Treatment of chronic hypertension for the prevention of stroke. (Featured CME Topic: Stroke).

Abstract: Because current therapies for acute stroke are limited, attention must be paid to primary and secondary prevention of stroke. This article focuses on the treatment of chronic hypertension in particular. There is no "one-size-fits-all" treatment, although recent randomized trials have shown that certain agents may be more helpful. Although an exhaustive review would require a textbook, this article reviews some major recent trials and provides evidence-based guidelines for treatment of hypertension for both primary and secondary prevention of stroke.

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Nearly 750,000 strokes occur annually in the United States, (1) at an annual cost of nearly $40 billion. (2) Stroke is the leading cause of disability and the third leading cause of death in the United States and Europe, making its prevention a topic of prime importance. The most common and treatable risk factor for stroke is hypertension.

Hypertension (HTN) is present in more than 40 million U.S. citizens, and more than one-fourth of patients are undertreated. (3) This risk factor has particular relevance for the southern United States, where there is an increased prevalence of HTN in multiple demographic groups. (4) The relationship between HTN and cerebrovascular events has been known for more than 30 years, (5) yet undertreatment is common. Many hypertensive patients are insured and see a physician regularly: examination of data from the third National Health and Nutrition Examination Survey found that 27% of a sample of more than 16,000 patients had HTN but less than one-fourth had a blood pressure of up to 140/90 mm Hg, usually with isolated systolic hypertension. Age greater than 65 years, black race, male sex, and no recent visit to a physician increased the risk. (6) Unfortunately, systolic hypertension carries a greater risk of future cardiovascular events than diastolic hypertension. (7) Some clinicians have been wary of aggressive blood-pressure-lowering therapy for fear of causing damage from hypoperfusion, but recent clinical trials have not borne this out. (8,9)

The relation between blood pressure and stroke is continuous, meaning that as blood pressure increases bit by bit, the risk of stroke increases with it, as opposed to a low risk up until some critical blood pressure and substantially higher risk above that level. Hence, it is probably more useful to think of stroke risk as gradually increasing with each millimeter of mercury increase in blood pressure rather than arbitrarily dividing blood pressures into "hypertensive" and "normotensive" categories. (10) Although it is difficult to show reductions in mortality among patients with relatively well-controlled blood pressure, at higher blood pressures the relation becomes strong. (9,11) The minimum blood pressure below which stroke risk increases has not been identified, but once patients have even mild elevations in blood pressure the risk increases with it. (12)

Selected Clinical Trial Data

Many randomized, prospective trials have shown the benefits of treating hypertension. A variety of agents have shown benefit directly through their antihypertensive effect, and some agents may have further benefits independent of their effects on blood pressure. The Blood Pressure Lowering Treatment Trialists' Collaboration performs regularly planned meta-analyses in an attempt to quantify differences in vascular endpoints between treatments (eg, calcium blockers versus f3-blockers and diuretics), diseases (eg, stroke versus myocardial infarction), and intensity of therapy (eg, lowering blood pressure more or less aggressively). (13)

Calcium Blockers

The Syst-Eur trial (14) was one of the early trials intended to show the benefit of antihypertensive therapy in the prevention of stroke in patients with isolated systolic hypertension. At the start of the trial, "isolated" systolic hypertension was defined as a systolic blood pressure higher than 160 mm Hg with a diastolic blood pressure less than 95 mm Hg, but it should be noted that many clinicians regard diastolic blood pressure of 90 to 94 mm Hg as requiring treatment. This early trial called for treatment with a calcium blocker with the addition of an angiotensin-converting enzyme (ACE) inhibitor or a diuretic if needed. Stroke was in fact reduced by 42%, showing the benefits of calcium blockers (with the addition of other agents) over placebo for stroke prevention.

The Hypertension Optimal Treatment trial (9) was intended to show the benefits of aggressive treatment of hypertension and to refine the goal of treatment. Patients with diastolic blood pressures of 100 to 15 mm Hg were randomly assigned to a goal diastolic blood pressure of 80, 85, or 90 mm Hg. A multistep regimen started with felodipine (a long-acting calcium blocker) and added other agents as necessary. By the end of the study period, most patients were on multiple medications (ACE inhibitors, [beta]-blockers, or diuretics in addition to felodipine). The lowest cardiovascular risk was found at a blood pressure of 138/82 mm Hg, with the strongest linear relationship between cardiovascular events and blood pressures of 130 to 170/75 to 95 mm Hg. A trend for prevention of stroke specifically was not seen between the varied intensities of therapy.

Calcium Blockers versus Diuretics/[beta]-blockers

The Nordic Diltiazem trial (15) randomized patients with hypertension to a regimen starting with diltiazem (a long-acting calcium blocker) or [beta]-blockers and diuretics. The rate of the prespecified composite endpoint of stroke, myocardial infarction, or vascular death was no different between the groups; the risk of stroke was (barely) significantly less in the diltiazem group, but many comparisons were made. A large number of changes were made in the regimens (which may have diluted significant benefits), and at the end of the trial only half of the patients randomized to diltiazem monotherapy were still taking diltiazem monotherapy compared with 45% of the patients randomized to [beta]-blockers and diuretics who were still taking either one or both. Lest one think that calcium blockers are especially good for stroke prevention, it should be noted that the INSIGHT trial (using extended-release nifedipine against a diuretic, reported in the same issue of the same journal) showed no such benefit in stroke prevention but a small increase in the risk of heart failure. (16)

Although the evidence seems to support the use of calcium blockers for the prevention of stroke compared with placebo, there have been concerns that these agents when used as first-line treatment may increase the risk of cardiac endpoints relative to other antihypertensives. In one large meta-analysis of over 27,000 patients studied in prospective, randomized trials of long-acting calcium blockers as opposed to [beta]-blockers, ACE inhibitors, diuretics, or clonidine, those randomized to calcium blockers had a substantially greater risk of congestive heart failure or myocardial infarction without benefits in terms of stroke or all-cause mortality. The blood pressures were essentially the same, differing by 0.1 mm Hg systolic and 0.2 mm Hg diastolic. (17)

ACE Inhibitors versus Diuretics/[beta]-blockers

The Captopril Prevention Project (18) randomized over 10,000 patients with HTN to conventional therapy (diuretics, [beta]-blockers) or captopril (an ACE inhibitor) and examined a variety of vascular endpoints. In this study, there were no significant differences, with the exception of a slightly higher risk of stroke in the captopril group. However, randomization was imperfect and patients randomized to captopril had slightly higher blood pressures, likely accounting for the results.

Those results concerning ACE inhibitors from a primary prevention standpoint are in stark contrast to trials of ACE inhibitors in patients at high risk or with a previous vascular event. The Heart Outcomes Prevention Evaluation (19) (HOPE) randomized nearly 10,000 patients who had a previous vascular event or who were diabetic and had an additional risk factor for vascular disease to ramipril or placebo. There were substantial reductions in a variety of vascular endpoints; the relative risk of stroke was 0.68 (95% confidence interval, 0.56-0.84). There was little difference in the blood pressure between the treatment and control groups (3/2), implying that ACE inhibition had benefits over and above blood pressure lowering alone. This hypothesis is often repeated but is not yet proved.

The PROGRESS Collaborative Group (20) examined the benefits of adding an ACE inhibitor (perindopril) with the possible addition of a diuretic specifically in patients with a history of stroke or transient ischemic attack. Like HOPE, there were modest reductions in blood pressure, but in patients given both an ACE inhibitor and a diuretic, there were dramatic reductions in the risk of another cerebrovascular event. Reductions in risk were seen among patients both with and without hypertension. The benefits were not limited to any specific subgroups in terms of qualifying event, comorbid conditions, or background therapy. Curiously, no benefit was seen with the ACE inhibitor alone, although the confidence interval was wide and was consistent with other trials showing a relative risk reduction in vascular events of 15 to 20%. This leaves the question as to whether or not the benefits seen in HOPE are specific to ramipril, whether HOPE is after all a chance finding, or whether there is something particularly hel pful about the combination of an ACE inhibitor and a diuretic. Although HOPE seems especially powerful, no study has shown antihypertensive treatment of any type to be worse than placebo, and in metaregression the benefits of antihypertensives (including ramipril) can be mostly explained by the reduction in blood pressure.(21)

With all of these separate agents, one might wonder whether any agent is as good as another, but there are a few generally agreed-on exceptions. [alpha]-Blockers (doxazosin) are also available for the treatment of hypertension and were one of the initial choices in the continuing Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. However, the doxazosin arm was discontinued early after a prespecified interim analysis found increased rates of cardiovascular death compared with a diuretic.(22) This agent has since fallen out of favor, especially for first-line treatment.

For patients with diabetes and hypertension, treatment with ACE inhibitors is considered mandatory. The Appropriate Blood Control in Diabetes trial studied the treatment of hypertension in this particularly high-risk group of patients.(23) Nisoldipine (a long-acting calcium blocker), despite giving similar blood pressure control compared with enalapril (an ACE inhibitor), was associated with a substantially higher risk of myocardial infarction. The HOPE trial (reviewed above) and other studies in the nephrology literature also make the case that this class of drugs is especially helpful in diabetics. Atrial fibrillation is also associated with hypertension and stroke, but this is a distinct clinical entity and is not considered further here.

Angiotensin receptor blockers are newer agents that block the receptor for angiotensin II directly, rather than blocking the precursors of angiotensin II (the mechanism for ACE inhibitors). These agents are gaining popularity and may have special benefits for the treatment of heart disease and nephropathy, but experience for stroke is lacking.

Conclusions

With a few exceptions, it is unclear whether certain agents are superior to others for the prevention of stroke. The question of the "best" agent may only be answerable by trials directly randomizing patients to specific agents while mandating equal blood pressure control. Meta-analyses are often necessary because small effects may not be seen even with the relatively large trials reviewed here (approximately 10,000 patients each).

Some general principles seem reasonable, although there is no individual clinical trial proving them.(24) In general, hypertension in patients without other serious comorbidities should be treated with diuretics or [beta]-blockers. Patients at especially high risk of congestive heart failure or with diabetes should be treated with ACE inhibitors. Patients at particularly low risk of coronary artery disease (with no other risk factors and family history) might do well with calcium blockers. The PROGRESS and HOPE trials provide good evidence that patients who have already sustained a stroke or transient ischemic attack should be treated with an ACE inhibitor (there are arguments for and against a class effect), and probably a diuretic as well. The results of future trials (such as the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial,(25) comparing calcium blockers, diuretics, and ACE inhibitors) and meta-analyses will provide future guidance. Whatever agents are chosen, aggressive tr eatment is mandatory, with blood pressures of <140/80 mm Hg being desirable.

Accepted November 7, 2002.

References

(1.) Broderick J, Brott T, Kothari R, Miller R, Khoury J, Pancioli A, et al. The Greater Cincinnati/Northern Kentucky Stroke Study: Preliminary first-ever and total incidence rates of stroke among blacks. Stroke 1998;29:415-421.

(2.) Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke 1996;27:1459-1466.

(3.) Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997;157:2413-2446.

(4.) Obisesan TO, Vargas CM, Gillum RF. Geographic variation in stroke risk in the United States: Region, urbanization, and hypertension in the Third National Health and Nutrition Examination Survey. Stroke 2000;31:19-25.

(5.) Kannel WB, Wolf PA, Verter J, MeNamara PM. Epidemiologic assessment of the role of blood pressure in stroke: The Framingham Study. JAMA 1970;214:301-310.

(6.) Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States. N Engl J Med 2001;345:479-486.

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(8.) Bloom BS. Continuation of initial antihypertensive medication after 1 year of therapy. Clin Ther 1998;20:671-681.

(9.) Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial--HOT Study Group. Lancet 1998;351:1755-1762.

(10.) Kannel WB, Wolf PA, Verter J, McNamara PM. Epidemiologic assessment of the role of blood pressure in stroke: The Framingham Study. 1970. JAMA. 1996;276:1269-1278.

(11.) Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks: US population data. Arch Intern Med 1993;153:598-615.

(12.) Vasan RS, Larson MG, Leip EP, Evans JC, O'Donnell CJ, Kannel WB, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345: 1291-1297.

(13.) Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: Results of prospectively designed overviews of randomised trials. Lancet 2000;356:1955-1964.

(14.) Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension: The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757-764.

(15.) Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH, Syvertsen JO, et al. Randomised trial of effects of calcium antagonists compared with diuretics and [beta]-blockers on cardiovascular morbidity and mortality in hypertension: The Nordic Diltiazem (NORDIL) study. Lancet 2000;356:359-365.

(16.) Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000;356:366-372.

(17.) Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Cavazzini C, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: A meta-analysis of randomised controlled trials. Lancet 2000;356:1949-1954.

(18.) Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353:611-616.

(19.) Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients: The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-153.

(20.) PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033-1041.

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RELATED ARTICLE: Key Points

* Thiazide diuretics should be the first-line agent for primary prevention.

* Treat hypertension aggressively to <140/80 mm Hg.

* Patients with a history of stroke should receive an ACE inhibitor and a diuretic independent of blood pressure.

From the Dcpartments or Internal Medicine and Psychiatry and Neurology, Tulane University Health Sciences Center, New Orleans, LA. (Dr. Naidech is now with the Department of Critical Care Neurology, Columbia Presbyterian Medical Center, New York, NY.)

Reprint requests to Leon A. Weisberg, MD, Department of Neurology TB-52, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans LA 70112.

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9604-0359