Renin-Guided Treatment of Hypertension: Time for Action

In this issue of the Journal, three articles1,2,3 deal with the heterogeneity of blood pressure responses to antihypertensive treatment. Although it has been known for decades that hypertensive subjects respond differently to the many classes of antihypertensive agents, we have failed to translate this knowledge into treatment that can be adapted for individual patients. The “one size fits all” approach must be abandoned.

Even the landmark studies of Laragh and colleagues documenting the pathophysiological heterogeneity of hypertension in the early 70s4,5 have not resulted in clinically meaningful applications. The time for action is long overdue. We must redirect our efforts away from the strategy of treating hypertension as one condition (the way our colleagues treated fever centuries ago6) toward building a treatment algorithm that incorporates the varying pathophysiologies of hypertension.

Based on the work by Laragh and colleagues, there appear to be four major types of hypertension defined by their pathophysiology:6

1. Low-renin hypertension, constituting approximately one-third of all hypertensives;

2. Medium-/high-renin hypertension, representing more than one-third of all hypertensives;

3. “Resistant” hypertension, requiring ≥3 hypertensive drugs;

4. Secondary hypertension, occurring in renovascular and endocrine conditions.

Low-renin hypertension usually responds very favorably to sodium volume-depleting natriuretic drugs such as thiazide diuretics. Medium-/high-renin hypertension responds very well to agents such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers, all of which block plasma renin activity, although addition of a sodium-volume depleting drug is sometimes required to control blood pressure.

The studies of Turner et al.1 and Alderman et al.2 provide direct support for the Laragh classification, and the report by Gupta et al.3 offers indirect support. Using renin profiling before and during treatment, Turner et al. described different blood pressure responses to either a renin blocker (atenolol) or to a natriuretic antivolume drug (hydrochlorothiazide) used as mono- and as add-on therapy. As predicted, the higher the renin the more likely a favorable response to atenolol, so that those with the highest renins had mean decreases in systolic blood pressure (SBP) of 10–12mmHg but only 6–7mmHg with hydrochlorothiazide. Thus, there is about a twofold difference in mean SBP reduction. It is possible that the difference would be greater if patients were given a more potent renin blocker. However, as expected, at the low end of the renin spectrum, the reverse was true, with hydrochlorothiazide being more effective, reducing mean SBP 10–12mmHg. The mean SBP response to atenolol monotherapy was weaker, only 1mmHg. But, as an add-on, atenolol reduced mean SBP by 7mmHg. It is clear from these findings that both baseline and treatment renin levels have striking predictive value. This was strongly supported in multivariate analyses.

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Alderman et al.2 showed similar results in their low plasma renin tertile. Thus, the proportion of hypertensive patients who responded to diuretics with a ≥10mmHg fall in SBP was 40% higher than the proportion of patients responding to an antirenin agent. Correspondingly too, in the higher plasma renin tertile, the antirenin drugs were more likely to lower SBP by ≥10mmHg compared to diuretics (63% vs. 54%).

A most remarkable finding relates to the so-called pressor responses reported by Alderman, defined as an increase in SBP of ≥10mmHg. This paradoxical response to antihypertensive treatments confirms and extends the reported findings for aliskiren.7 Pressor responses were more common with antirenin drugs than with diuretics (11% vs. 5% (P = 0.001)). This difference was most pronounced in the lowest plasma renin tertile (17% vs. 6%) compared to the highest tertile (9% vs. 6%). These observations that antihypertensive drugs—and especially antirenin drugs—can raise SBP by 10mmHg are quite remarkable. We urgently need to understand the clinical relevance of this observation. Does this pressor response increase the risk of stroke, myocardial infarction, and congestive heart failure?

Gupta et al.3 examined the role of ethnicity in predicting blood pressure response. Their findings indirectly support the Laragh classification. African Americans have, on average, lower renin compared to Caucasians and increased salt sensitivity. Thus, one would expect a smaller mean reduction in SBP with the renin blocker atenolol in African Americans than in Caucasians. The reliance on ethnicity for selection of antihypertensive agents, however, appears limited. A more productive method would be to stratify hypertensive patients based on their plasma renin levels.

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The take-home messages from the three articles are as follows:

1. The time has come for classification of hypertensive type based on underlying pathophysiology. New national and international treatment guidelines should recommend stratification of hypertension based on plasma renin activity, preferably prior to initiation of treatment.

2. Plasma renin activity during treatment should also factor into decisions regarding subtracting or adding drugs.

3. Prescription of the “wrong” drug (e.g., a renin blocker for low-renin patients) can trigger a pressor response that could undermine the whole premise of antihypertensive treatment.

4. A renin test–guided treatment strategy is rational and has shown that better blood pressure control can be achieved without increasing the number of antihypertensive agents.8

5. The initiation of treatment with fixed-drug combinations may be of limited value for individualized antihypertensive treatments. A pressor response to one of the components might interfere with the antihypertensive effect of the other, leading to the further addition of unnecessary drugs.

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About the Author: Tung Chi