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Targeted RAS Blockade in the Spectrum of Cardiovascular and Renal Disease: Opportunities for Early Intervention and End-Organ Protection

Endothelial Dysfunction and Atherosclerosis: Emerging Evidence for ARBs

The endothelium is a biologic organ serving to regulate vessel wall structure and function. Endothelial dysfunction can occur early in life, increasing the risk for cardiovascular and other serious disease. “Research studies have shown potential benefits of both angiotensin- converting enzyme [ACE] inhibitor and angiotensin receptor blocker [ARB] agents in treating endothelial dysfunction; however, further investigation is needed to determine whether one drug class is more effective than the other,” said Domenic Sica, MD, Professor of Medicine and Pharmacology; and Chair, Section of Clinical Pharmacology and Hypertension, Division of Nephrology, Medical College of Virginia Commonwealth University, in Richmond. According to Dr. Sica, this effort may prove challenging due to the variability of properties and effects of individual ACE inhibitor and ARB agents.

Endothelial Dysfunction
The endothelium is an immense biologic organ, comprising more than 14,000 square feet of surface area and having a variety of important properties and functions (Table 1). Disturbance in endothelial function—which leads to structural and functional abnormalities—can begin to develop with a number of conditions, including obesity (especially visceral obesity), hypertension, and hypercholesterolemia (Tounian et al, Lancet 2001; Mancini, Can J Cardiol 2002; Li et al, Endothelium 2003).

The effects of endothelial dysfunction are serious, and include vascular remodeling and increased risk for cardiovascular disease. Importantly, vasodilating agents, such as acetylcholine, can become vasoconstrictive in the presence of endothelial dysfunction.

“A key factor in endothelial dysfunction is the tug of war that occurs between nitric oxide bioavailability and angiotensin II accessibility,” Dr. Sica explained. A primary angiotensin-related change is an increase in reactive oxygen species or oxidative stress, creating a change in endothelial function and modifying a wide range of smooth muscle cell processes. Angiotensin II creates an overabundance of reactive oxygen species, which alter the bioavailability of nitric oxide. In turn, changes occur in endothelium-dependent vasodilation and potential for angiotensin II to facilitate oxidation of LDL and upregulation of LOX-1 receptors, resulting in tissue injury and ultimately atheromatous lesions.

Treatment strategies to modify endothelial function serve to increase nitric oxide bioavailability or decrease the quantity or qualitative function of angiotensin II. ACE inhibitors serve to produce the first effect, ARBs the second.

Treatment Options
ACE inhibitors and ARB agents are two treatment types used to interrupt the renin-angiotensin system (RAS). ACE inhibitors operate by reducing the activity of ACE, producing a short-term reduction in angiotensin II. ARBs work by binding to the AT1 receptor, slowing angiotensin II activity. Both drug classes produce similar results in blood pressure reduction and hemodynamic, antiproteinuric effects. In terms of endothelial function, ACE inhibitors have been shown to modify bradykinin balance, which may favorably modify nitric oxide bioavailability. However, studies in patients who are elderly and/or have coronary artery disease (CAD), hypertension, or diabetes have raised more questions than answers about therapeutic effects on endothelial function. “In studies that utilize full-dose ACE inhibitor and ARB agents, benefits on endothelial function have been comparable,” Dr. Sica said (Mancini, Can J Cardiol 2002; Taddei et al, Curr Hypertens Rep 2000; Schiffrin et al, Am J Hypertens 2002).

In one parallel study, patients received either ramipril or losartan therapy for 4 weeks. The findings showed comparable effects on vasodilation and extracellular SOD. In another study, normotensive patients with CAD received irbesartan for 6 months, resulting in a dramatic decrease in VCAM, tumor necrosis factor, and superoxide levels (Horning et al, Circulation 2001; Khan et al, J Am Coll Cardiol 2001).

In another study, hypertensive patients underwent gluteal biopsy, and received atenolol for approximately 1 year. This regimen produced good blood pressure reduction, but no change in vessel structure. Patients then received irbesartan for approximately 1 year, with gluteal re-biopsy. These results showed changes in intimal to medial ratio, and return to normal function of the endothelium. “ARB therapy has shown improved vasomotor endothelial function, modified inflammatory markers, and structural remodeling of small caliber vessels, in timewise fashion,” Dr. Sica said (Schiffrin et al, J Hypertension 2002).

Conclusion
In closing, Dr. Sica noted that “while preliminary studies indicate that positive effects of ACE inhibitors and ARBs on endothelial function are likely comparable, head-to-head trials are needed to compare the two drug classes as well as individual ACE inhibitor and ARB agents,” the speaker concluded.

 

 


 Microalbuminuria as a Biomarker for Cardiovascular and Renal Disease: The Case for Early Intervention

Patients with hypertension and/or diabetes are at increased risk for renal damage and cardiovascular disease. “These patients need early intervention for
better control of all cardiovascular risk factors, including blood pressure, cholesterol, and glucose,” said Matthew R. Weir, MD, Professor of Medicine and Director, Division of Nephrology, University of Maryland Medical School in Baltimore. According to Dr. Weir, an important screening tool for the early identification of those at high risk for myocardial infarction and stroke may be a spot urine albumin to creatinine ratio.

Biomarker for Cardiovascular Disease
Patients with diabetes and hypertension are at increased risk for chronic kidney disease and end-stage renal disease (ESRD). However, they are five times more likely to die of a heart attack or stroke before they develop kidney failure. “Thus, it is important to develop screening techniques to identify patients who are at increased risk,” said Dr. Weir. The presence of microalbumin in the urine indicates small blood vessel disease not only in the kidney, but throughout the systemic vasculature. Microalbumin-uria is predictive of increased cardiovascular morbidity and mortality in diabetic and non-diabetic patients. Although the new guidelines recommend a blood pressure target of 130/80 mmHg in diabetic hypertensives (JAMA 2003; 289), an even lower blood pressure goal may be necessary to normalize micro-albumin excretion in the urine.

Glomerular Hemodynamics
In the kidney, the afferent glomerular arteriole serves as the gatekeeper to limit systemic blood pressure from injuring the delicate filtering apparatus of the kidney. Normally, glomerular capillary pressure is about one half to two thirds of systemic blood pressure. The efferent glomerular arteriole is designed to vasoconstrict when there is diminished effective arterial blood volume. The two glomerular arterioles work together to autoregulate the amount of pressure within the glomeruli to maintain filtration yet avoid mechanical injury. In patients with diabetes, early vascular injury leads to an impaired renal autoregulatory response. There is diminished afferent resistance and increased efferent glomerular resistance, resulting in a rise in glomerular capillary pressure. The presence of microalbumin in the urine may indicate that autoregulation is deficient. According to Dr. Weir, a combination of lower systemic blood pressure and dilatation of the efferent glomerular arteriole is most effective in protecting the glomerular microcirculation from injury in patients with diabetes. Clinical studies are needed to determine the appropriate target blood pressure to minimize renal injury. This, in fact, may be tied to normalization of microalbuminuria.

The Data
Clinical trial data on drugs that block the renin-angiotensin system, such as the angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (ARB), provide evidence that reducing not only systemic blood pressure but also glomerular capillary pressure, is critical for protecting kidney function. In the Irbesartan Microalbuminuria-2 trial, patients with type 2 diabetes, hypertension, normal renal function, and microalbuminuria were randomized to receive one of three antihypertensive regimens for 2 years: placebo and traditional antihypertensive medications, or either irbesartan 150 mg or 300 mg in addition to other antihypertensive drugs. Blood pressure was reduced identically in all three arms during the study. Patients receiving the 300-mg dose of irbesartan experienced the greatest benefit, with a 70% reduction in the risk for progression from microalbuminuria to clinical proteinuria. Indeed, having full-dose irbesartan as part of the antihypertensive regimen increased the normalization rate by approximately 50% (Parving et al, N Engl J Med 2001).

Likewise, both the Irbesartan Diabetic Nephropathy Trial and the Reduction of Renal Endpoints in Type 2 Diabetes with Antiotensin II Antagonism with Losartan trial evaluated irbesartan or losartan, respectively, in patients with diabetes, hypertension, chronic renal insufficiency and proteinuria. The results demonstrated that having irbesartan 300 mg or losartan 100 mg as part of the multidrug antihypertensive regimen dramatically cut the risk for progression of kidney disease as determined by doubling of serum creatinine, reaching ESRD, or death. Both ARB therapy and lower blood pressure reduced the risk for progression of renal disease and proteinuria. For every 50% reduction of proteinuria, there was a 50% reduction of risk for progression to ESRD (Lewis et al N Engl J Med 2001; Brenner et al N Engl J Med 2001).

Dr. Weir concluded that ARBs provide a definitive therapy for reducing blood pressure and proteinuria (or microalbuminuria), and thus risk of progression of renal disease, in patients with hypertension and type 2 diabetes. “It is also likely that preventing doubling of serum creatinine will be beneficial in reducing the risk for cardiovascular events,” he said (Table 1).

ARBs and ACE Inhibitors for LVH and Heart Failure: What We Know and What We Need to Find Out

Heart failure is the most common complication of hypertension. In turn, hypertension is the risk factor responsible for the greatest proportion of heart failure incidence. “An increased understanding of the progression from hypertension to heart failure may allow for improved treatment of hypertension and reduction of cardiovascular risk,” said Barry M. Massie, MD, Professor of Medicine, University of California, San Francisco School of Medicine; Chief, Cardiology Division; and Director, Hypertension Clinic and Heart Failure Program, at the San Francisco VA Medical Center.

Progression to Heart Failure
There are two sometimes overlapping pathways from hypertension to heart failure (Vasan & Levy, Arch Intern Med 1996). In many patients with hypertension, heart failure follows myocardial infarction (MI), which in turn leads to progressive left ventricular dilatation, systolic dysfunction as evidenced by reduced ejection fractions, and ultimately heart failure. At least as frequently, however, hypertensive patients develop heart failure despite having normal systolic function. In these patients, changes in the arteries and myocardium secondary to hypertension and aging play an important mechanistic role. The arterial systemic becomes more rigid as a result of changes in elasticity and smooth muscle hypertrophy, atherosclerosis, and endothelial dysfunction. Important changes occur in the myocardium, both as a result of aging and of the increased vascular load, causing left ventricular hypertrophy (LVH), increases and alterations in collagen tissue, and alterations in calcium handling. The end result is heart failure due to diastolic dysfunction.

Left Ventricular Hypertrophy
LVH is both an important predictor and as a major mechanism in the development of heart failure. LVH is a multi-determined phenomenon, with hypertension and a number of factors playing a causative role. Beside hypertension and age, the renin-angiotensin-aldosterone system (RAAS), and perhaps to a lesser extent sympathetic nervous system, play important roles. Genetic factors (as yet not well understood) are involved, as are obesity and the metabolic syndrome. Women appear to be more predisposed to LVH for any given systolic blood pressure, and they are much more likely to develop heart failure in the presence of preserved systolic function (Krumholz et al, Am J Cardiol 1993; Masoudi et al, J Am Coll Cardiol 2003).

According to Dr. Massie, the importance of the syndrome of heart failure in the absence of systolic dysfunction has only recently recognized, but a series of epidemiologic studies indicate that it may be responsible for 40% to 50% of heart failure cases. Individuals who present with heart failure and preserved ejection fraction tend to be older (90% older than 60 yrs; large majority over 80 yrs who develop heart failure are in this category) and they tend to be female (70%). In addition, heart failure patients with preserved ejection fraction are less likely to have had an MI and are more likely to have both a history of hypertension and current hypertension. Importantly, these patients have a relatively poor prognosis despite their normal systolic function. Although their survival appears to be somewhat better than patients with low ejection fractions, it remains poor compared to non-heart failure patients, and their hospitalization rates for heart failure and other cardiovascular conditions are similar to patients with systolic dysfunction (Masoudi et al, J Am Coll Cardiol 2003; Dauterman et al, Am Heart J 1998).

Opportunity for Intervention
“Effective control of hypertension can significantly reduce the risk of LVH and cardiovascular morbidity and mortality,” Dr. Massie said. Treatment of hypertension reduces the development of heart failure by 50%. Much of this effect likely occurs in those with preserved ejection fraction, with regression of LVH playing an important role in heart failure prevention. One study, for example, found that those with increased left ventricular mass (>125 g/m2) who had regression (<125 g/m2) had a significantly lower risk than those without regression for cardiovascular complications.

The key is to control systolic blood pressure aggressively. Usually this will take a combination of agents, one of which should be a diuretic (ALLHAT study group, JAMA 2000; ALLHAT study group, JAMA 2002). Because RAAS inhibitors appear to be particularly effective in regressing LVH and preventing the adverse outcomes of hypertensive patients with LVH, the combination of a diuretic with an ACE inhibitor or ARB makes sense, Dr. Massie noted (Schmieder et al, JAMA 1996; LIFE study group, Am J Hypertens 2000).

Unfortunately, despite the growing appreciation of heart failure with preserved ejection fraction, treatment trials in these patients are sorely lacking, thus guidelines provide few recommendations for treatment. Dr. Massie described the ongoing Irbesartan in Heart Failure with Preserved Ejection Fraction (I-Preserve) trial. This study will be the largest focused on this population. Approximately 4000 patients with confirmed heart failure and ejection fractions > 45% will be enrolled, and randomized to treatment with irbesartan or placebo. The primary endpoint, a composite of all cause mortality and cardiovascular hospitalizations, will capture the spectrum of outcomes characteristic of this patient group. To date, approximately 2000 subjects have been entered, and completion is anticipated in 2005.


Treatment of Hypertension: Focus on Combination Therapy

In persons with hypertension, new guidelines support the use of multiple drug therapy to achieve a target goal of < 130/80 mmHg. In certain special populations—those with diabetes, renal disease, or heart failure—a lower target goal may be appropriate, said Henry Black, MD, Associate Vice President for Research, Rush-Presbyterian-St. Luke’s Medical Center, Chicago. According to Dr. Black, a combination of diuretics, angiotensin receptor blocker (ARB) agents, and/or angiotensin-converting enzyme (ACE) inhibitors is required to achieve the blood pressure target goal for many hypertensive patients. “The single overriding message of both JNC-VI and JNC-VII is to go for the goal, and not settle for less,” Dr. Black said.

The Data on Combination Therapy
In the CONVINCE study, patients with hypertension were randomized to receive either verapamil, atenolol, or hydrochlorothiazide, with increased dosage or an added agent when blood pressure goal of < 140/90 was not achieved. After 2 years, approximately 70% of patients had controlled blood pressure and 45% were receiving more than one medication (Black et al, Hypertension 2001).

In the prospective collaborative study group, 61 observational studies were analyzed. Findings showed a linear relationship between usual systolic blood pressure and coronary heart disease mortality hazard ratio, regardless of patient age, diabetes, or organ damage. “Between 130 and 180, a 25% decrease in risk occurred for each 20-mm reduction in systolic blood pressure,” Dr. Black said (Lewington et al, Lancet 2002). Indeed, Dr. Matthew Weir has suggested the Rule of 10, indicating a 10-mm decrease in systolic blood pressure for each drug used. Recent clinical trials—including the LIFE, CONVINCE, and ALLHAT trials—have utilized multiple drug regimens in achieving optimal results.

In a study by Singer and colleagues, patients with difficult-to-manage hypertension were treated with multiple-drug antihypertensive therapy, and achieved 63% control of systolic blood pressure and 86% control of diastolic pressure. However, despite multiple drug therapy, only 22% of diabetic patients had an end blood pressure of < 130/85 (Singer et al, Hypertension 2002).

“Combination therapy is required for many hypertensive patients, particularly those at high risk for cardiovascular events. This approach allows us to achieve improved blood pressure control, reduce dose-dependent side effects, and utilize additive or synergistic benefits,” Dr. Black explained.

Fixed Dose Combination Therapy
Multidrug therapy can be prescribed for many hypertensive patients, without compromising compliance, said Dr. Black. Regimens such as the fixed-dose combination of ARBs and diuretic agents may offer both clinical benefit and convenience. This may be particularly beneficial in patients with diabetes, who are taking numerous medications.

In one study, the combination of losartan and hydrochlorothiazide resulted in continual blood pressure reduction. In another study, irbesartan plus hydrochlorothiazide achieved superior blood pressure control, compared with either drug alone. Side effects of the combination were comparable to those with irbesartan alone (Weber et al, J Hypertension 1998; suppl 2: Abstract S129).

“A number of antihypertensive guidelines now recommend the initial use of fixed-dose combination therapy [Chobanian et al, JAMA 2003]. In patients who have systolic blood pressure > 160 mmHg, diastolic blood pressure > 100 mmHg, or are 20 mmHg or 10 mmHg [respectively] over the target goal, first-line therapy with two drugs is recommended. Finally, a combination of an ARB or ACE inhibitor with a diuretic may provide optimal clinical benefit for those at increased risk for cardiovascular events,” the speaker concluded.

 

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