Does the aldosterone: renin ratio predict the efficacy of spironolactone over bendroflumethiazide in hypertension? A clinical trial protocol for RENALDO (RENin-ALDOsterone) study

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Abstract

Background: High blood pressure is an important determinant of cardiovascular disease risk. Treated hypertensives do not attain a risk level equivalent to normotensives. This may be a consequence of suboptimal blood pressure control to which indiscriminate use of antihypertensive drugs may contribute. Indeed the recent ALLHAT[1] study suggests that thiazides should be given first to virtually all hypertensives. Whether this is correct or whether different antihypertensive therapies should be targeted towards different patients is a major unresolved issue, which we address in this study.

The measurement of the ratio of aldosterone: renin is used to identify hypertensive subjects who may respond well to treatment with the aldosterone antagonist spironolactone. It is not known if subjects with a high ratio have aldosteronism or aldosterone-sensitive hypertension is debated but it is important to know whether spironolactone is superior to other diuretics such as bendroflumethiazide in this setting.

Methods/design: The study is a double-blind, randomised, crossover, controlled trial that will randomise 120 hypertensive subjects to 12 weeks treatment with spironolactone 50 mg once daily and 12 weeks treatment with bendroflumethiazide 2.5 mg once daily. The 2 treatment periods are separated by a 2-week washout period. Randomisation is stratified by aldosterone: renin ratio to include equal numbers of subjects with high and low aldosterone: renin ratios.

Primary Objective – To test the hypothesis that the aldosterone: renin ratio predicts the antihypertensive response to spironolactone, specifically that the effect of spironolactone 50 mg is greater than that of bendroflumethiazide 2.5 mg in hypertensive subjects with high aldosterone: renin ratios.

Secondary Objectives – To determine whether bendroflumethiazide induces adverse metabolic abnormalities, especially in subjects with high aldosterone: renin ratios and if baseline renin measurement predicts the antihypertensive response to spironolactone and/or bendrofluazide Discussion: The numerous deleterious effects of hypertension dictate the need for a systematic approach for its treatment. In spite of various therapies, resistant hypertension is widely prevalent. Among various factors, aldosteronism is an important cause of resistant hypertension and is now more commonly recognised. More significantly, hypertensives with primary aldosteronism are also exposed to various other deleterious effects of excess aldosterone. Hence treating hypertension with specific aldosterone antagonists may be a better approach in this group of patients. It may lead on to better blood pressures with fewer medications.

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Background
Epidemiology
One approach to more effective antihypertensive control would be to target aldosterone antagonists towardspatients in whom these drugs are likely to work best. Hyperaldosteronism is characterised by excessive excretion of aldosterone with concomitant suppression of enin associated with hypertension. However, neither aldosterone excretion nor plasma renin activity alone has proved useful in screening for this condition for a variety of reasons. Hiramatsu and colleagues have suggested that the aldosterone: renin ratio may be a useful screening test2. Using the aldosterone: renin ratio to find possible cases, Gordon and colleagues reported that hyperaldosteronism was more common than suspected, with 8% of cases referred to his clinic having this condition3. A high aldosterone: renin ratio has been found in 15% of a UK hypertension clinic4 and the general community5. There is debate as to whether a raised ratio defines aldosteronism or whether it detects a subgroup of subjects with aldosterone-sensitive hypertension, although subjects ith a raised ratio do appear to have genetic differences from those who do not6. If further testing is undertaken, 94% of clinic subjects with a raised ratio did not suppress plasma aldosterone with salt loading, a test many regard as diagnostic4. However, salt-loading is not without risks7 and a simple blood test that was able to guide appropriate therapy is an attractive concept./>/>/>

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