Routine Measurement of Plasma Renin Activity in the Management of Patients With Essential Hypertension: Notes From the 19th Annual ASH Meeting

At the 19th annual meeting of the American Society of Hypertension, an afternoon symposium was devoted to the “;Laragh method” of hypertension (HTN) management. This method is based on the principle that “HTN is caused by an abnormal relationship between plasma renin and body salt.” ¹ In other words, HTN is a spectrum with two “polar extremes”: primary hyperaldosteronism, which is a salt‐sensitive form of HTN with low plasma renin activity (PRA) (i.e., volume mediated or “V”) and renin‐mediated malignant HTN with a high PRA (i.e., “R”). Thus patients with essential HTN fall within this spectrum and can have primarily “V” type HTN, primarily “R” type HTN, or a combination thereof. Likewise, the management scheme proposes that antihypertensive drugs can be divided into two categories: diuretics (i.e., “V” drugs, including thiazide, loop and potassium sparing diuretics, as well as calcium channel blockers and α blockers) and drugs that interrupt the renin‐angiotensin‐aldosterone axis (i.e., “R” drugs including angiotensin‐converting enzyme inhibitors [ACEIs], angiotensin receptor blockers,βblockers, clonidine, reserpine, and α‐methyldopa). The simplest way to determine if a given hypertensive patient is a “V” or an “R” patient, requiring a “V” or an “R” drug, respectively, is to measure the PRA. Consequently, this approach mandates the testing of PRA in every hypertensive patient to determine both the initial selection of antihypertensive therapy as well to guide subsequent adjustment of the medication regimen. ² , ³

Here is a summary of this method: “V” patients will have a PRA <0.65 ng/mL/h and should be started on a “V” drug. If the patient's blood pressure (BP) is not adequately controlled after several weeks, the PRA should again be checked. If it is still suppressed, a second “V” drug should be added. If, however, it is elevated (>0.65 ng/mL/h), an “R” drug should be added to the regimen. “R” patients, on the other hand, will have an initial PRA>0.65 ng/mL/h and should be started on an “R” drug. If their BP is not adequately controlled after several weeks, then their PRA should be checked again. An ACEI or angiotensin receptor blocker would be expected to induce a nearly 10‐fold rise in the PRA. Thus, if the PRA is now >6.5 ng/mL/h, a second “R” drug should be added. If, however, the PRA is <6.5 ng/mL/h, then a “V” drug should be added to the regimen. This method is supposed to predict that the addition of a diuretic (or low‐salt diet) to a patient with pure “R” HTN may induce a paradoxical rise in BP!

There are several caveats to this method. First, the protocol does not address drug dosage. In other words, as just described, the protocol mandates, in certain situations, the simultaneous usage of two drugs of the same class (i.e., two “V” drugs or two “R” drugs) when, in fact, simply increasing the dosage of the first drug might produce the desired effect. Second, β blockers are “R” drugs that interfere with renin secretion from the kidney and should always suppress the PRA. Thus it is unclear how to proceed if an “R” patient is persistently hypertensive after being treated initially with a β blocker. Third, abundant literature supports the usage of certain medications in specific clinical situations, such asβ blockers and ACEIs for congestive heart failure, and ACEIs or angiotensin receptor blockers for proteinuric renal diseases, without any consideration of the PRA. How should one treat, for example, a “V” patient who also has congestive heart failure or proteinuria? Finally, no large clinical trial has tested this method. On the contrary, numerous large clinical trials, including the Antihypertensive and Lipid‐Lowering treatment to prevent Heart Attack Trial (ALLHAT), ⁴ have shown impressive outcomes without utilizing renin profiling.

The leaders of this symposium addressed these issues. Clearly, some clinical acumen must accompany the usage of any medical algorithm. The "Laragh method" should be no different. Furthermore, they encourage practitioners who try this method to give feedback by e‐mail (renintest@aol.com); they offer guidance in return. Regarding the scarcity of prospective clinical evidence supporting this method, the symposium leaders are currently collecting data. With respect to ALLHAT, the symposium leaders illustrated a possible bias in its design: In ALLHAT, if a patient was randomized to the diuretic arm, he could receive atenolol, clonidine, or reserpine (all “R” drugs) if his BP was not optimally controlled on chlorthalidone alone. Thus, even if this patient had renin‐mediated HTN (“R”), he was likely to attain adequate control by step two of the protocol. On the other hand, if a patient with salt‐sensitive HTN (“V”) were randomized to the lisinopril arm, at no point in the treatment protocol could he receive a diuretic (although ≥20% plus patients did). Furthermore, ALLHAT had a very high percentage of black, diabetic, and elderly subjects (35%, 36%, and 57%, respectively), among whom salt‐sensitive HTN is particularly prevalent. ⁵ Consequently, the symposium leaders were critical of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ⁶ guidelines, which, they stated, were based primarily on the results of ALLHAT and propose a "one size fits most" approach to HTN management. In fact, these guidelines were based on the results of numerous trials, none of which utilized renin testing to determine therapy. Furthermore, the symposium leaders were critical of the JNC 7 guidelines for recommending the addition of second and third agents but at no point advising the removal of diuretics in patients who do not respond to them, even though such patients might actually have renin‐mediated HTN. The logic in the Laragh method is intrinsically appealing. Hopefully, outcome data will be presented at some point to give us a better idea of how often using this system achieves BP control, particularly in the older, predominantly systolic, HTN population, where the biggest challenges to BP control lie.