Your Drug, My Drug, or Our Drugs: How Aggressive Should We Be With Antihypertensive Therapy?

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In the prevention of hypertensive complications, especially stroke and kidney disease, “lower is better” because for each decrease of 20 mm Hg systolic or 10 mm Hg diastolic pressure in the population, cardiovascular risk is halved. Ideally, the goal for each patient should be to reach the lowest blood pressure that is well tolerated, a value that may be well below the arbitrary thresh-old value of 140/90 mm Hg. For the majority of “uncomplicated hypertensives,” the question of single-drug therapy is essentially moot, because more than one agent is almost always required to optimally control blood pressure. In individuals who already have heart or kidney disease, there are compelling indications for the use of drugs that block the renin-angiotensin system, but the large outcome studies that spawned these recom-mendations are themselves combination trials. Thus, in virtually all patients, more than one drug is indicated. The best combinations take advan-tage of long durations of action and complemen-tary mechanisms of action of the component and are not only able to effectively lower blood pres-sure, but also to favorably affect the natural his-tory of hypertensive complications. Regimens—

including fixed-dose combination products—that combine a thiazide diuretic or calcium antagonist with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker are most efficient. In summary, why would an astute clinician (or informed patient) be satisfied with the relatively limited effects of any single class of antihyperten-sive agents when better overall protection is pos-sible? (J Clin Hypertens. 2005;7(8 suppl 2):5–7) ©2005 Le Jacq Ltd.

Despite the fact that we have several classes of very effective, well tolerated antihyper-

tensive drugs, blood pressure (BP) control rates remain relatively low, and cardiovascular (CV) and renal complications of hypertension still abound.1 Barriers to better BP control today include issues related to cost and patient acceptance of therapy, but these barriers are also a product of provider inertia—including the misguided belief that it is wise to use single-drug regimens in most patients. In reality, it is absolutely clear from clinical trial data that more than one agent is necessary to attain sufficient BP control to substantially reduce CV risk. In population studies, for each 20 mm Hg systolic or 10 mm Hg diastolic decrease in BP, CV risk is halved.2 To meet the challenge of better BP control, the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) adopted the “20/10 rule” and incorporat-ed it into a new streamlined risk-based classifica-tion and management model that links the aggres-siveness of therapy to the degree of BP elevation

C o m m e n t a r y

Your Drug, My Drug, or Our Drugs: How Aggressive Should We Be With Antihypertensive Therapy?

Joseph L. Izzo, Jr., MD

From Erie County Medical Center and the Department of Medicine, Division of Clinical Pharmacology, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NYAddress for correspondence: Joseph L. Izzo, Jr., MD, Department of Medicine, ECMC, 462 Grider Street, Buffalo, NY 14215E-mail: [email protected]

www.lejacq.com ID: 4609

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Ltd., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2005 by Le Jacq Ltd., All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Sarah Howell at [email protected] or 203.656.1711 x106.

THE JOURNAL OF CLINICAL HYPERTENSION SUPPL. 2 VOL. 7 NO. 8 AUGUST 20056

and the presence of complications of hypertension (“compelling indications”).1

OPTIMAL TREATMENT OF UNCOMPLICATED HYPERTENSIONBased on the potential benefits that are achievable, lowering a patient’s BP is the most important pre-ventive health objective the clinician should have. Much less attention should be paid to the choice of agents compared with the effectiveness of therapy. The rough equivalence of various drug classes in lowering BP in the population is evident from stud-ies such as ALLHAT,3 INVEST,4 ANBP2,5 VALUE,6 and the recently released ASCOT trials, which dem-onstrated nil or small differences in CV outcomes among various drug classes. Of interest, all of these studies actually depend on combination therapy. Overall, it is generally accepted now that BP lower-ing is far more important than choice of agents in improving overall CV and renal health.1,7

A more important question is “What is the opti-mal goal of therapy in a given patient?” To achieve optimal societal benefit, it is reasonable to argue that two separate criteria should be used: 1) a reduc-tion in CV disease by at least 50% (equivalent to a reduction in systolic BP of at least 20 mm Hg); and 2) meeting or exceeding the published goal BP tar-gets (140/90 mm Hg generally, and 130/80 mm Hg in diabetes or kidney disease). In reality, a patient’s optimal BP is an unknown—but a reasonable defini-tion of optimal BP is the lowest value possible that sustains the full functional status of the individual’s systems. To achieve this goal requires more than one drug. Each antihypertensive agent lowers systolic BP by roughly 10 mm Hg in the population at large, so it follows that two drugs are generally needed to lower systolic pressure by at least 20 mm Hg. In this light, the question of potential superiority of one class over another is moot if truly meaningful reductions in CV and renal disease risk are to be achieved. More to the point is which classes should be combined.

HETEROGENEITY IN ESSENTIAL HYPERTENSION: TO PROFILE OR NOT?From a population perspective, there is demon-strable heterogeneity in the contributions of the various hypertension-sustaining mechanisms (car-diac and vascular remodeling, activation of the sympathetic nervous system and renin-angiotensin system, and abnormal renal salt and water han-dling) in the broad population. As a result, some investigators have promulgated the notion that knowing an individual’s physiologic profile can lead to targeted individualized therapy.8 At first,

the notion is intellectually attractive. In the end, however, it is an argument that can be dismissed rather easily based on the dynamic nature of BP control systems and the idea that there is no single physiologic or pathologic change that can alone sustain an elevated BP, even in secondary forms of hypertension. As a result of therapy, there is always a degree of physiologic activation of any unblocked BP defense mechanisms (sympathetic nervous system, renin-angiotensin system, or the kidney), which attempt to return BP levels back to pretreatment values. Even if a single system domi-nates the profile in a given individual, further BP lowering is still possible if a complementary agent is used. Thus, if optimal BP is the goal, profiling is meaningless and unnecessarily costly.9

COMPLICATED FORMS OF HYPERTENSION: COMPELLING INDICATIONSJNC VI and JNC 7 were constructed as risk-based approaches to hypertension in that they separated “uncomplicated” hypertension from more compli-cated forms of hypertension that have “compelling indications” for the choice of specific agents.1 To qualify as therapy for a compelling indication, a particular drug class needed to demonstrate both BP effectiveness and an ability to favorably alter the natural history of the associated complication. In JNC 7, six compelling indications were noted: heart failure, high risk for coronary artery disease, post-myocardial infarction status, diabetes mel-litus, chronic kidney disease, and recurrent stroke prevention.1 In each of these classifications, stud-ies were available indicating that certain specific drug classes exerted outcome benefits. Not all drug classes have been tested in these conditions and not all drug classes have achieved equal benefits in each of the individual compelling indications, however. In fact, a trend has emerged that stroke protection is especially favorable with diuretics and calcium antagonists,10 whereas cardiac and renal protection is especially favorable with drugs that block the renin-angiotensin system.11 From a logical stand-point, this differential outcome benefit by itself fully justifies the use of combination drug therapy.

EFFECTIVE DRUG COMBINATIONSTo combine agents most effectively, a series of requirements must be met. First, the combination should be effective in two major ways: 1) the degree of BP-lowering achieved; and 2) the proven efficacy of that particular drug class to prevent or improve a particular complication of hypertension. At the same time, there must be a minimization of adverse


SUPPL. 2 VOL. 7 NO. 8 AUGUST 2005 THE JOURNAL OF CLINICAL HYPERTENSION 7

events, patient adherence to and persistence with therapy should be high, and finally, the therapy must be affordable. The best combinations are those that take advantage of complementary mechanisms of action of long-acting agents. Fixed-dose agents can also be useful. Those regimens that combine a thiazide diuretic or calcium antagonist with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker are currently the most attractive two-drug combinations. If three drugs are necessary, a combination of diuretic, calcium antag-onist, and ACE inhibitor or angiotensin receptor blocker is highly effective. Beta blockers are useful additions in patients with heart disease.

THE CHALLENGE TO INDUSTRY AND THE HEALTH CARE SYSTEMThe core multibillion-dollar questions are therefore: “How can we deliver effective drug combinations to the majority of the hypertensive population? And accordingly, how can we convince dollar-driven insurance executives or government bureaucrats that earlier, more effective antihypertensive therapy is the right thing to do?” Many of us who have studied hypertension for a few decades have reached the conclusion that we wait far too long for treatment and stop far short of the optimal goals. To justify an aggressive approach in today’s climate, it would be ideal if we had a believable, rigorous, cost-benefit analysis based on long-term outcome data for each class of agents. So far, appropriate methods do not exist, and such data are only a dream. It therefore comes down to the belief structure and the analytical skills of practicing clinicians regarding the right thing to do. The government, the health insurers, and the pharmaceutical industry must be more farsighted as well. Wasteful marketing campaigns touting single-drug superiority as initiated by industry and govern-ment (via ALLHAT) would be stopped if physicians uniformly rejected these pseudoscientific “head-to-

head comparison” trials. What if all those billions had been spent on real science, or on improved deliv-ery systems? Wouldn’t we actually be farther ahead?

REFERENCES 1 The Seventh Report of the Joint National Committee on

Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: JNC 7 Express. JAMA. 2003;289:2560–2572.

2 Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913.

3 ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel block-er vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981–2997.

4 Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs. a non-calcium antagonist hyper-tension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290:2805–2816.

5 Wing LMH, Reid CM, Ryan P, et al. Second Australian National Blood Pressure Study (ANBP2): Australian com-parative outcome trial of ACE inhibitor- and diuretic-based treatment of hypertension in the elderly. Clin Exp Hypertens. 1997;19:779–791.

6 Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hyper-tensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:2022–2031.

7 Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis [erratum appears in Lancet. 2002;359:360]. Lancet. 2001;358:1305–1315.

8 Laragh JH. Hypertension is not all alike nor are its treat-ments: where would a better calcium-channel blocker fit in a modern treatment system? Clin Cardiol. 2003;26:II21–II22.

9 Moser M, Izzo JL Jr. Plasma renin measurement in the management of hypertension: the V and R hypothesis. J Clin Hypertens (Greenwich). 2003;5:373–376.

10 Angeli F, Verdecchia P, Reboldi GP, et al. Calcium channel blockade to prevent stroke in hypertension: a meta-analy-sis of 13 studies with 103,793 subjects. Am J Hypertens. 2004;17:817–822.

11 Izzo JL Jr, Moser M. Clinical impact of renin-angiotensin system blockade: angiotensin-converting enzyme inhibi-tors vs. angiotensin receptor antagonists. J Clin Hypertens (Greenwich). 2002;4:11–19.


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Your Drug, My Drug, or Our Drugs: How Aggressive Should We Be With Antihypertensive Therapy?