Cardiovascular disease (CVD) is a highly prevalent

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1 Journal of Cardiovascular Nursing Vol. 21, No. 6S, pp S20YS42 x B 2006 Lippincott Williams & Wilkins, Inc. Cardiovascular Disease Strategies for Risk Assessment and Modification Lynne T. Braun, PhD, RN, FAHA Cardiovascular disease is the leading cause of death among men and women in the United States. Silent myocardial ischemia, defined as documentation of ischemia in the absence of angina or anginal equivalents, affects up to 4 million Americans and carries a poor prognosis. The assessment of the presence of subclinical coronary atherosclerosis affords an opportunity to identify patients who may be at risk for coronary artery disease over the long term. In addition to traditional risk factors (such as lipid parameters, diabetes, hypertension, smoking, and age), a variety of novel factors (such as lipoprotein[a], homocysteine, and C-reactive protein) may enhance assessment of risk in specific populations. Risk modification should be aimed at achieving recommended levels of lipids and blood pressure, reducing obesity, facilitating optimal management of diabetes and the metabolic syndrome, and encouraging smoking cessation and physical activity. Clinicians should be knowledgeable regarding the application of national guidelines for the reduction of cardiovascular risk so as to maximize the prospects for both the primary and secondary prevention of coronary artery disease and associated adverse outcomes. KEY WORDS: cardiovascular disease, diabetes, homocysteine, hypertension, inflammatory factors, lipids, lipoprotein (a), obesity, smoking Cardiovascular disease (CVD) is a highly prevalent condition that carries a significant risk of mortality. Assessment of the risk of CVD and related adverse outcomes can be accomplished through appropriate evaluation of factors such as lipid profiles, blood pressure, obesity, presence of diabetes, smoking, and physical inactivity. Risk stratification can help classify individuals into categories of low, intermediate, or high risk to guide the selection of management strategies. Interventions for each modifiable risk factor should be optimized through adherence to national guidelines. This article will address prognostic issues as well as diagnostic and management paradigms that should be implemented in clinical practice to facilitate primary and secondary prevention of CVD. Prevalence Cardiovascular disease is the leading cause of mortality in men and in women in the United States, Lynne T. Braun, PhD, RN, FAHA Nurse Practitioner, Preventive Cardiology Center; Associate Professor, College of Nursing, Rush University, Chicago, Ill. Corresponding author Lynne T. Braun, PhD, RN, FAHA, College of Nursing, Rush University, 600 S. Paulina, Suite 1080, Chicago, IL ( lynne_t_braun@rush.edu). accounting for nearly 40% of all deaths annually. 1 According to the Centers for Disease Control and Prevention, more than 70 million people in the United States have CVD, and approximately 930,000 people die of the condition each yearvapproximately 1 death every 35 seconds. 2 Although CVD, composed of largely preventable conditions, is more common among people 65 years of age or older, the number of sudden deaths from heart disease among people aged 15 to 34 years has increased. 2 Silent myocardial ischemia, defined as objective documentation of myocardial ischemia in the absence of angina or anginal equivalents, is now established as an integral part of the ischemic spectrum, with substantial evidence linking it to a clinically poor prognosis. 3 As many as 3 to 4 million Americans may experience silent ischemic episodes annually. 4 For individuals with silent ischemic episodes, a myocardial infarction (MI) or sudden cardiac death is often the first indication of heart disease. In fact, 50% of men and 64% of women who die suddenly of coronary artery disease (CAD) have no previous symptoms. 4 Therefore, early detection and intervention is the single best way to improve the likelihood of effective treatment. Evidence of silent myocardial ischemia may be identified through diagnostic testing. Exercise testing or ambulatory monitoring shows transient ST-segment S20

2 Strategies for Risk Assessment and Modification S21 changes. Nuclear imaging studies, generally performed with exercise or pharmacologic stress, demonstrate myocardial perfusion defects. Stress echocardiography (performed with exercise or dobutamine) shows regional wall motion abnormalities. In asymptomatic individuals without known CAD, several studies have estimated the frequency of silent ischemia to be approximately 2.5%. 5Y7 In one of the earliest studies, conducted by the US Air Force, 111 of 1,390 men were found to have positive exercise tests. 6 Of these 111 men, 34 (2.5% of the overall group) had arteriographic coronary lesions with Q50% stenosis. In the Oslo Ischemia Study of 2,014 men, coronary arteriography in those with positive exercise tests showed that 69 had Q50% stenosis in a coronary artery and 50 (2.5% of the overall group) were totally asymptomatic. 7 Using findings both from exercise electrocardiography and from thallium scans in 407 asymptomatic volunteers, the Baltimore Longitudinal Aging Study showed the prevalence of silent ischemia to be 2.5% for subjects younger than 60 years, increasing with age to 910% for those older than 70 years. 5 Other investigators found that the severity of coronary artery calcification (CAC) on electron beam computed tomography is predictive of silent ischemia. 8 This prospective study focused on 3,895 generally asymptomatic subjects who underwent EBCT, 411 of whom also underwent stress single-photon emission computed tomography (SPECT). The total CAC is used to identify a population at high risk for having myocardial ischemia by SPECT, regardless of age or sex. No subjects with a CAC G10 had an abnormal SPECT, compared with 2.6% of those with scores of 11 to 100 (indicating mild calcification). The incidence of silent ischemia increased at higher scores, from 11.3% at a CAC of 101 to 399 (moderate) to 46% at scores 9400 (severe). Patients with previous MI may complain of angina, but may also have episodes of myocardial ischemia that are unaccompanied by chest pain. In a study of 210 post-mi patients, 42% had ischemic episodes on exercise electrocardiography and 2-dimensional exercise echocardiography. 9 Of this group, 61% experienced anginal pain or its equivalents and 39% had silent myocardial ischemia. Patients with stable or unstable angina have both symptomatic and asymptomatic ischemic episodes, although the exact prevalence of silent ischemia remains unknown. In a study of 105 patients with stable angina receiving conventional antianginal drug therapy, silent ischemia was detected in 43% during ambulatory electrocardiographic monitoring. 10 Of a total 188 ischemic episodes, 87% were silent. Special populations at increased risk for silent ischemia include patients with diabetes, renal disease, peripheral vascular disease, or erectile dysfunction. The Detection of Ischemia in Asymptomatic Diabetics study evaluated 522 diabetic patients with no known or suspected CAD, through the use of stress testing with adenosine technetium-99m sestamibi SPECT. 11 Of this group, 22% had silent ischemia. In a study of 370 asymptomatic diabetic patients with at least 2 additional cardiovascular risk factors, 35.4% had evidence of silent ischemia on at least 1 noninvasive test. 12 Depending on the criteria used for diagnosis of silent ischemia, other studies of diabetic patients have found rates ranging from 6% to 30%. 13Y16 The incidence of clinically silent ST-segment depression in patients with renal disease was examined using Holter monitoring in 67 individuals on hemodialysis. 17 Of this group, 23% exhibited at least 1 minute of ST-segment depression, indicating the presence of silent ischemia. In a study of 176 patients with peripheral vascular disease assessed via Holter monitoring, 18% had a total of 75 episodes of ischemia, of which 97% were asymptomatic. 18 In an assessment of 47 men with erectile dysfunction of vascular origin, investigators identified angiographically documented silent coronary disease in 19%. 19 In a group of 260 men with erectile dysfunction and uncomplicated type 2 diabetes, 133 had angiographically verified silent ischemia. 20 The prevalence of erectile dysfunction was significantly higher in patients with than without silent ischemia (33.8% vs 4.7%, respectively; P =.000). These observations underscore the need for a high suspicion of silent myocardial ischemia in these atrisk groups. Cardiovascular disease is the primary cause of death in American womenva population at high risk but low suspicion for CAD, a disease responsible for more than 500,000 deaths in women each year. 4 More women die of CVD each yearv1 of every 2Vthan from the next 7 leading causes of death combined. 4 Although death rates from CVD in men have been decreasing over the past 2 decades, most notably since the introduction of statin therapy, rates have continued to rise in women. Despite these statistics, surveys show that neither women nor their physicians appreciate the magnitude of this risk. In a survey of 1,024 women aged 25 years and older, only 13% cited CVD as their greatest health concern, and 38% reported that their physician had discussed heart disease with them. 21 An updated survey of 1,008 women showed that the rate of awareness of CVD as the leading cause of death has nearly doubled since 1997 (55% vs 30%), although there were significant racial and ethnic disparities. White women had a significantly greater rate of awareness compared with black and Hispanic women (62% vs 38% and 34%, respectively). 22

3 S22 Journal of Cardiovascular Nursing x November/December 2006 Furthermore, women are more likely than men to have multiple risk factors for coronary heart disease (CHD), 23 so health professionals and patients alike need to recognize the existence of risk factors and the potential for developing future cardiovascular risk. In addition, they need to remain alert to any signs and symptoms suggestive of overt CVD. Ongoing cardiovascular risk assessment should be a part of every woman s medical care. The clinical presentation of CVD in women may be atypical and can be subtle, leading to a lack of recognition by clinicians. Although chest pain is the most common symptom of MI in men and women alike, some reports suggest that it is not as predictive in women compared with men and tends to subside more quickly. 24 Women are more likely to experience atypical symptoms, such as shortness of breath, nausea, loss of appetite, and back pain. 24 Diagnosing CVD based only on the symptoms common in men can cause evidence of the disease in women to be overlooked. Finally, even when women are identified as having risk factors for CVD, there is less use by physicians of standard accepted therapy in women than in men. In comparisons of women and men with similar cardiovascular risk profiles, women were significantly less likely than men to undergo additional coronary evaluation (38% vs 62%; P =.002) or coronary revascularization (2% vs 5%; P =.03). 25 Less aggressive lipid-modifying strategies are used to treat women than men with similar risk profiles. In a 3-year study of 825 men and women with CHD, use of lipid-modifying therapy increased and low-density lipoprotein cholesterol (LDL-C) decreased in men but use of therapy and, not surprisingly, LDL-C levels remained the same in women despite abovegoal LDL-C levels in the women in the study. 26 Another analysis of 8,353 high-risk women found that only 7% had initially optimal lipid levels, and this figure increased to 12% after 36 months of follow-up. 27 Lipid-modifying therapy was initiated in 32% of women overall, but in only 35% of those with LDL-C levels Q100 mg/dl. These findings highlight the need for greater vigilance in the identification and management of cardiovascular risk factors in women. Risk Assessment Framingham Risk Score Assessment for the presence of risk factors provides an opportunity to identify asymptomatic patients who are at risk for developing clinical CAD over the long term. The Framingham Risk Score (FRS), based on a number of traditional risk factors including age, total cholesterol, high-density lipoprotein cholesterol (HDL-C), systolic blood pressure, and cigarette smoking, is expressed as a number reflecting the likelihood of cardiovascular death or nonfatal MI over a 10-year period. Patients who have less than a 10% risk of events are considered low risk, a 10% to 20% likelihood of events are at intermediate risk, and those with more than 20% likelihood are at high-risk. 28 The FRS serves as the basis for identifying asymptomatic adults who should be managed aggressively for primary prevention. Approximately one third of Americans 40 to 70 years of age are at intermediate risk for CAD, as defined by the FRS. 29 Although consideration of major risk factors, such as serum cholesterol levels, hypertension, and smoking status, plays a role in the overall evaluation, this approach may not always provide an accurate risk assessment. A limitation of the Framingham criteria is the exclusion of significant risk factors such as family history and visceral obesity. In several studies, the FRS has been found to underestimate risk in women by its failure to include family history in the scoring criteria. 30,31 Currently, the FRS frequently classifies women as being lowrisk, even in the presence of significant CAC. Researchers have found that CAC and sibling history of premature CHD more strongly associated than parental history with estimation of long-term risk. 32 A lifetime risk estimate denotes absolute risk and may be more easily understood than a relative risk estimate. Lloyd-Jones and colleagues 33 estimated lifetime risk in all Framingham Heart Study participants who were free of CVD at 50 years of age. At age 50, the average lifetime risk of developing CVD was 52% for men and 39% for women. Lifetime risk increased to 69% in men and 50% in women who had 2 or more major CVD risk factors. Individuals with optimal risk factor levels at age 50 had a much lower lifetime risk for CVD (5% in men and 8% in women). Lipoprotein (a) A variety of novel factors have been identified that may enhance assessments of risk, including lipoprotein (a) and homocysteine. Lipoprotein (a), also known as Lp(a), consists of a particle of LDL-C linked to a large glycoprotein, apolipoprotein (a). In theory, Lp(a) could promote CVD in 2 ways: its apolipoprotein(a) moiety could promote thrombogenesis, because it is structurally similar to plasminogen, and its LDL-C moiety could promote atherogenesis. 34,35 Levels above 30 mg/dl are generally considered elevated, a threshold exceeded by approximately 25% of American men and women. 36 Lp(a) levels are higher in patients with chronic renal failure, the nephrotic syndrome, and diabetic nephropathy. 37,38

4 Strategies for Risk Assessment and Modification S23 Numerous retrospective, case-control studies demonstrated an association between elevated levels of Lp(a) and increased risk for CHD, ischemic stroke, and peripheral arterial disease. 39Y42 Lp(a) elevations have also been linked to restenosis after angioplasty and progression of angiographically documented CHD. 43,44 Lp(a) excess is the most common inherited lipid disorder in patients with premature CHD. 45 Prospective studies, on the other hand, present a slightly more complex picture. Some studies suggested that Lp(a) is a strong, independent predictor of CHD, particularly in women and young men, 46 whereas others found no such association. 47 One prospective trial found that Lp(a) screening may be useful to predict heart disease risk in men, but not in women, older than 65 years. 48 Until more consistent prospective trial data or interventional evidence is available, a patient s Lp(a) level is insufficient data for predicting CVD risk in the general population and does not warrant its inclusion in a standard screening evaluation. However, clinicians should be aware of the Lp(a) level in special populations: patients with premature CHD, those with a strong family history of CVD, those who have undergone angioplasty or coronary artery bypass grafting, and those with documented CVD in the absence of traditional risk factors. In addition to aggressive lowering of elevated levels of LDL-C, 49 attempts to lower Lp(a) in these groups may be warranted, especially in light of the efficacy and tolerability of the newer forms of niacin and fenofibrate. Finally, elevated Lp(a) should be considered in patients with hypercholesterolemia that is refractory to standard statin therapy. Because the calculated value of LDL-C includes the LDL contained in Lp(a) and Lp(a) will not respond to statin therapy, significant hidden elevations of Lp(a) may account for the treatment failure. Homocysteine Elevated plasma homocysteine concentration is considered a risk factor for CVD and may also be associated with hypertension. 50 Although links have been established between hyperhomocysteinemia and elevated risk for cardiovascular events, the precise role of plasma homocysteine in CVD remains unclear. Elevated levels of homocysteine are believed to cause vascular disease by increasing oxidant stress, impairing endothelial function, and inducing thrombosis. 51 Both case-control and prospective studies have shown that plasma total homocysteine is a strong, independent risk factor for CAD and stroke. 52Y54 According to prospective studies, elevated plasma homocysteine concentrations increase the risk of CVD by 2-fold. Plasma homocysteine increases with aging and is associated with other health-related behaviors, including smoking and diet patterns. Confounding risk factors have made identifying homocysteine as an independent risk factor for CVD or hypertension difficult. Levels of homocysteine can be modified to some extent by vitamin supplementation. Reduction of homocysteine levels may have some benefit in reducing cardiovascular risk in some patients, particularly the elderly. Although elevated homocysteine is a risk factor for CVD, a recent study showed that lowering homocysteine with folate and vitamins B6 and B12 in patients who had an acute MI did not lower the risk of recurrent CVD, and a harmful effect from combined B vitamin treatment was suggested. 55 Furthermore, a higher rate of in-stent stenosis was observed in CAD patients who received 6 months of folate, vitamin B 6, and vitamin B 12 therapy, as compared with patients who received placebo. 56 Therefore, the independent role of homocysteine on risk for CVD has not been determined; thus, the assessment and treatment of homocysteine should be approached in the context of other modifiable risk factors. C-reactive Protein Multiple risk factors for atherosclerosis and CVD act in synergy through inflammatory pathways. Chronic inflammation is a key feature of the atherosclerotic process. Serum levels of high-sensitivity C-reactive protein (hs-crp) are useful to identify the presence and severity of inflammation. Recent studies reporting that moderate elevations of hs-crp correlate with future cardiovascular events validate the use of this test to assess cardiovascular risk. 57 In fact, hs- CRP seems to be a stronger predictor than LDL-C and adds prognostic information at all levels of calculated Framingham risk and at all levels of the metabolic syndrome. 57Y59 In outpatient settings, as an adjunct for global risk assessment, the primary use of hs-crp should be at the time of cholesterol screening. Pharmacologic intervention should be aggressively encouraged in individuals with an elevated hs-crp level and LDL-C levels above 160 mg/dl. 57 An elevated hs-crp indicates an elevated risk in individuals with LDL-C levels between 130 and 160 mg/dl. For individuals with LDL levels below 130 mg/dl, an elevated hs-crp indicates a substantially higher risk than that based primarily on LDL-C levels. Such individuals will have risk estimates comparable to individuals with overt hyperlipidemia. Individuals with low LDL-C and elevated hs-crp levels are at elevated risk of having the metabolic syndrome and should have fasting glucose levels measured.

5 S24 Journal of Cardiovascular Nursing x November/December 2006 Although hs-crp seems to add predictive value above that of currently established risk factors, the evidence is not entirely consistent across published studies; in particular, additional prospective studies are needed to more precisely define risk at various strata and to ensure consistency in other age, sex, and racial/ethnic groups. According to the American Heart Association Scientific Statement on Markers of Inflammation and Cardiovascular Disease, 60 based on available evidence, measurement of hs-crp in primary prevention is best used with intermediaterisk patients to gauge the need for intensive medical therapy for risk reduction and to motivate some patients to adopt lifestyle modifications or comply with prescribed medications. A conservative approach in primary prevention is to measure hs-crp only in those at intermediate risk as defined by the FRS. 57 However, because this requires a second office visit and additional laboratory testing, the approach is both less efficient and less cost effective. Patients at risk may easily be lost to follow-up with this approach. In secondary prevention, the potential utility of hs-crp remains unclear, as aggressive therapies should already be instituted and LDL-C evaluation provides an excellent method to assess statin efficacy. Lipoprotein-associated Phospholipase A 2 Another marker of inflammation is lipoproteinassociated phospholipase A 2 (Lp-PLA 2 ), an enzyme that generates potent proinflammatory products. Elevated levels of Lp-PLA 2 have been found to predict coronary events in apparently healthy middleaged men with moderately elevated total cholesterol, independent of hs-crp levels. 61 This observation suggests that Lp-PLA 2 and hs-crp may be additive in their ability to predict CAD risk. Risk Stratification Global, office-based assessment of CAD risk is recommended as standard practice for all individuals. 62 Patients can be classified in 1 of 3 risk categories (low, intermediate, or high) based on Framingham score, presence of CAD risk factors, family history of CAD, and presence of other forms of atherosclerotic disease (Figure 1). Patients at low risk require periodic follow-up or only minimal therapy, whereas those at intermediate risk require more intensive risk reduction to meet recommended goals for individual risk factors. In addition, a variety of noninvasive techniques can be used to enhance risk assessment in individuals at intermediate risk. Depending on the results, such patients may be reclassified as being at high risk. In individuals with abnormal findings on measurements of ankle-brachial index, for example, carotid B-mode ultrasound measurement of intima media thickness, EBCT coronary calcium score, and exercise stress testing (in men only) have been shown to indicate appreciably elevated CAD risk sufficient to move the degree of risk from intermediate to high. 62 Nuclear perfusion imaging and stress echocardiography are also useful methods for evaluating patients at intermediate risk. 63 FIGURE 1. Risk assessment for coronary artery disease in asymptomatic adults. Adapted with permission from Lippincott Williams & Wilkins B

6 Strategies for Risk Assessment and Modification S25 Dyslipidemia and Cardiovascular Risk Goals of Lipid-altering Therapy According to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP Adult Treatment Panel [ATP] III), a fasting lipoprotein profile should be obtained every 5 years. 28 The profile should include total cholesterol, LDL-C, HDL-C, and triglycerides. The NCEP ATP III classification of lipoporotein levels is shown in Table 1. Risk determinants, apart from elevated LDL-C, include the presence or absence of CAD, other clinical forms of atherosclerotic disease, cigarette smoking, hypertension, low HDL-C (G40 mg/dl), a family history of premature CAD, and age (men, Q45 years; women, Q55 years). Diabetes is considered a CAD risk equivalent. The LDL-C goal should be modified depending on these other risk determinants. Specifically, the LDL-C goal is G100 mg/dl in patients with CAD and CAD risk equivalents, G130 mg/dl in those with multiple (2 or more) risk factors, and G160 mg/dl in those with no or 1 risk factor. An optional LDL-C goal of G70 mg/ dl may be selected for highest risk patients, such as those with established CVD plus multiple major risk factorsvespecially the severe and poorly controlled risk factors of diabetes and the metabolic syndrome, continued cigarette smoking, and the presence of acute coronary syndrome. 64 Effects of Lowering LDL-C With Statins Numerous large-scale, randomized, controlled trials have confirmed that statins reduce the risk of mortality and cardiovascular events across a TABLE 1 National Cholesterol Education Program Adult Treatment Panel III Classification of Lipoprotein Levels Lipoprotein Level, mg/dl Classification LDL-C G100 Optimal 100Y129 Near or above optimal 130Y159 Borderline high 160Y189 High Q190 Very high Total cholesterol G200 Desirable 200Y239 Borderline high Q240 High HDL-C G40 Low Q60 High HDL indicates high-density lipoprotein; LDL, low-density lipoprotein. Reprinted with permission from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 28 wide range of lipid levels in patients with or without a history of CAD. 65Y71 A meta-analysis of 5 major controlled trials of at least 4 years duration, 23,67Y69,71 with a total of 30,817 participants, showed that LDL-C reduction with statins decreased the risk of major coronary events by 31% and all-cause mortality by 21%. 72 The degree of risk reduction was similar in men and women as well as in older (Q65 years of age) and younger individuals. Other work has demonstrated that the benefits of statin therapy extend to a broad variety of high-risk patients, irrespective of initial cholesterol concentrations. One such trial, the Heart Protection Study, randomized 20,536 patients with coronary disease, other occlusive arterial disease, or diabetes to receive simvastatin 40 mg/d or placebo for 5 years. 66 The rate of all-cause mortality was significantly reduced with simvastatin versus placebo (12.9% vs 14.7%, respectively; P =.0003) owing to a highly significant, 18% proportional reduction in coronary death (5.7% vs 6.9%, respectively; P =.0005). Simvastatin also produced a significant, 24% reduction (P G.0001) in the first occurrence of any major vascular event (nonfatal MI, coronary death, nonfatal or fatal stroke, and coronary or noncoronary revascularization). The proportional reduction in the event rate was similar and significant in all subgroups analyzed, including patients without diagnosed CAD who had cerebrovascular disease, peripheral artery disease, or diabetes; men and women; those either younger or older than 70 years; and those who presented with LDL-C concentrations G116 mg/dl or total cholesterol G193 mg/dl. An issue of particular interest has been whether aggressive lowering of LDL-C, beyond current target levels, might further enhance the beneficial impact of statins on outcomes. Several investigations have now addressed this question. The A to Z trial enrolled 4,497 patients who were randomized to receive 40 mg/d of simvastatin for 1 month followed by 80 mg/ d thereafter, or placebo for 4 months followed by 20 mg/d of simvastatin. 73 The primary end point was a composite of cardiovascular death, nonfatal MI, readmission for acute coronary syndrome, or stroke. Follow-up was conducted for at least 6 months and up to 24 months. With the conservative strategy, the median LDL-C level was 122 mg/dl with placebo at 1 month and 77 mg/dl with simvastatin at 8 months. With the intensive strategy, the median LDL-C level was 68 mg/dl with simvastatin 40 mg/d at 1 month and 63 mg/dl with simvastatin 80 mg/dl at 8 months. The primary end point occurred in 16.7% of patients randomized to the conservative strategy and in 14.4% of those randomized to the intensive strategy, a nonsignificant difference. However, the incidence of cardiovascular death was

7 S26 Journal of Cardiovascular Nursing x November/December 2006 significantly lower with intensive than conservative treatment (4.1% vs 5.4%, respectively; hazard ratio, 0.75: 95% confidence interval [CI], 0.57Y1.00; P =.05), although there were no differences in the other components of the primary end point. Additional insights emerged from the Pravastatin or Atorvastatin Evaluation and Infection Therapy- Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. 74 The objective was to compare outcomes with the standard degree of LDL-C lowering (to approximately 100 mg/dl) with pravastatin 40 mg/d versus more intensive LDL-C lowering (to approximately 70 mg/dl) with atorvastatin 80 mg/d. A total of 4,162 patients who had been hospitalized for acute coronary syndrome within the preceding 10 days were randomized to the 2 treatment arms. The primary end point was a composite of death from any cause, MI, documented unstable angina requiring rehospitalization, revascularization performed at least 30 days after randomization, or stroke. After a mean follow-up of 24 months, the median LDL-C level was significantly lower with high-dose atorvastatin compared with standard-dose pravastatin (62 vs 95 mg/dl, respectively; P G.001). Kaplan-Meier estimates of the rates of the primary end point were 22.4% with atorvastatin versus 26.3% with pravastatin, indicating a 16% decrease favoring the more intensive regimen (P =.005; Figure 2). Analysis of the individual components of the primary end point showed that high-dose atorvastatin, compared with standard-dose pravastatin, significantly reduced the need for revascularization (by 14%; P =.04) and the risk of recurrent unstable angina (by 29%; P =.02). However, the more intensive regimen did not significantly lower rates of death from any cause, death from CAD or MI, or death from other causes. Another analysis of data from the PROVE IT- TIMI 22 trial explored the contribution of early FIGURE 2. Incidence of the combined end point of death from any cause or a major cardiovascular event in the PROVE IT- TIMI 22 trial. Reprinted with permission from Massachusetts Medical Society B All Rights Reserved. 74 effects to the overall clinical efficacy of intensive statin therapy. 75 At 30 days, the composite end point of death, MI, or rehospitalization for recurrent acute coronary syndrome occurred in 3.0% of patients receiving atorvastatin 80 mg versus 4.2% of those receiving pravastatin 40 mg (hazard ratio, 0.72; 95% CI, 0.52Y0.99; P =.046). Among stable patients, the composite event rates were 9.6% and 13.1% in the 2 groups, respectively (hazard ratio, 0.72; 95% CI, 0.58Y0.89; P =.003). Also in stable patients, intensive statin therapy was associated with a long-term reduction in clinical events. The investigators concluded that intensive statin treatment provides 2 windows of cardioprotection in patients with acute coronary syndrome. Therefore, such patients should start intensive statin therapy in the hospital and continue the treatment over the long term. Further observations with regard to intensive lipid lowering were obtained in the Treating to New Targets study, in which 10,001 patients with clinically evident CAD were randomized to receive atorvastatin 10 or 80 mg for a median of 4.9 years. 76 The primary end point was the occurrence of a first major cardiovascular event (death from CAD, nonfatal nonyprocedure-related MI, resuscitation from cardiac arrest, or fatal or nonfatal stroke). During treatment, mean LDL-C levels were 101 mg/dl with atorvastatin 10 mg/d and 77 mg/dl with atorvastatin 80 mg/d. The primary end point occurred in 10.9% and 8.7% of the 2 groups, respectively, a relative risk reduction of 22% (hazard ratio, 0.78; 95% CI, 0.69Y0.89; P G.001). There were no differences between treatment groups with regard to all-cause mortality (hazard ratio, 1.01; 95% CI, 0.85Y1.19; P =.92) or cardiovascular mortality (hazard ratio, 1.25; 95% CI, 0.99Y1.57; P =.06). Other work likewise found that intensive lowering of LDL-C did not result in further reductions in all-cause mortality, although favorable effects on secondary end points were noted. These observations came from the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study, in which 8,888 patients with previous MIs were randomized to receive high-dose atorvastatin (80 mg/d) or usual-dose simvastatin (20 mg/d). 77 The primary end point was the occurrence of a major coronary event (coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation). During treatment in IDEAL, mean LDL-C levels were 81 mg/dl with atorvastatin 80 mg/d and 104 mg/dl with simvastatin 20 mg/d. At a median follow-up of 4.8 years, a major coronary event had occurred in 9.3% of the atorvastatin group and 10.4% of the simvastatin group, a nonsignificant difference. Nonfatal acute MI was documented in

8 Strategies for Risk Assessment and Modification S27 6.0% versus 7.2% of the 2 groups, respectively (hazard ratio, 0.83; 95% CI, 0.71Y0.98; P =.02), but there were no significant differences in the other 2 components of the primary end point. Death from any cause occurred in 8.2% of patients receiving atorvastatin and 8.4% of those receiving simvastatin, which again was not statistically significant (hazard ratio, 0.98; 95% CI, 0.85Y1.13; P =.81). Nonetheless, high-dose atorvastatin significantly reduced the occurrence of any coronary event (hazard ratio, 0.84; 95% CI, 0.76Y0.91; P G.001) and major cardiovascular events (hazard ratio, 0.87; 95% CI, 0.77Y0.98; P =.02). The benefits of high-dose atorvastatin were also apparent in the 16-week Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering study. 78 A total of 3,086 patients with unstable angina or nonyst-segment-elevation acute MI were randomized to receive atorvastatin 80 mg/d or placebo 24 to 96 hours after hospital admission. At study close, the mean LDL-C level had fallen from 124 to 72 mg/dl in the atorvastatin group. The primary composite end point (death, nonfatal MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization) occurred in significantly fewer patients in the atorvastatin group than in the placebo group (14.8% vs 17.4%, respectively; relative risk, 0.84; 95% CI, 0.70Y1.00; P =.048). With respect to the individual components of the end point, there were no significant between-group differences in the risk of death, nonfatal MI, or cardiac arrest. Notably, however, symptomatic ischemia was significantly less common with atorvastatin than placebo (6.2% vs 8.4%, respectively; relative risk, 0.74; 95% CI, 0.57Y0.95; P =.02). Intensive LDL-C lowering with statins has also been found to reduce progression or induce regression of coronary atherosclerosis. In the Reversal of Atherosclerosis with Aggressive Lipid Lowering trial, 502 evaluable patients had intravascular ultrasound examinations at baseline and after 18 months of randomized treatment with pravastatin 40 mg or high-dose atorvastatin 80 mg. 79 The baseline LDL-C level (mean mg/dl in both groups) was reduced to 110 mg/dl with pravastatin and to 79 mg/dl with atorvastatin (P G.001). Analysis of the primary end point (percent change in atheroma volume) revealed a significantly lower progression rate with atorvastatin than pravastatin (P =.02). In fact, compared with baseline, no change in atheroma burden was evident with atorvastatin, whereas progression of atherosclerosis was seen with pravastatin. The effects of very high-intensity statin therapy on atherosclerosis were assessed in the recent open-label Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID). 80 A total of 349 evaluable patients received 24 months of treatment with rosuvastatin 40 mg/d and underwent intravascular ultrasound examinations at baseline and follow-up. The mean baseline LDL-C level of mg/dl decreased to 60.8 mg/dl, a reduction of 53.2% (P G.001). The mean baseline HDL-C level rose from 43.1 to 49.0 mg/dl, an increase of 14.7% (P G.001). The mean change in percent atheroma volume was j0.98%, with a median of j0.79% (97.5% CI, j1.21% to j0.53%; P G.001 vs baseline). The ASTEROID investigators concluded that treatment to LDL-C levels below currently accepted guidelines, when accompanied by significant increases in HDL- C, can regress atherosclerosis in patients with coronary disease. Effects of Raising HDL-C With Fibrates Other investigations have examined the impact of therapy specifically aimed at raising levels of HDL- C. Observational studies have shown that low HDL- C levels are strongly and independently associated with an increased risk of CAD. 81Y83 Moreover, 20% to 30% of patients with CAD have low levels of HDL-C without excessively high levels of LDL-C. 84,85 Focusing on the effects of raising HDL-C, the Veterans Affairs Cooperative Studies Program High- Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) compared gemfibrozil 1,200 mg/d with placebo in 2,531 men with CAD, an HDL-C level e40 mg/dl, and an LDL-C level e140 mg/dl. 86 At 1 year, the mean HDL-C level was 6% higher, mean triglycerides were 31% lower, and mean total cholesterol was 4% lower with gemfibrozil versus placebo. LDL-C levels did not differ significantly between the groups. Over a median follow-up of 5.1 years, a primary event (nonfatal MI or death from coronary causes) occurred in 17.3% of the gemfibrozil group compared with 21.7% of the placebo group, a relative risk reduction of 22% (P =.006; Figure 3). The VA-HIT investigators also observed a 24% reduction in the combined end point of death from CHD, nonfatal MI, and stroke (P G.001). These findings suggest that the rate of coronary events can be reduced by raising HDL-C and lowering triglycerides without reducing LDL-C in patients whose primary lipid abnormality is low HDL-C. Fibrates are also useful in patients with type 2 diabetes who have dyslipidemia. Although people with diabetes generally have total and LDL-C concentrations similar to or lower than those in people without diabetes, 87 lipid patterns differ. Specifically,

9 S28 Journal of Cardiovascular Nursing x November/December 2006 may have been due to the significantly greater use of statins in the placebo group and the unexpectedly small difference in HDL-C levels between the 2 groups. FIGURE 3. Incidence of the combined end point of nonfatal myocardial infarction and death from coronary artery disease in the VA-HIT study. Reprinted with permission from Elsevier B Copyright patients with diabetes are more prone to have small, dense LDL as well as lower levels of HDL-C and higher triglycerides. 88,89 This pattern can be corrected with fibrate treatment. 90 The effects of fenofibrate on cardiovascular events in patients with type 2 diabetes, with or without previous CVD, were explored in a 5-year, randomized, controlled trial. 90 This study, Fenofibrate Intervention and Event Lowering in Diabetes (FIELD), enrolled 9,795 patients who were not taking statins at study entry. Significantly more patients randomized to placebo than fenofibrate started other lipid treatments (predominantly statins) during the trial. Relative to placebo, fenofibrate 200 mg/d reduced total cholesterol by 11%, LDL-C by 12%, and triglycerides by 29%, while increasing HDL-C by 5% after 4 months of treatment. These differences were generally maintained among patients not receiving other lipid medications, although the difference in HDL-C decreased to 2% by the close of the study. The overall primary composite end point of coronary events (CAD death or nonfatal MI) occurred in 5.2% of the fenofibrate group and 5.9% of the placebo group, a nonsignificant difference. On the other hand, the incidence of nonfatal MI was reduced significantly, by 24%, with fenofibrate (hazard ratio, 0.76; 95% CI, 0.62Y0.94; P =.010). Total CVD events were also significantly lowered, from 13.9% with placebo to 12.5% with fenofibrate (hazard ratio, 0.89; 95% CI, 0.80Y0.99; P =.035). This finding included a 21% reduction in coronary revascularization (hazard ratio, 0.79; 95% CI, 0.68Y0.93; P =.003). The FIELD investigators speculated that the lack of a more pronounced treatment effect on the primary end point Hypertension and Cardiovascular Risk The risk of hypertension has been linked to a variety of factors, such as sleep apnea, chronic kidney disease, primary aldosteronism, renovascular disease, chronic steroid therapy and Cushing syndrome, pheochromocytoma, coarctation of the aorta, thyroid or parathyroid disease, chronic low-grade inflammation (as reflected in hs-crp levels), smoking, heavy alcohol use, alcohol consumption outside meals, and abdominal obesity. 91Y93 A correlation between systolic blood pressure and death from CVD was demonstrated in the landmark Multiple Risk Factor Intervention Trial (MRFIT), which enrolled 347,978 men ages 35 to 57 years. 94 Follow-up at 12 years revealed that systolic blood pressure was positively linked to a significant risk of cardiovascular mortality both in diabetic and in nondiabetic men (P G.001). The age-adjusted death rate per 10,000 person-years increased from 53.6 to as systolic pressure rose from G120 to Q200 mm Hg among men with diabetes. Among those without diabetes, the rate rose from 12.2 to per 10,000 person-years. At every level of systolic blood pressure, the mortality rate was markedly higher among diabetic than nondiabetic men. A multivariate regression analysis showed that a 20-mm Hg higher systolic pressure was associated with a relative risk of 1.60 for nondiabetic and 1.41 for diabetic men, whereas a 20-mm Hg lower level was associated with relative risks of 0.63 and 0.71, respectively. Associations between hypertension and CVD were examined in the Strong Heart Study, which collected data on 4,549 American Indians. 95 After adjustment for all other risk factors, patients with pretreated, untreated, controlled, and uncontrolled hypertension had approximately 1.74, 1.81, 2.10, and 2.77 times higher risks, respectively, for the development of CVD when compared with normotensive individuals. The Blood Pressure Lowering Treatment Trialists Collaboration conducted a meta-analysis of 29 randomized trials (N = 162,341) to investigate the effects of hypertension treatment on CVD events. 96 Specifically, they analyzed studies of the following 7 treatment regimens. h Regimens targeting different blood pressure goals (more intensive vs less intensive goals) h Calcium-channel blocker (CCB) regimens vs placebo

10 Strategies for Risk Assessment and Modification S29 h Angiotensin receptor blocker (ARB) vs control regimens h Angiotensin-convertinig enzyme inhibitor (ACEI) regimens vs placebo h ACEI vs diuretic or "-blocker regimens h ACEI vs CCB regimens h ACEI vs ARB regimens The investigators found that lower blood pressure targets produced greater relative-risk reductions of total major cardiovascular events, as did the CCB-, ARB-, and ACEIYbased regimens. For every outcome analyzed (major cardiovascular events, CAD, heart failure, stroke, cardiovascular death, and total mortality) except heart failure, the differences between the randomized groups in achieved blood pressure reduction were directly associated with the differences in relative risk. No significant differences in total major cardiovascular events were observed between regimens based on ACEIs, CCBs, diuretics, or beta blockers. Most importantly, fewer cardiovascular events occurred when blood pressure was lowered by any commonly used regimen. The efficacy of different classes of antihypertensive agents was the object of study in the Anglo- Scandinavian Cardiac Outcomes Trial (ASCOT) blood pressureylowering arm. 97,98 It has been suggested that the newer antihypertensive agents would have greater effectiveness in lowering blood pressure and reducing cardiovascular events. Investigators of ASCOT randomized 19,257 patients with hypertension (aged 40Y79 years) with Q3 other cardiovascular risk factors to either the amlodipine-based regimen (5Y10 mg amlodipine [CCB] + 4Y8 mg perindopril [ACEI], as needed) or the atenolol-based regimen (50 mg atenolol [beta blocker] + bendroflumthiazide and potassium, as needed). The primary end point was nonfatal MI and fatal CAD. The study was stopped prematurely because there was a significant cardiovascular mortality and stroke benefit in the amlodipine-based regimen after 106,153 patient-years of observation. The difference between the 2 groups for the primary end points, however, did not reach statistical significance when the trial was halted (P =.11). These results are shown in Table 2. Another interesting finding of ASCOT was a highly significant lower incidence of developing diabetes in the amlodipine-based group compared with the atenolol-based group (567 vs 799, respectively; P G.0001). 97 The ASCOT-LLA was the first trial using statins to assess the benefits of lipid lowering in the primary prevention of CHD in patients with hypertension who were not deemed by conventional measures to have dyslipidemia. 99 The 5-year prospective study was stopped after 3.3 years owing to the superiority TABLE 2 Results from ASCOT Blood PressureYLowering Arm 97 Amlodipinebased Regimen (n) Primary end point Nonfatal myocardial infarction or coronary artery disease death Secondary endpoints Fatal and nonfatal stroke Total cardiovascular disease events and procedures Cardiovascular disease mortality Atenololbased Regimen (n) ,362 1,602 G All-cause mortality ASCOT indicates Anglo-Scandinavian Cardiac Outcomes Trial. Adapted with permission from Elsevier B Copyright of atorvastatin 10 mg over placebo in reducing the primary end point of nonfatal MI and fatal CHD. Patients receiving atorvastatin experienced a significant reduction in total cholesterol (50 mg/dl [1.3 mmol/l]) and LDL-C (46 mg/dl [1.2 mmol/l]) levels after 1 year compared with those who received placebo. Cholesterol lowering with atorvastatin was associated with a highly significant reduction in the primary end point of nonfatal MI and fatal CHD (36%, P =.0005). The observed benefit was consistent across the secondary end points and the 18 prespecified subgroups. The ASCOT-LLA findings have influenced lipid-lowering guidelines and support the concept that treatment strategies to reduce CVD should be based on the assessment of all cardiovascular risk factors, rather than on numerical thresholds of individual risk factors. The classification of blood pressure in adults, according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), is shown in Table The JNC 7 goal is to achieve and maintain a systolic pressure G140 mm Hg and a diastolic pressure G90 mm Hg, although Boptimal[ BP is G120/80 mm Hg. For individuals with diabetes or renal disease, the BP goal is G130/80 mm Hg. 91,100 Obesity and Cardiovascular Risk Obesity (defined as a body mass index Q30.0 kg/m 2 in adults) is an independent risk factor for CVD. 101 Obesity affects the heart through its influence on risk factors such as dyslipidemia, hypertension, glucose intolerance, inflammatory markers, obstructive sleep P

11 S30 Journal of Cardiovascular Nursing x November/December 2006 TABLE 3 Classification of Blood Pressure According to JNC 7 90 Systolic Blood Pressure, Classification mm Hg Normal G120 and G80 Prehypertension 120Y139 or 80Y89 Stage 1 140Y159 or 90Y99 hypertension Q160 or Q100 Stage 2 hypertension Diastolic Blood Pressure, mm Hg JNC 7 indicates Joint National Committee on Prevention, Detection, Evaluation and treatment of High Blood Pressure. apnea or hypoventilation, and the prothrombotic state. Both obesity and overweight (defined as a body mass index of 25.0 to 29.9 kg/m 2 ) predispose to or are associated with cardiac complications, including CAD, heart failure, and sudden death. The relationship between obesity and the incidence of CAD was assessed among 5897 women with type 2 diabetes in the Nurses Health Study. 102 These women had no history of CVD at the beginning of the follow-up period, which was up to 20 years. After adjustment for age, smoking, and other coronary risk factors, current body mass index was strongly associated with an increased risk of CAD. The relative risk increased as the body mass index increased. Weight gain before the diagnosis of diabetes was related to an increased risk of CAD, whereas no such association was evident for weight change after the diagnosis of diabetes. Abdominal obesity in particular has been documented as a risk factor for CVD throughout the world. 103,104 Abdominal fat distribution is part of the metabolic syndrome, which also includes insulin resistance, dyslipidemia, and hypertension. Studies have shown that abdominal adiposity is a strong marker for and a major determinant of insulin resistance independent of total adiposity or degree of risk for type 2 diabetes (based on factors such as family history and past gestational diabetes). 105 In addition to energy restriction, other lifestyle modifications should be initiated for obese patients. Increased physical activity is an important component because it leads to increased expenditure of energy and may also inhibit food intake. Evidence has suggested that physical activity has a favorable effect on distribution of body fat, decreasing abdominal obesity. 106 Furthermore, sustained physical activity reduces overall CAD risk beyond that produced by weight reduction alone. 106 Potentially helpful behavioral therapies include stress management, stimulus control, cognitive restructuring, and social support. Type 2 Diabetes and Cardiovascular Risk Compared to people without diabetes, patients with type 2 diabetes are at increased risk of cardiovascular death, particularly CAD death, according to a 12-year follow-up of 347,978 men in the MRFIT study. 94 The number of deaths was per 10,000 person-years in diabetic patients versus 53.2 per 10,000 person-years in those without diabetes. Mortality from CVD, especially CAD, largely accounted for the excess mortality in men with diabetes. Cardiovascular deaths represented 55% of total deaths in men with diabetes and 43% in men without diabetes. Crude CAD and cardiovascular death rates were approximately 5 times higher in men with diabetes compared with men without diabetes. After adjustment for age, race, systolic blood pressure, serum cholesterol level, and number of cigarettes smoked per day, the relative risks for CAD and CVD were 3.2 (P G.0001) and 3.0 (P G.0001), respectively. Other work compared rates of fatal and nonfatal MI among 1,372 nondiabetic subjects and 1,059 patients with type 2 diabetes. 107 The 7-year incidence of MI in patients with diabetes with and without prior MI at baseline was 45.0% and 20.2%, respectively (P G.001). The incidence in people without diabetes with and without prior MI was 18.8% and 3.5%, respectively (P G.001). These data suggest that diabetic patients without previous MI have as high a risk of infarction as do nondiabetic patients with previous MI. Kaplan- Meier estimates of the probability of death from CAD showed that diabetic patients with prior MI had the worst prognosis, whereas nondiabetic subjects without prior MI had the best prognosis (Figure 4). FIGURE 4. Probability of death from coronary artery disease in patients with type 2 diabetes and nonpatients with diabetes with or without prior myocardial infarction. Reprinted with permission from Massachusetts Medical Society B All Rights Reserved. 107

12 Strategies for Risk Assessment and Modification S31 Several studies have attested to the positive effects of specific antihypertensive agents on cardiovascular morbidity and mortality in patients with type 2 diabetes. 108Y111 Another issue of interest in this population is the effect of certain antihypertensive agents on the risk of nephropathy. Insights into this matter came from a trial in which 590 hypertensive patients with type 2 diabetes and microalbuminuria were randomized to receive the angiotensin II receptor blocker irbesartan (150 or 300 mg/d) or placebo for 2 years. 112 Diabetic nephropathy developed in 5.2% of the irbesartan 300 mg group, 9.7% of the irbesartan 150 mg group, and 14.9% of the placebo group (hazard ratios, irbesartan 300 mg: 0.30 [95% CI, 0.14Y0.61; P G.001] and irbesartan 150 mg: 0.61 [95% CI, 0.34Y1.08; P =.08]). The renoprotective benefits of irbesartan were independent of effects on blood pressure, as the average trough blood pressure during the study was only minimally lower in the irbesartan groups than in the placebo group. The impact of irbesartan on progression of nephropathy has been examined as well. In the Irbesartan Diabetic Nephropathy Trial, 1,715 hypertensive patients with nephropathy caused by type 2 diabetes were randomized to treatment with irbesartan 300 mg/d, the CCB amlodipine 10 mg/d, or placebo. 113 The primary end point was the composite of a doubling of the baseline serum creatinine concentration, the development of end-stage renal disease, or death from any cause. At a mean followup of 2.6 years, the occurrence of the primary end point with irbesartan was 20% lower than with placebo (P =.02) and 23% lower than with amlodipine (P =.006). These differences were not explained by differences in blood pressures achieved. The investigators interpreted the findings as demonstrating that irbesartan is renoprotective in patients with nephropathy caused by type 2 diabetes solely because of its restriction of angiotensin activity. Of additional interest are the risks posed by the metabolic syndrome. The NCEP ATP III defines the metabolic syndrome as a constellation of factors including insulin resistance (with or without glucose intolerance), abdominal obesity, atherogenic dyslipidemia (elevated triglycerides, small LDL particles, and low HDL-C), raised blood pressure, and prothrombotic and proinflammatory states. 28 A diagnosis of metabolic syndrome may be made when 3 or more of the risk determinants shown in Table 4 are identified. The age-adjusted prevalence of metabolic syndrome, according to the NCEP ATP III definition, has been estimated to be 23.7% in the United States. 114 The impact of the metabolic syndrome on CAD, cardiovascular, and overall mortality was examined in a prospective cohort study involving 6,255 sub- TABLE 4 Criteria for Clinical Diagnosis of Metabolic Syndrome Measure (any 3 of 5 constitute a diagnosis of metabolic syndrome) Defining Level Abdominal obesity (waist circumference) Men Q102 cm (Q40 in) Women Q88 cm (Q35 in) Triglycerides Q150 mg/dl -or- Drug treatment for elevated triglycerides HDL-C Men G40 mg/dl Women G50 mg/dl -or- Drug treatment for reduced HDL-C Blood pressure Q130 mm Hg systolic -or- Q85 mm Hg diastolic -or- Antihypertensive drug treatment Fasting glucose Q100 mg/dl -or- Drug treatment for elevated glucose HDL indicates high-density lipoprotein. Reprinted with permission from American Heart Association, Inc B jects followed for a mean of 13.3 years. 116 Of this group, 26.0% had metabolic syndrome and 19.8% had preexisting CVD. After adjustment for age, gender, smoking status, physical activity, and total serum cholesterol levels, the metabolic syndrome was associated with a hazard ratio for CAD mortality of 2.02 (95% CI, 1.42Y2.89). A similar increase was apparent with respect to cardiovascular mortality. In addition, the metabolic syndrome was associated with an increase in overall mortality (hazard ratio, 1.40; 95% CI, 1.19Y1.66). The presence of type 2 diabetes or the metabolic syndrome warrants a multifactorial management approach aimed at reducing cardiovascular risk. 28,117 Such an approach was evaluated in an open-label trial in which 160 patients with type 2 diabetes and microalbuminuria were randomized to receive conventional treatment or intensive treatment, the latter composed of behavior modification (such as diet, exercise, and smoking cessation) and pharmacologic therapy (targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria). 117 At a mean follow-up of 7.8 years, decreases in glycosylated hemoglobin, systolic and diastolic blood pressure, serum cholesterol and triglycerides, and urinary albumin excretion rate were all significantly greater in the intensive-therapy than in the conventional-therapy group. In addition, intensive therapy reduced the risk of cardiovascular and microvascular events by approximately 50%. Specifically, the intensive-therapy

13 S32 Journal of Cardiovascular Nursing x November/December 2006 group had significantly lower rates of CVD (hazard ratio, 0.47; 95% CI, 0.24Y0.73), nephropathy (hazard ratio, 0.39; 95% CI, 0.17Y0.87), retinopathy (hazard ratio, 0.42; 95% CI, 0.21Y0.86), and autonomic neuropathy (hazard ratio, 0.37; 95% CI, 0.18Y0.79). Smoking Cigarette smoking has long been recognized as a major risk factor for the development of CAD. 118,119 Smoking exposes an individual to a broad array of substances such as nicotine, carbon monoxide and other gaseous products, and free radicals, all of which may affect the processes of atherogenesis and thrombosis. 120,121 Smoking may adversely influence additional lifestyle factors (such as diet or physical activity), further contributing to the risk of CAD. 122Y124 Furthermore, the 2006 Surgeon General s Report 125 concludes that secondhand smoke has immediate adverse effects on the cardiovascular system and causes CHD. Adverse changes in lipids have likewise been observed in smokers. In the M[nster Heart Study, lipid profiles were evaluated in 20,696 men (36% of whom smoked) and 10,212 women (32% of whom smoked). 120 Compared to nonsmokers, smokers had higher mean levels of LDL-C, total cholesterol, triglycerides, and fibrinogen. These levels were, respectively, 1.4%, 0.9%, 15%, and 12.1% higher in male smokers and 2.0%, 5.5%, 12%, and 3.4% higher in female smokers. Mean HDL-C levels were reduced by 6.4% in male smokers and by 6.7% in female smokers. In a subgroup of 4,639 men with 8 years of follow-up, the rate of coronary events (definite MI or sudden cardiac death) was more than twice as high in smokers (9.1%) than in nonsmokers (3.9%) with otherwise identical risk factors. Other work examined the effects of smoking cessation on lipid levels. 126 Of 26 women who had smoked a minimum of 20 cigarettes per day for the previous 5 years, 12 stopped smoking for 60 days (Bex-smokers[), 6 stopped smoking for 30 days then resumed smoking for an additional 30 days (Bresmokers[), and 8 continued to smoke for 60 days (Bsmokers[). Another 10 nonsmokers served as controls. At baseline, HDL-C levels were 15% to 20% lower (P G.05) in smokers than in nonsmokers. By day 30 after smoking cessation, HDL-C levels increased by 5.7 mg/dl in ex-smokers and by 10.6 mg/dl in re-smokers and were significantly higher than in smokers. By day 60, HDL-C levels of exsmokers further increased (by another 6.8 mg/dl, to 63.9 mg/dl), whereas levels of re-smokers returned to precessation levels (50.7 mg/dl; P G 0.05). These results suggest that low levels of HDL-C associated with smoking are not cumulative and can be reversed in as little as 30 days. Despite heightened awareness of the consequences of smoking, recent statistics indicate that more than 20% of adults in the United States continue to smoke. 127 Behavioral therapy alone is associated with cessation rates of approximately 20%. 128 Nicotine replacement by any delivery system has been shown to double the smoking cessation rate. 128 To maximize the prospects for successful smoking cessation, strategies should integrate both behavioral changes and drug treatment. 129 Through motivational interviewing techniques, healthcare professionals can help patients move from the precontemplation stage to the contemplation stage to the preparation stage. 129 At the latter stage, plans should be made for initiation of nicotine replacement therapy and/or bupropion treatment when indicated. Importantly, continued motivation and support should be provided during the action stage, when the patient has stopped smoking. Group or individual behavioral therapy at this stage can improve quit rates, and the combined use of behavioral and drug therapies can dramatically increase prospects for sustained abstinence. Physical Inactivity Strong evidence from both observational and randomized trials has attested to the fact that regular physical activity contributes to the primary and secondary prevention of CVD and lowers the risk of premature death. 130 The 2006 American Heart Association (AHA)/American College of Cardiology (ACC) guidelines emphasize secondary preventive measures, such as smoking cessation, blood pressure control, lipid management, physical activity, weight management, antiplatelet agents/anticoagulants, renin-angiotensin-aldosterone system blockers, beta blockers, and influenza vaccination for patients with coronary and other atherosclerotic vascular disease. 131 In combination with weight reduction, exercise can also reduce LDL-C levels. In patients with CAD, regular physical activity has been shown to improve exercise capacity and quality of life while reducing symptoms and the risk of new coronary events. 132 A current meta-analysis of exercise-based cardiac rehabilitation included 48 trials (8,940 patients) and showed a reduction of total mortality by 20% and cardiac mortality by 26% in cardiac rehab patients versus controls. 133 Compared with usual care, cardiac rehabilitation was associated with reduced all-cause mortality and cardiac mortality; greater reductions in total cholesterol level, triglyceride level, and systolic blood pressure; and lower rates of self-reported smoking. There were no significant

14 Strategies for Risk Assessment and Modification S33 differences in the rates of nonfatal MI and revascularization and changes in HDL-C and LDL-C levels and diastolic pressure. Health-related quality of life improved to similar levels with cardiac rehabilitation and usual care. Physical activity confers its benefits through favorable effects on coronary risk factors as well as on endothelial dysfunction, inflammation, tendency to thrombosis, autonomic tone, and myocardial ischemia. 132 Public health recommendations have pointed to the value of moderate-intensity aerobic exercise in improving cardiovascular health and reducing the risk of CAD. 134,135 Recent work has suggested that exercise performed at a vigorous intensity may convey even greater cardioprotective benefits. 136 Many health professionals recommend a minimum level of energy expenditure of 1,000 kcal/wk, equivalent to approximately 1 hour of walking on each of 5 days, while acknowledging the additive effects of greater levels of exercise. 137 Nonetheless, even lower levels may offer benefits. The American College of Sports Medicine has advised that energy expenditures as low as 700 kcal/wk provide health benefits, with additional benefits occurring at higher levels. 138 For patients with stable CVD, other observers have recommended a goal of 30 minutes or more of moderate-intensity physical activity on most, if not all, days of the week. 139 Less-intense and shorter durations of activity may suffice for patients with advanced CVD. In recognition of the benefits of physical activity, Medicare has covered cardiac rehabilitation services after MI, coronary artery bypass surgery, and angina since the 1980s. In 2006, after an extensive review of the evidence, Medicare expanded coverage for cardiac rehabilitation to beneficiaries who have undergone percutaneous transluminal coronary angioplasty or stenting, heart valve repair or replacement, or heart or combined heart-lung transplant. 140 National Guidelines for Cardiovascular Risk Reduction Several national organizations have issued guidelines for the reduction of cardiovascular risk. The AHA guidelines for the primary prevention of CVD list recommendations for smoking cessation, blood pressure control, dietary intake, the use of aspirin, blood lipid management, physical activity, weight management, diabetes management, and treatment of chronic atrial fibrillation in adults without coronary or other atherosclerotic vascular diseases. 141 The AHA/ACC guidelines for secondary prevention likewise specify goals for smoking cessation, blood pressure control, lipid management, physical activity, weight management, and diabetes management in patients with atherosclerotic CVD. 131 In addition, direction is given for the use of antiplatelet agents or anticoagulants, ACEIs, and beta blockers. The NCEP ATP III guidelines are aimed at reducing cardiovascular risk primarily though treatment designed to achieve goal LDL-C levels. The Panel advises that when initiating LDL-lowering therapy, the intensity of therapy should be sufficient to achieve at least a 30% to 40% reduction of LDL-C levels. 64 The cutpoints at which lifestyle changes and drug therapy should be initiated are shown in Table 5. The 2006 AHA/ACC Secondary Prevention Guidelines 131 state that, based on current clinical trial evidence, it is reasonable to treat to an LDL G 70 mg/dl in patients with CHD and other clinical atherosclerotic disease. The JNC 7 algorithm for the treatment of hypertension is shown in Figure TABLE 5 National Cholesterol Education Program Adult Treatment Panel III Low-density Lipoprotein Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy According to Risk Categories and Proposed Modifications Based on Recent Clinical Trial Evidence 64 Risk Category High risk: Coronary heart disease (CHD) or CHD risk equivalents (10-year risk 920%) Moderately high risk: 2+ risk factors (10-year risk 10% to 20%) LDL-C Goal, mg/dl LDL-C Level at Which to Initiate Therapeutic Lifestyle Changes, mg/dl LDL-C Level at Which to Consider Drug Therapy, mg/dl G100 Q100 Q100 (Optional goal: G70) (G100: consider drug options) G130 Q130 Q130 (100Y129: consider drug options) G130 Q130 Q160 Moderate risk: 2+ risk factors (10-year risk G10%) Lower risk: 0Y1 risk factor G160 Q160 Q190 (160Y189: LDL-lowering drug optional) HDL indicates high-density lipoprotein; LDL, low-density lipoprotein. Adapted with permission from the American Heart Association, Inc B

15 S34 Journal of Cardiovascular Nursing x November/December 2006 FIGURE 5. JNC 7 algorithm for the treatment of hypertension. Reprinted from Chobanian et al. 91 The American Diabetes Association notes that diabetes and its commonly coexisting conditions, especially hypertension and dyslipidemia, are independent risk factors for CVD. Therefore, the American Diabetes Association recommends ongoing monitoring and, if necessary, treatment both of blood pressure and of lipid levels in addition to usual glycemic control. Furthermore, the American Diabetes Association recommends that patients with diabetes should be treated to a goal blood pressure of G130/80 mm Hg. For lipid control, patients without overt CVD should be treated to a goal of G100 mg/dl for LDL-C and G150 mg/dl for triglycerides. For HDL-C, men optimally should be treated to a goal of 940mg/dL and women to 950 mg/dl. Patients older than 40 years should be treated with a statin to achieve an LDL-C reduction of 30% to 40% regardless of baseline LDL-C. All patients with overt CVD should be treated with a statin to achieve an LDL-C reduction of 30% to 40% and optionally, using highdose statins, to achieve a goal of G70 mg/dl (Table 6). 142 The adherence of healthcare professionals to national guidelines for CVD is not always optimal. 143Y145 This shortcoming is of particular concern in light of studies demonstrating that implementation of guidelines can improve patient outcomes. In the Cardiac Hospitalization Atherosclerosis Management Program (CHAMP), for instance, a systematic approach was implemented to increase use of the AHA/ACC guidelines. Among patients with MI, 14.8% had recurrent infarction or died before CHAMP was initiated. 146 After CHAMP, the rate decreased to 6.4%. Similarly, an analysis of trends from the National Registry of Myocardial Infarction, including data from more than 1.5 million patients, showed that improved adherence to current guidelines for the management of MI reduced in-hospital mortality by 16%. 147 Investigators have identified several potential barriers that should be addressed to improve adherence to guidelines. Examples of such barriers are lack of awareness, familiarity, agreement, self-efficacy TABLE 6 American Diabetic Association Standards of Care: Lipid-level Goals for Diabetic Patients With and Without Cardiovascular Disease 142 LDL-C HDL-C Triglycerides Without cardiovascular disease G100 mg/dl; Men: 940 mg/dl G150 mg/dl 940 years: statin use to achieve 30Y40% Women: 950 mg/dl reduction regardless of baseline LDL levels With cardiovascular disease Statin use to achieve 30Y40% reduction; Men: 940 mg/dl G150 mg/dl Consider high-dose statin to achieve goal G70 mg/dl Women: 950 mg/dl HDL indicates high-density lipoprotein; LDL, low-density lipoprotein

16 Strategies for Risk Assessment and Modification S35 (physician believes he/she cannot perform guideline recommendations), outcome expectancy, and ability to overcome the inertia of previous practice. 142 Through the identification of specific barriers, effective interventions may be applied to improve adherence to guidelines. Examples of such strategies, shown in Table 7, have been suggested to improve physician adherence to preventive cardiology guidelines for women, 148 as well as to provide a useful framework for advancing adherence of all healthcare professionals to the application of guidelines across different patient populations. Two major initiatives directed toward addressing barriers and enhancing adherence are the AHA s Get With the Guidelines program and the ACC s Guidelines Applied in Practice program. Statistically significant and clinically meaningful increases in rates of adherence to recommendations have been documented through the use of these programs. 149,150 It is hoped that continuing efforts to optimize adherence will advance the application of national guidelines in the future and improve outcomes among patients at risk for CAD and related events. TABLE 7 Potential Strategies for Addressing Barriers to Adherence With National Guidelines for Primary and Secondary Prevention of Coronary Artery Disease Barrier Possible Intervention Lack of awareness Traditional continuing medical education (CME) Increased distribution of guidelines Mass media to increase patient awareness Lack of familiarity CME that focuses on specific guideline recommendations Lack of agreement Opinion leaders Physician participation in guideline development Specialty society endorsement of guideline Lack of selfefficacy interactive learning CME focuasing on skills development, Audit and feedback of individual Lack of outcome expectancy Inertia of previous practice External barriers performance Audit and feedback of practice-wide performance Citation of previous published success at improving outcomes through guideline implementation Motivational strategies that utilize audit and feedback Opinion leaders Address specific barrier, such as lack of a reminder system, poor staff support to implement guidelines, poor reimbursement for guideline adherence, etc. Reprinted with permission from Elsevier B These guidelines generally measure myocardial infarction and stroke risk by calculation of the traditional FRS. Although) this approach may suffice for people at very high or very low risk of myocardial infarction within the next 10 years, the predictive power of the FRS is quite lacking for the majority of the population that falls in the intermediate-risk group. The limitations of the current guidelines are recognized by the national organizations, such as the AHA and the NCEP Expert Panel, as well as international groups such as the European Third Joint Task Force. These organizations recommend the use of noninvasive screening tests that identify abnormal arterial structure and dysfunction for people who have multiple risk factors and are stratified to the intermediate-risk group according to the FRS. As stated, CHD is the number 1 cause of death in both men and women and is responsible for more deaths and disability than all cancers combined. Stroke is the leading cause of severe, long-term disability. Still, 30% to 50% of people with atherosclerosis are unaware that they have it until their first acute myocardial infarction. 4,151 Atherosclerosis is responsible for nearly all cases of CHD and many cases of stroke. It begins early in life and is a progressive disease. However, the speed of progression remains unpredictable. 152,153 Despite all this, while screening for breast and colon cancers has become a widely accepted public health policy, screening for subclinical (asymptomatic) atherosclerosis to prevent CVD in at-risk adults is not currently recommended by the US Preventive Services Task Force. 154 The Screening for Heart Attack Prevention and Education (SHAPE) Task Force has recently proposed more aggressive guidelines for determining CVD risk in the general population. The identification and stratification of the Bvulnerable[ patients and their aggressive treatment is the focus of the proposed SHAPE Guidelines. 155 Based on the rapid growth of both the number of people with post-mi heart failure and the cost of clinical care during and after an acute myocardial infarction, the Task Force believes that it is critical to develop a new paradigm to screen for subclinical atherosclerosis. 155Y157 To that end, the SHAPE Guidelines recommend noninvasive screening for atherosclerosis in asymptomatic men 45 to 75 years of age and asymptomatic women 55 to 75 years of age except those who fall into the very low-risk group. Specifically, they recommend measurement of CAC by computed tomography scanning and carotid artery intimaymedia thickness and plaque by ultrasonography to determine the presence and extent of atherosclerosis rather than the traditional

17 S36 Journal of Cardiovascular Nursing x November/December 2006 indirect approach (FRS). This strategy is built around the evidence-based proposition that the major determinant of risk for atherosclerosis in asymptomatic adults is the presence of the underlying subclinical atherosclerosis itself. This new paradigm is outlined in Figure Patients who test positive for atherosclerosis are stratified into 1 of 3 categories (moderately high risk, high risk, and very high risk) based on the magnitude of atherosclerotic burden. Lifestyle modifications and specific LDL cholesterol targets are recommended. Patients who test negative are categorized as lower risk if they are without conventional risk factors and as moderate risk if they have risk factors. Treatment recommendations are according to NCEP ATP III guidelines. The Task Force includes several caveats in their recommendations. First, the importance of therapeutic lifestyle modifications recommended by current guidelines remains applicable in all SHAPE risk categories. In addition, while CAC and carotid artery intimaymedia thickness and plaque scanning are older and have evidence-based validity supporting them, other, newer noninvasive tests, such as MRI of the aorta and carotid arteries and assessment of systemic endothelial dysfunction, which have been shown to predict events, require further validation of their additive value to the sensitivity and specificity of detecting subclinical atherosclerosis. 155 Conclusions The high prevalence of both known and suspected CVD mandates close attention to strategies for risk assessment and modification. Assessment of the cardiovascular risk and related adverse outcomes is traditionally accomplished through appropriate evaluation of factors such as lipid profiles, blood pressure, obesity, smoking, physical inactivity, and especially the presence of diabetes. In many cases, diabetes can be considered a CVD risk equivalent. Studies suggest that diabetic patients without previous MI have as high a risk of infarction as do nondiabetic patients with previous MI. FIGURE 6. The first SHAPE Guideline. 155 Reprinted with permission from Elsevier B