BHS Collaborative Research Working Party

PATHWAY Research Project

PATHWAY consists of 3 complementary studies. The unifying themes (a necessary component of obtaining programme support from the BHF) are that measurement and interpretation of a patient's renin status permit more rational, less empirical, treatment decisions than have been traditional in hypertension; and that with hypertension now clearly recognised as a complex disorder, rational therapy in most patients means choosing the appropriate combinations.

The first study - Monotherapy vs. Combination for initial treatment - tests the hypothesis that patients treated with a single drug never catch-up with the blood pressure control achieved with initial combination, because of compensatory vasoconstriction or Na+-retention. Previously untreated patients will be randomised, double-blind, to losartan or hydrochlorothiazide or their combination for 16 weeks (phase 1), followed by combination in all patients for a further 16 weeks (phase 2), followed by forced addition of amlodipine or placebo dependent on blood pressure control. The endpoints are blood pressure at the end of phase 2, the proportion of patients requiring a 3rd drug by the end of phase 3. and the prediction of best initial therapy by baseline plasma renin. This study, if positive, will probably have most radical impact on our current treatment of hypertension.

The second study - Optimal therapy of resistant hypertension - tests the hypotheses that spironolactone is the best overall treatment for patients at step 4 of the NICE/BHS algorithm, and that the best drug for individual patients can be determined by measurement of plasma renin. Since the 3 possibilities to be compared against placebo, in a double-blind crossover of 8 weeks per treatment, are α-blockade, β-blockade, or different diuretic (i.e. spironolactone), the 'α,β,∆' rule predicts that the 3 classes will be found most effective in, respectively, the middle, top, and bottom tertiles of plasma renin. This study is the most likely to define a role for plasma renin measurements in routine management of hypertension.

The third study - Single vs Combination diuretic in patients with low-renin hypertension - tests the hypotheses that multiple nephron blockade is more effective than single, and that addition or substitution of K+-sparing diuretic for thiazide in patients with features of metabolic syndrome will prevent deterioration of glucose tolerance. Patients who are either biochemically low-renin, or have their renin system blocked by an ACEi or ARB, will be randomised to double-blind treatment for six months with either hydrochlorothiazide, amiloride, spironolactone, or combination of thiazide + K+-sparing drug. The primary endpoint is blood pressure, and secondary endpoint change in glucose tolerance. This study, if positive, could change the routine choice of diuretic, and lead to longer-term outcome comparisons.