ROUNDTABLE DISCUSSION: IMPLICATIONS OF ADULT TREATMENT PANEL (ATP) III GUIDELINES AND EMERGENT RESEARCH FOR CLINICAL PRACTICE

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1 ROUNDTABLE DISCUSSION: IMPLICATIONS OF ADULT TREATMENT PANEL (ATP) III GUIDELINES AND EMERGENT RESEARCH FOR CLINICAL PRACTICE The following are excerpts from a roundtable discussion with faculty co-chairs Peter O. Kwiterovich, Jr, MD, and Roger S. Blumenthal, MD; and panel members Sherita Hill Golden, MD, MHS; Howard Knapp, MD, PhD; William C. Little, MD; James J. Maciejko, MD, PhD; and David G. Robertson, MD. THE ROLE OF ANTIOXIDANTS Dr Kwiterovich: Dr Little, as a general cardiologist who is very involved in the field of atherosclerosis as well as heart failure, what is your impression of the new cholesterol guidelines overall, as well as their strengths and weaknesses? Dr Little: I think the statement in the new guidelines that patients hospitalized with acute coronary events should start therapy to reduce LDL [low-density lipoprotein] levels during the hospitalization period is very important. This practice is likely to improve compliance. You have the patient s attention, the patient will almost certainly require therapy to get to LDL goal, and starting therapy early may provide other benefits. Based on the Heart Protection Study, I suspect the guidelines are, in fact, far too conservative in that they only mandate therapy for LDL > 130 mg/dl. The Heart Protection Study suggests that almost every patient who has been hospitalized for coronary artery disease, regardless of LDL-C levels, would probably benefit from LDL-reduction therapy, initiated with statins, during their hospitalization. In our practice, essentially every patient who is admitted to the cardiology service returns home with LDL-C reducing therapy. Dr Kwiterovich: That really raises the issue about whether cutpoints are necessary in secondary prevention to initiate therapy because some clinicians believe that all patients with coronary artery disease will benefit from statins. However, the LDL-C should be monitored at regular intervals because the statin alone may be insufficient. The statin dose may need to be increased later, or a second agent added, so while initiating therapy in the hospital is important, the patients should be reassessed to determine the adequacy of the therapeutic regimen and whether more aggressive treatment is needed. Dr Little: I think cardiologists, are becoming much better about initiating therapy in patients. However, I do not think we are doing nearly as good a job at titrating the therapy and actually getting patients to goal once we have started it. Dr Robertson: One of the important new steps in the discussion of treatment in ATP [Adult Treatment 158 Vol. 2, No. 5 March 2002

2 Panel] III is the emphasis on the need for early reassessment, titration, and second-line and third-line therapy being initiated at the 6-week interval. I think that is a big step forward. The idea that titrating a patient takes months, and that a prolonged period of safety monitoring is necessary, has obviously outlived its utility. One of the important additions to clinical practice outlined by ATP III was to provide an algorithm for rapid assessment of benefit and advancement of therapy as appropriate. Dr Kwiterovich: I would like to follow up on your comment that cardiologists are doing better and ask the question, how are endocrinologists and surgeons doing? Endocrinologists, in regard to treatment of type 2 diabetes as a CAD [coronary artery disease] risk equivalent, and surgeons who do [coronary artery] bypasses, peripheral artery bypasses for people with peripheral vascular disease, carotid endarterectomies, and other procedures, are they being aggressive enough? Dr Golden: I think the appropriate management of cardiovascular risk factors, as well as treating the hyperglycemia needs to be an integral part of diabetes management in clinical endocrinology. The United Kingdom Prospective Diabetes Study showed us that in terms of macrovascular complications, better blood pressure control was probably more important than tighter blood glucose control. Over the next several years, we will most likely see a shift to more intensive management of cholesterol as well as hypertension in patients with diabetes. I realize I may be biased because I am in the Hopkins preventive cardiology center, but when I initially see a patient, I simultaneously focus on management of hypertension, cholesterol, and blood glucose level. Typically, the blood pressure and cholesterol can be managed much more quickly, while appropriate management of hyperglycemia can take several weeks to months of insulin or oral hypoglycemic agent titration. In addition, I think clinicians have been reluctant to use combination therapy with a statin and a fibrate. Typically, a patient with diabetes ends up needing both therapies to treat high LDL- Cholesterol and high triglycerides. The concern regarding risk of myositis is justifiable, but in most patients, the risk of myositis is going to be much lower than the risk for a cardiovascular event. Dr Kwiterovich: In your patients with diabetes who also have dyslipidemia and hypertension that have been treated, what criteria do you use for then treating them with an oral anti-hyperglycemic agent? Dr Golden: After the other cardiovascular risk factors have been adequately managed, the goal for treating their hyperglycemia is to reduce the hemoglobin A 1 c to less than 7%. The American Diabetes Association states that if the A 1 c is between 7% and 8%, you do not necessarily have to change therapy. Their recommended target for changing therapy is an HbA 1 c of 8%, but my target for instituting or changing therapy is above above 7%. Many diabetic patients need combination therapy for adequate blood glucose control as well as for adequate blood pressure and cholesterol control. These treatments involve important cost issues because most of the patients are going to potentially need double therapy for each of those disorders. Dr Kwiterovich: Please clarify the value of a hemoglobin A 1c of 7%; what is that equivalent to in terms of average blood glucose level? Dr Golden: That is equivalent to an average blood glucose level of about 150 mg/dl. It incorporates both fasting postprandial glucose levels. Dr Robertson: For management of diabetes, we should be headed more toward the same set of guidelines as the NCEP [National Cholesterol Education Program]; in our view, in favor of secondary prevention. In the United Kingdom Prospective Diabetes Study, the mechanism by which the intensively treated patients received benefit versus the conventionally treated patients was not a different drug regimen, nor a different treatment algorithm, nor a different medical protocol; it was timing of the onset of therapy. The intensive therapy meant on the day of diagnosis the patients received medical intervention, while the conventionally treated patients deferred the onset of medical therapy until diet and exercise failed to impact fasting hyperglycemia. The cutoff in that study was fasting blood glucose levels of 180 mg/dl, which is obviously too generous. But the lesson from the United Kingdom Prospective Diabetes Study is that immediate attention to glycemic control will provide long-term benefits. However, with that in mind, we need to be very careful about stepping on the toes of those who have worked hard to establish a precedent for glycemic control. The way I usually state the case is that the return on the investment from hypertension and lipid management is very rapid, compared to the return on Advanced Studies in Medicine 159

3 the investment for glycemic control, although they are all very important parts to the puzzle. Close to a decade is needed for glycemic control to demonstrate its benefit, while only months to a year or so, at the most, is needed for antihypertensive and cholesterol-lowering therapy to demonstrate benefit. PROMPTING TREATING PHYSICIANS TO ASSUME A ROLE IN CHOLESTEROL MANAGEMENT Dr Kwiterovich: Do any of the panel members here have programs at their institutions that help motivate the bypass surgeons, vascular surgeons, and interventional radiologists to pay more attention to cholesterol management any chart prompters or other tools? Dr Little: We are looking at that as part of the quality factors for the care of all of the patients with vascular disease. The entry criteria for the Heart Protection Study included not only evidence of coronary disease but also peripheral vascular disease, diabetes, and hypertension. All of these groups benefited equally from statin therapy. Based on the findings of the Heart Protection Study, not only should patients admitted with coronary artery disease be even more aggressively treated than the guidelines suggest, but LDL-lowering therapy should be instituted in all patients with vascular disease, hypertension, and diabetes as well. The point you have raised about having systems in place for the other specialists is well taken, in particular for our surgical colleagues, who are not accustomed to thinking about the more comprehensive medical management of the underlying cause of the vascular disease that they are palliating with surgery. Dr Knapp: Systems improvement is really quite important, particularly in light of several very highprofile lawsuits related to repairs of vascular damage without attention to underlying causes of vascular damage. Having a system in place that ensures the patients are all getting everything they need as part of their care seems to help everyone be on the same page regarding treatment. DISCUSSION POINT I measure Lp(a) levels in all my new patients, and I often find it not all that unusual for patients who have a family history of very premature disease and normal lipids to have an elevated Lp(a). Peter O. Kwiterovich, Jr, MD Dr Maciejko: At out institution, we have found that one way to effectively work with our surgical colleagues is actually through the patients. We have discharge protocols that prompt the surgeons, to be aggressive with risk factor management and with lipid-lowering agents, although at times they seem to be reluctant. Our nurses on the units educate the patients and frequently the patient then challenges the surgeon to take action in these areas. We find this to be effective. Dr Kwiterovich: We would very much like to have our patients be educated with an A, B, C lesson, similar to the one outlined here by Dr Blumenthal today, but designed for the lay person so that they know what the targets are for blood pressure, cholesterol, and glucose, with an emphasis on exercise, cardiac rehabilitation, and smoking cessation. Hopefully, the AHA [American Heart Association] and other groups can develop this type of program to help hospitals around the country educate providers and patients alike. THE VALUE OF C-REACTIVE PROTEIN, LP(A), AND HOMOCYSTEINE MEASURES IN DETERMINING THERAPEUTIC REGIMENS Dr Kwiterovich: I just wanted to ask the panel what their approaches were in regard to some of the emerging risk factors. Specifically, do you measure highly sensitive C-reactive protein, homocysteine, or Lp(a) lipoprotein? Dr Maciejko: We do not measure high sensitivity C-reactive protein (hs-crp). We are not sure how to use this information in making a clinical judgment or decision about risk factor modification. We have to recognize that the vast majority of the data that Dr Paul Ridker and colleagues have provided is observational data from large population studies. The only information that we have with evidence for measuring hs-crp was the recent analysis of the AFCAPS/TEX- CAPS [Air Force/Texas Coronary Atherosclerosis Prevention Study] data suggesting that in the primary 160 Vol. 2, No. 5 March 2002

4 prevention setting, the level of hs-crp was predictive of an atherosclerotic event. Despite this information, we are aggressive in managing CHD risk factors and do not feel at this time that the level of hs-crp would alter this approach. But right now, it is not measured because we do not believe this will provide any additional information to what we already have in making a decision about the intervention program for our patients. As far as homocysteine is concerned, we do measure it in certain subgroups of patients. These groups include individuals with diffuse vascular disease, premature vascular disease, and patients enrolled in our preventive cardiology program. Folic acid and vitamins B 6 and B 12 are recommended to reduce the homocysteine concentration below 12 µmol/l. We measure Lp(a) in patients who have been diagnosed with familial hypercholesterolemia or a marked polygenic hypercholesterolemia. We know that these individuals generally are not going to be managed adequately with a statin alone, and the Lp(a) level helps us determine the second agent of choice for treatment. A normal Lp(a) level prompts us to add a bile acid binding resin, whereas an elevated Lp(a) suggests the use of Niacin as the second agent. Additionally, Dr Mary Seed and her associates observed that elevated Lp(a) levels in individuals with marked hypercholesterolemia predicted the occurrence of CHD events earlier than in hypercholesterolemic patients with low levels of Lp(a). Dr Golden: I do not tend to measure the inflammatory markers in patients with diabetes because many epidemiologic studies have shown that they are elevated in these patients whose endothelium is already activated. Because they are already being treated as secondary prevention patients, measuring these markers really does not have much effect on their therapy. However, I have found such markers to be useful in young patients with an isolated elevated LDL cholesterol and a positive family history of cardiovascular disease. Frequently, they are reluctant to be committed to lifelong statin or other therapy, and if an elevated Lp(a) or a higher homocystine level can be demonstrated, that will usually prompt me to convince them they should start the therapy. Dr Knapp: While inflammatory markers are useful in epidemiologic surveys, they are quite variable within an individual over the course of time, for example, during influenza season, so we have not found measuring inflammatory markers to be very helpful on an individual basis. These measurements are good for looking at large studies to determine what factors may be associated with the progression of vascular disease. As far as homocysteine measurement is concerned, we still do not have clinical trial data showing that decreasing the level of homocysteine, compared with placebo, makes a difference in the average patient. Certainly, a few people have inborn errors, of which some are and some are not associated with vascular disease. Interestingly, a number of the patients referred to me for high homocysteine levels have been taking niacin and fibrates, both of which elevate homocysteine levels. We have several sets of drugs with established ability to reduce vascular endpoints, yet at the same time may elevate homocysteine levels, this makes interpreting the pathogenic role of homocysteine in vascular disease a little more difficult from the pharmacologic standpoint. Folate therapy is inexpensive and not known to produce any complications, so many of our patients just take folate as part of their vascular management. Dr Blumenthal: In terms of C-reactive protein, I am very impressed with the data Paul Ridker published from AFCAPS/TEXCAPS. If a patient has borderline LDL-C and another CAD risk factor, or family history of CAD, or a high CRP, that would probably sway me more to treatment, much as a markedly elevated coronary calcium score does. Measurement of C- reactive protein costs $40, and a measurement of coronary calcification by electron beam computed tomography (EBCT) costs $490. I believe measuring CRP does have a role in certain cases. I think, Dr Kwiterovich, your influence led a lot of us in cardiology to more routinely measure Lp(a) and apo B [apolipoprotein B], especially in patients with borderline risk factors. The presence of an elevation in apo B or Lp(a) in the setting of average LDL or triglyceride levels sways me to be much more aggressive. In terms of homocysteine, a new article in the New England Journal of Medicine suggests that lowering it decreases the risk of restenosis. I agree that for the vast majority of patients, I would just have them take a multivitamin, but probably there is a little bit more to the story that will be reported in the next year or so. Dr Little: As a cardiologist dealing almost exclusively with secondary prevention, we do not routinely analyze C-reactive protein or Lp(a). We do measure homocysteine, as several others have men- Advanced Studies in Medicine 161

5 tioned, in patients with premature cardiovascular disease, especially if many other apparent risk factors are not seen. We have, for some time, recommended that almost all of our patients take a multivitamin containing folate it is inexpensive, has no risks, and may be of benefit. The study that Dr Blumenthal just referred to showed a decreased restenosis rate following coronary intervention in patients who were treated with folate to lower homocysteine. While I do not consider that treatment with multivitamins and folate, for patients who have coronary disease, currently falls into the realm of evidence-based medicine, we are getting closer to such a conclusion. Because this treatment is inexpensive and well tolerated, it is something we recommend. We currently consider measuring homocysteine only in patients with unexplained premature vascular disease. Dr Robertson: I agree that measuring C-reactive protein in patients with diabetes is of limited benefit. However, I do believe that measuring C-reactive protein is appropriate for those patients who are encouraged to make lifestyle changes as the dominant therapy, if for no other reason than to exclude the possibility that it is elevated. In patients with high total cholesterol to HDL [high density lipoprotein] ratios, but below average LDL levels, they may still benefit from intervention if they have elevated C-reactive protein levels. I have felt the need to reassure those patients that lifestyle changes were an appropriate therapeutic approach by also reassuring them that they did not have elevated C-reactive protein levels. I have found that measuring the homocysteine and Lp(a) levels is important in any patients with premature disease or more extensive disease than would otherwise be suspected based on other risk factors. While I cannot say I use any systematic analysis, for the past few years, I have been measuring homocysteine levels in all patients referred to me for recurrent stenosis and restenting. In retrospect, analyzing homocysteine levels in that subgroup was probably appropriate. Dr Kwiterovich: My practice is somewhat biased in that I run a university lipid clinic where most of the patients that are sent to me either have recalcitrant dyslipidemia, combined hyperlipidemia, or premature disease with normal lipid profiles, and they may have no clear reason for having these conditions. I measure Lp(a) levels in all my new patients, and I often find it not all that unusual for patients who have a family history of very premature disease and normal lipids to have an elevated Lp(a). I have been impressed that healthy, younger women, even with a positive family history of CAD and elevated Lp(a), often have very high calcium score by EBCT despite a normal lipid profile. Lp(a) appears particularly important in women. I like to know what the Lp(a) level is because it gives me a better idea of what is going on, (even though we do not really even have the clinical trial data to support treating Lp(a) levels). If LDL is lowered to < 100 mg/dl, the Lp(a) appears to become of less importance. If I know the Lp(a) is elevated, I am more intent on getting the LDL as low as possible. If the homocysteine is elevated, not only will I have the patient take folic acid, I will also take a more aggressive approach to lipid-lowering therapy and management of other risk factors, because I think these risk factors interact in ways that we do not completely understand. Dr Maciejko: Several years ago in the Journal of the American Medical Association, Rimm and associates published a paper summarizing the results of the Nurses Health Study. The data indicated that nurses who ingested more than 600 µg of folic acid per day had statistically fewer cardiovascular and cancer events than nurses who did not. That publication generated interest, particularly by nutritional boards in the country, as to whether or not the minimum daily requirement for folic acid should be increased. So while I agree we do not have interventional data, we do have some data that would suggest that supplementation of the diet with folic acid is beneficial. 162 Vol. 2, No. 5 March 2002