Risk Factor Assessment and Modification
James B. Froehlich
A discussion of risk factors for most diseases is usually an epidemiologic exercise. It typically centers around identifying factors or characteristics that place individuals at an increased risk of acquiring or suffering the consequences of a certain disease. In the case of atherosclerotic vascular disease, however, the treatment of risk factors is far more important than that. Most of the well-established risk factors for atherosclerotic disease are, in fact, mediators of the disease, not merely markers of increased risk. The identification of these well-known risk factors for atherosclerotic disease is one of the triumphs of modern epidemiology. These risk factors, including diabetes, dyslipidemia, hypertension, smoking, obesity, and sedentary lifestyle, are much more than markers of risk. They are, in fact, some of the most important causes of this disease. Furthermore, the modification of these risk factors has led to the development of the most effective treatment strategies for atherosclerotic vascular disease. This intellectual odyssey began with early epidemiologic studies that produced observations of the association of both lifestyle and genetic abnormalities that predispose to the development of atherosclerosis. Among these early studies was the Framingham Heart Study. This original, and now much imitated, study produced and continues to produce observations about the nature of atherosclerosis and atherogenesis that identify not only avenues for treatment but lead to our improved understanding of the cause of this disease. Mechanical attempts to overcome arthrosclerotic obstruction of arteries with modalities such as angioplasty, stenting, and bypass surgery have had far less impact on survival and modification of the disease than interventions to lower blood pressure, treat diabetes, and encourage smoking cessation.
This chapter will focus on four areas of risk factor assessment and modification that appear to have the biggest potential impact on outcomes for patients with arthrosclerotic disease. Those areas are lipid lowering, hypertension treatment, smoking cessation, and manipulation of the renin angiotensin system. This last topic, while not a “risk factor” in the conventional sense, represents an opportunity of great potential impact on not only outcomes for patients with arthrosclerotic disease but also directly on the arthrogenic process.
Lipid Lowering
Background
Exactly as was hoped more than 40 years ago when it was observed that increased levels of serum cholesterol confer a greater risk for cardiovascular events, therapeutic interventions to lower serum cholesterol levels are highly effective therapy for this disease. We have the luxury today of benefiting from years of research that first established a relationship between elevated serum cholesterol and atherosclerotic disease, then established the possibility of chemically lowering serum cholesterol levels, and finally, with great success, established that therapeutic attempts to lower serum cholesterol confer great benefit by reducing cardiovascular events, and even arresting or reversing the arthrogenic process itself.
Early clinical trials evaluating the effect of lipid lowering included the Helsinki and other studies evaluating the effect of gemfibrozil as well as cholestyramine. Most of these studies were weakened by either inadequate size given the relative scarcity of end points, or by the use of a low-risk population for study, which again resulted in the low incidence of end points. Nonetheless, despite medication side effects, the studies did demonstrate an improvement in lipid profiles and clinical outcomes. Similarly, the MRFIT study, which attempted to intervene in a wide range of risk factors and high-risk behavior for arthrosclerotic disease, produced extremely modest results, which required a decade of follow up to identify. In this study, many subjects were randomized to either routine care or an aggressive multifaceted risk factor intervention program. The benefits of this program, which included exercise counseling, smoking cessation attempts, and aggressive treatment of blood pressure, were modest. The reason for these meager results appears to be twofold. Again, the subjects were relatively low risk and therefore had few adverse outcomes, making the identification of treatment benefit difficult. Also, patients in the “usual care” group received more than usual care and saw an improvement in their risk factors merely as a result of being involved in a study and receiving closer scrutiny.
All of this changed dramatically with the publication of the 4S study in 1994. This study, the first large clinical trial to evaluate the effectiveness of HMG Co-A reductase inhibitor (statin) therapy on outcomes from arthrosclerotic disease, was both well designed and dramatic in its results. This study evaluated the effect of titrated simvastatin therapy in patients at extremely high risk for cardiovascular events, specifically those with history of myocardial infarction (MI) or coronary disease who also had high or elevated serum cholesterol levels. They found a
dramatic reduction in cardiovascular events over 5-year follow up, without any evidence of increased risk of side effects or development of malignancy. This study has been followed by a series of studies, of increasing size and with a wide range of drugs in this class, all of which have demonstrated a dramatic improvement in cardiovascular event rate for patients at varying levels of risk. Patients with history of coronary disease, without a history of coronary disease but with elevated serum cholesterol, and even with “normal” serum cholesterol and no history of coronary disease, have benefited from intervention with lipid-lowering “statin” therapy. These studies have led to the creation of guidelines recommending the use of statin therapy in a wide range of patients with atherosclerotic disease.
dramatic reduction in cardiovascular events over 5-year follow up, without any evidence of increased risk of side effects or development of malignancy. This study has been followed by a series of studies, of increasing size and with a wide range of drugs in this class, all of which have demonstrated a dramatic improvement in cardiovascular event rate for patients at varying levels of risk. Patients with history of coronary disease, without a history of coronary disease but with elevated serum cholesterol, and even with “normal” serum cholesterol and no history of coronary disease, have benefited from intervention with lipid-lowering “statin” therapy. These studies have led to the creation of guidelines recommending the use of statin therapy in a wide range of patients with atherosclerotic disease.
More recently, the larger and more diverse heart protection study has broadened this understanding to an even wider range of patients. This study examined the efficacy of pravastatin therapy in patients with known coronary disease, known peripheral vascular disease (PAD), or in patients who had a high-risk profile for the development of atherosclerotic disease. A significant decrease in cardiovascular events such as death, MI, and stroke, roughly 24%, was seen in all groups regardless of the presence or absence of atherosclerotic disease. The accumulation of all of these clinical trials has led to the recommendation that all patients with coronary disease, all patients with PAD, and all patients with diabetes should be aggressively treated with statin therapy.
Table 6-1 Approach to Lipid Lowering in Patients with Atherosclerosis: LDL Goals and Treatment Levels for Primary and Secondary Prevention of Atherosclerotic Disease Complications | ||||||||||||||||||||||
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Approach to Patients
It is now widely accepted, and promulgated in guidelines, that all patients with any form of atherosclerotic disease should be treated similarly and aggressively with lipid-lowering therapy. This begins with a fasting lipid profile assessment in all patients who have atherosclerotic disease of any kind, who have diabetes, or who are at increased risk for the development of atherosclerotic disease. The National Cholesterol Education Program (NCEP) guidelines suggest the initiation of medical therapy to lower serum cholesterol levels for low-risk patients with low-density lipoprotein (LDL) cholesterol greater than 180, for patients at increased risk with LDL cholesterol greater than 160, and for patients with known atherosclerotic disease who have serum LDL cholesterol greater than 130 (Table 6-1). These guidelines, while easy to follow, leave logical gaps and a number of conundra for the practicing clinician. For example, if patients with coronary disease whose serum cholesterol is 140 warrant treatment to lower LDL cholesterol to a level below 100, why should such a patient with LDL cholesterol of 120 go untreated and not have a similar goal? Nonetheless these are useful guides for the majority of patients. Certainly, for all patients with PAD, aggressive lipid-lowering therapy with a target LDL less than 100 is the standard of care.
Recently, a publication by a subset of the NCEP members has suggested that, because there appears to be a continuum of risk associated with LDL cholesterol, and benefit from LDL-lowering therapy, for patients at high risk or with well-documented significant atherosclerotic disease, an LDL target range near 70 is warranted. This is not yet part of the NCEP official guideline. Suffice it to say that aggressive lipid-lowering therapy with a target LDL cholesterol of well below 100 is now considered standard of care for all patients with atherosclerotic disease. It is incumbent upon those who care for these patients to participate in providing access to this type of medical therapy for all of their patients.
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