The effective treatment of hypertension is surprisingly. Unsolved Problems in Treating Hypertension. Rationale for New Approaches. Michael A.

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1 AJH 1998;11:145S 149S Unsolved Problems in Treating Hypertension Rationale for New Approaches Michael A. Weber Two major problems continue to challenge hypertension experts and clinical practitioners. The first is the apparently simple issue of controlling blood pressure; only one-quarter of hypertensive patients in the United States have blood pressures reduced to less than 140/90 mm Hg. Even those known to be receiving treatment have barely a 50% success rate. Explanations include inadequate commitments by physicians to achieve target blood pressures, but it is also likely that effectively decreasing blood pressure despite the currently available panoply of antihypertensive agents is a truly difficult task. The second problem is that despite our success in decreasing stroke incidence, hypertension treatment with traditional agents, largely diuretic-based, has not adequately protected patients against coronary events and renal insufficiency. Such new drug classes as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and calcium channel blockers exhibit vascular effects that might inhibit The effective treatment of hypertension is surprisingly difficult. The Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure recommended in its Fifth Report (JNC V) that blood pressure be reduced to less than 140/90 mm Hg. 1 This criterion, which has not substantively changed with the Sixth Report, is based on epidemiologic evidence that the From the Department of Medicine, The Brookdale University Hospital and Medical Center, Brooklyn, New York. Address correspondence and reprint requests to Michael A. Weber, The Brookdale University Hospital and Medical Center, Department of Medicine, One Brookdale Plaza, Brooklyn, New York atherosclerotic changes and reduce clinical events, but we are still awaiting definitive confirmation of these properties from ongoing clinical outcomes studies in hypertension. Therapy with fixed combinations of antihypertensive drugs is now recognized as a potentially useful approach. Innovative combinations, including ACE inhibitors and calcium channel blockers, can provide enhanced antihypertensive efficacy while avoiding or minimizing adverse metabolic and clinical side effects. These approaches are also convenient and cost-effective. It remains to be learned whether newer drug combinations might exhibit additive cardiovascular protective actions. Am J Hypertens 1998;11:145S 149S 1998 American Journal of Hypertension, Ltd. KEY WORDS: Antihypertensive therapy, combination therapy. risk of serious cardiovascular events starts to increase steeply when blood pressures exceed this level. 2 Data from the National Health And Nutrition Examination Survey (NHANES), however, point out that barely one-quarter of hypertensive individuals in the United States have blood pressures that meet this goal. 3 Of particular note, even in those patients considered to be receiving treatment, this goal is achieved in fewer than half. There are some ready explanations for this disappointing finding. Patients, despite filling their prescriptions, often do not take their medications according to instructions. And just as importantly, physicians often are not sufficiently aggressive in adjusting antihypertensive therapy to achieve meaning by the American Journal of Hypertension, Ltd /98/$19.00 Published by Elsevier Science, Inc. PII S (98)

2 146S WEBER AJH OCTOBER 1998 VOL. 11, NO. 10, PART 2 ful blood pressure reductions. It also is likely that despite the wide array of drugs currently available for treating hypertension, it remains genuinely difficult in many instances to bring blood pressure down to acceptable levels. Even though most drug classes can work effectively against the primary mechanisms that elevate blood pressure, compensatory mechanisms frequently are activated and thereby prevent optimal blood pressure responses. Skillfully constructed combination drug regimens may be an answer to this problem. OTHER ISSUES IN TREATMENT The principal reason for treating hypertension is to protect patients from such serious consequences as coronary disease and strokes. Reviews of clinical trials that have examined these outcomes have revealed that the incidence of stroke is reduced dramatically during drug therapy for hypertension, regardless of the agent used. Coronary events, however, which are perhaps the most common result of hypertension, have been reduced less effectively by traditional drugs. Clearly, high blood pressure alone cannot be the full explanation for why hypertensive patients are so susceptible to coronary disease. We know that hypertension most commonly is a syndrome of risk factors, including abnormalities of lipids, glucose, and insulin metabolism. Likewise, intrinsic abnormalities of the structure and function of the left ventricle, arteries, and kidneys are part of what is now usually called the Hypertension Syndrome. 4 But beyond these obvious risk factors lies a possibility that changes in the arterial wall, which might be present throughout life, could be a key characteristic of hypertension that, independently of blood pressure itself, explains the high occurrence rate of vascular events. 5 This raises an obvious but pragmatic clinical question of which drugs might have the ability to work directly at the arterial wall to provide protection for critical parts of the circulation. These two issues, optimizing blood pressure control and improving cardiovascular prognosis in hypertensive patients, lead the discussion into some of the newer drug classes. For the purpose of this very brief review, we will consider the roles of the angiotensinconverting enzyme (ACE) inhibitors and the calcium channel blockers in potentially addressing these problems. And, in particular, we will consider whether concomitant administration of these two drug classes might, at the very least, provide a strong measure of antihypertensive efficacy. Although some clinical outcomes data are already available for each of these drug classes separately, there are as yet no studies that have examined their combined effects on cardiovascular event rates. THE RENIN-ANGIOTENSIN SYSTEM It is now 25 years since Laragh and colleagues first proposed that the renin-angiotensin system, independent of its hemodynamic effects, might directly produce adverse effects on the vasculature. 6 Based on a retrospective analysis of data, these investigators asserted that high-renin hypertensive patients were more likely than low-renin patients to experience myocardial infarctions and other major cardiovascular events. Subsequently, a prospective follow-up of a hypertensive cohort by this group of investigators confirmed their earlier discovery. 7 At the same time, these investigators also proposed a vasoconstrictor:volume hypothesis of hypertension in which two principal mechanisms could account for the raised blood pressure. 8 In high-renin hypertensives, the renin-angiotensin system itself was primarily responsible for sustaining the hypertension, whereas expanded volume, which has an inhibitory effect on renin release from the kidney, largely accounted for the high blood pressure in low-renin hypertension. Normal renin patients had elements of both mechanisms. These theories underscore the potential importance of antihypertensive drugs that block the renin-angiotensin system. Not only might these agents effectively reduce blood pressure, particularly in patients with high or normal renin values, but they might also protect key parts of the arterial circulation and thus reduce the probability of major cardiovascular events. The hemodynamic effects of such drugs are by now well established; the ACE inhibitors have been shown to be highly effective in reducing blood pressure in hypertension and in another important clinical setting reducing afterload in congestive heart failure. Data are still continuing to emerge on the question of how blockers of the renin system can have antiatherosclerotic actions and possibly reduce clinical disease. There is a growing understanding of the effects of angiotensin II on the vascular wall, in particular how it stimulates vascular smooth muscle proliferation, the development of connective tissue matrix, while having a disruptive action on the protective endothelial layer. 9 In animal models of accelerated atherosclerosis, ACE inhibitors have been shown to be highly effective in reducing atherosclerosis. 10 Likewise, such agents as angiotensin receptor blockers can effectively reduce major events and improve survival in event-prone hypertensive animal models. 11 Although definitive studies on the efficacy of ACE inhibitors and angiotensin receptor blockers in reducing clinical endpoints in hypertension have not yet been completed, persuasive data using ACE inhibitors have emerged from patients studied under other conditions. During treatment of congestive heart failure,

3 AJH OCTOBER 1998 VOL. 11, NO. 10, PART 2 NEW TREATMENT APPROACHES FOR HYPERTENSION 147S for example, ACE inhibitors have been shown to significantly reduce the incidence of new myocardial infarctions. 12 Similarly, when used in patients who have suffered an initial myocardial infarction and who have reduced left ventricular systolic function, ACE inhibitors have also been shown to reduce the likelihood of further heart attacks. 13 And it has also been shown that ACE inhibitors provide clear-cut renal protection and possibly other cardiovascular benefits in patients with diabetic nephropathy. 14 For these reasons, such agents as ACE inhibitors and angiotensin receptor blockers have the potential to protect against cardiovascular endpoints, as well as contribute to blood pressure control. THE CALCIUM CHANNEL BLOCKERS The calcium channel blockers have been in wide use for the treatment of such conditions as hypertension and angina pectoris for more than 25 years. Beyond their efficacy for these indications, studies in animal models of atherosclerosis have suggested that these drugs might also possess vascular protective properties. 15 In studies with the earlier short-acting agents the drugs appeared to offer some similar benefits in humans, though there were no clinical benefits with these immediate-release formulations. 16 Approximately 2 years ago there was an uproar when investigators claimed that calcium channel blockers, far from protecting against coronary events, actually seemed to increase the probability of myocardial infarctions. 17 In particular, a retrospective analysis of data (also termed a case-control study) obtained from the records of a health maintenance organization (HMO) appeared to show that hypertensive patients treated with calcium channel blockers were 60% more likely than those treated with diuretics to suffer a heart attack. Explanations for this startling claim were quickly apparent. First, it is common practice among physicians to prescribe calcium channel blockers for their patients who have concomitant hypertension and angina or other signs of coronary disease. Therefore, a retrospective study in which detailed clinical information could not reliably be obtained may well have included patients already identified as having a high susceptibility to myocardial infarction. A second major explanation was based on the types of agents used. For reasons of cost-saving, the drug formulary of the HMO from which the data were obtained limited the calcium channel blocker selection to older, short-acting generic agents. 18 Two of the three immediaterelease formulations involved (nifedipine and diltiazem) were not even approved by the US Food and Drug Administration (FDA) for hypertension treatment because of their unsuitable pharmacokinetic and hemodynamic properties. TABLE 1. RATIONALE FOR COMBINATION DRUG THERAPY OF HYPERTENSION Increased antihypertensive therapy Additive efforts Synergistic efforts Reduced adverse events Low-dose strategy Drugs with offsetting actions Enhanced convenience and compliance Prolonged duration of action Potential for additive target-organ protection Cost-effectiveness Reassurance regarding the safety of the approved long-acting calcium channel blockers and formulations came from differing sources. A large well-conducted cohort study of hypertensive patients followed in the Greater New York area demonstrated a fascinating dichotomy between the short-acting and the long-acting blockers. Compared with diuretics, the short-acting drugs were almost three times as likely to be associated with a major cardiovascular event; in contrast, the long-acting calcium channel blockers were about 40% less likely than diuretics (a nonsignificant difference) to be associated with major events. 19 Experience with the long-acting calcium channel blockers in patients with congestive heart failure, a group with obvious susceptibility to major events, provided further reassurance that these agents did not have an adverse influence on cardiovascular endpoints. 20 Most recently, data have emerged from hypertension trials to provide evidence that the long-acting calcium channel blockers may actually confer clinical benefits. One study performed in an elderly Chinese population showed that a long-acting dihydropyridine, when compared with a placebo, reduced both stroke incidence and death rate. 21 Unfortunately, methodologic problems, including the open study design and the system of patient allocation to treatment, flawed this study and weakened its conclusions. On the other hand, the recently completed Systolic Hypertension Europe (Syst-Eur) trial, again performed in older patients with systolic hypertension, demonstrated that a long-acting dihydropyridine reduced strokes by 40% and also showed an encouraging trend toward reducing cardiac events. 22 It is noteworthy that the JNC VI report has recommended the longacting dihydropyridines as suitable agents for the treatment of systolic hypertension in the elderly. THE ROLE OF COMBINATION THERAPY There has been a regrowth of interest in the concept of fixed-combination therapy for hypertension. Table 1 lists some of the reasons why this approach might

4 148S WEBER AJH OCTOBER 1998 VOL. 11, NO. 10, PART 2 provide solutions to some of the problems associated with managing hypertension. The most obvious benefit of combination treatment is enhanced efficacy, especially when agents with complementary actions are used. Good examples of this are combinations that incorporate a low dose of a diuretic with such drugs as -blockers, ACE inhibitors, or angiotensin receptor blockers. Other recent fixed combinations have focused on ACE inhibitors and calcium channel blockers. Because the ACE inhibitors appear to be most effective in younger patients and in white hypertensives, whereas calcium channel blockers are particularly effective in the elderly and in African-Americans, it seems likely that their different modes of action would provide complementary effects. Clinical trials with such agents as benezapril and amlopidine have confirmed the efficacy of this combined approach. 23 Another strong reason for considering combination therapy lies in the possibility of achieving efficacy while minimizing the adverse effects associated with certain drug classes. One approach is to use very low doses of the two components. For example, very low doses of the -blocker bisoprolol and the diuretic hydrochlorothizide, each at subtherapeutic levels, create a fixed combination that is efficacious yet avoids the well-known symptomatic and metabolic adverse effects of these drug classes. 24 An equally interesting approach is to combine an ACE inhibitor with a calcium channel blocker; the peripheral edema that can be associated with dihydropyridine therapy is largely abolished when combined with an ACE inhibitor such as benezapril. 23 It is reasonable to assume that the simplicity of fixed combinations, often providing a logical drug regimen in a single daily administration, will facilitate patient compliance with treatment. In addition, the pricing of these products is often advantageous, typically providing two agents for little more than the cost of one. The recent JNC VI report has acknowledged these attributes of fixed combination therapy. Unlike for individual agents, there are little or no data for fixed combinations on their ability to protect hypertensive patients from cardiovascular events. This poses an interesting question. Because, for example, ACE inhibitors and calcium channel blockers are each believed to provide protective effects in hypertension, can we assume that these benefits would be additive when the two drugs are taken in combination? Because hypertension is rarely controlled by monotherapy much of what we now know about cardiovascular prevention in hypertension has come from studies in which patients have received more than one agent. Indeed, most of the ongoing clinical trials in hypertension, although designed to compare the protective effects of two separate first-line drugs, anticipate the need to add further agents to the treatment groups as the studies progress. 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5 AJH OCTOBER 1998 VOL. 11, NO. 10, PART 2 NEW TREATMENT APPROACHES FOR HYPERTENSION 149S 15. Weber MA, Graettinger WF: Calcium channel blockers as hypotensive agents, in Singh B (ed): Cardiovascular Pharmacology and Therapeutics. Churchill Livingstone, 1993, pp Lichtlen PR, Hugenholtz PG, Rafflenbeaul W, et al: Retardation of angiographic progression of coronary artery disease by nifedipine: results of the International nifedipine Trial on Antiatherosclerotic Therapy (IN- TACT). Lancet 1990;335: Psaty BM, Heckbert SR, Koepsell TD, et al: The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA. 1995;274: Group Health Cooperative of Puget Sound, Drug Formulary, Alderman MH, Cohen H, Roque R, Madhavan S: Effect of long-acting and short-acting calcium antagonists on cardiovascular outcomes in hypertensive patients. Lancet 1997;349: Packer M, O Conner CM, Ghali JK, et al: PRAISE Study: effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335: Gong L, Zhang W, Zhu Y, et al: Shanghai trial of nifedipine in the elderly (STONE). J Hypertens 1996;14: Staessen JA, Fagard R, Thijs L, et al: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350: Weber MA, Zola BE, Neutel JM: Combination drug therapy: focus on hypertension, in Frishman WH, Sonnenblick EH (eds): Cardiovascular Pharmacotherapeutics. McGraw-Hill, New York, 1997, pp Prisant LM, Weir MR, Papademetriou V, et al: Low dose drug combination therapy: an alternative first line approach to hypertension. Am Heart J. 1995;130: