Journal of Human Hypertension (2000) 14, Suppl 1, S51–S62 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh The modern treatment of hypertension JIS Robertson Elmbank, Manse Road, Bowling, Glasgow G60 5AA, UK Progress in the treatment of hypertension over the past of the large but seriously flawed American HDFP study 50 years is reviewed. While achievements have been especially have distorted appreciation of therapeutic considerable, they have sometimes been exaggerated benefits. Journal of Human Hypertension (2000) 14, Suppl by uncritical analyses and meta-analyses of trials. Data 1, S51–S62. Keywords: antihypertensive drugs; treatment trials; arteriosclerosis; stroke; coronary artery disease Introduction: a case history was noted to have pulsus alternans. Blood pressure readings continued generally high, varying from A 62-year-old male senior executive was referred for 170/88–240/130 mm Hg. Then, just over 1 year from medical examination. A heavy cigarette smoker, he the first consultation, the patient developed sudden was known to have been hypertensive for at least 4 severe headache, rapidly lost consciousness, and years, but remained untreated. His principal com- was found to have a right hemiplegia; he died 2 h plaints were of cough, together with worsening later. His widow refused permission for post-mor- fatigue and exertional dyspnoea over recent weeks. tem examination to be performed. That account1 is On examination he was found to have a blood press- of the last year of the life of an important historical ure of 186/108 mm Hg. Clinically there was gross figure, Franklin D Roosevelt, US President. The year left ventricular enlargement, confirmed both electro- in question, from March 1944 to April 1945, was one cardiographically and radiologically. Arterioscler- of the most fateful in the history of the Western otic changes were seen on examination of the optic world, and the patient was then supposedly in fundi, but there were no retinal haemorrhages or charge of the affairs of the most powerful nation in exudates. There was proteinuria. A diagnosis of the Western alliance. The occasion which engen- hypertensive heart failure was made, and therapy dered such concern from the two independent phys- was begun with cardiac glycosides. Neither a icians2,3 was the Yalta conference, held in February diuretic, nor any other antihypertensive treatment, 1 1945. Mistakes made by the sick Roosevelt at Yalta was given. During the following 3 months, severe have been widely held by historians to have led to hypertension was repeatedly confirmed, values major political problems over the ensuing 50 years.4 ranging around 218–240/118–130 mm Hg. Four The President’s own physician indeed later specu- months after the initial consultation he developed lated on ‘what turn the subsequent course of history retrosternal pain radiating to both shoulders. Myo- might have taken if modern methods for the control cardial infarction was suspected, although serial of hypertension had been available’.1 Such methods electrocardiography over several days disclosed no were of course not at hand in 1945, but have been diagnostic changes. Severe hypertension persisted introduced, with progressive refinement, over the throughout the next 6 months, during which he ensuing five decades. It may therefore be of interest experienced variable but progressively worsening to review the achievements of antihypertensive ther- lassitude and dyspnoea, punctuated intermittently apy during that period. by episodes of nausea and diarrhoea. The patient continued to serve at least nominally as the head of his organization, albeit with manifestly diminishing Complications of hypertension effectiveness, and with frequent periods off work for rest and recuperation. On the occasion of an official The complications of hypertension, which we seek photograph in connection with his occupation he to correct and/or prevent with therapy, are:5 malig- had difficulty in holding up his head unaided, and nant phase hypertension, in which the blood press- another doctor who saw him then was ‘shocked to ure has risen so high, especially if the increase has see a dying man’.2 A further physician, who was to taken place rapidly, that fibrinoid arterial necrosis observe him in more detail at that time, recorded is occurring; hypertensive encephalopathy, nearly that he was ‘very sick . with all the symptoms of always, when it occurs, superimposed on the malig- hardening of the arteries of the brain in an advanced nant phase; overt hypertensive heart failure; stroke, stage . I doubt, from what I have seen, whether he which can be haemorrhagic or thrombotic; an accel- is fit for his job here’.3 Four days later the patient erated decline of renal function with age; and hyper- tension-associated coronary artery disease and its sequelae. It will be noted that Roosevelt manifested Correspondence: JIS Robertson, Elmbank, Manse Road, Bowling, several of these complications in the last year of Glasgow G60 5AA, UK his life. The modern treatment of hypertension JIS Robertson S52 Drug treatment of hypertension: a critique of trials In scrutinising the capacity of antihypertensive ther- apy to limit complications, we are necessarily con- cerned exclusively with drug treatment.5,6 Surgical manoeuvres, including dorsolumbar sympathec- tomy and adrenalectomy, are no longer employed in this context, whilst a range of non-pharmacological approaches, whatever their effect may be on blood pressure, remain unassessed concerning any capacity to limit complications. Early uncontrolled observations Figure 1 Schematic diagram showing distribution of diastolic With the introduction of the first effective antihyper- blood pressures in a westernised adult population. Indicated are tensive drugs, it soon became apparent that they results from some trials conducted between 1964 and 1985 and could reverse the malignant phase, provided that the levels of presenting diastolic pressure above which a protec- tive effect was shown with antihypertensive drug treatment. renal failure was not too advanced, and also relieve 8 141 5,6 Adapted from Robertson. The first Australian report put that overt hypertensive heart failure. The prognoses, threshold at 100 mm Hg; the later account33 lowered it to 95 untreated, of these complications of severe hyper- mm Hg. The other trials indicated are from refs. 7, 9, 10, 11. Ham- tension were so rapidly and consistently dire, that ilton et al,7 MRC Working Party,9 and Veterans Admin Coop 10,11 controlled trials of therapy were unnecessary for the Study Group. demonstration of benefit, and would, indeed, have been unethical. These positive observations of thera- effect with presenting diastolic pressures as low as peutic benefit have been repeatedly confirmed clini- 90 mm Hg and upwards. cally. The inclusion of trials in Figure 1 should not be taken as suggesting that such studies were above reproach. In that of Hamilton et al,7 for example, Controlled trials while it was the first controlled trial to evince bene- However, the capacity of antihypertensive drug fit, patients were allocated to therapy alternately as treatment to prevent the supervention of compli- they presented at the clinic, rather than at random, cations not yet manifested required the prosecution and for that reason Hamilton’s study has often been of controlled clinical trials. Such studies have been excluded from meta-analyses. conducted with remarkably varying competence from the time of the pioneering work of Hamilton The US Veterans Administration trial and his colleagues in England in 1964.7 Because the evolution of increasingly more effective and accept- The US Veterans Administration Study,10,11 able antihypertensive agents has paralleled although for many years providing much of the case developing expertise in clinical trial methodology, it for prophylactic antihypertensive drug treatment, is perhaps inevitable that the frailties of some initial has been subjected to severe criticism, and some essays in this field have been exposed.6 Even so, it is regard it as now of historic interest only. Concerns disturbing to find several commentators overlooking about the VA Study have included the splitting of often major defects of certain trials, and, conse- the trial into two parts after its commencement; the quently, presenting over-optimistic interpretations loss of many patients to follow-up; that those of the benefits of therapy. included had already very prevalent cardiovascular Figure 1 is taken from a review I published in complications, and hence were unrepresentative of 19868 of some of the early trials of antihypertensive the bulk of patients presenting for therapy; and that drug treatment. The curve illustrates schematically the results were seemingly inspected continually the distribution of diastolic blood pressures to be and the trial discontinued arbitrarily when an appar- found in adult Western or Westernized populations. ently significant result was obtained.6,12 One critic Notably, in 1986 the focus both epidemiologically wrote in 1983: ‘The US Veterans Study broke almost and therapeutically was on the diastolic pressure every rule of trial design and analysis, and if it were value as presaging cardiovascular morbidity. It is offered to a medical journal today it would probably now recognised that systolic pressure also requires not be accepted for publication’.12 to be considered when evaluating the dangers of hypertension, and in analysing trial outcome. Indi- HDFP cated on Figure