Hypertension Update: New Targets and Treatment Strategies for Comprehensive Care

It is estimated that 25% of adult Americans have hypertension as defined by the Sixth Report of the Joint National Committee on the Prevention, Recognition, Evaluation, and Treatment of Hypertension (JNC-VI), issued in 1997. The prevalence of hypertension is age-related such that at age 50 years, approximately 40% of individuals are affected; but at age 60 years, about half of the population has hypertension. This is due primarily to isolated systolic hypertension, in which systolic blood pressure gradually increases in the presence of normal diastolic blood pressure, a phenomenon attributed to age-related loss of arterial elasticity. All forms of hypertension are risk factors for atherosclerosis and clinical events that are related to the formation of arterial stenoses or unstable plaques that rupture and occlude the vessel lumen with thrombosis. Atherosclerosis begins early in life, with 20% of individuals in their early 30s having some narrowing of the left anterior descending artery.

Recent research has elucidated the multiple intertwined pathways that relate risk factors to clinical events. Additionally, current understanding of the interdependence of blood pressure control, blood glucose control, and blood lipid control has generated new concepts of comprehensive cardiovascular care.

This program was sponsored byThe Johns Hopkins University School of Medicine and supported by an unrestricted educational grant from Pfizer Inc.

Atherosclerosis Today: Disease Progression and Prevention through Risk Management

Atherosclerosis originates with fatty streaks that may evolve into mild plaques and then to plaque rupture or the development of flow-limiting stenosis. This progression may manifest clinically as angina, claudication, transient ischemic attacks, or acute cardiac syndromes. Scott Kinlay, MD, PhD (Harvard Medical School) said that “with treatment, we may be able to reverse parts of this process and to stabilize plaques, thereby preventing progression to clinical events.”

Historic experience with coronary angiography has focused on atherosclerosis primarily as a luminal disease. With the advent of intravascular ultrasound (IVUS), however, it has been demonstrated that early atherosclerosis frequently includes compensatory enlargement (“positive remodeling”). Thus segments of coronary arteries that are undergoing atherogenesis appear normal on angiograms. It is only later in the natural history of atherosclerosis that the plaque impinges on the vessel lumen. This event heralds the onset of symptoms related to impaired perfusion such as exertional angina. Plaques that rupture and are responsible for acute coronary syndromes have large amounts of lipid, thin fibrous caps due to reduced collagen, and less calcium than stable plaques. The presence of lymphocytes, macrophages, and vascular smooth muscle cells in these lesions suggests an important role for inflammation in destabilizing atherosclerosis, leading to the vulnerable plaque. Because the content of unstable plaque is highly thrombogenic, rupture may result in thrombus that occludes the vessel lumen. Thus acute coronary events correlate more closely with plaque instability than with the degree of arterial stenosis, a distinction that cannot be observed by angiography.

Normal vascular endothelium conducts multiple functions that are important for preventing atherogenesis. One of these functions is to sense laminar blood flow and sheer stress, which induces the production of vasodilating substances such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor. It also decreases the production of vasoconstrictors such as endothelin. Sheer stress regulates the endothelial surface to inhibit adhesion of leukocytes and platelets. The endothelium also produces anticoagulant substances. However, the risk factors of atherogenesis and atherosclerosis disrupt these functions, leading in particular to reduced nitric oxide production, increased vasoconstrictors, recruitment of inflammatory cells, and shift of the thrombolytic balance to favor thrombosis. One of these risk factors is hypertension.

Mean blood pressure is regulated primarily by constriction and dilation of the resistance vessels, the small arterioles just before the capillaries. When these constrict, peripheral resistance increases and organ perfusion declines, leading over the long term to end-organ damage and clinical events. The conduit arteries in the extremities regulate the reflected wave component of blood pressure. Following each systole, the force generated by the left ventricle runs down the arterial tree, in which it encounters branch points. Here, some of the pressure is reflected back up the tree, creating the reflected wave that coincides with peak systolic pressure in the ascending aorta, accentuating systolic blood pressure. This wave is especially large in individuals with stiff arteries, and helps to explain the genesis of isolated systolic hypertension in the aging circulatory system.

The importance of vasodilator therapy in individuals with hypertension lies in the fact that it acts on the resistance and conduit vessels rather than on the more elastic aorta and carotid arteries. Vasodilators decrease the mean blood pressure by dilating the resistance vessels. They also increase the distensibility of the conduit arteries by relaxing vascular smooth muscle. This latter action decreases the reflective wave and reduces the strain on the left ventricle. Experimental studies show that endothelial nitric oxide regulates arterial distensibility. The endothelium has an important role, therefore, in hypertension. Nitric oxide deficiency is also involved in the endothelial expression of cellular adhesion molecules that project into the lumen, where they capture leukocytes and transport them into the vessel wall. This initiates the inflammatory process associated with plaque destabilization. In vulnerable plaque, inflammatory cells produce cytokines such as interleukin-6, which stimulates hepatic production of C-reactive protein (CRP) and serum amyloid A. The inflammatory cytokines also contribute to decreased production of anticoagulants in the endothelium, shifting the balance toward thrombogenic substances, and increase the expression of cellular adhesion molecules that recruit additional inflammatory cells into the vessel.

In atherosclerosis, activated macro-phages contribute to an increase in vascular tone by generating angiotensin-II within the vessel wall, resulting in proliferation of smooth muscle cells. Angiotensin-II influences surface enzymes of vascular smooth muscle cells to overproduce superoxide anion, a free radical that degrades nitric oxide. Oxidation of low-density lipoprotein cholesterol (LDL-C) in the vessel wall also stimulates the expression of cellular adhesion molecules and induces macrophages to produce more angiotensin-II, illustrating the close connection between risk factors and vascular biology.

Treatment that can reverse these events includes angiotensin-converting enzyme (ACE) inhibitors and lipid-lowering agents of the statin class. These agents increase the amount of nitric oxide in order to restore vasodilator and anticoagulant functions, and to prevent the development of vascular inflammation. Clinical studies have confirmed the improvement in endothelial function following long-term ACE inhibitor treatment. In studies using canine coronary arteries, amlodipine was equivalent to an ACE inhibitor in increasing the production of nitric oxide (Zhange X. Circulation 1998;97:576). Amlodipine, a calcium channel blocker (CCB), also has direct effects on lipid peroxide production in vitro that has not been observed in some other CCBs. In a trial designed to compare an aggressive lipid-lowering regimen with a more modest strategy, treatment with atorvastatin to a goal of 80 mg/dL resulted in a significant reduction in CRP, whereas a less intensive strategy of lovastatin and diet with a target of 135 mg/dL had a more modest effect on CRP (Kinlay S. Am J Cardiol 2002;89:1205).

Systolic Blood Pressure and Cardiovascular Risk: A Comprehensive Management Plan

Under the standards established by JNC-VI, hypertension begins at a systolic blood pressure of 140 mmHg or greater and/or a diastolic blood pressure of 90 mmHg or greater. Robert A. Kloner, MD, PhD (University of Southern California) cautioned, however, that individuals who fall into the high normal category (130-139/85-89 mmHg with no diabetes or symptomatic cardiovascular disease) merit close monitoring because of recent data suggesting that cardiovascular events may begin in this range. He emphasized that isolated systolic hypertension is present in 65% of women and 57% of men over the age of 60 years who have hypertension. The Framingham Study has demonstrated that systolic blood pressure correlates better than diastolic blood pressure with multiple end-organ diseases including myocardial infarction, congestive heart failure, left ventricular wall thickness, stroke, and renal atrophy and failure.

The JNC-VI treatment algorithm calls for the initial treatment of uncomplicated hypertension with diuretics and beta blockers, but suggests variations in therapy depending on concomitant conditions. In the case of isolated systolic hypertension, the algorithm recommends the use of diuretics or long-acting dihydropyridine CCBs.

The remainder of Dr. Kloner’s presentation consisted of a review of the advantages and disadvantages of the classes of antihypertensive medications. Diuretics have the advantages of decreasing cardiovascular morbidity and mortality, but the disadvantages of requiring monitoring for adverse effects on serum potassium, glucose, and lipids. They may also increase the risk of reduced glomerular filtration and hyperglycemia and other metabolic abnormalities. Clinical trials indicate that beta blockers also reduce cardiovascular morbidity and mortality, especially in younger patients. They are especially beneficial for secondary prevention, with studies indicating that they reduce the risk of second myocardial infarction and sudden death. These advantages are partially offset, however, by decreased insulin sensitivity that may lead to glucose intolerance. Diuretics may also adversely affect high-density lipoprotein cholesterol (HDL-C) and triglyceride levels.

The Systolic Hypertension in the Elderly Program (SHEP) was a landmark study of the efficacy of diuretics and beta blockers in older patients with isolated systolic hypertension. At the 5-year point in this trial, there was a 36% reduction in fatal and non-fatal stroke, a 27% decrease in non-fatal myocardial infarction and coronary death, a 32% reduction in major cardiovascular events, and a 13% reduction in all-cause mortality among patients randomized to the active treatment arm compared with patients in the placebo arm. Subsequently it was shown that antihypertensive therapy in this population reduced the incidence of non-fatal heart failure by 54% and combined fatal and non-fatal heart failure by 49%.

Long-acting dihydropyridine CCBs also reduce cardiovascular morbidity and mortality in patients with isolated systolic hypertension and are safe for long-term use. Some non-dihydropyridine CCBs are associated with cardiac induction abnormalities. Short-acting CCBs are not approved for treating hypertension and should not be used in this setting.

In the Amlodipine Cardiovascular Community Trial, in which more than 1,000 patients with mean blood pressure of 150/100 mmHg went through a phase-in period with placebo prior to treatment with amlodipine, 86% of patients achieved the pre-defined diastolic blood pressure goal of less than 90 mmHg with monotherapy. The response rates were greatest among women (91%) and older patients (92%). In another study, in which older patients with a mean blood pressure of 178/87 mmHg were randomized to hydrochlorothiazide or amlodipine, the mean systolic blood pressure reduction associated with the diuretic was 24 mmHg compared with 32 mmHg for the CCB. In the European systolic hypertension study (Syst-Eur), treatment with the CCB nitrendipine was associated with a significant reduction in fatal and non-fatal stroke at 4 to 6 months, and in fatal and non-fatal myocardial infarction at 12 months. Slow-release nifedipine was used in the Chinese systolic hypertension study (Syst-China) with a significant reduction in stroke mortality.

The Prospective Randomized Evaluation of the Vascular Effects of Norvasc® Trial (PREVENT) randomized patients with chronic coronary artery disease to amlodipine or placebo to evaluate the potential benefit of CCB therapy on atherosclerosis and coronary disease. Although coronary arteries thickened in the placebo group over a period of 3 years, this trend was blocked by amlodipine as evidenced by a 46% decrease in need for revascularization procedures. A trial currently in progress is evaluating the progression of atherosclerosis in coronary arteries using IVUS.

ACE inhibitors are the cornerstone of therapy for heart failure and are the preferred agents in patients with diabetes, proteinuria, and post-myocardial infarction with low ejection fraction. Their principal disadvantage is chronic cough. In the Heart Outcomes Prevention Evaluation (HOPE), treatment with ramipril was associated with a significant reduction in the composite outcome of myocardial infarction, stroke, and death from cardiovascular causes in a population of high-risk patients. The best outcomes were in the subpopulation with diabetes despite small blood pressure reductions, as a result of which ACE inhibition is recommended for diabetic patients with nephropathy.

Angiotensin receptor blockers (ARB) induce chronic cough in only approximately 3.5% of patients, giving them a major advantage over ACE inhibitors. They are useful alternatives for patients who cannot tolerate ACE inhibitors. Their role in heart failure remains undetermined because of conflicting results between the ELITE-I and ELITE-II studies, the first and second Losartan Heart Failure Survival Studies. These two trials compared captopril (ACE inhibitor) with losartan (ARB) using hospitalization and all-cause mortality as primary endpoints. In ELITE-II there was no significant difference in these endpoints, though there was a non-significant trend toward a greater incidence of resuscitated cardiac arrest and sudden death in the losartan group.

Despite the prevalence of hypertension and the variety of efficacious agents for treating it, only about 27% of patients in the United States are adequately controlled. One reason for this is that many patients, especially older patients with concurrent diseases, are not easily controlled with monotherapy. The
important Hypertension Optimal Treatment (HOT) study randomized patients to diastolic blood pressure goals of 90 mmHg or below, 85 mmHg or below, or 80 or below. In all three categories, the majority of patients required combination therapy to achieve and maintain the targets (63%, 68%, and 74%, respectively).

Goals and Strategies for Hypertension Control in Patients with Multiple Risk Factors

John M. Flack, MD (Wayne State University) cited data indicating that only 45% to 50% of individuals treated achieve blood pressures below 140/90 mmHg, the JNV-VI goal for uncomplicated hypertension. Among the remainder, systolic blood pressure remains the problem, in part because many physicians continue to consider diastolic control, which is easier to achieve, the critical issue in hypertension. “If I could erase one thing from your minds,” Dr. Flack told the audience, “it would be the primary focus on diastolic pressure.”

For patients with diabetes, renal insufficiency, and/or heart failure, the JNC-VI blood pressure target is less than 130/85 mmHg. For patients with proteinuria, it is less than 125/75 mmHg. Individuals in these high-risk categories for cardiovascular events almost invariably require multiple drugs of different classes to achieve these stringent targets. Furthermore, even compliant patients miss an occasional dosing cycle and, therefore, have occasional vulnerable periods. Medications with long half-lives help them over these intervals. Dr. Flack prefers chlorthalidone to hydrochlorothiazide, for example, because its half-life is approximately 80 hours. The half-life of amlodipine, approximately 60 hours, makes these two agents a good combination from the viewpoint of continuous coverage.

Survey data indicate that 30% to 50% of patients discontinue antihypertensives medications within 12 months of the original prescription. There are many reasons for this noncompliance, one of which is intolerability. Interestingly, however, in the Treatment of Mild Hypertension Study (TOMHS), 83% of patients treated with amlodipine were still taking it after 4 years. Acebutolol, a cardioselective beta blocker with intrinsic sympathomimetic activity, was almost as well tolerated. Selected diuretics, ACE inhibitors, and alpha blockers were tolerated by 65% to 70% of patients for 4 years.

Another reason for noncompliance is that drug doses are frequently inadequate to achieve blood pressure goals, leading to patient frustration. Thus, titration may be necessary, but the optimal frequency for increasing doses is not well understood. The Quinapril Titration Interval Management Evaluation conducted by the ATIME Research Group examined this issue by assigning patients to titration every 6 weeks (“slow group”) or every 2 weeks (“fast group”). Following the third visit, control to target had been achieved by 68% of patients in the slow group and 62% in the fast group. Although there was no difference in the rate of adverse effects, they tended to be more severe in the fast group. These data argue for slow titration.

The “cardinal rule” for combination therapy is that one medication must be a diuretic. However, treating patients with renal insufficiency presents challenges that may not be apparent from creatinine levels. Thiazides are the preferred agents for patients with glomerular filtration rates (GFR) of 45 mL/ minute or above, but metolazome is better suited to patients with reduced kidney function. Thiazide diuretics will not work in patients with GFR in the low 40s. Albuminuria is the most important measure for predicting attenuated blood pressure response to diuretic therapy. Macro-albuminuria, detectable by dipstick, is a reliable predictor of attenuated response; and if it is overlooked in favor of monitoring creatinine, a patient inappropriately treated with a thiazide diuretic may be placed at very high renal arterial risk. In a local pilot trial, approximately 80% of patients with GFR above 48 mL/minute achieved blood pressure control using thiazides. By replacing thiazides with other diuretics, control rose from 20% to approximately 50% among patients with lower GFR. Dr. Flack recommended that patients with GFR below 60 mL/minute be placed on either ACE inhibitors or ARBs to achieve blood pressures of 130/85 mmHg.

Data from the African-American Study of Kidney Disease (AASK) that randomized patients to amlodipine (CCB), ramipril (ACE inhibitor), or metoprolol (beta blocker) indicate that renally-driven endpoints cannot be achieved with CCB therapy unless the angiotensin-renin system is simultaneously blocked. This was confirmed in the Reduction in Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin-II Antagonist Losartan (RENAAL) study in patients with hypertension, diabetes, and macroproteinuria using kidney-related endpoints, and by the Irbesartan Diabetic Nephropathy Trial (IDNT). In the latter, however, fatal and non-fatal cardiovascular and cerebrovascular events were significantly higher in the ARB trial arm.

ACE inhibitors and ARBs are frequently associated with increases in creatinine levels upon initiation because of a drug-induced drop in intra-glomerular pressure. Although it may be tempting to discontinue the drug under these circumstances, it is precisely individuals whose glomeruli cannot self-regulate who need these agents. Dr. Flack recommended a 30% increase in creatinine level as a threshold for discontinuing these agents. On the other hand, he cautioned against using diuretics to excess, the other common reason for the failure of glomerular self-regulation.