- Email: [email protected]
From the Editor: What are the important questions for clinical trials?
Journal of Clinical Lipidology (2012) 6, 299–300
Foreword
From the Editor: What are the important questions for clinical trials? As we await the new Guidelines for management of lipid disorders in the United States (Adult Treatment Panel IV), lipidologists should consider the purpose of guidelines in clinical practice and the source of the information on which they are constructed. I believe that the clinician should view guidelines as tools to help them design improved preventive care for their individual patients. This guidance should have been built on the best observational data and adequate clinical trials to provide specific information regarding targets of treatment (what you are treating) and goals for treatment (the range of values) that are appropriate for a given patient. This should allow maximum reduction of disease-related events with a reasonable cost and acceptable risk of adverse effects from the therapy. Unfortunately, clinical trials address group changes but are somewhat peripheral to the needs of the individual patient. Therefore, clinical judgment as based on the totality of all pertinent scientific information and the patient’s personal characteristics must be brought to bear on the process of treatment. So what should we trust regarding the targets and the goals? With regard to lipoproteins, there is only one target that has been prospectively tested in large well-done clinical trials: low-density lipoprotein cholesterol (LDLC). All others are the result of retrospective analysis or examination of subgroup data. Investigators from the Treating to New Targets (TNT) trial compared the incidence of major vascular disease events in patients with known coronary artery disease at baseline by lowering LDL-C to an average value of 100 mg/dL versus approximately 75 mg/dL. The actual values achieved were 102 mg/dL (atorvastatin 10 mg/day) versus 77 mg/dL (atorvastatin 80 mg/day). In both groups, less than one-half actually achieved the goal. Investigators of the Post-Coronary Artery Bypass Graft (Post-CABG) and GREek Atorvastatin and Coronary-heartdisease Evaluation (GREACE) studies also set goals with similar success. These and all other trials suffer from lack of compliance and superimposed therapies in the less aggressively treated control group. However, the very large body of randomized clinical trial data has provided clear evidence that the lower the LDL-C, the lower the incidence of myocardial infarction, stroke, and other atherosclerotic
events. This is true in several different population groups including those without clinical evidence of arteriosclerosis (see the article by Sniderman et al in this issue). As clinicians, we are frequently faced with patients who would not have been included in adequate clinical trials, including patients whose risk is based on factors other than elevated LDL-C. These patients include those with hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), high Lp(a), and those with vascular disease or diabetes whose LDL-C is within the current goals of therapy. There appear to be enough data on the risk related to triglyceride levels greater than 200 mg/dL, particularly when the HDLC is low, to use the recommended target of non-HDL-C and to set a goal consistent with the previous National Cholesterol Education Program guidelines. A growing body of evidence suggests that apolipoprotein B (apoB) or measures of LDL particle number are reasonable goals in many patients who may have small cholesterol-poor LDL particles. We desperately need better prospective data on these issues. Is there added benefit in treating these measures as targets in certain subgroups? Using other targets of therapy such as measures of HDL, either with lipid content, apolipoprotein content, particle number, or particle size distribution may lead to effective preventive therapy. However, to date we have no convincing data that changing any of these parameters with current therapeutic options will change the rate of vascular disease events. This is an area of active research, and such research should be encouraged. Another promising area for therapy is the inflammatory process in the arterial wall that marks the early phases of arteriosclerotic plaque development. It seems highly likely that interrupting that process at some stage would lead to the less-rapid development of lesions. This broad concept is the subject of several clinical trials that are in development, and like HDL alteration, we are hopeful that a new mode of attack on cardiovascular disease will result. At present, I believe that HDL or inflammatory signals are not targets of treatment with any proven value, and therefore, more harm than good may come from their specific treatment with current methods. The article by Toth et al in this issue provides data that remind us of the tens of millions of people in the United
1933-2874/$ - see front matter Ó 2012 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2012.06.003
300 States who have lipoprotein values that are appropriate targets of treatment. These individuals need both lifestyle changes and medical therapy to lower LDL-C and nonHDL-C. It is difficult to provide accurate estimates of the actual benefit because of the nature of the trial evidence that is currently available (see the article Sniderman in this issue). However, the evidence is overwhelming that we can make a very significant difference in disease rates by following our current guidelines and that should stimulate us all to be more effective in the practice of clinical lipidology. When it comes to the individual, it seems evident that the clinician needs scientific evidence regarding process rather than simply testing one drug or one dose of a given drug against another. In several studies, researchers are attempting to demonstrate the value of adding another drug, such as niacin, ezetimibe, or omega-3 fatty acids, to statins, and these results should provide valuable data. However, the targets and the goals should be more thoroughly tested. Is treating non-HDL-C effective in patients whose LDL-C is already within the goal range? By addressing patients with low HDL-C and modestly elevated triglycerides, the authors of AIM-HIGH study attempted to address this issue indirectly but did not include an adequate number of subjects with sufficiently elevated triglycerides (see the article by Brinton in this issue). Will lowering apoB or particle number in those at the LDL-C (or non-HDL-C) goals provide additional risk reduction? In such trials, the therapeutic regimens could involve several different drugs as needed to achieve the goal in most patients. Such studies should be undertaken in patients who have small dense LDL at values associated with risk in observational studies. From recent community-based studies such as the MultiEthnic Study of Atherosclerosis (MESA), we know that perhaps 15% of the population of middle-aged men and women would fall into this category. New drugs such as, PCSK-9 inhibitors, mipomersen, and MTP inhibitors, are in development and are likely to add
Journal of Clinical Lipidology, Vol 6, No 4, August 2012 greatly to the LDL particle number reduction achieved with statins. Studies that could demonstrate the value of reducing apoB or LDL particles as opposed to achieving current LDL-C and non-HDL-C goals would require the recruitment of tens of thousands of patients. They might best be done in health care systems that are very large and that could provide multiple, geographically separate centers to allow isolation of clinical groups using the new process in question from similar groups using the traditional approach. Systems such as the Veteran’s Healthcare Administration, or the Kaiser Permanente group with their electronic medical record systems would seem to be ideal laboratories for these investigations. There is no question that better drugs and documentation of new targets are appropriate subjects for active research in prevention of cardiovascular disease. However, appropriately testing the drugs already available to fully derive their potential benefit under conditions that address the current needs of the clinician is also very important. Because such trials are unlikely to address the business needs of large pharmaceutical companies and because very large trials will be necessary, these questions could be addressed most appropriately by government entities. The value of providing physicians and patients with this information would help close the extremely costly gap between current approaches to treatment of vascular disease and more complete success in the preventive effort. The increasing cost of medical care as currently conducted should be highly motivating to a government that claims to desire a more efficient and effective system. W. Virgil Brown, MD Editor-in-Chief Charles Howard Candler Professor of Medicine Emeritus Emory University School of Medicine Atlanta, GA E-mail address: [email protected]
Foreword
From the Editor: What are the important questions for clinical trials? As we await the new Guidelines for management of lipid disorders in the United States (Adult Treatment Panel IV), lipidologists should consider the purpose of guidelines in clinical practice and the source of the information on which they are constructed. I believe that the clinician should view guidelines as tools to help them design improved preventive care for their individual patients. This guidance should have been built on the best observational data and adequate clinical trials to provide specific information regarding targets of treatment (what you are treating) and goals for treatment (the range of values) that are appropriate for a given patient. This should allow maximum reduction of disease-related events with a reasonable cost and acceptable risk of adverse effects from the therapy. Unfortunately, clinical trials address group changes but are somewhat peripheral to the needs of the individual patient. Therefore, clinical judgment as based on the totality of all pertinent scientific information and the patient’s personal characteristics must be brought to bear on the process of treatment. So what should we trust regarding the targets and the goals? With regard to lipoproteins, there is only one target that has been prospectively tested in large well-done clinical trials: low-density lipoprotein cholesterol (LDLC). All others are the result of retrospective analysis or examination of subgroup data. Investigators from the Treating to New Targets (TNT) trial compared the incidence of major vascular disease events in patients with known coronary artery disease at baseline by lowering LDL-C to an average value of 100 mg/dL versus approximately 75 mg/dL. The actual values achieved were 102 mg/dL (atorvastatin 10 mg/day) versus 77 mg/dL (atorvastatin 80 mg/day). In both groups, less than one-half actually achieved the goal. Investigators of the Post-Coronary Artery Bypass Graft (Post-CABG) and GREek Atorvastatin and Coronary-heartdisease Evaluation (GREACE) studies also set goals with similar success. These and all other trials suffer from lack of compliance and superimposed therapies in the less aggressively treated control group. However, the very large body of randomized clinical trial data has provided clear evidence that the lower the LDL-C, the lower the incidence of myocardial infarction, stroke, and other atherosclerotic
events. This is true in several different population groups including those without clinical evidence of arteriosclerosis (see the article by Sniderman et al in this issue). As clinicians, we are frequently faced with patients who would not have been included in adequate clinical trials, including patients whose risk is based on factors other than elevated LDL-C. These patients include those with hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), high Lp(a), and those with vascular disease or diabetes whose LDL-C is within the current goals of therapy. There appear to be enough data on the risk related to triglyceride levels greater than 200 mg/dL, particularly when the HDLC is low, to use the recommended target of non-HDL-C and to set a goal consistent with the previous National Cholesterol Education Program guidelines. A growing body of evidence suggests that apolipoprotein B (apoB) or measures of LDL particle number are reasonable goals in many patients who may have small cholesterol-poor LDL particles. We desperately need better prospective data on these issues. Is there added benefit in treating these measures as targets in certain subgroups? Using other targets of therapy such as measures of HDL, either with lipid content, apolipoprotein content, particle number, or particle size distribution may lead to effective preventive therapy. However, to date we have no convincing data that changing any of these parameters with current therapeutic options will change the rate of vascular disease events. This is an area of active research, and such research should be encouraged. Another promising area for therapy is the inflammatory process in the arterial wall that marks the early phases of arteriosclerotic plaque development. It seems highly likely that interrupting that process at some stage would lead to the less-rapid development of lesions. This broad concept is the subject of several clinical trials that are in development, and like HDL alteration, we are hopeful that a new mode of attack on cardiovascular disease will result. At present, I believe that HDL or inflammatory signals are not targets of treatment with any proven value, and therefore, more harm than good may come from their specific treatment with current methods. The article by Toth et al in this issue provides data that remind us of the tens of millions of people in the United
1933-2874/$ - see front matter Ó 2012 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2012.06.003
300 States who have lipoprotein values that are appropriate targets of treatment. These individuals need both lifestyle changes and medical therapy to lower LDL-C and nonHDL-C. It is difficult to provide accurate estimates of the actual benefit because of the nature of the trial evidence that is currently available (see the article Sniderman in this issue). However, the evidence is overwhelming that we can make a very significant difference in disease rates by following our current guidelines and that should stimulate us all to be more effective in the practice of clinical lipidology. When it comes to the individual, it seems evident that the clinician needs scientific evidence regarding process rather than simply testing one drug or one dose of a given drug against another. In several studies, researchers are attempting to demonstrate the value of adding another drug, such as niacin, ezetimibe, or omega-3 fatty acids, to statins, and these results should provide valuable data. However, the targets and the goals should be more thoroughly tested. Is treating non-HDL-C effective in patients whose LDL-C is already within the goal range? By addressing patients with low HDL-C and modestly elevated triglycerides, the authors of AIM-HIGH study attempted to address this issue indirectly but did not include an adequate number of subjects with sufficiently elevated triglycerides (see the article by Brinton in this issue). Will lowering apoB or particle number in those at the LDL-C (or non-HDL-C) goals provide additional risk reduction? In such trials, the therapeutic regimens could involve several different drugs as needed to achieve the goal in most patients. Such studies should be undertaken in patients who have small dense LDL at values associated with risk in observational studies. From recent community-based studies such as the MultiEthnic Study of Atherosclerosis (MESA), we know that perhaps 15% of the population of middle-aged men and women would fall into this category. New drugs such as, PCSK-9 inhibitors, mipomersen, and MTP inhibitors, are in development and are likely to add
Journal of Clinical Lipidology, Vol 6, No 4, August 2012 greatly to the LDL particle number reduction achieved with statins. Studies that could demonstrate the value of reducing apoB or LDL particles as opposed to achieving current LDL-C and non-HDL-C goals would require the recruitment of tens of thousands of patients. They might best be done in health care systems that are very large and that could provide multiple, geographically separate centers to allow isolation of clinical groups using the new process in question from similar groups using the traditional approach. Systems such as the Veteran’s Healthcare Administration, or the Kaiser Permanente group with their electronic medical record systems would seem to be ideal laboratories for these investigations. There is no question that better drugs and documentation of new targets are appropriate subjects for active research in prevention of cardiovascular disease. However, appropriately testing the drugs already available to fully derive their potential benefit under conditions that address the current needs of the clinician is also very important. Because such trials are unlikely to address the business needs of large pharmaceutical companies and because very large trials will be necessary, these questions could be addressed most appropriately by government entities. The value of providing physicians and patients with this information would help close the extremely costly gap between current approaches to treatment of vascular disease and more complete success in the preventive effort. The increasing cost of medical care as currently conducted should be highly motivating to a government that claims to desire a more efficient and effective system. W. Virgil Brown, MD Editor-in-Chief Charles Howard Candler Professor of Medicine Emeritus Emory University School of Medicine Atlanta, GA E-mail address: [email protected]