Risk in the wake of ATP III

1. Risk in the wake of ATP III Valentin Fuster MD (Chair) Director, Cardiovascular Institute Mount Sinai Medical Center New York, NY Christopher Cannon MD Cardiologist Brigham and Women’s Hospital Boston, MA Michael Weber MD Professor of Medicine SUNY Downstate College of Medicine Brooklyn, NY James Cleeman MD Coordinator National Cholesterol Education Program NHLBI Bethesda, MD Richard Pasternak MD Director of Preventive Cardiology Massachusetts General Hospital Boston, MA

2. Risk in the wake of ATP III Prevention at different levels of risk

3. Risk in the wake of ATP III Acute Coronary Syndrome

4. Risk in the wake of ATP III Educating the public • "Once they get to the hospital, we have lots of things to do and making sure people get there is the key thing." • National Heart Attack Alert Program is aimed at increasing public awareness • More and more AEDs are available in public places • C Cannon ACS

5. Risk in the wake of ATP III Educating the public • "Thinking through and improving the whole chain of events that occurs from the onset of a symptom to dealing with a symptom […] is a major effort of the acute disease programs within the American Heart Association." • Also need to think of prevention of sudden cardiac death separately from ACS, and be aware of the different electrophysiologic underpinnings involved. • R Pasternak ACS

6. Risk in the wake of ATP III MIRACL 14.8% of patients on atorvastatin demonstrated a primary endpoint vs 17.4% on placebo (16% reduction, p=0.048). This 16% reduction was primarily due to a favorable effect of atorvastatin on recurrent symptomatic myocardial ischemia (26% reduction, p=0.02). Levels of LDL fell by 40% in those patients treated with atorvastatin. ACS

7. Risk in the wake of ATP III Straight to the statins • "The view of the guidelines [NCEP] is that this [MIRACL] does support an early benefit from statin treatment in hospital, which is a good idea in any case since it means these people will not be lost to follow-up and will be discharged on a statin." • Anyone admitted to hospital should have an LDL drawn and LDL > 100 mg/dL should be treated with a statin in hospital • J Cleeman ACS

8. Risk in the wake of ATP III Straight to the statins • "I can't see any downside to starting a statin as early as possible. And I like the idea of getting these patients, of whom I would suspect 70 or 80% in any case are going to have LDLs above 100, on treatment as rapidly as possible." • M Weber ACS

9. Risk in the wake of ATP III Straight to the statins • "So far, we still don’t have data to support the necessity of treating people with an LDL under 100 and this trial doesn't confirm that that is absolutely the case. I think there are a couple of other large trials that will help us with that issue. So I'm in favor of measuring it in everybody and treating those who are over 100 before they leave the hospital." • R Pasternak ACS

10. Risk in the wake of ATP III CURE Benefit of clopidogrel (+ ASA) for the chronic treatment of ACS Aspirin + clopidogrel (n=6259) Relative risk p value Endpoint Aspirin (n=6303) CV death, MI, stroke (primary endpoint) 11.47% 9.28% 0.80 0.00005 5.06% CV death 5.4% 0.92 N/A MI 6.68% 5.19% 0.77 <0.001 Stroke 1.4% 1.2% 0.85 N/A Non-CV death 0.70% 0.67% 0.96 N/A ACS

11. Risk in the wake of ATP III Clopidogrel with IIb/IIIa • The trial data support using clopidogrel right away on a patient coming to the emergency room with unstable angina. • There aren't data on upstream Gp IIb/IIIa inhibition and clopidogrel but one would expect they would be additive. • C Cannon ACS

12. Risk in the wake of ATP III Clopidogrel post MI • Don't use clopidogrel in an MI patient who is receiving thrombolysis. • "Definitely not. There, with thrombolysis, there is a large 40 000 patient trial ongoing and one really needs the safety data." • We have data on clopidogrel benefit in: unstable angina and non-ST elevation MI, stenting, long-term secondary prevention • C Cannon ACS

13. Risk in the wake of ATP III Surgical risk • "The same type anecdotes used to be present for aspirin, that the surgeons wouldn't operate on anyone who had taken aspirin in the last week. I think we really need to wait and see what the data look like." • C Cannon ACS

14. Risk in the wake of ATP III Length of clopidogrel treatment • Patients should get clopidogrel for at least 1 year, possibly for life. • If the data shows benefit from 1 month to 1 year, why wouldn't the benefit continue beyond that? • We also have data from CAPRIE for stable patients showing benefit out to several years. • C Cannon ACS

15. Risk in the wake of ATP III Chronic coronary atherosclerosis

16. Risk in the wake of ATP III Clopidogrel for angina? • CAPRIE showed a benefit for clopidogrel over aspirin for people with recent MI. • I would target the higher risk patient. • I would tend to the combination of clopidogrel and aspirin, since that's what we have the data on. • C Cannon Coronary disease

17. Risk in the wake of ATP III EuroASPIRE Prophylactic drug use among patients enrolled in EUROASPIRE 1 and 2 Drug use EuroASPIRE 1 EuroASPIRE 2 84% Aspirin / antiplatelet 81% Beta blocker 66% 54% ACE inhibitors 43% 30% Lipid lowering drugs 63% 32% Anticoagulants 8% 7% Coronary disease

18. Teach and remind peers about lipid guidelines • Follow-up on missed appointments • Develop a standardized treatment plan • Use patient feedback to improve care For Doctors • Simplify drug regimens • Involve patients, family, friends • Use systems to reinforce and reward adherence • Maintain contact with patient and increase convenience For Patients • Use lipid clinics & case management by nurses • Deploy telemedicine • Collaborate with pharmacists • Use/create critical care pathways in hospitals For Health Delivery Systems Risk in the wake of ATP III Achieving compliance Coronary disease adapted from the NCEP Adult Treatment Panel III Guidlines

19. Risk in the wake of ATP III One pill only? • A single pill with aspirin, a statin, ACE inhibitor or some other effective combination will be part of the future. • M Weber Coronary disease

20. Risk in the wake of ATP III Difficulty with compliance • One of the reasons the guidelines weren't updated earlier was because of problems with compliance. • "Although obviously physicians intend to do the right thing, it's extraordinarily complicated and I think, given the pressures of managed care and other pressures of managed care, it's extremely difficult." • R Pasternak Coronary disease

21. Risk in the wake of ATP III Out with the old, in with the new • Trials show benefit for new interventions, but we only have some subgroup analyses that suggest a combination pill would be effective. • "For example with clopidogrel, that's one area where I’m concerned. As we push that on the front of the truck, I'm afraid that other important things with even more convincing data fall off the back of the truck." • R Pasternak Coronary disease

22. Risk in the wake of ATP III LDL goals in ATP I, II, and III • ATP I • Primary CHD prevention in people with: • LDL > 160 mg/dL or LDL 130-159 mg/dL and multiple (2+) risk factors (LDL goal <130 mg/dL) • ATP II • Intensive management of LDL in people with CHD • (LDL goal < 100mg/dL) • ATP III • Primary CHD prevention in people with multiple risk factors • People with diabetes patients categorized as CHD "risk equivalents" • LDL goals in CHD patients and risk equivalents: < 100mg/dL Coronary disease

23. Risk in the wake of ATP III LDL lowering methods • LDL goal < 100 mg/dL • LDL  100 mg/dL • Initiate lifestyle changes, drug treatment optional • LDL  130 mg/dL • Consider full intensive therapy – drugs plus lifestyle changes adapted from the NCEP Adult Treatment Panel III Guidlines Coronary disease

24. Risk in the wake of ATP III Vascular disease

25. Risk in the wake of ATP III Mortality in peripheral disease • The principal cause of mortality in patients with peripheral vascular disease is coronary artery disease. It is appropriate to be aggressive in treating these patients to prevent coronary disease. • R Pasternak Vascular disease

26. Risk in the wake of ATP III Statins against stroke CARE and LIPID (secondary prevention) trials: 22% reduction in total strokes 25% reduction in nonfatal strokes WOSCOPS, (primary prevention) trial: 23% reduction in total nonhemorrhagic stroke No significant reduction in hemorrhagic stroke Byington RP et al. Circulation 2001;103:387-92 Vascular disease

27. Risk in the wake of ATP III Other statin effects • "It is increasingly clear that statins have many favorable effects. I'd still argue that most of them are mediated through LDL lowering, but I'm sure it's not true of all of them." • R Pasternak Vascular disease

28. Risk in the wake of ATP III Subclinical disease

29. Risk in the wake of ATP III EBCT Score No identifiable atherosclerotic plaque 0 Minimal identifiable plaque Significant CAD unlikely 1-10 Definite but mild plaque. Risk factor modification recommended 11-100 • Definite, moderate plaque. Aggressive risk factor modification, noninvasive stress testing 101-400 • Major plaque. Likelihood of "significant" stenosis. Aggressive risk factor modification recommended, noninvasive stress testing + angiography >400 Subclinical disease

30. Risk in the wake of ATP III EBCT as supplemental information • "The view of the guidelines is that EBCT is an emerging risk factor. It can tip you over the edge in a particular patient and convince you that this person deserves more aggressive attention, but it does not displace the standard risk factors." • J Cleeman Subclinical disease

31. Risk in the wake of ATP III Ankle-Brachial Index ABI score Severity 0.97-1.0 Normal 0.8-0.96 Mild ischemia 0.4-0.79 Moderate-severe ischemia <0.4 Severe ischemia Subclinical disease

32. Risk in the wake of ATP III Patients with multiple risk factors

33. Risk in the wake of ATP III New Features of ATP III • Focus on Multiple Risk Factors • Diabetes: CHD risk equivalent • Framingham projections of 10-year CHD risk • Identify certain patients with multiple risk factors for more intensive treatment • Multiple metabolic risk factors (metabolic syndrome) • Intensified therapeutic lifestyle changes adapted from the NCEP Adult Treatment Panel III Guidlines High risk

34. Risk in the wake of ATP III Metabolic syndrome • "I think as we look forward to trying to prevent where this country is going with risk factors it's an extraordinarily important area to look at because we're getting heavier, less glucose-tolerant, and having higher blood pressures and higher lipids as a result." • R Pasternak High risk

35. Risk in the wake of ATP III Coronary risk equivalents • Patients with coronary disease have a MI risk >20% in the next ten years. • Patients with diabetes or with a Framingham risk of >20% in the next ten years have an equivalent risk • "They need to have their LDL lowered to less than a 100 and they qualify for intensive therapy at just the same levels as the people who have overt, established coronary disease." • J Cleeman High risk

36. Risk in the wake of ATP III Primary vs secondary prevention • "I think the line between those [primary and secondary prevention] deserves to be very blurry. The patient the moment before the infarction may not be altogether different than the moment after the infarction in terms of the basic biology." • J Cleeman High risk

37. Risk in the wake of ATP III HDL in ATP III • HDL is an enormously important predictor of coronary disease. • Low HDL has been raised to < 40 mg/dL • "We just don't have enough clinical trial evidence to set an actual goal of therapy, how high should you shoot for. Moreover we don't have agents that would let you get to a goal if you actually set one." • J Cleeman High risk

38. Risk in the wake of ATP III Raising HDL Veterans Affairs HDL Intervention Trial (VA-HIT) Treatment with 1200 mg/day of gemfibrozil resulted in a significant 22% reduction in the combined incidence of nonfatal MI and CHD death over 5 years of follow-up.1 Bezafibrate Infarction Prevention (BIP) study Treatment with 400 mg bezafibrate resulted in an 18% increase in HDL, but no significant reduction in MI or sudden death.2 1. Haffner S. Circulation 2000; 102: 2-4 2. BIP Study Group. Circulation 2000; 102: 21-2 High risk

39. Risk in the wake of ATP III Evidence based medicine • There has been a move from expert consensus reports to evidence based reports. • ATP III is directly related to specific evidence. • We don't yet have clinical trial evidence that supports a specific HDL target. • R Pasternak High risk

40. Risk in the wake of ATP III HDL dilemma • Patient with HDL 27 mg/dL, LDL 104 mg/dL • No other risk factors. • My approach is to lower LDL even further, because if you cannot attack one parameter, you can attack the others to get a good result. • The ratio can be used as an important goal. • V Fuster High risk

41. Risk in the wake of ATP III HDL and triglyceride as targets • Attacking triglyceride/cholesterol ratio type can have benefit • Many trials have suggested that if you modify the ratio you have a significant benefit • "I would try to give the physician a little bit of hope." • V Fuster High risk

42. Risk in the wake of ATP III Problems with ratios • We've been nervous about making the ratio as a target of therapy because it submerges the individual components of the ratio. • You lose track of which components you are addressing with your intervention. • J Cleeman High risk

43. Risk in the wake of ATP III Global risk score • "We should begin to think of the global risk score as a kind of a vital sign that should be in everyone's chart, that should be communicated to patients. And I hope we will see a sea change of thinking because of this." • R Pasternak High risk

44. Risk in the wake of ATP III Motivational tool • A powerful patient education and motivation tool • Not only on the Palm for the doctors, it is also in the patient literature and available on the web for patients to use. • J Cleeman High risk

45. Risk in the wake of ATP III Compliance • "One thing I've come to learn is that even knowing that you are at high risk doesn't necessarily make people do the right thing. […] There's a lot we still have to learn about what motivates people to follow treatment even when the benefit of treatment is very, very well established." • M Weber High risk

46. Risk in the wake of ATP III Understanding the patient • "Maybe we have to understand better the psychology of the patient; why the patient is obese, or why the patient smokes, and then maybe attack the problem at a different level. • "However, I don't think the health system is prepared to do such a thing when in fact we have trouble even giving a pill." • V Fuster High risk

47. Risk in the wake of ATP III A wake-up call • "This is the kind of red flag that wakes people up and gets the ball rolling […] • And once these things are prescribed, then that's the first step in getting compliance." • C Cannon High risk

48. Risk in the wake of ATP III Overall population

49. Risk in the wake of ATP III CHD prevention: Finland Mean level of coronary risk factors and ischemic heart disease mortality in Finnish men Risk factors and mortality 1972 1992 Mean cholesterol (mmol/L) 6.78 5.90 Diastolic BP (mm Hg) 92.8 84.2 Percent smokers 53 37 Mean mortality from ischemic HD (per 100 000) 647 289 Vartiainen et al. BMJ 1994; 309: 23-7 Overall population

50. Risk in the wake of ATP III Advocacy • "We have to be much more aggressive advocating in the public health forum […] • With legislators, with policy makers, with insurance companies, and with organizations that have the power to change things for a whole population." • R Pasternak Overall population