exercise ECG and thallium results are shown in Table 5 . Clinical CHD developed in 3% of siblings who were normal by both tests compared with 7% of those who were abnormal only by ECG, 13% of those abnormal only by thallium, and 50% of those abnormal by both tests. An abnormal exercise ECG had a predictive value of 27% for the development of future clinical CHD; of those developing CHD, 37% were abnormal by exercise ECG at the time of screening ("sensitivity" of the test). For an abnormal thallium scan, the predictive value for clinical CHD was slightly lower (20%), but the sensitivity was nearly doubled (63%). A combined abnormal ECG and thallium scan had a predictive value of 50% and a sensitivity of 32%. RR indicates relative risk. 1 Kaplan-Meier survival curves (�2 SE). 2 Cox proportional hazards analysis (95% confidence intervals). 3 Adjusted for age 45 years vs <45 (RR=3.62 [0.97-13.5], P=.06) and sex (RR=3.29 [0.70-15.5], P=.13). 4 P<.05, 5 P<.01, 6 P<.0001. Prediction of Individuals Developing Clinical Coronary Heart Disease Events Crude incidence rates for first coronary events in siblings with different exercise ECG and thallium results are shown in Table 5 . Clinical CHD developed in 3% of siblings who were normal by both tests compared with 7% of those who were abnormal only by ECG, 13% of those abnormal only by thallium, and 50% of those abnormal by both tests. An abnormal exercise ECG had a predictive value of 27% for the development of future clinical CHD; of those developing CHD, 37% were abnormal by exercise ECG at the time of screening ("sensitivity" of the test). For an abnormal thallium scan, the predictive value for clinical CHD was slightly lower (20%), but the sensitivity was nearly doubled (63%). A combined abnormal ECG and thallium scan had a predictive value of 50% and a sensitivity of 32%.

29. Results: Figure 2. Kaplan-Meier survival curves for each combination of exercise test results (normal ECG and thallium scan, only ECG abnormal, only thallium scan abnormal, or both ECG and thallium scan abnormal). Curves are drawn until the end of follow-up for each group. Survival analysis was conducted to predict the risk of developing clinical CHD for different combinations of exercise test results after accounting for possible differences in censoring and follow-up time among groups (Fig 2 ). Examination of 5-year cumulative incidences shows a 2.5% incidence in siblings with both tests normal, compared with 8% in those abnormal only by ECG, 12% in those abnormal only by thallium, and 64% in those abnormal by both tests.  The relative risk (RR) of having a first CHD event was significantly increased in siblings who were abnormal by thallium only (RR=4.45, P<.01) and most notably in siblings abnormal by both tests (RR=33.3, P=.0001) compared with siblings with both tests normal. After adjusting for age and sex using a Cox proportional hazards model, relative risk was still significantly increased in siblings with abnormal thallium only (3.6, P<.03) and in siblings with both thallium and ECG abnormal (14.5, P<.0001). The results were similar when first CHD events were restricted to death and myocardial infarction: such events occurred in 2% of siblings normal by both tests, 9% of those abnormal only by ECG, 7% of those abnormal only by thallium, and 17% of those abnormal by both tests. The relative risk of having a myocardial infarction or death was increased in siblings abnormal by ECG (RR=6.8, P=.03), thallium (RR=3.8, P=.10), or both (RR=61.3, P=.01). The statistical significance of these relationships was reduced due to the limited number of these types of events. Comparing all siblings with abnormal exercise ECGs with those with normal exercise ECGs (in Table 5 ), the relative risk of having an abnormal exercise ECG, adjusted for age and sex, was 3.9 (95% CI, 1.4 to 10.3, P<.007). Comparing all siblings with abnormal exercise thallium scans to those with normal scans (in Table 5 ), the relative risk of having an abnormal thallium scan, adjusted for age and sex, was 5.3 (95% CI, 2.0 to 13.9, P=.0006). Among siblings with normal exercise ECGs, those with abnormal thallium scans had a relative risk of 4.5 (95% CI, 1.5 to 14.1, P=.009) compared with those with normal scans. Similarly, among siblings with abnormal exercise ECGs, an abnormal thallium scan resulted in a relative risk of 11.1 (95% CI, 1.3 to 93, P=.03). Finally, comparing siblings with abnormal thallium scans with those with normal ones, relative risk was 4.7 (95% CI, 1.8 to 12.5, P=.002) after adjusting for age, sex, and exercise ECG results. Compared with siblings with a normal thallium scan, those with an abnormal scan had a lower mean high-density lipoprotein (HDL) cholesterol (45.4 versus 52.6 mg/dL, P=.001) and more frequent hypertension (58% versus 38%, P=.008). There were no significant differences in LDL cholesterol or in the prevalence of current smoking. An abnormal exercise ECG was significantly associated only with a lower HDL cholesterol (44.9 versus 51.7 mg/dL, P=.003). Nevertheless, none of these coronary risk factors were significantly associated with the development of clinical CHD in the Cox proportional hazards model. Controlling explicitly for HDL cholesterol and hypertension had no influence on the results presented in Table 5 . Before adjustment for stress test results, both older age (age 45, RR=5.6, P=.003) and male sex (RR=6.2, P=.02) predicted the risk of developing clinically manifest CHD. After adjustment for ECG and thallium results, age was still associated with CHD events (P=.05), while the association of sex with CHD events was still present but was no longer statistically significant (P=.13). Although the primary analysis used age dichotomized at 45 (the median value) to simplify interpretation of the results, the results were virtually identical in all respects when age was used as a continuous variable except that after adjustment for ECG and thallium results, age was no longer statistically significant (P=.13). Because the overall results were strongly influenced by the high prevalence of CHD events in men (17 of 19), the analyses were all repeated for men alone. The results were the same in men with lower levels of statistical significance, principally because of smaller sample size. Within male siblings, the relative risk was increased in the three groups with any abnormal test results, but only double-positives were statistically significant. Age-adjusted relative risk was 1.4 in male siblings abnormal by ECG only (95% CI, 0.2 to 12.5), 3.1 in those abnormal by thallium only (95% CI, 0.9 to 10.9), and 12.4 in those abnormal by both ECG and thallium (95% CI, 3.6 to 42.8, P=.0001). Male siblings with an abnormal thallium scan had a relative risk of 4.3 (95% CI, 1.5 to 11.9, P=.006) after adjusting for age and exercise ECG results. Outcomes were too few in women to allow the genesis of a stable multivariate analysis. Additional analyses were performed to examine the possible confounding effect of certain additional variables on the results. The MET level achieved during exercise was significantly lower for those with an abnormal ECG (11.1 versus 12.8, P=.003). However, MET level was not associated with the occurrence of CHD events, and explicit adjustment of the Cox proportional hazards model for MET level did not change the results. Since 16 subjects had planar rather than tomographic thallium studies, all analyses were repeated with these individuals excluded. The results were virtually identical to the primary analysis of all subjects. Finally, the statistical analysis treats each sibling as an independent observation despite multiple siblings coming from some families. To control for the familial clustering of CHD, the analysis was repeated using only the oldest sibling in each family. The main results remained unchanged: the crude incidence of clinical CHD was 4% among the 110 siblings with both normal ECG and thallium scan, 13% among the 30 siblings with normal ECG/abnormal thallium scan, 0% among the 9 siblings with abnormal ECG/normal thallium scan, and 45% among the 11 siblings with both tests abnormal. Relative Risk (or Risk Ratio (RR)): The relative measure of the difference in risk between the exposed and unexposed populations in a cohort study. The relative risk is defined as the rate of disease among the exposed divided by the rate of the disease among the unexposed. A relative risk of 2 means that the exposed group has twice the disease risk as the unexposed group. Relative Risk (RR) This is defined as: (The probability of an event in the active group) divided by ( the probability of the event in the control group). For the high risk group this is 0.014/0.02 and for the low risk it is 0.007/ 0.01, i.e 0.7 for both. A benefical treatment will give an RR less than one, so it looks like beta-blockers offer benefit to both groups. In other words, in both groups those who are beta-blocked have only 70% of the risk of a cardiac event of those who are not beta-blocked. As a rough rule of thumb, a RR of over 50% is regarded as definitely clinically significant and one between 25 and 50% probably clinically significant. Figure 2. Kaplan-Meier survival curves for each combination of exercise test results (normal ECG and thallium scan, only ECG abnormal, only thallium scan abnormal, or both ECG and thallium scan abnormal). Curves are drawn until the end of follow-up for each group. Survival analysis was conducted to predict the risk of developing clinical CHD for different combinations of exercise test results after accounting for possible differences in censoring and follow-up time among groups (Fig 2 ). Examination of 5-year cumulative incidences shows a 2.5% incidence in siblings with both tests normal, compared with 8% in those abnormal only by ECG, 12% in those abnormal only by thallium, and 64% in those abnormal by both tests.

30. Discussion: 7.2% of the 264 siblings developed clinical CHD over a mean of 6.2 years of follow-up Both abnormal exercise ECGs and thallium scans were predictive of CHD events thallium was more predictive; after adjusting for age, sex, and exercise ECG results, the relative risk of having a CHD event in those with an abnormal thallium scan was 4.7, and the relative risk associated with a "double-positive" stress ECG and thallium scan was 14.5. It should be noted that 6 of the 19 siblings who developed a CHD event had a normal stress thallium test, which may indicate hemodynamically insignificant coronary artery stenoses at the time of screening. Despite being apparently healthy, asymptomatic, and relatively young at the time of screening, 7.2% of the 264 siblings developed clinical CHD over a mean of 6.2 years of follow-up. Although abnormal exercise ECGs and thallium scans were both predictive of CHD events, thallium was more predictive; after adjusting for age, sex, and exercise ECG results, the relative risk of having a CHD event in those with an abnormal thallium scan was 4.7, and the relative risk associated with a "double-positive" stress ECG and thallium scan was 14.5. Despite being apparently healthy, asymptomatic, and relatively young at the time of screening, 7.2% of the 264 siblings developed clinical CHD over a mean of 6.2 years of follow-up. Although abnormal exercise ECGs and thallium scans were both predictive of CHD events, thallium was more predictive; after adjusting for age, sex, and exercise ECG results, the relative risk of having a CHD event in those with an abnormal thallium scan was 4.7, and the relative risk associated with a "double-positive" stress ECG and thallium scan was 14.5.

31. Others� �Two Cents� American Academy of Family Physicians ETT for those people who have jobs linked to public safety or require high CV performance American College of Sports Medicine ETT for men > 40, women > 50, others w/ mult. risk factors prior to a vigorous exercise program American College of Physicians No routine screening ETT in asymptomatic adults United States Preventive Services Task Force Insufficient evidence to vote for or against ETT Pilots, air traffic controllers; police officers, firefighters Pilots, air traffic controllers; police officers, firefighters

32. Cost: Medicare RVUs (relative value units) provide an estimate of cost Comparisons: Stress echo 2.1 times higher than ETT SPECT myocardial imaging 5.7 times higher Alludes? To lower cost of ETT does not necessarily result in overall lower cost to the pt considering possible sum of additional testing and intervention ACC/AHA Practice GuidelinesACC/AHA Practice Guidelines

33. Cost:Medicare reimbursement/Typical Office Charge From American Family Physician Jan 15, 1999 Standard exercise stress test (treadmill or bicycle) $99 / $175-250 Exercise stress scintigraphy (eg thallium) $298 / $350-450 Pharmacologic stress scintigraphy $298 / $350-450 Echocardiography with some type of stress $239 / $350-600

34. Hindsight: Baseline EKG Argument for 3 factors including high non-HDL cholesterol Check homocysteine Discuss with patient his sister�s risks J Am Coll Cardiol 19:472-481, 1992. PATIENTS WITHOUT KNOWN OR SUSPECTED HEART DISEASE For patients without evidence suggesting cardiovascular disease, ECGs were considered appropriate during the baseline evaluation in the ACC/AHA guidelines for those aged 40 years or older. The ACC/AHA guidelines also recommended ECGs for patients for whom drugs with a high incidence of cardiovascular effects (e.g., chemotherapy) or exercise testing was planned and for people of any age in occupations with high cardiovascular demands or whose cardiovascular status might affect the well-being of many other people (e.g., airline pilot). These guidelines are similar to those of the U.S. Preventive Services Task Force, [2] which suggested ECG screening for those with occupations in which the cardiovascular health might jeopardize the lives of others. Guidelines vary on the performance of baseline ECGs. An American Heart Association panel recommended in 1987 that ECGs be obtained at ages 20, 40, and 60 years in persons with normal blood pressure,[3] while a task force assembled by the Canadian government has discouraged the use of any screening ECGs.[4] Before cardiac or noncardiac surgery, the ACC/AHA guidelines recommend ECGs for all people aged 40 years or older,[1] and ECGs are considered equivocal in appropriateness (Class II) for surgical patients aged 30 to 40 years. Guidelines issued by the American College of Physicians [5] recommend ECGs preoperatively and upon hospital admission for men aged 40 years or older and women aged 50 years or older, as well as all patients having elective intrathoracic, intraperitoneal, or aortic surgery; elective major neurosurgery; or emergency operations under general or regional anesthesia. J Am Coll Cardiol 19:472-481, 1992. PATIENTS WITHOUT KNOWN OR SUSPECTED HEART DISEASE For patients without evidence suggesting cardiovascular disease, ECGs were considered appropriate during the baseline evaluation in the ACC/AHA guidelines for those aged 40 years or older. The ACC/AHA guidelines also recommended ECGs for patients for whom drugs with a high incidence of cardiovascular effects (e.g., chemotherapy) or exercise testing was planned and for people of any age in occupations with high cardiovascular demands or whose cardiovascular status might affect the well-being of many other people (e.g., airline pilot). These guidelines are similar to those of the U.S. Preventive Services Task Force, [2] which suggested ECG screening for those with occupations in which the cardiovascular health might jeopardize the lives of others. Guidelines vary on the performance of baseline ECGs. An American Heart Association panel recommended in 1987 that ECGs be obtained at ages 20, 40, and 60 years in persons with normal blood pressure,[3] while a task force assembled by the Canadian government has discouraged the use of any screening ECGs.[4] Before cardiac or noncardiac surgery, the ACC/AHA guidelines recommend ECGs for all people aged 40 years or older,[1] and ECGs are considered equivocal in appropriateness (Class II) for surgical patients aged 30 to 40 years. Guidelines issued by the American College of Physicians [5] recommend ECGs preoperatively and upon hospital admission for men aged 40 years or older and women aged 50 years or older, as well as all patients having elective intrathoracic, intraperitoneal, or aortic surgery; elective major neurosurgery; or emergency operations under general or regional anesthesia.

35. Looking Forward: New screening tests: Ultrasound measurement of endothelial dysfunction (flow-mediated vasodilation) Use of Electron-Beam Computer Tomography and calcium scores Measurement of C-Reactive Protein

36. Other sources: �Guidelines for the Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery,� Journal of the American College of Cardiology. Vol 39 (2): 257-65. Mary C. Corretti MD et al �The Use of Electron-Beam Computed Tomography as a Tool for Primary Prevention,� American Journal of Cardiology; 88 (suppl):28J-32J. Paolo Raggi MD �Combined Use of Computed Tomography Coronary Calcium Scores and C-Reactive Protein Levels in Predicting Cardiovascular Events in Nondiabetic Individuals,� Circulation. 2002; 106:2073-2077. Robert Park MD et al.

37. Exercise clearance Mets on bottom familydoctor.org MET Activities Sitting in a chair1.0 Sweeping the floor1.5 Driving a car2.0 Ironing3.5 Showering3.5 Bowling3.5 Sex 3.7-5.0 Golfing4.0 Gardening4.5 Playing tennis6.0 Mowing lawn by hand6.5 Shoveling7.0 Skiing8.0 Light Activity (50 to 200 calories per hour) Lying or Sleeping (80 kcals/hour or 1.0 METS) Desk Work (110 kcals/hour or 1.5 METS) Driving (120 kcals/hour or 1.6 METS) Fishing (130 kcals/hour or 1.8 METS) Sitting (100 kcals/hour or 1.4 METS) Standing (140 kcals/hour or 2 METS) Housework (180 kcals/hour or 2.5 METS) Moderate Activity (200 to 350 calories per hour) Bicycling Pace: 5.5 mph (220 kcals/hour or 3 METS) Pace: 11 mph (440 kcals/hour or 6 METS) Pace: 16.5 mph (660 kcals/hour or 9 METS) Boating Canoeing at 2.5 mph: 230 kcals/hour or 3 METS Row boat at 2.5 mph: 300 kcals/hour or 4 METS Bowling (270 kcals/hour or 4 METS) Golf Golf cart: 150 kcals/hour (2 METS) Walking: 300 kcalks/hour (4 METS) Swimming at 0.25 mph (300 kcals/hour or 4 METS) Walking (approximately 100 calories per mile) Pace: 2 mph (150 kcals/hour or 2 METS) Pace: 4 mph (330 kcals/hour or 4 METS) Yard Work Gardening: 220 kcals/hour or 3 METS Power Lawn Mower: 250 kcals/hour or 3 METS Strenuous Activity (over 350 kcals/hour) Dance Slow Step: 300 kcals/hour or 4 METS Square Dancing: 350 kcals/hour or 5 METS Fast Step (Aerobic): 490 kcals/hour or 6 METS Racquet Sports Badminton (350 kcals/hour or 5 METS) Racquetball Singles (775 kcals/hour or 10 METS) Squash or Handball (600 kcals/hour or 8 METS) Tennis Singles (420 kcals/hour or 5 METS) Running (approximately 100 calories per mile) Jogging: 5 mph (640 kcals/hour or 8.7 METS) Moderate: 6 mph (750 kcals/hour or 10.2 METS) Fast: 10 mph (1200 kcals/hour or 16.3 METS) Shoveling (400 kcals/hour or 5 METS) Skating at 10 MPH (400 kcals/hour or 5 METS) Skiing Cross Country Skiing (900 kcals/hour or 12 METS) Downhill skiing (600 kcals/hour or 8 METS) Waterskiing (460 kcals/hour or 6 METS) http://www.fpnotebook.com/SPO34.htmfamilydoctor.org MET Activities Sitting in a chair1.0 Sweeping the floor1.5 Driving a car2.0 Ironing3.5 Showering3.5 Bowling3.5 Sex 3.7-5.0 Golfing4.0 Gardening4.5 Playing tennis6.0 Mowing lawn by hand6.5 Shoveling7.0 Skiing8.0 Light Activity (50 to 200 calories per hour) Lying or Sleeping (80 kcals/hour or 1.0 METS) Desk Work (110 kcals/hour or 1.5 METS) Driving (120 kcals/hour or 1.6 METS) Fishing (130 kcals/hour or 1.8 METS) Sitting (100 kcals/hour or 1.4 METS) Standing (140 kcals/hour or 2 METS) Housework (180 kcals/hour or 2.5 METS) Moderate Activity (200 to 350 calories per hour) Bicycling Pace: 5.5 mph (220 kcals/hour or 3 METS) Pace: 11 mph (440 kcals/hour or 6 METS) Pace: 16.5 mph (660 kcals/hour or 9 METS) Boating Canoeing at 2.5 mph: 230 kcals/hour or 3 METS Row boat at 2.5 mph: 300 kcals/hour or 4 METS Bowling (270 kcals/hour or 4 METS) Golf Golf cart: 150 kcals/hour (2 METS) Walking: 300 kcalks/hour (4 METS) Swimming at 0.25 mph (300 kcals/hour or 4 METS) Walking (approximately 100 calories per mile) Pace: 2 mph (150 kcals/hour or 2 METS) Pace: 4 mph (330 kcals/hour or 4 METS) Yard Work Gardening: 220 kcals/hour or 3 METS Power Lawn Mower: 250 kcals/hour or 3 METS Strenuous Activity (over 350 kcals/hour) Dance Slow Step: 300 kcals/hour or 4 METS Square Dancing: 350 kcals/hour or 5 METS Fast Step (Aerobic): 490 kcals/hour or 6 METS Racquet Sports Badminton (350 kcals/hour or 5 METS) Racquetball Singles (775 kcals/hour or 10 METS) Squash or Handball (600 kcals/hour or 8 METS) Tennis Singles (420 kcals/hour or 5 METS) Running (approximately 100 calories per mile) Jogging: 5 mph (640 kcals/hour or 8.7 METS) Moderate: 6 mph (750 kcals/hour or 10.2 METS) Fast: 10 mph (1200 kcals/hour or 16.3 METS) Shoveling (400 kcals/hour or 5 METS) Skating at 10 MPH (400 kcals/hour or 5 METS) Skiing Cross Country Skiing (900 kcals/hour or 12 METS) Downhill skiing (600 kcals/hour or 8 METS) Waterskiing (460 kcals/hour or 6 METS) http://www.fpnotebook.com/SPO34.htm