Treatment Strategies: An Evaluation of Antihypertensive Therapy VICTOR J. DLAU, M.D. ~osfon. Massachusetts

H ypertension is a major risk factor for coronary heart disease. It is a condition for which long-

term treatment is frequently required [l]. However, the decision to prescribe for a patient a lifetime of an- tihypertensive drug therapy poses special therapeutic considerations, especially m hypertensive patients with additional risk factors. For example, it has been determined that patients with even relatively mild elevations in serum cholesterol levels have an in- creased overall risk of coronary heart disease I21, and a powerful interaction between high blood pressure and elevated serum cholesterol levels contributes sig- nificantly to coronary heart disease morbidity and mortality 1231.

Efforts to reduce serum cholesterol levels by diet, pharmacologic intervention with lipid-lowering agents, or both, have been demonstrated to reduce the incidence of coronary artery disease L4,5]. Al- though the primary goal of antihypertensive drug therapy has been to lower blood pressure, reduction of elevated serum cholesterol levels also needs to be con- sidered in the overall coronary risk factor manage- ment of hypertensive patients.

In addition to patients with elevated serum choles- terol levels, hypertensive patients who smoke ciga- rettes, or have left ventricular hypertrophg, or cliabe- tes mellitus require antihypertensive therapy that will have either a neutral or favorable effect on these cardiovascular risk factors [3,6,‘7]. Other factors, such as race and age, also play a role in determining the appropriate treatment regimen for patients with es- sential hypertension [6]. Consequently, it has become increasingly recognized that effective treatment for one risk factor, such as hypertension, should not ad- versely affect another risk factor, such as lipid levels, or result in metabolic disturbances such as hypokale- mia, hyperkalemia, hyperglycemia, or hyperuricemia. For these reasons, many clinicians are now reassess- ing their treatment strategies for hypertension in par- ticular and coronary heart disease in general.

EFFECTS OF ANTIHYPERTENSIVE AGENTS ON LIPID LEVELS

Although lowering cholesterol levels tends to cle- crease coronary events [8], treatment of hypertension per .ye has not appreciably reclucecl the incidence of myocardial infarction or sudden death [61. Several hypotheses have been proposed to explain this phe- nomenon. A popular explanation is that the adverse effects of some antihypertensive agents-for exam- ple, diuretics and beta-blockers-on serum lipid and

From the D~won of Vascular Medlclne and Atherosclerox, Department of Medune, Brigham and Women’s Hospital and Harvard MedIcal School, Boston. Massachusetts Requests for reprints should be addressed to Dr Victor I. &au. DIVISION of Vascular Medicine and Atherosclerosis Brlgham and Women’s Hospttal. 75 FrancIs Street,

potassium levels [1,6,9] may offset the beneficial ef- fects of blood pressure lowering. Specifically, the ad- verse effects of thiazide diuretics on lipid levels in- clucle a reduction of cardioprotective high-density lip- oprotein levels and increases in very low-density lipo- protein, lowdensity lipoprotein, and plasma triglycer- ides 121. Antihypertensive treatment with beta-block- ing agents may result in a decrease in high-density lipoprotein cholesterol levels accompanied by an in- crease in triglyceride levels 123. In addition, thiazicle diuretics also decrease potassium levels and increase uric acid and glucose [G]. Similar effects have been noted when beta-blockers and diuretics were adminis- tered concomitantly [lo].

Clinical studies indicate that some antihypertensive therapies appear to have either neutral or beneficial effects on lipid component levels [1,21. Prazosin has been shown to have no adverse effect on blood lipids [1,2]. More clinical trials need to be carried out to test whether the lipid-neutral or lipid-beneficial effects of antihypertensive drugs will help to reduce the overall incidence of coronary artery disease. Nevertheless, most clinicians agree that the choice of drug treatment for hypertension should include an assessment of the effect of each specific agent on plasma lipid lipoprotein levels and other metabolic parameters.

TREATMENT OF DIABETIC PATIENTS WITH HYPERTENSION

The presence of both hypertension and diabetes is an additional treatment challenge to clinicians. In se- lecting an antihypertensive agent, it is important to consider the drug’s effects on glucose and insulin lev- els. In this supplement, Chen et nl [ll] reported that insulin resistance, glucose intolerance, and hyperinsu- linemia can occur in hypertensive patients. Both hy- perglycemia and hgperinsulinemia have been assocl- ated with an increased risk of coronary artery disease [12]. Results of the study by Chen et al [l l] show fur- ther that the insulin-resistant state that has been ob- served in some hypertensive patients may be lowered as a consequence of long-term therapy with prazosin. This improvement was associated with a significant reduction in total cholesterol concentrations and fast- ing plasma triglyceride levels. This association be- tween alpha-blocker therapy and improvement in the insulin state provides an additional factor to be consicl- erecl in the selection of antihypertensive therapy in obese patients and in patients with concomitant dlabe- tes mellitus [X3].

Other papers in this supplement, such as those pre- sented by Tzagournis [14] and Kwan et nl [15], report that alpha-blockers do not have an adverse effect on the control of diabetes. Whether these drugs have an effect on vascular disease in these patients, however, is not presently known. It has been demonstrated that beta-blockers may cause reflex peripheral vasocon-

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striction. Kwan and associates [15] carried out a clini- cal study of a hypertensive diabetic population to de- termine whether atenolol and prazosin have different effects on vascular resistance and blood flow in skin as well as muscle. It is interesting to note that these in- vestigators demonstrated that antihypertensive ther- apy with prazosin increased forearm blood flow. Since both systemic hypertension and diabetes mellitus are considered to be risk factors for the development of reduced peripheral perfusion as well as occlusive pe- ripheral vascular disease, the effect of antihyperten- sive agents on the peripheral circulation of these pa- tients is another important factor to be considered.

HYPERTENSION MANAGEMENT IN OTHER SPECIAL POPULATIONS

Cigarette smoking is not only a highly significant risk factor for coronary heart disease, but it also acts to potentiate the risks of hypertension as well as hy- percholesterolemia [3]. Clinical trials have shown that hypertensive patients who smoke cigarettes have a threefold increase in the lo-year incidence of cardio- vascular morbidity as compared with that of nonsmok- ers 1161. Additionally, there is increasing evidence that a causal relationship exists between cigarette smoking, increased serum cholesterol levels, and ele- vated blood pressure that results in a higher incidence of morbidity and mortality from coronary heart dis- ease 131.

It is very important, then, to evaluate not only the risk factors for coronary heart disease for each indi- vidual patient but to determine the synergistic inter- action of these factors prior to treatment with any an- tihypertensive agent. In the Medical Research Coun- cil Trial, beta-blockers did not affect coronary heart disease risk in hypertensive patients who smoked [17]. On the other hand, beta-blockers reduced coro- nary events as compared with placebo in the nonsmok- ers. Thus, the complex interactions of smoking, lipid disorders, and hypertension raise important questions about our current use of conventional antihyperten- sive drugs in this population. Alternative therapy with alpha-blockers, angiotensin-converting enzyme inhibitors, or calcium antagonists is emerging as the treatment of choice in these complex, high-risk pa- tients [6].

This supplement also focuses on the clinical pharma- cology of the alpha-blocker prazosin, and its effects in other special populations. Investigations in other pop- ulations indicate that prazosin is effective across a broad range of patient groups regardless of age, race, or concomitant conditions. In a clinical trial that com- pared prazosin with enalapril in elderly patients, effi- cacy rates were reported to be similar between treat- ments. Interestingly, in this crossover study, half of the patients responded to only one of the two drugs [181. These results suggest that elderly patients are not a homogeneous population, and they may have hypertension of differing origin.

Black patients are often considered to be a distinct clinical group because their degree of hypertension is characteristically more severe as well as more difficult to manage than that of white patients [19]. Treatment with the alpha-blocker prazosin has been shown to be equally efficacious in both black and white hyperten- sive patients. Treatment with prazosin is also associ-

ated with a decrease in serum cholesterol, triglycer- ides, and low-density lipoprotein cholesterol in both patient groups [19].

The effect of antihypertensive therapy on patients with left ventricular hypertrophy is another impor- tant area to address. Antihypertensive agents affect left ventricular hypertrophy in different ways. Beta- blockers have an inconsistent and somewhat variable effect on left ventricular hypertrophy. Several studies have shown that diuretics do not readily reverse left ventricular hypertrophy, whereas there are promis- ing indications from studies by Leenen et al [20] and Ram et al [Zl] that therapy with prazosin may be asso- ciated with regression or prevention of left ventricular hypertrophy. This effect is comparable with that seen with angiotensin-converting enzyme inhibitors and centrally acting sympatholytic agents.

QUALITY OF LIFE The degree to which one can function, enjoy a sense

of well-being, and experience satisfactory social, emo- tional, physical, and intellectual aspects of living can be considered an individual’s quality of life. Planning involved in any long-term drug treatment regimen for a chronic disorder such as hypertension requires con- sideration of the patient’s self-assessment of physical and social well-being. Treatment with antihyperten- sive agents may affect the patient’s emotional state, intellectual functioning, work performance, exercise and sexual capacity, or social participation. Further- more, the degree to which any of these parameters detrimentally influences a patient’s quality of life has been shown to have a direct effect on patient compli- ance with the drug treatment regimen. Recently, this issue was studied in a comparative trial of three differ- ent antihypertensive agents 1221. As discussed by Weinberger [23] and Lasser et al 1241 in their articles, in terms of cognitive or physical functioning, it ap- pears that alpha-blockers have little or no negative effect on these parameters.

COMMENTS Ultimately, clinicians and patients alike need to rely

on antihypertensive agents that are metabolically safe and that can help reduce the incidence of coronary ar- tery disease as well as preserve left ventricular func- tion. Furthermore, these drugs also should not impair the quality of life.

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9. Leren P: Comparison of effects on lIpId metabolism of antihypertensive drugs with alpha- and beta-adrenerglc antagonist propertles Am J Med 1987: 82 (suppl 1A) 31-35 10. Weinberger MH AntihypertensIve therapy and lIpids Paradoxical Influences on cardio- vascular disease risk Am J Med 1986; 80 (suppl ZA). 64-70. 11. Swlslockl ALM. Hoffman BB, Sheu WHH. Chen Y-DI, Reaven GM Effect of prazosln treatment on carbohydrate and llpoprotetn metabolism In patients wtth hypertension. Am J Med 1989. 86 (suppl 15) 14-18 12. Welborn TA. Wearne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations Diabetes Care 1979, 2 154-160 13. Shlonoir H, Noda K. Karumasa N. Mlyamoto K. eta/ Glucose tolerance during chronic prazosin therapy n patients with essential hypertension Curr Ther Res 1986. 40: 171- 180. 14. Tzagoums M Interaction of diabetes with hypertension and lIpIds-patients at high risk an overvIew Am J Med 1989. 86 (suppl 16) 50-54 15. Kwan CM. Shepherd AMM Johnson J, Taylor WF Forearm and finger hemodynamlcs, blood pressure control, and lIpId changes In diabetic hypertenslves treated with atenolol and prazoslr a brief report Am J Med 1989. 86 (suppl 1B) 55-58 16. Sam&son 0. Wllhelmsen L. Elmfeldt D, et al, Predictors of cardiovascular morbldlty

in treated hypertension. results from the Primary Preventive Trial In Goteborg. Sweden J Hypertens 1985, 3: 167-176. 17. Medical Research Council Working Party MRC trial of treatment of mild hypertension prlnclpal results Br Med J 1985; 291, 97-104 18. Chetrng DG, Hoffman CA, RICCI ST, Weber MA. Mild hypetienslon in the elderly a comparison of prarosln and enalaprll Am J Med 1989: 86 (suppl 1B): 87-90 19. Weber MA Management of hypertension patients with special problems. Am J Med 1989, 86 (suppl 1B) 70-73 20. Leenen FHH, Smith DL, Farkas RM. Reeves RA. Marquez-Julio A: Vasodilators and regressfan of left ventricular hypertrophy Hydratarrne versus prarosin in hypertensive humans. Am J Med 1987; 82 969-978 21. Ram CVS, Gonzalez D. Kulkarnt P. et a/ Regression of left ventricular hypertrophy In hypertension. effects of prarosln therapy Am J Med 1989, 86 (suppl 18): 66-69 22. Croog SH, Levine S, Testa MA, et al The effects of antihypertensIve therapy on the quailty of life. N Engl J Med 1986, 314 1657-1664 23. Welnberger MH Lowering blood pressure wIthout lowering the patlent’s quality of IIfe. Am J Med 1989: 86 (suppl IB), 94-97. 24. Lasser NL. Nash J, Lasser VI. HamIll SJ. Batey DM. Effects of antIhypertensIve therapy on blood pressure control, cognition, and reactlvlty a comparison of prarosln. propranolol, and hydrochlorothlarlde Am J Med 1989, 86 (suppl 15) 98-103

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