PAPERS BMJ: first published as 10.1136/bmj.297.6641.95 on 9 July 1988. Downloaded from The case for low dose diuretics in hypertension: comparison of low and conventional doses of cyclopenthiazide Gary McVeigh, David Galloway, Dennis Johnston Abstract hypertension. The original observations of Cranston In a double blind placebo controlled randomised et al clearly indicated, however, that these drugs parallel study the antihypertensive activity and showed a flat dose-response relation in reducing arterial adverse biochemical effects of three doses of cyclo- blood pressure and that increased doses caused greater penthiazide were evaluated in patients with mild upset to the biochemical profile.7 Equivalent diuretic essential hypertension that had been recently doses of each of the drugs had similar antihypertensive diagnosed or was being treated with a single drug. effects. Much evidence suggests that the attenuation of After a four week placebo washout period 53 patients the hypotensive response to an increasing dose of with diastolic blood pressures between 90-110 mm diuretic is mediated through a reactive rise in plasma Hg were randomly assigned to 50, 125, or 500 Ftg renin activity and angiotensin II concentration to try to cyclopenthiazide or matching placebo for an eight maintain blood pressure in the face ofincreased sodium week period of treatment. Blood pressure was and water depletion.8'0 measured in thepatients' homes bythe same observer Many deleterious metabolic effects have been every two weeks. Serum urea, electrolytes, urate, associated with the use of thiazide diuretics." 12 The and creatinine concentrations and 24 hour urinary relation with hypokalaemia in particular has provoked sodium excretion were monitored every four weeks much debate since publication of the results of the and serum magnesium concentration and plasma multiple risk factor intervention trial.'3 Analysis of the renin activity at the end ofthe washout and treatment data suggested that a subgroup of patients requiring periods. After eight weeks of treatment systolic and special intervention care were at increased risk of diastolic blood pressures were significantly reduced sudden death; such patients were taking high doses of in patients taking 125 and 500 tg cyclopenthiazide diuretics and had minor baseline electrocardiographic when compared with those taking placebo. The abnormalities. These findings continue to cause con- decrement in serum potassium concentration (0.6 cern, even though they have not been substantiated'4 http://www.bmj.com/ mmol/l) and increase in serum urate concentration and are questionable because the analysis of the results (0.06 mmol/l) were greatest with the 500 [tg dose, the for the subgroup lacked statistical power.'" The results increase in serum urate concentration alone being of the previous studies suggest that the adverse effects significant. No change in serum magnesium con- may be minimised by reducing the dose of these centration or 24 hour urinary sodium excretion was drugs.I16 7 noted with any dose of cyclopenthiazide. Only the Cyclopenthiazide is the most popular thiazide 500 ig dose of cyclopenthiazide significantly in- diuretic for the treatment of essential hypertension in the United Kingdom. The aims of this community creased the mean plasma renin activity (1.8 (95% on 29 September 2021 by guest. Protected copyright. confidence interval 0*2 to 3.4)-5-4 (3.9 to 6.8) nmol based study were to define the lowest dose of drug angiotensin I/l/h); the other doses like the placebo showing significant antihypertensive activity and to had no effect. monitor the effect ofreducing the dose on the metabolic Cyclopenthiazide 125 Fg, a dose lower than is profile. In addition, in measuring 24 hour urinary currently marketed, produced a similar hypotensive excretion of sodium we tried to relate the natriuretic response to 500 tg of the drug without upsetting the effect of the various doses to their antihypertensive biochemical profile. efficacy. Introduction Patients and methods Benzothiadiazine diuretics have remained a popular Patients in whom hypertension had been newly treatment for arterial hypertension since their intro- diagnosed and those with hypertension receiving a Department ofTherapeutics duction into clinical practice in 1957.' They are a single treatment-for example, a [1 blocker, thiazide and Pharmacology, Queen's cheap, effective, well tolerated, and once daily treat- diuretic, calcium antagonist, and so on-who were University ofBelfast, Whitla ment and in combination potentiate the hypotensive willing to alter their treatment for the purposes of the Medical Building, Belfast activity of other first line agents. All the large scale trial were recruited from general practices in the BT97BL Gary McVeigh, MD, registrar clinical trials of mild hypertension have used thiazide Belfast area. With the general practitioners' permission and tutor diuretics as part of their treatment regimens.2-5 patients with hypertension were identified from repeat Dennis Johnston, MD, Analysis ofthese studies confirms a small but consistent prescription books and disease indices or referred consultantphysician and senior benefit of treatment, with a reduction in the incidence directly after consultation with their family doctor. lecturer of known complications of hypertension. Letters were then circulated to each patient explaining Napp Research Centre, The antihypertensive mechanism of action of these the nature of the project. If patients were willing to Cambridge drugs is still debatable, although achieving a negative participate in the study an acknowledgement slip was David Galloway, MRCP, sodium balance with an attendant reduction in plasma returned in the stamped-addressed envelope provided. director ofclinical research and extracellular fluid volume seems to be important.6 These patients were screened in the department of Correspondence to: Dr Perhaps for this reason most clinical trials continue to therapeutics and the study protocol was explained in Johnston. use high doses of diuretic drugs to control essential detail. Possible secondary causes ofhypertension were BMJ VOLUME 297 9 JULY 1988 95 excluded by a full history and examination, which venous blood samples were taken for estimating urea, included chest radiography and electrocardiography. electrolyte, urate, and creatinine concentrations. At the Reasons for exclusion from the study included impor- end of the placebo washout and active periods of tant cardiac, hepatic, renal, cerebrovascular, or ocular treatment, samples of venous blood were taken for (grade III-IV retinopathy) disease; previous sensitivity estimating serummagnesiumconcentration and plasma to thiazide diuretics; abuse of drugs or alcohol; and a renin activity. The sample for plasma renin activity was history ofgout or diabetes mellitus. Ifat any time during withdrawn after the patient had been resting supine for BMJ: first published as 10.1136/bmj.297.6641.95 on 9 July 1988. Downloaded from the trial the diastolic blood pressure exceeded 110 mm an hour. It was collected in a tube that had been Hg the patient's original treatment was restarted and his previously cooled and was immediately centrifuged at or her general practitioner contacted. Informed verbal 4°C. Plasma renin activity was measured by the consent was obtained from suitable patients who radioimmunoassay of generated angiotensin I, with a entered into a four week single blind placebo washout generation time of90 minutes at pH 6. '9 The intra-assay and compliance period. and interassay coefficients of variation were 7 and 6%, Throughout the trial patients were seen in their own respectively. Twenty four hour urine samples were homes every two weeks by the same investigator. Blood collected every four weeks during the trial, and the pressure readings were taken at the same time of day, sodium content of the samples was estimated by flame for each patient, on every occasion. Recordings were photometry. taken from both arms initially, but subsequent Statistical methods-A 10 mm Hg drop in diastolic measurements were taken from the arm with the highest blood pressure with treatment was considered to be a diastolic pressure. A Hawksley random zero sphygmo- clinically relevant effect. To detect such a difference manometer was used to measure arterial pressure to the between groups (at the 5% alpha level and with 80% nearest 2 mm Hg. The cuffand bladder size were 14 x 90 power) with a standard deviation of 5 mm Hg, six or cm and 12 5 x 22 cm, respectively. Readings were taken more patients were required ineach group.20 An analysis once only while the patients were seated and after they of variance (Anova) was used to determine differences had rested for 10 minutes. The arm was supported at the with treatment in each variable, and Neuman-Keuls level ofthe heart during the procedure. 18 Disappearance multiple range test2' was applied to determine between of the Korotkoff sounds (phase V) was taken as a which treatments these occurred only if the overall measure of diastolic blood pressure. The arterial probability ofan effect with dose was less than 10%. The pressure reading against which the effects of treatment level of significance was chosen at the 5% level. The differences between the values at week 0 (end ofthe run TABLE I-Clinical data on patients who completed trial in period) and week 8 (end of the active period of treatment) were compared with the differences between Dose of cyclopenthiazide ()g) the corresponding values for the placebo at weeks 0 and Placebo 50 125 500 Total 8. Results are expressed as means (SD). Noofpatients 12 13 15 13 53 No of men 7 5 5 5 22 No of women 5 8 10 8 31 Mean age (range) (years) 58 (47-70) 59 (47-70) 56 (45-73) 55 (45-72) 57 (45-73) Results Mean (SD) weight (kg): Men 75 (5-8) 81 (5-8) 77 (5 8) 72 (5-2) 76 (5-8) Eighty three patients with presumed mild essential Women 71 (5-4) 66 (4 9) 70 (5 3) 66 (4-8) 68 (5 2) hypertension entered the study, and 53 fulfilled the http://www.bmj.com/ criteria for entry into the active phase of treatment of the trial.