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An Evidence-based Approach to Managing the Hypertensive Syndrome

Effects of Pharmacologic Agents on the Hypertensive Syndrome

Henry A. Punzi, MD, FCP, Trinity Hypertension Research Institute in Carrollton, Texas, explained that the hypertensive syndrome includes many risk factors that become aggregated and compounded with age. These include obesity, abnormal lipid metabolism, accelerated atherogenesis, decreased arterial compliance, endothelial dysfunction, abnormal glucose and insulin metabolism, neurohormonal dysfunction, changes in renal function and blood clotting, and left ventricular hypertrophy (LVH) and dysfunction (Kannel WB. JAMA. 1996;275:1571-1576; Weber MA et al. J Hum Hypertens. 1991;5:417-423; Dzau V et al. J Cardiovasc Pharma-col .1993;21(suppl 1):S1-S5).

Only about 27% of the US population treated for hypertension is controlled to blood pressure (BP) of < 140/90 (JNC VI. Arch Intern Med. 1997;157:2413-2446). The new JNC 7 recommendations (Chobanian AV et al. JAMA. 2003;289: 2560-2570) redefine optimal BP as < 120/80. Only about 8% of the treated population is controlled to 120/80, Dr. Punzi said. Healthcare providers need to be much more aggressive in hypertension management because “it’s achievable now,” given the plethora of pharmacologic agents available.

Choice of antihypertensive therapy must involve consideration of concomitant conditions. The metabolic syndrome is a constellation of risk factors that occurs in about 23% of US adults; prevalence rises with advancing age (Ford ES et al. JAMA .2002;287:356-359). It is defined as the presence of three of the following five factors: abdominal obesity (waist circumference < 40 cm for men or < 35 cm for women), elevated BP, elevated fasting glucose, elevated triglycerides, and low levels of high-density lipoprotein cholesterol (Third Report of NCEP. 2001. NIH publication 01-3670). JNC 7 recommendations permit use of diuretics, beta blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin-II-receptor blockers (ARBs) as first-line therapy. However, a diuretic or beta blocker will worsen insulin resistance in persons with the metabolic syndrome. Alpha blockers, ACE inhibitors, and ARBs have beneficial effects on the metabolic syndrome; CCBs have a neutral effect.

BP lowering is especially important in persons with diabetes, as it reduces risk of cardiovascular (CV) events. In the diabetic cohort of the Hypertension Optimal Therapy (HOT) trial, incidence of major CV events per 1000 patient-years fell with achieved diastolic BP (DBP) (Hansson L et al. Lancet 1998; 351:1755-1762). Benefit was continuous through all levels of BP reduction. “The lower you go, the better you are,” said Dr. Punzi. Baseline therapy was felodipine, with other agents added. Numerous major trials with varying agents have shown that reducing blood pressure in diabetics reduces mortality (e.g., UKPDS, SHEP, Syst-Eur, Syst-China). This benefit accrues to the elderly in the short-term, he emphasized. Therefore, it is worthwhile to treat
hypertension aggressively in older diabetics.

ACE inhibitors
ACE inhibitors in hypertension offer several class benefits. Their excellent side effect profiles promote compliance and improve quality of life. Additionally, ACE inhibitors reduce LVH. Numerous studies show that lowering LVH improves morbidity and mortality, said Dr. Punzi. However, all ACE inhibitors are not the same (Table 1). Choice of an ACE inhibitor should include evaluation of its trough:peak ratio. This is the ratio of the minimum to maximum antihypertensive effect. If the antihypertensive effect at peak is 10 mm Hg, and at trough it is 6 mm Hg, trough:peak ratio is 60%. Trough:peak ratios vary widely among ACE inhibitors, Dr. Punzi noted.

ACE inhibitors also can provide vasculoprotection and anti-ischemic effects. The former includes improving endothelial dysfunction in hypertension and heart failure, as well as reversing vascular remodeling (e.g., LVH) in hypertension. “One hundred percent of the hypertensive population is going to have endothelial dysfunction,” Dr. Punzi stated.

All ACE inhibitors do not have the same effects on endothelial function. Quinapril has been shown to improve endothelial function, based on sonography of subjects’ brachial arteries. Enalapril, losartan, and amlodipine did not produce this benefit (Anderson TJ et al. J Am Coll Cardiol. 2000;35:60-66). Other studies have indicated that perindopril (Zhuo JL,et al. Circulation. 1997;96:174-182), trandolapril, eprosartan, and tasosartan improve endothelial function; captopril, lisinopril, and valsartan do not have this effect.

Endothelial benefit does not always correlate with improved CV outcomes. Quinapril did not reduce risk of cardiac ischemic events in the Quinapril Ischemic Event Trial (QUIET) (Pitt et al. Am J Cardiol. 2001;87:1058-1063). Ramipril has been demonstrated to improve CV outcomes (Heart Outcomes Prevention Evaluation [HOPE] Study Investigators. N Engl J Med. 2000;342:145-153). The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) demonstrated that each of the study drugs—chlorthalidone, amlodipine, and lisinopril—reduced morbidity and mortality for high-risk patients after 5 to 6 years (ALLHAT Officers. JAMA. 2002;288:2981-2997).

Secondary Stroke Prevention—ACE Inhibitor plus Diuretic, Even for Normotensives

Susan C. Fagan, PharmD, Professor of Pharmacy at the University of Georgia and Adjunct Professor of Neurology at the Medical College of Georgia in Augusta, reported that stroke is the third leading cause of death in the US, and affects about 20% of long-term care facility residents. It is the leading cause of adult disability, and a major factor in dementia. Risk of stroke doubles with every decade after age 55. Hypertension is the most prevalent—and therefore the most important—risk factor for stroke (Sacco RL. Neurology. 1995;45(2 suppl 1):S10-S14). Patients who have had 1 stroke face up to 40% risk of having another stroke within 5 years (Feinberg WM et al. Heart Dis Stroke.1994;3:275-283; Sacco RL. Neurology. 1997;49(5 suppl 4):S39-S44; Sacco RL et al. Neurology.1994;44:626-634; Broderick J et al. Stroke. 1998;29:415-421).

The new JNC 7 guidelines recommend an ACE inhibitor and a diuretic for patients who have a history of stroke. Dr. Fagan presented the evidence
supporting that recommendation.

HOPE
“This (trial) got our attention in the stroke world” because relative risk (RR) of stroke was reduced more than risk of other components of the primary
outcome (myocardial infarction [MI], CV death), Dr. Fagan said. Patients (N = 9297; age > 55 years) with known diabetes or vascular disease plus one other CV risk factor were randomized to receive ramipril with or without vitamin E. Ramipril significantly reduced RR of the combined endpoint and of each component, with the largest impact on stroke (32% RR reduction) (HOPE Investgators. N Engl J Med. 2000;342:145-153). A HOPE subanalysis revealed that ramipril reduced RR of a second stroke by 32%, and of fatal stroke by 61%. Significantly fewer patients receiving ramipril developed cognitive or functional impairment from their stroke (Bosch J et al. BMJ. 2002;3241:1-5).

The primary HOPE paper reported relatively small BP reduction with ramipril (3/2 mm Hg), suggesting that BP effects could not have produced the beneficial outcomes. However, a small HOPE sub-study using ambulatory BP monitoring in 38 patients reported a much larger BP reduction (10/4 mm Hg) (Svensson P et al. Hypertension. 2001; 38:e28-e32). This indicates that BP lowering may account for the benefits seen in the trial, Dr. Fagan said.

“I’m on the side that the blood pressure lowering is probably the most important effect of the ACE inhibitor…in this study,” said Dr. Fagan. “But I also think that angiotensin II is an important contributor to vascular damage.”

PROGRESS
The study that “really convinced us that we need to consider ACE inhibitors for patients who have had a previous stroke” is the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) (PROGRESS Collaborative Group. Lancet. 2001; 358:1033-1041). The goal of PROGRESS was to measure the effect of BP-lowering on risk of stroke and other major vascular events. HOPE, in contrast, was designed to prevent cardiovascular outcomes rather than to lower BP. All PROGRESS subjects had a history of stroke or transient ischemic attack (TIA), while only 11% of HOPE patients had this risk factor.

PROGRESS patients were randomized to receive perindopril 4 mg/d or placebo. Indapamide could be added to perindopril at the discretion of the treating physician. After about 4 years of follow-up, RR of stroke was reduced by 28% (95% CI 17%–38%; P < .0001) (Table 2). Treated patients’ mean BP was 9/4 mm Hg lower than that of the placebo group. Reduction in RR of stroke begins within the first year, she noted. “This is important to your patients of advanced ages. You want to make a difference early,” Dr. Fagan emphasized.

Risk of all stroke subtypes measured was reduced. “Whereas antithrombotic therapy only reduces ischemic strokes, treatment of blood pressure reduces both hemorrhagic and ischemic strokes, highly significantly,” Dr. Fagan pointed out. Patients receiving both perindopril and indapamide experienced even greater BP lowering (12/5 mm Hg) and larger RR reductions than the overall active treatment group. Those who were not hypertensive also benefited from blood pressure reduction.

PROGRESS, like HOPE, left unanswered the question of whether the ACE inhibitor benefits are related to angiotensin II or to other effects. If the
effect is angiotensin-II-related, then an ARB should work at least as well as an ACE inhibitor, said Dr. Fagan.

ARBs, diuretics, CCBs
The LIFE study, comparing losartan to atenolol, further supported the role of angiotensin-II blockade. Patients in this trial (N = 9193; follow-up at least 4 years) were severely hypertensive but had not had strokes. Up to 66% of patients received hydrocholorothiazide along with their assigned study drug. BP-lowering achieved by both study drugs was on the order of 30/17 mm Hg. RR of stroke was reduced by 24.9% with losartan (P = .001). (Dahlöf B et al. Lancet. 2002;359:995-1003). Most patients (92%) were Caucasian.

ALLHAT, however, called into question the idea that ACE inhibitors and ARBs reduce stroke risk because of their effects on angiotensin II. This study reported that the diuretic chlorthalidone reduced stroke risk by 15% compared to lisinopril (P = .02) (ALLHAT Collaborative Research Group. JAMA. 2002; 2981-2997). Dr. Fagan noted that ALLHAT, unlike some other studies she discussed, had a sizable African-American cohort (35% of N = 33 367) and followed patients for 4 to 8 years. “The follow-up SBP was higher in the lisinopril group than in the chlorthalidone group,” by 2 mm Hg (P < .001) for the population overall and by 4 mm Hg for the African-American cohort, said Dr. Fagan. For the African-Americans, RR of stroke was 40% higher with lisinopril than with chlorthalidone. For Caucasians, stroke risk was the same with either drug. The amlodipine arm had more heart failure, but the same stroke risk as chlorthalidone.

ALLHAT demonstrated the benefit of diuretics, Dr. Fagan said. “But …we still think that the other data is strong to support ACE inhibitors.” She suggested that lisinopril may not have been dosed correctly, may not be the right ACE inhibitor, or that ACE inhibition “may be a strategy that doesn’t work as well in African-Americans.”

CCBs are touted by some as the best agent for reducing risk of stroke, Dr. Fagan said. This is based on the NORDIL (Nordic Diltiazem) study, which showed that diltiazem was more effective than a diuretic and a beta blocker in reducing stroke, by about 20% (RR = .8; CI .65–.99; P = .04) (Hansson L et al. Lancet. 2000;356:359-365) The primary endpoint, however, was not stroke but a composite of stroke, MI, or cardiovascular death. There was no difference in the primary endpoint in this study. The significant results for stroke alone occurred despite a higher SBP (by 3 mm Hg) in the diltiazem group. The authors said the stroke findings may have occurred by chance, said Dr. Fagan.

Practical implications
What does this mean for evaluating and managing residents? Following acute stroke, consider an ACE inhibitor plus a thiazide diuretic for BP lowering—even in patients who are normotensive. This is recommended in JNC 7, said Dr. Fagan. Consider substituting an ARB for patients who cannot tolerate an ACE inhibitor, she advised. Even for patients with a past history of stroke or TIA, “it’s never too late to initiate treatment,” she emphasized. “Remember, the PROGRESS Trial enrolled patients up to 5 years after they had their event.” Caution is advised in BP lowering during the first week or two after stroke because of the risk of infarct extension, she said.

 

 

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