An American TROPHY in the prevention of hypertension

The common nomenclature used for the blood pressure range between normal and clearly hypertensive levels has shifted from transient hypertension (the 1940s) to borderline hypertension (the 1970s), further to high normal blood pressure (the 1990s) and finally most recently to prehypertension. This is a condition regarded as a precursor of more established hypertension and it is associated with increased cardiovascular mortality and morbidity [1]. There is also a rather strong association of prehypertension with other cardiovascular risk factors [2,3]. The recently published TRial Of Preventing HYpertension (TROPHY; 4) was an investigator‐initiated study to examine whether early treatment of prehypertension might prevent or delay the development of subsequent hypertension requiring treatment. The TROPHY study protocol included use of an angiotensin receptor blocker (ARB), which was justified for the following reasons:

1. In prehypertension, blood pressure remains a strong predictor of cardiovascular events even after adjustment for other risk factors suggesting that blood pressure lowering may have a beneficial effect. Hypertension is by itself a self‐accelerating condition. The transition from prehypertension to established hypertension in part reflects such ongoing changes as arteriolar hypertrophy [5] and endothelial dysfunction [6]. Increased vasoconstriction and diminished vasodilatation, consistent with these structural and functional findings, have been described in prehypertension [7]. Since high blood pressure itself can further accelerate vascular changes [5], it can readily be explained how established hypertension could occur.

2. Growth stimuli such as sympathetic stimulation [8] and increased activity of the renin–angiotensin system [9] tend to promote vascular hypertrophy by direct as well as hemodynamic effects. Plasma noradrenaline and plasma renin [10,11] are elevated in prehypertension. In humans, antihypertensive treatment with angiotensin‐converting enzyme (ACE) inhibitors or ARBs, but not beta‐blockers, causes a regression of arteriolar hypertrophy [12,13]. Short‐term treatment with ACE inhibitors during the early life of spontaneously hypertensive rats attenuates development of hypertension [14,15].

3. Guidelines recommend that prehypertension should be managed with lifestyle measures. Weight loss, salt restriction, exercise and dietary modifications reduce blood pressure in clinics specialized in management of lifestyle modifications. However, the prevalence of prehypertension has increased despite intensive efforts to promote such healthy lifestyles [16]. In the absence of evidence for long‐term efficacy of lifestyle approaches for preventing hypertension, the TROPHY Study measured the efficacy of pharmacological intervention.

Thus, the TROPHY Study investigated whether or not pharmacological treatment of prehypertension prevents or postpones stage 1 hypertension. TROPHY recruited participants with repeated blood pressures of 130–139/⩽89 or ⩽139/85–89 mmHg who were randomized to receive either blinded candesartan or placebo for 2 years followed by 2 years of placebo in both groups [17]. When a participant reached the study endpoint of hypertension, antihypertensive treatment was initiated. Both groups were instructed to follow lifestyle measures for blood pressure reduction throughout the trial. Of 772 participants available for the intention‐to‐treat analysis (mean age 48.5 years, 59.6% men), 391 were randomized to candesartan and 381 to placebo. During the first 2 years, 154 participants in the placebo and 53 in the candesartan group developed hypertension, indicating a 66.3% relative risk reduction (p<0.001). After 4 years, 240 in the placebo and 208 in the candesartan group had hypertension, a 15.6% relative risk reduction (p<0.007). Thus, over 4 years, nearly two‐thirds of untreated participants with prehypertension developed stage 1 hypertension. Treatment of prehypertension with candesartan was well tolerated and TROPHY proved the principle that treatment of prehypertension is safe and feasible.

The TROPHY study results thus show that pharmacological treatment of prehypertension can prevent or postpone the development of hypertension. Two years after discontinuing candesartan, there was a significant reduction of hypertension in the previously candesartan treated group. The relative proportion of hypertension‐free cases was 26.5% greater in the candesartan group. The median hypertension‐free time was 1.1 years longer in the candesartan group. Results of the 2 years of candesartan treatment suggest that pharmacological treatment of prehypertension can suppress the future development of hypertension. There was a 66.3% relative reduction and a 26.8% absolute reduction of hypertension in the candesartan group. Using the absolute difference between groups, one can calculate that four people with prehypertension need to be treated to prevent one case of hypertension in 2 years.

Current guidelines recommend lifestyle measures for management of prehypertension. TROPHY results can be compared to findings in TOPH [18] – the only lifestyle trial of similar duration. The absolute incidence reduction at 2 years with candesartan was 26.8% compared to 8% with the most successful lifestyle intervention in TOPH. During the study, 63% of patients in the placebo group in TROPHY developed hypertension. Among an estimated 65 million people in the U.S.A. with prehypertension [16] approximately 25 million have blood pressure comparable to TROPHY participants. Almost 16 million will become hypertensive over the next 4 years based on experience of the TROPHY placebo group. A successful intervention in such a large population could therefore have a major public health impact. The recommended life style measures for blood pressure control in prehypertension had no demonstrable effect on public health [16]. If non‐occurrence of hypertension during the active treatment is considered as the goal, then success was achieved in 86.4% of the candesartan group. TROPHY also suggested that the effect of active treatment in delaying hypertension can extend up to 2 years after discontinuing treatment.

Whereas the findings are positive, TROPHY is not advocating treatment of prehypertensives. Hopefully, however, TROPHY will stimulate further research which might prove to have important public health implications. The mean age of 48.5 years in TROPHY participants is lower than other recent studies of hypertension. Whether treatment in still younger subjects could bring further prevention of hypertension is presently unknown. It is also not known if longer periods of treatment or a larger degree of blood pressure lowering would yield even better results. Whether TROPHY results reflect only the blood pressure lowering actions of the drug or other effects of angiotensin blockade has so far not been resolved. In terms of prevention, the largest potential impact could come from a study of clinical outcomes with early pharmacological intervention in prehypertension. Finally, the issue of cost effectiveness in treating prehypertension needs to be elucidated. A head‐to‐head comparison of the cost effectiveness of lifestyle modification and pharmacological treatment of prehypertension would therefore be of great interest.