ABSTRACT: In high-risk patients with vascular disease, blockade of the renin- angiotensin system (RAS) can help prevent cardiac remodeling that ultimately results in left ventricular hypertrophy (LVH) and heart failure. Optimal treatment of these patients, who often have diabetes or renal disease, usually involves a combination of agents-1 of which should be a thiazide diuretic-to reduce blood pressure, control the comorbid condition, and prevent end-stage organ damage. The manner in which the RAS is interrupted may be important. For example, although a thiazide diuretic and an angiotensin-converting enzyme (ACE) inhibitor are recommended for hypertensive patients with LVH, an angiotensin II receptor blocker (ARB) in combination with a diuretic was recently found to reduce cardiovascular morbidity and mortality in these patients to a greater degree than a ß-blocker/diuretic. Both ACE inhibitors and ARBs delay the progression of diabetic nephropathy and reduce albuminuria. ARBs were recently shown to reduce progression from microalbuminuria to macroalbuminuria. In patients with systolic heart failure who cannot tolerate ACE inhibitors, an ARB can be used with a ß-blocker.
In many patients, hypertension is not an isolated condition. Particularly when hypertension is long-standing or poorly controlled, other manifestations of cardiovascular disease, such as generalized atherosclerosis and coronary heart disease (CHD), are often present. Moreover, hypertension may lead to the development of end-stage organ disease, such as left ventricular hypertrophy (LVH) and left ventricular dysfunction (LVD).
The combination of hypertension and LVD and/or CHD places patients at high risk for heart failure, which results from the continuum of pathophysiologic changes that begins with stress placed on the heart and ends with pump failure and death(Figure 1).1 Any of several adverse conditions, including chronic myocardial ischemia and increased workload of the heart, may stress the heart and initiate the changes that lead to heart failure. Diabetes, for example, increases the risk of heart failure 2-fold in men and 5-fold in women.2
The presence of comorbid conditions,such as LVH, diabetes, or CHD, affects the choice of antihypertensive medication. Patients often require 2 or more drugs to control blood pressure (BP); those with diabetes and hypertension often need 3 or more drugs, because their BP goals are lower. In these settings, it may not be sufficient simply to reduce BP; optimal management also may involve a combination of agents to treat or control the comorbid condition and prevent end-stage organ damage.
For example, in a patient with diabetes and hypertension who has or is at high risk for heart failure, the most appropriate initial combination of medications is a thiazide diuretic and a drug that blocks the action of the renin-angiotensin system (RAS).3 The rationale for selecting a medication that blocks the RAS is based on the central role of this system in producing or perpetuating hypertension and also on the intimate involvement of the RAS in the progressive structural remodeling that occurs in the chronically stressed heart and peripheral vasculature.1
Here I review the deleterious effectsof the RAS and offer guidance on tailoring an antihypertensive regimen for patients with high-risk comorbid conditions. I also discuss the most effective means of blocking the RAS in various clinical settings (Algorithm).
ROLE OF THE RAS
The classic sequence by which angiotensinogen is converted to angiotensin I, which, in turn, is converted to angiotensin II, may be initiated by the RAS as well as by nonrenin enzymes (such as cathepsin) and non-ACEs (such as chymase) and may take place entirely within the heart and blood vessels.4,5 Hence, endocrine (systemic circulating), paracrine (locally generated), and autocrine (locally self-regulating) systems all contribute to the workings of the RAS.
Many actions of angiotensin II depend on the stimulation of the angiotensin receptors AT1 and AT2. Stimulation of AT1 receptors is responsible for vasoconstriction, sodium and water retention, suppression of renin release, and other effects that include remodeling within the heart and blood vessels.6 AT2 receptors-which normally lie dormant unless activated by injury-inhibit cell growth and promote cell differentiation, tissue repair, apoptosis, vasodilation, and synthesis and release of both prostaglandins and bradykinin from the kidneys.7 Through its action on the AT1 receptor, angiotensin II promotes hypertrophy of cardiomyocytes and proliferation of fibroblasts.8 The long-term effects of chronic activation of the RAS include angiotensin II-induced cardiac remodeling, consisting primarily of LVH, left ventricle dilation, and changes in the configuration of the left ventricular chamber, all of which translates into LVD and, ultimately, clinically apparent heart failure.9
Because angiotensin II may be produced by alternative pathways through non-ACE mechanisms, ACE inhibition may not completely inhibit the formation of angiotensin II. In fact, angiotensin II levels are often elevatedin patients who are treated for long periods with ACE inhibitors-the so-called ACE escape phenomenon-the clinical significance of which is unclear.10,11 Angiotensin II receptor blockers (ARBs) inhibit the deleterious effects of angiotensin II "downstream," regardless of how it is formed, by selectively blocking the AT1 receptor, which leaves the AT2 receptor available to exert its beneficial effects (Figure 2).12
TREATING THE HIGH-RISK HYPERTENSIVE PATIENT
In recent randomized placebo-controlled trials, ACE inhibitors and ARBs were equally effective in reducing BP.13,14 The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that inhibition of the RAS with the ACE inhibitor ramipril significantly reduced the risk of death, myocardial infarction (MI), and stroke compared with placebo in a diverse group of high-risk patients, most of whom had underlying vasculardisease.15,16 These effects were observed in patients with and without hypertension and with and without diabetes at baseline.15 ACE inhibitor therapy significantly reduced the risk of complications related to diabetes and new diagnoses of diabetes in patients who did not have the disease at randomization; it was also associated with a 23% reduction in the incidence of heart failure of new onset.17
The ongoing Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial will compare initial treatment with the ARB valsartan and the calcium channel blocker amlodipine in more than 15,000 hypertensive patients who are at risk for coronary events.18 The primary end point is the time to cardiac mortality, first nonfatal acute MI, or hospitalization for heart failure. Secondary end points include all-cause mortality, angina, stroke, and end-stage renal failure.19 Results of the VALUE trial, which are expected in 2004, will provide further information on the effect of an ARB on outcome for these high-risk patients.
Take-home point. Based on the HOPE and the Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO)-HOPE trials, ACE inhibitors-because of their cardioprotective effects-remain the agents of choice for those with diabetes or underlying vascular disease.20
Hypertension and end-stage organ disease. LVH is an independent risk factor for cardiovascular disease. Regression of LVH with combined ACE inhibitor and ARB therapy has been noted in observational studies. However, no clinical trial in patients with LVH has demonstrated that ACE inhibitor therapy reduces cardiovascular morbidity and mortality.
In the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, initial therapy with the ARB losartan was significantly more effective than initial therapy with the β-blocker atenolol in reducing cardiovascular morbidity and mortality in patients with hypertension and LVH demonstrated on ECG.21 In both groups, 70% of patients were also taking a diuretic.Most of the benefit was driven by a 25% reduction in risk of stroke and a 25% lower incidence of diabetes of new onset. Benefits were also observed in patients with diabetes22 and isolated systolic hypertension.23 Losartan and atenolol were equally effective in reducing BP,21 which suggests that blockade of the AT1 receptor has benefits independent of reductions in BP. This single study supports the use of an ARB-thiazide diuretic combination for the high-risk patient with ECG-demonstrated LVH and hypertension.
Take-home point.An ACE inhibitor or an ARB in combination with a thiazide diuretic is recommended for patients with LVH and hypertension. More trial-based evidence exists for the ARB-diuretic combination.
Hypertension and type 1 diabetes with nephropathy. A randomized, double-blind, placebo-controlled study of ACE inhibition in patients with diabetic nephropathy showed that captopril protects against deterioration in renal function.24 Significantly fewer patients in the captopril group than in the placebo group reached the primary end point of doubling of serum creatinine concentration. In addition, captopril was associated with a 50% reduction in the combined end point (death, dialysis, and transplantation). It is difficult to separate out the benefit of the additional BP reduction in the ACE inhibitor group (3 mm Hg lower systolic BP than the placebo group). ARBs have not been studied for long-term nephroprotection in patients with type 1 diabetes.
Take-home points.Recent guidelines recommendACE inhibitors for patients with type 1 diabetes with or without hypertension, whether or not nephropathy is present.25 Because the risk of nephropathy and end-stage renal disease may be similar in patients with type 1 and type 2 diabetes,26 the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) does not differentiate between these 2 conditions in its guidelines for antihypertensive treatment.27 For diabetic patients with no evidence of nephropathy (proteinuria or renal insufficiency), diuretics, β-blockers, ACE inhibitors, ARBs, and calcium channel blockers are all recommended.
Hypertension and type 2 diabetes. Four recent clinical trials support the initial use of ARBs in hypertensive and nonhypertensive patients with type 2 diabetes and nephropathy:
In the Irbesartan in Diabetic Nephropathy Trial (IDNT), ARB treatment was associated with a 37% lower risk of doubling of serum creatinine concentration and a 23% lower risk of end-stage kidney disease compared with amlodipine therapy.28
In the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial, the ARB group demonstrated a 25% and 28% risk reduction in the same end points, respectively, compared with placebo.29
In the Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA 2) trial, irbesartan was found to be renoprotective in hypertensive patients, independent of its BP-lowering effects.30
In the Microalbuminuria Reduction With Valsartan (MARVAL) trial, valsartan lowered the urinary albumin excretion rate more effectively than amlodipine. The benefits were independent of BP reduction.31
Take-home points.Thiazide diuretics, β-blockers, ACE inhibitors, ARBs, and calcium channel blockers all help reduce cardiovascular disease and stroke incidence in patients with diabetes and hypertension. Two or more drugs-1 of which should be a thiazide diuretic-are usually necessary to achieve the target BP goal of less than 130/80 mm Hg in patients with diabetes.27 An ACE inhibitor improves outcome in patients with type 2 diabetes who are not hypertensive but who have 1 additional risk factor (proteinuria).15 Although no trial has directly compared an ACE inhibitor with an ARB, both classes delay the progression to macroalbuminuria in patients with type 2 diabetes, hypertension, and microalbuminuria.25 In patients with type 2 diabetes, hyperten- sion, and macroalbuminuria (more than 300 mg/d), nephropathy, or re-nal insufficiency, an ARB should be strongly considered.25
Heart failure. The Evaluation of Losartan in the Elderly (ELITE) study compared the safety and efficacy of the ARB losartan and the ACE inhibitor captopril on renal function in 722 patients with systolic heart failure.32 Results of this 48-week randomized double-blind trial showed no difference in the primary end point-persistent increases in serum creatinine. However, a surprisingly lower all-cause mortality rate was noted as a secondary end point in the losartan group compared with the captopril group (4.8% vs 8.7%). Losartan was better tolerated than captopril in this trial: significantly fewer patients in the losartan group discontinued therapy because of side effects, including cough (12.25% vs 20.8%).32 One potential advantage of ARB therapy is a more favorable side-effect profile. ACE inhibitors cause a dry cough in up to 20% of patients, whereas ARBs are no more likely than placebo to cause cough.
The follow-up Losartan Heart Failure Survival Study ELITE II, which included 3152 patients with symptomatic heart failure, was undertaken to confirm whether losartan was more effective than captopril in improving survival.33 However, no significant differences in end points (all-cause mortality, sudden death, and resuscitated cardiac arrests) were noted. As in the first ELITE trial, losartan was better tolerated;patients receiving captopril experienced a greater frequency of drug-related adverse events, chiefly cough.
The value of ARBs in the treatment of heart failure was demonstrated in the Valsartan Heart Failure Trial (Val-HeFT), a randomized, double-blind, placebo-controlled study of 5010 patients who received either valsartan or placebo in addition to optimal heart failure therapy (a diuretic, digoxin, an ACE inhibitor, and/or a β-blocker).34 Valsartan reduced the relative risk of the combined end point of mortality and morbidity by 13.2% and the risk of first heart failure hospitalization by 27.5%, and significantly improved left ventricular ejection fraction, New York Heart Association classification, and clinical manifestations of heart failure (dyspnea, fatigue, edema, and pulmonary rales).
These improvements extended across all subgroups (older and younger patients, men and women, patients with and without diabetes or coronary heart disease) except those receiving triple neurohormonal blockade (ARB, ACE inhibitor, and β-blocker). However, the investigators suggested that the increased risk of mortality in patients receiving triple blockade was most likely the result of chance in patients who were at low risk because they were already receiving adequate therapy.35
In the 7% of patients in Val-HeFT who were not taking an ACE inhibitor, valsartan conferred significant benefits: the combined morbidity and mortality risk was reduced 49%; hospitalization risk, 57%; and mortality risk, 41%.34
Take-home points. Even with effective therapy, patients with symptomatic systolic heart failure have an extremely poor long-term prognosis.36,37 The optimal regimen includes a diuretic and digoxin, plus an ACE inhibitor and a β-blocker.38 Valsartan may be substituted in patients who cannot tolerate ACE inhibitors. Because the exact dosage and dosage frequency have not been tested with other ARBs, these should not be substituted for valsartan.
WHAT ROLE FOR COMBINATION ACE INHIBITOR-ARB THERAPY?
Intuition suggests that combination therapy with an ACE inhibitor and an ARB-which would restrict production of angiotensin II and block its deleterious actions at the AT1 receptor-would be more effective than equivalent dosages ofeither agent alone. Studies that demonstrated a greater decrease in proteinuria with the combination of an ACE inhibitor and an ARB did not control for the additional BP reduction that occurred in the combination therapy group.39 Although subgroup analyses of patients in Val-HeFT showed that the combination of valsartan and an ACE inhibitor was associated with greater risk reduction for the combined morbidity/mortality end point than an ACE inhibitor alone,35 future studies will be designed to answer this question more effectively.40
The recently completed Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Nondiabetic Renal Disease (COOPERATE) trial showed that despite equivalent reductions in BP, treatment with losartan and trandolapril more effectively prevented the combined primary end point of time to doubling of serum creatinine level or end-stage renal disease in patients with nondiabetic renal disease than either agent alone.41 The COOPERATE trial was terminated early because of a significant difference in survival at year 3 between the combination and monotherapy groups.
The results of trials currently under way are expected to provide a more definitive understanding of the relative roles of ACE inhibitors, ARBs, and their combination in treating hypertension, diabetes, and heart failure. The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) will follow 23,400patients with established vascular disease or diabetes (but not heart failure) for 5.5 years.42 The parallel Telmisartan Randomized Assessment Study in ACE-Inhibitor Intolerant Patients with Cardiovascular Disease (TRANSCEND) will assign 5000 patients to either telmisartan or placebo.42 In both trials, the primary end point is a composite of cardiovascular death, MI, stroke, and hospitalization for heart failure; secondary end points are development of diabetes, nephropathy, dementia, or atrial fibrillation.
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