Cardiovascular Disease Update: New Concepts and Management Strategies for Front-Line Clinicians

Only a decade ago, the principal target in treating cardiovascular disease, especially coronary artery disease, was ischemia. Today, however, with the broad array of drug classes for treating hypertension and the tolerability of agents for achieving lipid control, aggressive preventive care focusing on atherosclerosis and other risk factors for cardiovascular events is the first treatment objective. Lipid-control guidelines released by the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP) and the 2003 revisions for blood pressure control provided in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) form the basis of treatment. Each set of recommendations is based on up-to-date clinical evidence regarding potential risk reduction associated with lipid and blood pressure control.

During an adjunct symposium conducted in conjunction with the 31st Annual Meeting of the American Academy of Physician Assistants (AAPA), the faculty discussed these therapeutic guidelines, the clinical trials from which they were derived, and appropriate drugs and drug combinations for specific risk factors. The symposium took place in New Orleans on May 26, 2003 and was chaired by Lisa Mustone Alexander, EdD, PA-C of George Washington University.

This program was supported by an unrestricted educational grant from Pfizer Inc.

Targeting and Treating Patients with Lipid Disorders: Optimal Care Guidelines and Strategies

Based on the ATP III guidelines, Peter H. Jones, MD, of Baylor College of Medicine, asserted that “the intensity of our management should correspond to the patient’s risk for coronary heart disease.” He focused initially on individuals whose risk is calculated to be at least 20% over the next 10 years.

Low-density lipoprotein cholesterol (LDL) is the first target of therapy. Patients with LDL values of 130 mg/dL and above should be treated with “statin” agents and with lifestyle changes consisting of smoking cessation, weight loss to a body mass index (BMI) of 18.5 to 24.9, reduced alcohol and sodium consumption, low-fat dairy products, and moderate daily aerobic exercise. For patients whose LDL readings are between 100 mg/dL and 130 mg/dL, lifestyle change is essential, and treatment with either statins or fibrate drugs, derivatives of fibric acid, may be advisable. In all cases, the goal is to reduce the LDL value to below 100 mg/dL.

For patients with normal LDL levels who already have evidence of coronary heart disease or equivalents (e.g., non-coronary atherosclerosis, diabetes), there has until recently been no evidence that further lipid lowering will reduce coronary events. However, evidence emerging from the Heart Protection Study (HPS) suggests that lipid-lowering may be appropriate in these patients as well. This was a large (N=approximately 20,000) placebo-controlled study in which half of patients at elevated risk for cardiovascular events were randomized to receive simvastatin. Over a period of 5 years, there was an overall 25% reduction in major coronary events and strokes in the treatment arm compared with patients taking placebo. Importantly, when the patient population was aggregated into three groups according to baseline LDL values, there were no significant differences in major coronary events or stroke among the groups. Instead, patients with baseline LDL values of less than 100 mg/dL tended to have the same risk reduction as those with LDL readings in excess of 130 mg/dL. This suggests that statin therapy reduces major coronary events and strokes irrespective of baseline LDL. It also suggests that statins may have pleiotropic effects, that is, effects on vascular biology that are independent of their ability to reduce circulating LDL.

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which was designed principally as a hypertension study, contained a subset of patients whose risk for major cardiovascular events was high because of three or more concurrent risk factors including moderate LDL elevation. These patients were randomized to hypertension therapy alone or to both antihypertensive therapy and lipid-lowering treatment with atorvastatin. In this subset of patients, over the following 42 months of treatment with dual therapy there was a 36% reduction in major cardiovascular events, a 27% reduction in stroke, and a 13% decrease in all-cause mortality. The mean reduction in circulating LDL was 30% to 35%. As in the HPS, these outcomes did not correlate with baseline LDL values, suggesting two things. First, an aggressive approach to preventive treatment targeting both lipids and blood pressure in high-risk patients is superior to a single strategic target. Second, preventive treatment targeting lipids should be based on the global risk of cardiovascular disease rather than on baseline LDL.

The Antihypertension and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) randomized a subset of patients (approximately 10,000) with hyperlipidemia to either usual care or lipid treatment with pravastatin and followed them for almost 5 years. There was no significant reduction in cardiovascular events (9%; p>0.05) and the mean decrease in LDL was 17% (as compared with 30% or more in ASCOT). The differences in the outcomes of these trials may have been due to an older and more ethnically diverse population in ALLHAT or to the fact that some patients in the usual-care arm were taking statins. Nevertheless, it illustrates that in order to achieve improved cardiovascular outcomes, the patient must take a statin dose sufficient to achieve a reduction of at least 20% in circulating LDL.

It is estimated currently that almost 25% of Americans over the age of 20 years have metabolic syndrome, with a disproportionately high prevalence among the Hispanic population (up to 35%) and in the older population (potentially as high as 55%). In a cardiology or endocrinology practice, probably half of patients have metabolic syndrome.

Metabolic syndrome, also referred to as syndrome X and cardiometabolic syndrome, is a complex of cardiovascular risk factors including hypertension, decreased high-density lipoprotein cholesterol (HDL), obesity (especially central adiposity), elevated triglycerides, and impaired fasting glucose with insulin resistance (pre-diabetes). The presence of any three of these risk factors justifies a diagnosis of metabolic syndrome.

In the ATP III, diabetes is not considered a risk factor for cardiovascular disease, but a risk equivalent, meaning that it imparts a risk of a major cardiovascular event equivalent to that of an individual who has had one such event. Remarkably, however, many of the components of metabolic syndrome are not listed as risk factors in ATP III nor are they included in the Framingham Risk Score. From a pathophysiological perspective, pre-diabetes is thought to be the stage in which most large vessel atherosclerotic disease occurs, whereas microvascular disease (retinopathy, nephropathy) occurs after the onset of overt hyperglycemia. Thus, metabolic syndrome may be a disease continuum in which a high risk for cardiovascular damage commences early, requiring early intervention. “I consider the metabolic syndrome to be close to a coronary heart disease equivalent,” Dr. Jones said.

In addition to high LDL cholesterol and the metabolic syndrome, age is a significant risk factor for cardiovascular events. Both the HPS and the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) have demonstrated that the treatment of high-risk patients aged 70 years or older for 5 years reduces all cardiovascular events, including stroke, and is a very safe strategy.

Low HDL is another risk factor for cardiovascular disease. It is typically treated with exercise, weight loss, and smoking cessation. Whether or not pharmacologic intervention is beneficial is unresolved, although there does appear to be some benefit from the use of fibrate drugs. Furthermore, in the HPS, patients with low baseline HDL values had the highest risk of coronary disease in the placebo group and the greatest risk reduction in the statin group. Thus, a two-step approach to low HDL may be warranted in patients with coronary heart disease or diabetes: lowering LDL cholesterol to less than 100 mg/dL with statin therapy plus use of a fibrate drug to increase HDL. Supporting evidence for the use of fibrate agents comes from the Veterans Affairs HDL Intervention Trial (VA HIT), in which the trial drug was gemfibrozil. For patients with mixed lipid abnormality consisting of non-optimal LDL, slightly elevated triglycerides, and low HDL, statin-based combination therapy with a fibrate or niacin may be beneficial.

Many patients with cardiovascular risk factors are inquiring about C-reactive protein (CRP) as a marker for disease risk. It is currently the only candidate for use as a marker for inflammation, but it is not a routine screening instrument. It should be reserved exclusively for assessing intermediate-risk primary prevention patients where it may indicate a need for more aggressive management strategies than usual.

In the secondary prevention setting, life-long statin treatment should begin in the hospital at the time of an acute coronary syndrome. In a Swedish study, statin therapy initiated in the hospital and continued thereafter was associated with a 1-year decrease in all-cause mortality of 25% to 30% compared with patients who did not take statins. The goal is to achieve a durable reduction in LDL of 20% or more, which can be reached or improved with upward dose titration.

The JNC 7 guidelines establish the upper limit of normal blood pressure as systolic pressure of less than 120 mm Hg and diastolic pressure of less than 80 mm Hg. What was previously called borderline hypertension is now prehypertension, the boundaries of which are 120-139/80-90 mm Hg. Blood pressures in the range of 140-159/90-99 mm Hg comprise Stage I hypertension, and Stage II hypertension is defined as systolic pressure greater than 160 mm Hg or diastolic pressure greater than 100 mm Hg. In Stages I and II, the therapeutic goal is to achieve and maintain a blood pressure of less than 140/90 mm Hg except in patients with diabetes or chronic renal disease, for whom the goal is blood pressure of less than 130/80 mm Hg. Robert A. Kloner, MD, PhD of the University of Southern California, discussed treatments for hypertension.

All patients with elevated systolic and/or diastolic blood pressures are treated with lifestyle changes. At Stage I, patients with no “high-risk conditions with compelling indications for individual antihypertensive drug classes” (see Table 1) are treated with thiazide-based diuretics. This treatment may be taken in combination with angiotensin-converting enzyme (ACE) inhib-itors, angioten-sin receptor blockers (ARB), beta-blockers, or calcium channel blockers (CCB). Stage II hypertension should be treated initially with combination therapy including diuretics. Some patients may require triple therapy. If a patient fails to achieve the treatment goal, doses should be increased and drug classes added.

The risk for hypertension increases with age; and in individuals over the age of 60 years, the most common form is isolated systolic hypertension. The Systolic Hypertension in the Elderly Program (SHEP), a randomized and placebo-controlled study in which elderly patients with isolated systolic hypertension were treated with chlorthalidone diuresis with or without the beta-blocker atenolol, demonstrated a 36% decrease in stroke rate and significant reductions in coronary artery events and heart failure over 60 months. CCBs are also effective in the treatment of systolic hypertension. In a study comparing
the responses of older patients with moderate-to-severe hypertension to mono-therapy with either amlodipine or hydrochlorothiazide, the CCB was associated with a mean reduction in systolic pressure of 32 mm Hg compared with 23 mm Hg in patients taking the diuretic (p<0.001). In the European Systolic Hypertension (SYST-EUR) study, treatment with long-acting dihydropyridine CCB nitrendipine significantly reduced fatal and nonfatal stroke and, after a year, fatal and nonfatal myocardial infarction as well.

Dr. Kloner pointed out, however, that some CCBs may worsen heart failure. These include diltiazem, varapamil, and nifedipine. In contrast, the second Prospective Randomized Amlodipine Survival Trial (PRAISE II) demonstrated that amlodipine is neutral in this regard. In other studies, felodipine and nisoldipine did not worsen heart failure. He also noted that subsets of patients may respond differently to single-agent therapies. In one VA study, for example, older African-Americans responded best to the CCB diltiazem, followed by hydrochlorothiazide diuresis. Their response to the ACE inhibitor captopril was generally poor. In contrast, elderly Caucasian patients responded best to beta-blockers and CCBs, with less of a response to diuretics. The Amlodipine Cardiovascular Community Trial (ACCT) looked specifically for differential responses to CCB therapy related to age, gender, and race. Ninety-two percent of older patients achieved the goal of diastolic pressure of less than 90 mm Hg compared with 84% of younger patients. There were no differences between races. Over 90% of women and 83% of men achieved the blood pressure goal.

In a study of diastolic hypertension, the Hypertension Optimal Treatment (HOT) study randomized 18,000 patients with diastolic pressures in the range of 100 mm Hg to 115 mmHg to be treated to goals of 90 mm Hg or less, 85 mm Hg or less, and 80 mm Hg or less. All patients started on felodipine, but ACE inhibitors, beta-blockers, and/or diuretics could be added to achieve targets. The optimal diastolic pressure for reducing risk for major cardiovascular events was 82.6 mm Hg. In the subset of patients with diabetes, significant risk reduction was associated with diastolic pressures below 80 mm Hg.

ACE inhibitors are the cornerstone of therapy for heart failure as demonstrated in the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), in which the trial drug was associated with a significantly decreased probability of death. In the Survival and Ventricular Enlargement (SAVE) study, captopril was associated with a 24% reduction in death from cardiovascular causes in post-myocardial patients with left ventricular dysfunction. In the Heart Outcomes Prevention Evaluation (HOPE), in which the trial drug was ramipril, there was a multi-year reduction in the composite outcome of myocardial infarction, stroke, and death in the treatment arm. This was not expressly a hypertension trial. Nevertheless, monitoring of trough blood pressure 24 hours after the drug was taken revealed a mean reduction in systolic pressure of 3 mm Hg and in diastolic pressure of only 2 mm Hg. However, a more recent analysis of patients who had ambulatory monitoring of blood pressure in the trial suggested much greater decreases—10 mm Hg in systolic and 4 mm Hg in diastolic pressures. The initial interpretation of HOPE data was that risk reduction was due to the fact that ramipril is highly specific for the tissue angiotensin system. The revised blood pressure data suggest, rather, that it may be due at least in part to decreased blood pressure. In HOPE, the greatest benefit from ACE inhibition was observed in patients with diabetes. Captopril has subsequently been shown similarly to benefit patients with insulin-dependent diabetes with nephropathy, in whom it reduces blood pressure, preserves the glomerular filtration rate, and reduces albumin excretion.

ACE inhibitors frequently induce a chronic cough, so ARBs may be preferable for some patients. Losartan, which is effective in monotherapy for hypertension, has recently been compared with amlodipine for the control of sitting systolic and diastolic blood pressures. In the comparison, losartan induced mean reductions of approximately 14 mm Hg and 10 mm Hg, compared with 16 mm Hg and 13 mm Hg for amlodipine. The role of ARBs in heart failure is controversial. In the first Evaluation of Losartan in the Elderly (ELITE I) trial, treatment with losartan appeared to provide a survival benefit compared with captopril. However, in ELITE II, no difference was observed between the two treatments with respect to hospitalization and all-cause mortality. During this trial, however, there was a greater incidence of sudden cardiac death and resuscitated cardiac arrest in the losartan arm that was of borderline significance. This outcome contrasts with that of the Valsartan-Heart Failure Trial (Val-HeFT), in which the treatment drug appeared to have a beneficial effect on morbidity. Nonetheless, because the controversy remains unresolved, ACE inhibitors remain the preferential agent in the setting of heart failure. However, in patients with hypertension and type 2 diabetes, ARBs are quite effective in inducing improvements in proteinuria.

Dr. Kloner characterized the ALLHAT study as “the largest NIH-sponsored outcome trial in hypertension that has ever been done, including 42,448 patients with systolic blood pressures of 140 mm Hg or greater and diastolic blood pressures of 90 mm Hg or more over several visits.” Patients were randomized to receive thiazide-based diuresis (chlorthiadone), a long-acting dihydropyridine CCB (amlodipine), an ACE inhibitor (lisinopril), or an alpha blocker (doxazosin), the last of which was subsequently discontinued because of frequent signs and symptoms of heart failure. In each arm, other classes of drugs were added after 3 months if patients failed to reach and sustain blood pressures of 140/90 mm Hg or below. At the end of 5 years, all drugs had decreased systolic blood pressures significantly. Importantly, there were no significant differences among treatments in relative risk of cardiac death or nonfatal myocardial infarction. In comparison with the diuretic, the relative risk of stroke associated with amlodipine was lower, but the difference was not statistically significant. There was, however, a significantly higher risk of stroke with lisinopril versus the thiazide diuretic.

Following the formal presentations, Dr. Alexander introduced two case studies that illustrated the importance of treating global risk for cardiovascular events with both antihypertensive and lipid-controlling agents.