High-Risk Patients Along the Cardiovascular Continuum

Despite advances in treatment modalities in recent years, cardiovascular disease (CVD) remains one of the largest contributors to morbidity and mortality throughout the industrialized world. Hypertension, diabetes, and other risk factors initiate a succession of pathophysiologic changes constituting a continuum of cardiovascular damage that may eventuate in end-stage organ disease, including congestive heart failure and kidney failure, leading to death. Thus, the effective treatment of hypertension and other risk factors for CVD is essential to prevent progression along the continuum. Evidence-based lipid control guidelines were released in 2001 by the Adult Treatment Panel of the National Cholesterol Education Program; and in 2003 the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) announced revised guidelines.

At present, heart failure constitutes the foremost financial burden of Medicare, costing an estimated total in 2003 of approximately $24.3 billion, and half of all patients starting hemodialysis annually have diabetes. The population with diabetes and hypertension, therefore, is at particularly high risk for cardiovascular events and is an important source of enrollees for trials evaluating new drugs for hypertension, heart failure, and nephropathy.

These issues were discussed by the faculty of a satellite symposium conducted in New Orleans during the 2003 Annual Meeting of the American Academy of Physician Assistants.

This program was supported byan unrestricted educational grant from Novartis Pharmaceuticals Corporation.

Current Perspectives and Future Outlook

Twelve years ago, Dzau and Braunwald proposed a model of cardiovascular disease as a continuum that starts with risk factors leading to atherosclerosis and left ventricular hypertrophy (LVH) followed by myocardial infarction, vascular remodeling, ventricular dilation, congestive heart failure, end-stage heart disease, and death (Dzau V, Braunwald E. Am Heart J 1991;121:1244). Prominent among the risk factors was hypertension, along with diabetes, hyperlipidemia, obesity (especially central adiposity), and smoking.

Michael A. Weber, MD, of the State University of New York Downstate College of Medicine in Brooklyn, presented recent evidence that even modest elevations in blood pressure may initiate this continuum. In the Framingham Heart Study, for example, a comparison of cardiovascular events among individuals with optimal blood pressures (below 120/80 mm Hg), those with normal blood pressures (120-129/80-84 mm Hg), and those with high normal blood pressures (130-139/85-89 mm Hg), the category that JNC 7 identifies as prehypertension, observed a very large increase in the incidence of cardiovascular events over 12 years associated with prehypertension with statistically identifiable separation within 2 years (Vasan RS. N Engl J Med 2001;345:1291). The increase in risk was significant for both men and women, but was considerably greater among women. Typically, individuals with prehypertension are not treated unless they have other risk factors such as diabetes.

Additional evidence of the role of hypertension in the cardiovascular continuum comes from the United Kingdom Prospective Diabetes Study (UKPDS), in which patients with diabetes and a mean baseline blood pressure of 160/94 mm Hg were randomized for treatment to tight blood pressure control (144/82 mm Hg) versus less tight control (154/87 mm Hg). The difference of 10/5 mm Hg (p<0.0001) was associated with decreases in deaths by 22%, in myocardial infarction by 17%, and in stroke by 44% in the tight-control group (UKPDS 38. Br Med J 1998;317:703). Interestingly, classic diabetic endpoints such as dysautonomia, blindness, and sexual dysfunction were also improved with tight blood pressure control compared with tight glucose control alone.

Despite the compelling evidence of the long-term health consequences of inadequate blood pressure control, it is currently estimated that 53.1% of individuals treated for hypertension in the United States are not controlled to systolic blood pressure of less than 140 mm Hg (Hajjar I, Kotchen TA. JAMA 2003;290:199), indicating that their risk for myocardial infarction or stroke is multiplied by a factor of two to four depending on the degree of elevation in each individual. Note also that in UKPDS 38, tight blood pressure control was defined as 144/82 mm Hg, whereas JNC 7 recommends a treatment goal of below 130/80 mm Hg for patients with diabetes and/or proteinuria.

A review of five major clinical studies of hypertension concluded that achieving and maintaining normal blood pressure in patients with hypertension requires between three and four drugs of different antihypertensive classes (Bakris GL. J Clin Hypertension, in press). This requirement may be slightly high because the studies tended to enroll more difficult-to-treat patients than are seen in daily practice. Nevertheless, it is widely accepted that monotherapy will suffice for only a small fraction of patients.

The Losartan Intervention for Endpoint Reduction trial (LIFE) enrolled patients with hypertension and EKG evidence of left LVH, patients who were at high risk for cardiovascular events during the 5-year study. Patients were randomized to receive either losartan, an angiotensin receptor blocker (ARB), or atenolol, a beta blocker, together with hydrochlorothiazide for diuresis (Dahlof B et al. Am J Hypertension 1997;10: 705). Although the two regimens led to almost identical blood pressure control, the group treated with the ARB had 25% reductions in the incidence of stroke and new-onset diabetes, indicating that ARBs may have pharmacologic properties that are protective against critical endpoints. The German and Austrian Acute Candesartan Cilexitil Therapy in Stroke Survivors (ACCESS) trial randomized patients being released from hospitals following treatment for stroke to conventional antihypertensive regimens or to candesartan, another ARB, with other drugs added as necessary to control blood pressure. This secondary prevention trial was discontinued early because of clear evidence that although blood pressure control was the same in the trial arms, primary events (total mortality, stroke, all cardiovascular events) were significantly reduced with ARB therapy to 9.8% compared to 18.7% with conventional treatment.

Progressing along the continuum, Dr. Weber turned his attention to LVH. This is a common occurrence in patients with hypertension, and is usually detectable by electrocardiogram. LVH is an important predictor of cardiovascular disease. In an analysis of Framingham Heart Study data, for example, the annual rate of cardiovascular disease correlated with low, borderline, and definite LVH in both women and men ages 35 through 64 years, and definite LVH correlated strikingly with cardiovascular disease in older patients. In each age group, risk was higher among men than women (Cupples LA, D’Agostino RB. DHHS publication 87-2703, 1987). It has been demonstrated, however, that antihypertensive therapy may induce left ventricular mass regression. Improve-ments have been observed in association with beta blockers, calcium antagonists, diuretics, and angiotensin-converting enzyme (ACE) inhibitors with the greatest mean benefit (approximately 18%) associated with ACE inhibitors (Dahlof B et al. Am J Hypertension 1992;5:95). The trial was conducted prior to the advent of ARBs.

Referring once again to the Framingham Heart Study, Dr. Weber cited evidence that hypertension preceded heart failure in 91% of cases, and that it carried the greatest risk for development of heart failure among all risk factors. After adjustment for age and other risk factors, hypertension was associated with a two- to three-fold risk of heart failure (Levy D et al. JAMA 1996;275:1557). The cumulative incidence of heart failure increases with age and is correlated with the severity of hypertension. Heart failure is increasingly common, probably because contemporary treatments enable more patients to survive myocardial infarction and other cardiovascular events.

In light of the causal role of hypertension in heart failure, the effective treatment of high blood pressure is essential for prevention. For those patients who progress to heart failure, however, pharmacologic intervention may provide benefit. ACE inhibitors have been the cornerstone of treatment for the last half-decade. The more recent Valsartan-Heart Failure Trial (Val-HeFT) has provided evidence, however, that ARBs may have a role in this setting as well. In this study, 5,010 patients with heart failure, all of whom were taking conventional heart failure regimens, were randomized to additional valsartan or placebo (Cohn JN et al. N Engl J Med. 2001;345:1667). In the valsartan arm, there was a statistically significant but not dramatic decrease in morbidity (13.2%; p=0.009). For the combined endpoint of morbidity and mortality, however, there was a 44% risk reduction associated with ARB therapy (p<0.0002). Importantly, valsartan was also associated with a 25.7% risk reduction for first hospitalizations for heart failure (p<0.001). For a small number of patients who were not taking ACE inhibitors and were randomized to valsartan, the risk reduction for mortality and hospitalization was 44%. Based on data from this trial, the FDA has given an indication to valsartan for use in heart failure for patients who are intolerant of ACE inhibitors. If at least two more studies expected to come to completion in 2003 confirm the role of ARBs in heart failure, they may become the treatment of choice in this setting.

Domenic A. Sica, MD, of the Medical College of Virginia of Virginia Commonwealth University, addressed the role of hypertension in the development of chronic kidney disease (CKD), another life-threatening consequence of vascular dysfunction within the continuum of cardiovascular disease. CKD is defined as 3 months or longer of kidney damage with or without a decreased glomerular filtration rate (GFR), or GFR of less than 60mL/min.1.73 m2 for 3 months or longer with or without kidney damage. CKD affects approximately 17% of the United States population over the age of 20 years. Microalbuminuria indicates the onset of nephropathy irrespective of creatinine level or GFR. “Chronic kidney disease is a progressive disease that is driven by hypertension, diabetes, and probably by neglect,” Dr. Sica said. Thus, effective treatment of CKD also treats cardiovascular disease and vice versa.

The amount of albumin in a patient’s urine is predictive of myocardial infarction and stroke, reflects vascular endothelial damage, and is a component of the cardiometabolic syndrome. Progression from microalbuminuria to macroalbuminuria coincides with the progression of renal disease and, at the same time, increased risk for a cardiovascular event. “In fact,” Dr. Sica said, “the detection of albuminuria is the simplest and least expensive form of coronary artery risk assessment we have.” An analysis of multiple studies correlating microalbuminuria levels with cardiovascular morbidity and mortality in patients with type 2 diabetes has determined that the risk ratio is approximately 2.0 (range=1.1 to7.0) when microalbuminuria is present (Dinneen SF et al. Arch Intern Med. 1997;157:1413). Figure 1 depicts the relationship among systolic blood pressure, albuminuria, and the relative risk of ischemic heart disease. The data reported there indicate that the occurrence of albuminuria calls for aggressive antihypertensive therapy even in individuals with small elevations in systolic blood pressure. In a different study, there was a statistically significant (p<0.001) cor-relation between levels of urinary protein and the incidence of stroke and coronary heart events in patients with type 2 diabetes (Mietttinen H et al. Stroke. 1996;27:2033). Among individuals with type 2 diabetes and microalbuminuria, approximately one in six will progress to macroalbuminuria in any 2-year period.

In the pathophysiology of proteinuric CKD, the kidney attempts to recapture spilt protein and, in the process, it is called upon to metabolize the protein. This progression induces a wide range of inflammatory processes within the kidney that further accelerate renal functional decline. The therapeutic objective, therefore, is to prevent such loss of protein. Several clinical trials have demonstrated statistically significant renal benefit from treatment with ACE inhibitors (p<0.01 to <0.001). In the African American Study of Kidney Disease and Hypertension (AASK), patients randomized to ACE inhibitor-based antihypertensive therapy (ramipril) and those randomized to the calcium channel blocker amlodipine, both with additional drugs added as needed to achieve blood pressure targets, had equivalent blood pressure reductions. However, those in the ramipril trial arm had significantly fewer GFR events (or decline in renal function) and a reduced likelihood of end-stage renal disease, resulting in premature discontinuation of the amlodipine treatment arm. These events were most notable in AASK study subjects with proteinuria. (AASK Study Group. JAMA. 2001;285:2719).

These results are consistent with those observed in a subpopulation of the Heart Outcomes Prevention Evaluation (MICRO-HOPE), a ramipril-based study of patients at high risk for cardiovascular events. In this review of patients with albuminuria, randomization to ramipril was associated with slowed progression to overt nephropathy (The HOPE Study Investigators. Lancet 2000).

More than half of patients who commence hemodialysis annually in the United States have diabetes, predominantly type 2 diabetes. Therefore, individuals with diabetes and hypertension comprise an important trial population for the evaluation of drugs for slowing the progression of nephropathy. One such trial was the second Irbesartan in Patients with Diabetes and Microalbu-minuria study (IRMA 2), in which patients randomized to irbesartan 300 mg had significant improvement in albuminuria over 24 months compared with irbesartan 150 mg, placebo, and both non-ACE inhibitor and non-ARB conventional therapy (p<0.001 versus placebo). The differences appeared to be blood-pressure-independent (Parving H-H et al. N Engl J Med 2001;345:870). In a second trial, the Microalbuminuria Reduction with Valsartan (MARVAL) study, patients were randomized to receive either valsartan 80 mg or amlodipine 5 mg and followed for 6 months. In the amlodipine trial arm, there was virtually no reduction in the mean urinary albumin excretion rate compared with a mean 45% reduction with valsartan treatment despite equivalent blood pressure control (Viberti GC, Wheeldon NM. Circulation 2002;106:672). In the intent-to-treat population, 29.9% of patients treated with valsartan returned to normoalbuminuric status compared with only 14.5% in the amlodipine arm (p<0.001).

In addition to the foregoing trials, two outcomes trials add to the evidence of renal benefit from ARB therapy in patients with type 2 diabetes. In the Reduction of Endpoints in Type 2 Diabetes with the Angiotensin II Antagonist Losartan (RENAAL) trial, patients were randomized to conventional antihypertensive therapy or to losartan titrated up to 100 mg. Losartan therapy was associated with a 28% risk reduction for the development of end-stage renal disease (p=0.002) and a 20% risk reduction for death (p=0.01) during the almost 3.5 years of study followup (Brenner BHM et al. N Engl J Med. 2001;345:861). In the Irbesartan Diabetic Nephropathy Trial (IDNT), irbesartan was compared with conventional therapies and amlodipine. Over a median followup of approximately 30 months, patients treated with irbesartan had significantly longer time to doubling of serum creatinine and a significantly lower rate of onset of end-stage renal disease with a 23% risk reduction versus amlodipine (p=0.006) and 20% versus conventional therapies (p=0.024) (Lewis EJ et al. N Engl J Med. 2001;345:851). On the strength of the data from RENAAL and IDNT, the FDA approved a labeled indication to both losartan and irbesartan for use in type 2 diabetic nephropathy.

The American Diabetes Association now recommends the use of either ACE inhibitors or ARBs in patients with diabetic nephropathy. These two drug classes are comparably efficacious. One difference between the two classes, however, is that ARBs are cleared primarily by the liver, whereas ACE inhibitors are mostly cleared renally. The result is that upon repetitive dosing in the setting of CKD, ACE inhibitors may accumulate. The significance of this is currently unknown. In addition, while ACE inhibitors induce an annoying cough in approximately 15% of patients and induce angioneurotic edema of varying severity in about 0.5% of patients (1.5% of African- American patients), ARBs are generally devoid of adverse side effects. ARBs also produce a lesser increment in serum potassium values than is the case with ACE inhibitors.

Optimizing Outcomes: PA Contributions to Managing Cardiovascular Patients

Lisa Mustone Alexander, EdD, MPH, PA-C, of George Washington University, presented the case of a 52-year-old African American male referred from the Emergcncy Room because of elevated blood pressure. He reported the acute onset of episodes of numbness of his right arm and face over the last 12 months and shortness of breath upon walking moderate distances. Although he had previously been treated for hypertension, he had discontinued his medications. He had a 30 pack year history of smoking, and came from a family rife with diabetes, stroke, hypertension, and unspecified heart problems. His blood pressure at the time of referral was 180/105 mm Hg, his pulse was 88 beats per minute, and his weight was 235 pounds yielding a BMI of 33. The patient’s funduscopic examination showed grade 2 changes. Although his cardiac rhythm was normal, his PMI was displaced, and he had a slight carotid bruit. His EKG revealed LVH but no ischemic changes. His nonfasting glucose and cholesterol were elevated and his serum potassium slightly decreased.

Based on his presenting blood pressure and global evidence of high risk for cardiovascular disease, he was scheduled for a lipid profile, fasting glucose, and urinalysis. These tests revealed elevated triglycerides and LDL, low HDL, fasting glucose elevation, and 2+ proteinuria. These data indicated a likely diagnosis of metabolic syndrome with macroproteinuria indicating advanced nephropathy. The patient was started on antihypertensive therapy with a blood pressure target of less than 130/85 mm Hg. Renal involvement indicated the need for including either an ACE inhibitor or an ARB in his treatment. Medications for glucose control and lipid lowering were also initiated. The patient was advised on lifestyle modifications including smoking cessation, regular moderate exercise, a DASH (Dietary Approaches to Stop Hypertension) diet, and both sodium and alcohol restriction. Subsequently he was monitored for blood pressure, lipid profile, glucose control (HgbA1c [glycosylated hemoglobin] less than 7%), and waist circumference.

This case illustrates the urgency of aggressive behavioral and pharmacologic intervention in patients with multiple risk factors for cardiovascular disease even after the appearance of end-organ pathology. More importantly, perhaps, it illustrates the need for public education on the prevention of end-organ disease through the timely detection of and intervention in hypertension, diabetes, and hyperlipidemia.