The evolution of antihypertensive therapy

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  • Sm. Sci. Med. Vol. 31, No. II. pp. 1239-1243, 1990 Printed in Great Britain

    0277-9536/90 S3.00+0.00 Pergamon Press plc

    THE EVOLUTION OF ANTIHYPERTENSIVE THERAPY

    ICHIRO KAWACHI and NICHOLAS WILSON~ Department of Community Health, Wellington School of Medicine, P.O. Box 7343, Wellington, New

    Zealand and *National Health Institute, Department of Health, Wellington, New Zealand

    Abstract-The goal of antihypertensive therapy has changed dramatically over the past 40 years. What was once a treatment for a life-threatening disease has gradually evolved to become just one of the many ways of modifying a symptomless risk factor. The development of safer drugs throughout the 1970s resulted in treatment being offered at successively lower levels of blood pressure elevation, and consequently to an ever increasing proportion of the population. Based on new evidence from clinical trials, however, recent policy guidelines for the treatment of hypertension-especially mild hypertension- have become more conservative. Yet, there are a number of reasons for doubting that this policy reversal will LX transmitted into actual clinical practice, unless major changes are made to the arrangement of structural interests-professional, industrial and third-party funders-which currently support and maintain antihypertensive therapy on a mass scale. Meanwhile, control of blood pressure, quality of life, and compliance with therapy have become ends in themselves, often to the exclusion of much-needed discussion on the real therapeutic goal of antihypertensive medication, i.e. the prevention of cardiovascular and cerebrovascular morbidity and mortality and the question of whether drugs are always the best way to achieve this.

    Key words-hypertension, antihypertensive drug therapy, health policy

    INTRODUCTION

    The nature and rationale of antihypertensive drug treatment have changed dramatically over the past four decades. The first antihypertensive drugs were introduced in the 1950s for the treatment of malig- nant hypertension, a symptomatic disease, potentially lethal if left untreated [l]. The successful treatment of malignant hypertension was followed in the 1960s by randomized trials demonstrating the value of phar- macological therapy for severe hypertension [2,3].

    Since then, we have witnessed a progressive lower- ing of the cutoff level of blood pressure for treatment, until hypertension has become what it is today-no longer a disease, but a cardiovascular risk factor- and lowering the blood pressure with drugs can no longer be regarded as a treatment (as it used to be for malignant hypertension), but is in fact a form of prevention [4,5]. The development of safe and effec- tive drugs has led to a gradual shift in the locus of treatment away from the hospital and into the com- munity, where much of preventive activity takes place today. The advent of safer drugs has also tipped the balance between the risks and benefits in favour of offering treatment to asymptomatic people, so that we have witnessed a progressive redefinition of need in terms of lower levels of blood pressure requiring treatment.

    Over the last 4 years however, there has been an accumulation of new evidence from clinical trials about the benefits of treating mild to moderate hypertension [6]. This has prompted fresh debate about the wisdom of treating large numbers of indi- viduals in the population with mild to moderate elevations of blood pressure [7,8], and resulted in more conservative guidelines for pharmacological treatment [g-12]. While these guidelines suggest a retrenchment of opinion at the policy-making level,

    there are a number of reasons to doubt that estab- lished clinical practice will be influenced swiftly or significantly. In this paper, we analyse the history of hypertension from the viewpoint of the major interest groups and their interactions which have shaped the diffusion and evolution of drug treatment as it is practised today.

    THE EVOLUTION OF ANTIHYPERTENSIVE THERAPY-THE ROLE OF THE

    MEDICAL PROFESSION

    The risks associated with raised blood pressure were recognized as far back as in 1925. Data from the Actuarial Society of America demonstrated a con- tinuous rise in mortality associated with stepwise increases in blood pressure in an insured population [13]. Knowledge of the risks of raised blood pressure preceded the availability of hypotensive drugs, which were introduced for the first time in the 1950s. Their efficacy in reversing the effects of malignant hyperten- sion were so convincing that randomized trials were felt to be unnecessary [9].

    Once a new therapy has achieved success in one group of patients, there is an inevitable tendency to use it with other patients [14]described by McKinlay [15] as the process of professional adop- tion in his analysis of the diffusion of medical technology. Encouraged by the promising reports of the pharmacological reversal of malignant hyperten- sion, it was natural for clinicians to wonder if similar success might be obtained by treating people with blood pressures at levels lower than in malignant hypertension. After all, studies of the natural history of raised blood pressure, including the Framingham Heart Study [16], had shown that the risk of death rose steadily from the lowest to the highest levels of blood pressure. Reflecting on the implications of their

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  • 1240 ICHIRO KAWACHI and NICHOLAS Wnso~

    study, the Framingham investigators wrote in 1972: The usual medical practice focuses on the treatment of ill people, (however) the prevention of cardiovas- cular diseases may actually require the evolution of a new breed of physicians. . . Such practitioners must come to regard the occurrence of stroke, coronary heart disease, congestive heart failure and peripheral vascular disease. . . as a medical failure rather than the starting point of medical treatment (17, empha- sis in the original]. The evolution alluded to by these authors signalled the beginning of the process of widespread professional adoption and diffusion of drug treatment for hypertension. In 1972 the National Heart and Blood Pressure Education Pro- gramme launched a large-scale campaign to educate the American public about the risks of hypertension. Successive policy guidelines issued throughout the 1970-80s by this authoritative policy-making body led to the gradual lowering of the cutoff level of blood pressure recommended for drug treatment [18].

    A new breed of physicians were urged to extend their treatment to people with lesser degrees of blood pressure elevation, who were essentially asymp- tomatic. Strokes and heart attacks were to be re- garded as medical failures; an attitude that betrays the discomfort that many clinicians feel in merely observing people at risk of developing disease, and which turned into one of the potent forces fuelling the process of professional adoption [4].

    By 1980, the stage of professional adoption was virtually complete, and the pharmacological treat- ment of hypertension, even at the lowest levels of elevation, had attained the status of a standard procedure. The Joint National Committee report, published in that year (191 recommended that all patients with diastolic blood pressures above 90 mmHg ought to be treated, even in uncompli- cated cases. Defined in this way, nearly 20-30% of the population in many Western countries now had levels of blood pressure requiring drug treatment [20].

    The treatment of hypertension did not, however, attain the status of standard procedure without controversy. Sir George Pickering was one eminent authority who repeatedly deplored the arbitrary di- chotomization of normal blood pressure and hyper- tension, insisting instead that the differences are quantitative rather than qualitative [21]. The medical profession speak of hypertension as if at some point in the continuous distribution of blood pressure in the population, the risk of cardiovascular disease suddenly jumps, whereas epidemiological data have repeatedly demonstrated that the distribution of blood pressures within populations is unimodal, and that the relationship between blood pressure and the risk of complications is curvilinear [22]. Pickering felt that this transformation of quantity into quality was an indication of the inability of the medical pro- fession to conceive of patient characteristics in terms other than either/or, diseased/not diseased [21]. As it turns out, this conception of an arbitrarily defined level of blood pressure as diseased has led to the successive redefinition of the level of blood pressure needing treatment, as well as to far-reaching conse- quences for the labelling of large sections of the population, the creation of demand for medical treatment and for the supply of drugs to treat it.

    Randomized clinical trials of antihypertensive therapy were being conducted throughout the process of diffusion. However it is evident in retrospect that wide-ranging recommendations for treatment were often issued too early and with too much alacrity. It can be argued for instance that the recommendations of the Joint National Committee over the past 10 years have on occasions been based upon inadequate or inappropriate evidence. Their report in 1977 [23] which recommended the treatment of people with diastolic blood pressures above 105 mmHg (and the individualization of treatment for pressures between 90 and 104mmHg), was based upon the one single clinical trial which had been reported at that time, the Veterans Administration Cooperative Trial [24]. Yet the same trial was rejected from a recent meta- analysis of all the published trials in existence, on the grounds that the patients in it were hospitalized men, and consequently did not reflect the community management of hypertension [25]. Similarly, the 1980 report of the Committee [19] which recommended treatment of all levels above 90 mmHg was based mainly upon the results of the Hypertension Detec- tion and Followup Trial [26], which has itself been repeatedly criticized on the grounds that it was not placebo-controlled and hence it is difficult to disen- tangle the benefits of drug treatment from the effects of a comprehensive health promotion package [6,27].

    The case for arguing that the profession moved too far too quickly in setting guidelines for treating hypertension is supported by the observation that, since 1984, there has been a gradual retrenchment of the guidelines for treatment. Thus the 1984 Joint National Committee guidelines [28] recommended that treatment should now commence at levels above 95mmHg (although treatment should still be seriously considered as low as 90 mmHg), and in 1986, the combined WHO and International Society of Hypertension (ISH) guidelines [29] raised the cutoff level to 100 mmHg (or above 95 mmHg only after 3-6 months of observation).

    1985 was a watershed year in terms of re-opening the debate about the benefits of treating hyperten- sion. In that year, the single largest randomized trial of treating mild hypertension, the British MRC trial, was reported [30]. It initiated what may be termed the stage of professional denunciation of clinical trials, to use McKinlays taxonomy [15]. The MRC trial concluded that, on average, 850 patients with mild hypertension would need to be treated for a year to prevent one stroke. Furthermore, there was no over- all difference in total mortality or coronary heart disease incidence between the placebo and active treatment groups [30].

    In the wake of the MRC trial, there has been a virtual cascade of editorials and articles debating the question of whether or not to continue treating mild hypertension in the current way [8]. Two opposing viewpoints have emerged from this controversy. One approach has been to vigorously deny the validity of extrapolating from the results of the trial to formulate guidelines for treatment [31], ignoring the historical fact that the initial diffusion of antihypertensive therapy was itself based upon the results of earlier (and possibly less precise or valid) trials. The altema- tive viewpoint has emphasized the small magnitude of

  • Evolution of antihypertensive therapy 1241

    the achieved benefits, and questions the wisdom of continuing to treat mild hypertension.

    It is however evident from the recent guidelines issued by different policy makers [29,33], that there is an emerging trend to make the recommendations for the treatment of hypertension more conservative. At the same time, there are reasons to doubt that the new recommendations will be transmitted effectively into individual clinical practice. As McKinlay noted [ 151, the persistence of an established procedure has often little to do with its intrinsic worth, but is dependent on the power of the interests that sponsor and maintain it. In the case of antihypertensive therapy, there are a number of entrenched interests which may well prevent its more rational use. For instance, under a fee-for-services arrangement of physician remuneration, there is a powerful incentive to diagnose and treat hypertension. In fact, hyperten- sion has become the leading cause for physician consultation in several countries [34]. Rather than question the intrinsic value of treating mild hyperten- sion, the medical profession has diverted attention towards the need to develop more effective drugs with fewer side effects. The degree of blood pressure control and satisfactory quality of life under medi- cation have become therapeutic ends in themselves, and we have lost sight of the ultimate goal of antihypertensive therapy, viz., cardiovascular risk factor modification, of which treating hypertension is but one of the manifold approaches. We proceed now to analyze the role of the pharmaceutical industry in these developments.

    THE ROLE OF THE PHARMACEUTICAL INDUSTRY

    The innovation and development of antihyperten- sive drugs over the past 40 years is justifiably regarded as one of the triumps of modern medicine. The successive introduction of safer and more effec- tive medication has however, meant that the locus of treatment has shifted away from the hospital towards the primary care setting, with the consequence that much of antihypertensive therapy today is carried out by individual general practitioners in the community, each with their own preferences and criteria for treatment.

    This has left isolated practitioners particularly vulnerable to the somewhat one-sided involvement of the pharmaceutical industry in postgraduate medical education. Several studies have indicated that a phys- icians prescribing behaviour is directly influenced by the promotional activities of drug companies [35], which include the use of sales representatives, direct mailings, the donation of free drug samples, advertis- ing in medical journals and sponsorship of seminars and conferences. All of which is regarded as legiti- mate under a market economy-manufacturers must advertise their products in order to complete against rival manufacturers, and ensure adequately high levels of profit to enable investment in further research and development. The medical practitioners, for whom there is often no alternative source of continuing education, generally find it to their advan- tage to be at the receiving end of these promotional benefits.

    One significant development in the industrys response to the recent efforts by policy-makers to rationalize the treatment of hypertension has been the increasing attention paid by the industry to quality of life issues in drug therapy. The result of this has been to divert attention away from the more funda- mental question of whether current practice is justified in the first place. Drug companies have been subsidizing clinical trials which promote new prod- ucts such as indapamide [36] and the ACE-inhibitors [37] as a means to improve (sic) the quality of life of medicated patients. They have also been sponsor- ing journals with titles such as Quality of Life and Cardiovascular Care [38], the premier issue of which was circulated gratis to medical practitioners in New Zealand. The advertising slogan of one product goes so far as to suggest that Theres never been a better time to have hypertension [39], which makes hypertension seem like a good thing to have.

    The level of funds currently devoted to promoting the treatment of hypertension with drugs that offer an improved quality of life, stands in stark contrast to the paucity of existing research on such fundamental questions as: the possibility of withdrawing or reduc- ing the dose of drugs after a period of treatment [40]; the feasibility of non-pharmacological approaches to reducing blood pressure [8]; and the elicitation of patients preferences for antihypertensive treatment when informed of its benefits and risks [41].

    What is clear is that under the current organization of interests within the medical-industrial complex, there is not likely to be an immediate incentive to adopt a more rational approach to the treatment of hypertension at the level of individual clinical prac- tice. Our attention is drawn naturally to the role of the funder in this process. In New Zealand, the dominant funder of health services is currently the state.

    THE ROLE OF THE FUNDER

    The rapidity with which the diffusion of a medical technology takes place has been shown to depend, among other factors, on the endorsement of third party funding [14,42]. Moreover generally speaking, the state and other third parties do not act on the reasonable basis of reliable evidence, but on the basis of some combination of professional, organizational and public pressure* [15]. In the evolution of anti- hypertensive therapy, professional and industrial in- terests converged early in its history to demand full third party funding, which was promptly given.

    In New Zealand, the prescription of antihyperten- sive drugs, funded by the state, soared during the 197OGOs. During the same period, mechanisms to monitor and control the rise in pharmaceutical expenditure have been conspicuously lacking. A recent inquiry into this countrys massive pharmaceu- tical expenditure disclosed the virtual absence of an explicit policy of cost-containment within the govem- ment department responsible for negotiating with the industry over drug prices [43]. Countries involving other third party funders do not appear to perform significantly better so long as the providers have insisted upon preserving clinical freedom [44].

  • 1242 ICHIRO KAWACHI and NICHOLAS WILSOS

    In their negotiations with manufacturers, funders have at times been advised by parties with potential conflicts of interest. In New Zealand for example, the Health Department negotiators depended on the advice of the Department of Trade and Industry, when making decisions about the acceptability of prices charged by the pharmaceutical companies. The objective of the latter department, it turned out, was to ensure adequate profit margins for local manufac- turers [43].

    On balance it appears that the actions of funders have not succeeded in checking the uncritical accep- tance of antihypertensive treatment as a standard procedure. Once an innovation has successfully at- tained this status, it often proves difficult to reduce the level of state support due to the nature of entrenched interests, including industrial profits, pro- fessional credibility and public ignorance. It is par- ticularly difficult to reverse guidelines for a standard procedure if there is not an existing strategy available to replace it.

    THE ROLE OF CONSUMERS

    It is by no coincidence that discussion of the role of the consumer has been reserved to the last. The evolution of public policy for the treatment of hyper- tension has consistently excluded consumer partici- pation, even after it became evident that the ethics of risk factor modification demanded it [8]. Hyperten- sion, it may be argued, is a medically-engendered disease, in which a quantity (i.e. level of blood pressure) has become insidiously annexed into a quuliratiue abnormality [21]. Over the years, the medi- cal profession has continuously redefined the level of blood pressure to be regarded as diseased, according to which successively larger segments of the popu- lation have come to be considered in need of treatment. In turn, the disease has evolved to be- come a sickness-a societal construct-so that people with raised blood pressure have been cast into a sick role, with potentially adverse consequences for employment opportunities, insurance premiums and pension eligibility. The sickness is further trans- formed into an illness when previously symptomless persons, upon being labelled as hypertensive, begin to experience subjective symptoms [45].

    Yet our analysis of the nature of antihypertensive treatment indicates that we are not dealing with disease, but merely a marker of risk. In this respect, it has been argued that the idea of treating risk factors is misleading, self-deluding and semantically incorrect; the word treatment should be restricted to the amelioration of symptoms or signs of estab- lished disease [5]. It is not known exactly what proportion of people currently taking antihyperten- sive medication are aware of the true goal of treat- ment, or its risks and benefits. Examination of these important issues has only recently entered the agenda for medical research [8].

    THE FUTURE OF ANTIHYPERTENSIVE THERAPY

    Antihypertensive therapy continues to evolve. After two decades of campaigns to screen, detect and

    treat hypertension, policy-making bodies appear to be acknowledging that the message was perhaps oversold. There are however, a number of reasons to doubt that current clinical practice, now that it is firmly entrenched, will be easy to reverse: professional credibility is perceived to be at stake; there is a lack of research on alternative strategies to reduce blood pressure; pharmaceutical promotion-claiming im- proved quality of life with newer drugs-obscures the issues; and in the absence of effective counter- educational campaigns, both the profession and con- sumers remain ignorant. Furthermore, progress is hampered by conflicting guidelines issued at the policy-making level.

    The ability of current efforts to rationalize the treatment of hypertension will depend upon initiat- ives occurring at several levels. In New Zealand, the Department of Health as the principal funder of antihypertensive drug therapy is in a position to develop and coordinate a rational prevention and control policy for the country. The elements of such a policy would include: a much more critical attitude towards the licensing and reimbursement of newer (and more expensive) medicines; the allocation of resources to establish an educational programme (e.g. via state-funded drug detailers) to counterbalance the promotional claims made by pharmaceutical compa- nies; the creation of committees (with consumer and specialist representation) to monitor and regulate the promotional content and practices of the pharmaceu- tical industry; and ultimately the financing of research (e.g. through grants from the Medical Research Council) into primary prevention and non-pharmacological approaches to treatment.

    The emphasis of medical school training and post- graduate courses needs to move away from regarding hypertension as a disease mandating treatment; instead, raised blood pressure ought properly to be regarded as one of several markers of cardiovascular risk (like smoking, or being overweight), for which drug treatment is just one of the approaches to its modification.

    Finally, there needs to be much more emphasis on involving the consumers perspective in research and decision-making. To some extent, a model for greater consumer involvement in the management of hyper- tension can be found in the response to the HIV epi- demic. This response has involved the development of a number of voluntary organizations, many of which are based within groups in the community at the greatest risk of infection [46]. In many instances state funding has been provided to support the health pro- motion activities of these groups and some of their members have been co-opted onto national advisory committees concerned with policy development.

    And if all the outlined changes should succeed in rationalizing the management of hypertension, there is still little cause for complacency; there are already signs to indicate that we are travelling down the same pathway with hyperlipidaemia.

    Acknowledgements-The authors with to thank Geoff Fougere, Peter Davis and Ken Cooke for their critical comments on earlier drafts of the paper. Dr Kawachi is supported by a New Zealand Medical Research Council Training Fellowship.

  • Evolution of antihypertensive therapy 1243

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