antihypertensive therapy to maximally reduce coronary risk

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American Heart Journal Kaplan

9. Modan M, Halkin H, Almog S, Lusky A, Eshkil A, Shefi M, 11. Reaven GM. Role of insulin resistance in human disease. Di- Shitrit A, Fuchs A. Hyperinsulinemia: a link between hyper- abetes 19%$37:X95-607. tension, obesity and glucose intolerance. J Clin Invest 12. Cutler JA, MacMahon SW, Furberg CD. Controlled clinical 1985;75:809-17. trials of drug treatment for hypertension: a review. Hyperten-

10. Ferrannini E, Buzzigoli G, Bonadona R, Giorico MA, Oleggini sion 1989;13(suppl 1):1-36-I-44. M, Graziadei L, Pedrinelli R, Grandi L, Bevilacqua S. Insulin 13. Beard K, Bulpitt C, Mascie-Taylor H, O’Malley K, Sever P, resistance in essential hypertension. N Engl J Med 1987: Webb S. Management of elderly patients with sustained hy- 317:350-7. pertension. Br Med J 1992;304:412-6.

Antihypertensive therapy to maximally reduce coronary risk

Antihypertensive therapy as it is currently prescribed has not provided the degree of protection against coronary disease that was predicted by epidemiologic evidence. At least five steps can be taken to maximally reduce coronary risk: (1) more frequent, out-of-the-office monitoring of blood pressure, particularly during the early morning hours; (2) diligent search for other coexisting coronary risk factors; (3) vigorous use of various life-style modifications; (4) greater selectivity in the choice of antihypertensive agents, using those that may provide additional benefits for other coronary risk factors and other coexisting conditions; and (5) avoidance of coronary hypoperfusion by too great a reduction of blood pressure. (AM HEART J 1993;125: 1487-93.)

Norman M. Kaplan, MD Dallas, Texas

The increasingly widespread treatment of hypertension during the past 20 years has unquestionably contributed to the reduction in morbidity and mortality rates from cardiovascular diseases observed in the United States and elsewhere during that period. However, when major cardiovascular diseases are considered separately, the impact is seen to be variable: greatest on stroke; a likely significant postpone- ment if not prevention of congestive heart failure; a less than expected effect on coronary disease; and an uncertain influence upon renal damage.

The variable impacts of antihypertensive therapy on stroke, coronary disease, and congestive failure have recently been examined in large numbers of elderly hypertensive subjects in three trials, which markedly expanded on the limited data previously

From the Hypertension Division, University of Texas Southwestern Med- ical Center.

Reprint requests: Norman M. Kaplan, Professor of Internal Medicine, Uni- versity of Texas Southwestern Medical Center. 5323 Harry Hines Blvd., Dallas, TX 7523543899.

Copyright @ 1993 by Mosby-Year Book, Inc. 0002.8703/93/$1.00 + .I0 4/o/44734

available (Table I).le6 In most ways the data appear to be similar to those noted on the less than elderly populations with mild to moderate hypertension in eight trials reported in the 1970s and early 1980s7 Whereas stroke has been reduced by as much as 47 % , coronary disease has been reduced less and to a statistically significant degree in only one study.

Many possible explanations are offered for this less than expected protection against coronary disease compared with stroke,8 but the actual cause(s) likely will never be determined. Therefore rather than ex- pending unnecessary energy on a fruitless search, we need to consider ways in which antihypertensive therapy may be provided to maximally reduce coronary risk.

Before the specific steps are addressed, it is in- structive to recognize that even in the best of cir- cumstances, the overall management of hypertension has until now not been very effective in reducing the overall risks for coronary disease. The experiences of a special hypertension clinic in a major teaching hospital in Australia are revealing (Table II).g This clinic must provide as good care as is practiced anywhere since it was staffed by highly motivated and well-in-

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American Heart Journal

Table I. Effects of therapy in elderly hypertensive patient? -..

C’oopr und Australian E WPHE’ Warrnnder 1 .4’HfiP’ STOP HI” MR(“l

.-__- -______ - -_ Mean blood pressure at entry 165/101 182/101 197/100 170177 195/102 I%/91

I loo”, ISH) (43”s ISH) Events per 1000 patientyears (treated vs placebo)/relative risk

Stroke 0.67 0.64* 0 58’ .t (1.67,” 0.x1* 0.75 * Coronary disease 0.82 0.80 1.03 0.7:1* o.nTit 0.x1.$ Congestive failure 0.78 0.68 0.45* 0.49* All cardiovascular 0.69 0.71* 0.76* o.ta* 0.60* o.n:j 8

EWPHE, European Working Party on High Blood Pressure in the Elderly; SHEP, Systolic Hypertension in the Elderly Program; STOP HT. Swedish Trial

in Old Patients with Hypertension; MRC. Medical Research Council. *Statistically significant. tMyocardial infarction only. $Ischemic heart disease.

Table ii. Coronary risk factors in 131 patients treated from 1986 to 1990 at the Austin Hospital Hypertension Clinic

Risk factor (mean)

Blood pressure (mm Hg) Systolic Diastolic

Diastolic >90 Plasma cholesterol

(mmol/L [mg/dl])

1986 1988 1990

151 153 149 87 87 82

6.:;:2j 5.$& 5.&2,, ,

are mainly concentrated during the early morning hour& l2 and are usually preceded by abrupt increases in both heart rate and blood pressure.ls

Plasma high-density lipoprotein 1.25 (47) 1.25 (47) 1.32 (50) cholesterol (mmol/L [mg/dl])

Weight (kg) 79.4 78.4 78.0

Data from Straznicky NE, et al. Med J Au&r 1991;155:691-700.

The need for better monitoring of blood pressure may now be even greater than previously because of the increasing use of once-daily doses of antihypertensive drugs, some of which do not provide full 24- hour efficacy.14 Because the usual practice is to take the medication in the morning but not to have the blood pressure level checked until 2 to 8 hours later in the physicians’s office, the wearing off of antihypertensive efficacy after 18 to 20 hours may never be recognized but may leave the patient exposed to the dangers of abrupt increases in pressure during the early morning h0urs.l”

formed specialists who made intensive efforts to The problem should be addressed by self-moni- identify and modify elevated lipid levels and excess toring of the pressure, most conveniently by one of weight along with control of hypertension. However, the increasingly available, inexpensive, and accurate over a &year period from 1986 to 1990, the major fa- semiautomatic devices. I6 Automatic ambulatory vorable impact on coronary risk was through the im- monitors will of course provide the necessary infor- proved control of hypertension: About 60% of the mation, but their use is and will continue to be lim- patients still had total cholesterol levels above 5.5 ited. Patients should be asked to occasionally check mmol/L (210 mg/dl), and almost 90% remained their pressure soon after awakening and ambulating, above their maximum desirable weight. I will now as well as toward the end of the dosing interval for consider the ways by which better effects may be whatever drugs taken for hypertension, to ensure achievable. adequate control of the blood pressure.

IMPROVED MONITORING OF BLOOD PRESSURE

The first step must be the more intensive monitoring of blood pressure, particularly during the critical early morning hours after awakening when the larg- est portion of major cardiovascular catastrophes oc- cur.l” The need to assess the adequacy of therapy during these hours has been emphasized further by the recent recognition that silent myocardial ischemia and malignant ventricular arrhythmias are common in hypertensive patients without clinical evidence of coronary disease and that these events too

The appropriate time to take currentIy available medications that provide full 24-hour efficacy prob- ably remains as soon after awakening as possible rather than at bedtime so as to avoid a hypotensive response from the agent’s maximal efhcacy during the hours of sleep when most patient’s pressure fall spontaneously. Although more truly long-acting agents (such as trandolapril) are available, the need to ensure that each patient obtains the desired 24-hour effect remains, because not all patients fit the “average” as determined in the premarketing testing of new drugs.

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American Heart Journal Kaplan 1489

16

14

12

ia

6

a

0 Women q Merl

0.8 0.9 1 1.1 Waist to hip ratio

Fig. 1. Twelve-year incidence of coronary heart disease (CHD) by waist/hip ratio and sex gender in 1462 women, ages 50, 54, and 60 years, at baseline and 792 men, age 54 years, at baseline in Gothenburg, Swe- den. (From Larsson B, Bengtsson C, Bjorntorp P, et al. Is abdominal body fat distribution a major explanation for the sex difference in the incidence of myocardial infarction? Am J Epidemiol 1992;135:266.)

Hypertriglyceridemia

t

Obesity + Andrcgen -@ Increased Lip&& Release of Abdominal Fat - Free Fatty Acids

Type II Peripheral Diabetes c Insulin Mellitus Resistance

Increased Decreased - PallWSatiC Hepatii Insulin

Insulin Secretion Extraction

1 Hyperinsoiinemia

Nervous Activity

Sodium Vascular Retention HypefiwN’

I I

Hypertension

Fig. 2. Overall scheme for mechanism by which upper body obesity could promote glucose intolerance, hypertriglyceridemia, and hypertension by way of hyperinsulinemia. (From Kaplan NM. Arch Intern Med 1989;149:1514. Copyright 1989, American Medical Association.)

ASSESSMENT OF CORONARY RISK FACTORS

The second step in improving on current practices involves a more complete assessment of the coexisting coronary risk factors frequently found in patients with hypertension. As shown in Table I of the “Introduction” to this supplement, most hypertensive patients will have one or more other risk factors requiring attention.

Cigarette smoking. The major contribution of cigarette smoking to coronary risk places it at the top of the list, with an almost threefold increase in risk even if only one to four cigarettes are smoked per day.i7 Nonetheless, fewer than half of smokers in the United States have ever been asked to quit by their physicians, and only 3.6 % of successful quitters obtained help from a physician.i8 As noted in the “In-

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Table III. Lif’e-style modifications for hypertension

Proven value Weight reduction, particularly for upper kodj obesity Moderate sodium restriction to 2 gm Na+

(88 mmol)/dl Moderation in alcohol Regular isotonic exercise Increased potassium intake

Unproven value 6. Calcium supplements 7. Magnesium supplements 8. Fish oil supplements 9. Relaxation

10. Moderation in caffeine

troduction,” most of the repetitive pressor effect of smoking has been totally missed by the usual manner of measuring the blood pressure only after a period of abstinence. The lack of recognition of the pressor effect of smoking likely contributes to the neglect that this malignant addiction has been accorded in the past. Every hypertensive patient should be asked about their smoking status, and if they smoke, strongly and repeatedly urged to quit, using all of the proven techniques, including the use of nicotine gum and patches.

Dyslipidemia. As described previously in this supplement by Dr. Lithell, elevated total cholesterol levels and hypertension coexist much more often than by chance. The association has been repeatedly confirmed in multiple populations and can be only partly accounted for by the known mechanisms that might raise both levels, although obesity clearly plays a role. The manner by which dyslipidemia and hypertension interact to aggravate atherosclerosis likely involves disruption of the synthesis of endo- thelium-derived relaxing factor (nitric oxide) by ox- idized low-density lipoprotein cholesterol.lg Total and high-density lipoprotein cholesterol should be measured in every hypertensive patient, and appropriate dietary and drug therapies should be provided for those with abnormal values. Unfortunately, de- spite vigorous attempts, the abnormalities may per- sist, as noted in the Austin Hospital experience (Ta- ble II).”

Glucose intolerance and insulin resistance. Glucose intolerance is a common finding in hypertensive patients and may be noted years before the onset of the hypertension. 2o As described by Dr. Weidmann in a previous article in this supplement, overt diabetes is more common in hypertensive persons than nor- motensive persons, and significant resistance to the effects of insulin on glucose intake in peripheral

my 1993


muscles has been recognized in both obese and nonobese hypertensive persons.

Fasting and perhaps postprandial glucose levels should be measured in every hypertensive patient.. Assessment of’ insulin resistance remains too diffi- cult for routine clinical practice, and for now, it seems enough to know that virtually every obese hypertensive subject and about half of nonobese hypertensive subjects will be insulin resistant. At the same time, steps to minimize this resistance, as will be described, are appropriate for every hypertensive patient.

Obesity. The pathogenetic role of obesity in coronary disease is largely through its associations with dyslipidemia, glucose intolerance/insulin resistance, and hypertension. The associations are particularly strong in those with predominately upper body obesity, as best measured by the waist-to-hip ratio (Fig. l).‘l This simple measurement should be routinely recorded along with the weight and body mass index. The relationships have been nicely delineated through the work of many investigators,?s and the overall schema shown in Fig. 2 is composed from the multiple contributions of their research.

Left ventricular hypertrophy. Because this has been so thoroughly covered in the previous paper by Dr. Messerli, no additional comment is needed beyond the hope that relatively inexpensive, simplified echocardiograms for left ventricular wall thickness2” will become more widely available and used.

MORE EFFECTIVE USE OF NONDRUG THERAPIES

These therapies, better described as life-style modifications, deserve greater emphasis in the management of hypertension, because they will help not only control the blood pressure, but they will also favor- ably alter most other coronary risk factors. Of those listed in Table III, weight, loss and moderation of sodium intake have recently been shown to offer the prospect of the prevention of hypertension.24 Al- though not tested in that large-scale trial, regular physical activityg5 and daily consumption of small amounts of alcohol, that is, two usual-sized portions that add up to no more than 1 ounce of ethanol,z6 will almost certainly be effective in both the prevention and relief of hypertension and coronary disease. In the large proportion of hypertensive subjects who are obese and dyslipidemic, the need for a low-calorie, low-saturated fat diet is particularly critical, along with regular physical activity.

DRUGTHERAPY

Even with extensive modifications of life-style, most hypertensive subjects will need antihyperten-

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Table IV. Effects of antihypertensive agents on coronary risk factors

Risk factors Diuretic /LBlocker cu-Blocker Calcium blocker ACE inhibitor

Blood pressure Cholesterol High-density lipoprotein cholesterol Glucose intolerance Hyperinsulinemia Left ventricular hypertrophy

+ -

. - -

+I-

+ + + + + . . .

- . - + . f - + + + + + +

f, Positive effect; -, negative effect; ., neutral effect.

Table V. Selection of initial therapy of hypertension based on coexisting condition

Coexisting condition Diuretic P-Blocker a-Blocker Calcium-blocker ACE inhibitor

Older age ++ +I- + + + Black race ++ +I- + + +/- Coronary disease +I- ++ + ++ + Congestive failure ++ - + ++ Cerebrovascular disease + + +/- ++ + Renal insufficiency ++ +I- + ++ ++* Diabetes - - ++ + ++ Dyslipidemia - - ++ + + Asthma or chronic obstructive pulmonary disease + - + + + Peripheral vascular disease + - + ++ +*

+ +, Preferred; + , suitable alternative; + /-, usually not preferred; - , usually contraindicated; *, caution of occult renovascular disease.

sive drug therapy. The choices are divided between five major classes, which, while providing equipotent antihypertensive potency,27 differ in the effects on other major coronary risk factors (Table IV). The negative effects shown for diuretics may be reduced or avoided by lower doses that provide all of the antihypertensive effect but minimize the metabolic mischiefs of the higher doses usually prescribed.28

The negative effects of diuretics and P-blockers on insulin sensitivity have been described with moderate doses of hydrochlorothiazide, that is, 40 mg/day, and with multiple /3-blockers.2g Perhaps lower doses of diuretics and newer P-blockers that do not reduce peripheral blood flow may not induce these changes. For now, however, these agents should be given with caution in those hypertensive persons who are dyslipidemic, glucose intolerant, or insulin resistant, so as not to further aggravate these problems. On the other hand, cy-blockers and angiotensin-converting enzyme (ACE) inhibitors provide positive effects on glucose tolerance and insulin sensitivity. Although Lithell’s data2g are confined to captopril, at least four other ACE inhibitors have now been shown to improve insulin sensitivity,30 and this is almost certainly a class effect shared by all ACE inhibitors.

The differing effects of the various drugs on multiple coronary risk factors shown in Table IV may or may not translate into differing degrees of protection

against coronary disease. As of now, only diuretics and&blockers have been put to the test, and as noted earlier, they have clearly reduced strokes but have not reduced coronary disease as well as predicted from the degree of reduction of blood pressure obtained in the multiple clinical trials. In the absence of definitive data with the other agents, the 1993 Joint National Committee recommends that diuretics and P-blockers be “first-choice agents unless they are contraindicated or unacceptable, or unless there are special indications for other agents.“31

The special indications for other agents have been fairly well defined and are based primarily on the presence of other conditions (Table V). With the experience gained during the past 10 years with the use of a-blockers, calcium blockers, and ACE inhibitors, more and more special indications for these agents have been identified. As Dr. Messerli noted in the prior paper in this supplement, ACE inhibitors have been found to provide greater regression of left ventricular hypertrophy than other agents,32 and the rapidly expanding evidence of their ability to prevent both diastolic and systolic dysfunction33 suggests that this class of drugs will be used increasingly for both primary and secondary cardioprotection. The papers that follow will provide additional informa- tion about how an ACE inhibitor, trandolapril, will fit into this expanding usage.

1492 Kaplan

THEGOALOFTHERAPY

The last way in which antihypertensive therapy can be modeled to maximally reduce coronary risk relates to the degree of blood pressure reduction, that. is, the goal of therapy. Until recently, most believed that the goal was the lowest level obtainable by moderate doses of medication without inducing significant side effects. However, a series of reports have described a J-curve phenomenon: a progressive de- crease in morbidity and mortality rates from coronary disease as diastolic pressures are lowered to around 85 mm Hg, but an increase in coronary events at pressures below that level.“4

Debate continues about whether such a threshold exists. Those who believe it exists point to the presence of such a J curve in multiple therapeutic trials and to the logic behind the presence of such a threshold: The drugs used in the various trials show- ing a J curve have been diuretics and &blockers, both of which reduce coronary blood flow; the hypertro- phied myocardium of hypertensive subjects needs more nutrients, but typically has a limited reserve of coronary perfusion without the ability to efficiently increase coronary blood Aow in the face of lower perfusion pressures or to extract additional oxygen,

Those who question the existence of a J curve make several counter-arguments: the small number of events in the various clinical trials that are the ba- sis for the claim; the Iikelihood that the coronary events seen at lower blood pressures simply reflect reduced cardiac function in a rapidly failing heart rather than the effects of pressures lowered by antihypertensive drugs; the failure to show a J curve in the Systolic Hypertension in the Elderly Program trial, wherein diastolic pressure in this elderly popu- lation was reduced to an average of 69 mm Hg, and the existence of a J curve of both coronary and non- cardiovascular deaths without drug therapy at lower levels of blood pressure occurring naturally.“’

I remain convinced that a J curve exists, although I agree that the issue remains unsettled. A proper large-scale prospective study wherein diastolic pressures are purposefully reduced well below 85 mm Hg in half of the patients and kept at or above 85 mm Hg in the other half is clearly needed. In the meantime, caution is advised, particularly in patients with known preexisting coronary disease, not to lower pressures too much. Although maximal protection against strokes and even more so renal damage may require lower pressures, if coronary disease is the major threat as it is for most hypertensive patients, no real benefit has been shown, and there is a potential for harm when diastolic pressures are lowered below 85 mm Hg.

May 1993


Conclusion. The incorporation of these five general principles into specific practice should improve the protection provided against premature coronary disease, which remains the major threat to hypertensive patients.

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antihypertensive therapy to maximally reduce coronary risk

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