When encountering the patient with shock, we are accustomed to thinking through the possible etiologies and directing treatment accordingly. Is there a deficit of blood volume, such as from hemorrhage? Is the patient excessively vasodilated, as in sepsis or anaphylaxis? Is the shock cardiogenic?
However, when faced with the hypertensive patient, we tend to treat every patient the same, regardless of the underlying etiology. Has the time come for hypertension treatment directed at a patient’s individual pathophysiology? In the first part of today’s episode, Dr, Armando Lindner and I discuss the Laragh method of treating hypertension, which proposes to do just that. In part 2 of the episode, we discuss a few major hypertension trials, and their implications for the most important classes of antihypertensive medications.
Part 1: The Laragh method of treating hypertension
Dr. John Laragh was a clinician and hypertension researcher whose work was groundbreaking in describing the role of the renin-angiotensin axis in hypertension. He summarized his twenty-five lessons on treating hypertension and twelve clinical pearls in a 2001 review that serves as a complete primer on his method (2). A new review published in 2011 (3) provides a briefer and more recent summary.
Volume and Vasoconstriction
The first step in using Laragh’s method is understanding that patients with essential hypertension have an excess of blood volume, vasoconstriction, or both. Via the potent vasoconstricting effects of angiotensin II, the renin-angiotensin axis is largely responsible for causing vasoconstriction. The kidneys control blood volume. If a hypertensive patient has an appropriately suppressed renin level (<0.65ng/mL/hr), this suggests a renin-independent etiology of hypertension causing “low-renin,” a.k.a. “volume-mediated,” or “V-” type hypertension. If renin activity is inappropriately normal (0.65-6.5ng/mL/hr) despite a high blood pressure, or even elevated (>6.5ng/mL/hr), then there is a relative excess of renin causing “medium/high-renin” a.k.a. “vasoconstriction-mediated”, “resistance-mediated,” or “R” type hypertension.
V Drugs and R Drugs
The next key insight into Dr. Laragh’s method is that treatments correctly directed at the patient’s etiology of hypertension will be more effective and less toxic to the patient. Patients with volume-mediated hypertension will benefit most from thiazide and other diuretics, calcium-channel blockers, and alpha blockers (as the latter two cause vasoactive changes in the kidney leading to a diuresis) (12). Patients with medium to high renin levels will benefit from beta blockers, which decrease the production of renin, and ACEi/ARBs, which will block renin’s downstream effects. Patients may have both pathways at play and can certainly benefit from a mix of anti-V and anti-R therapies. In fact, hypertensive patients on more than one drug should be on a “VR combo” unless there is a strong reason to choose another combination (such as ischemic heart disease indicating BB + ACEi therapy, or a suppressed renin level even while taking one anti-V drug such as amlodipine, indicating the addition of a thiazide diuretic).
Determining a patient’s etiology of hypertension
There are three strategies to determine your patient’s renin status in order to direct the optimal therapy.
Strategy 1. Age, race, and comorbidities
First, you can use a patient’s age, race, and comorbidities. Current hypertension guidelines implicitly use this strategy (4,5,7,8,9). Patients older than 60 are generally more likely to have LREH (low renin essential hypertension), and younger patients (30-55) are more likely to have MREH/HREH. Black individuals are more likely to have LREH, hence why multiple guidelines recommend prescribing thiazides for black patients and white patients over 60 years old, while recommending ACE inhibition for younger patients (or B blockade for pregnant younger patients).
Strategy 2. Treatment response
If a patient’s blood pressure drops significantly in response to their treatment, you can assume they were correctly treated, confirming the etiology of their hypertension. If there is little response and they are confirmed to be adherant to the regimen, this might suggest that hypertension is due to the other etiology. Laragh calls this approach diagnosis ex juvantibus – diagnosis by finding which treatment helps.
Strategy 3. Plasma renin activity level
For initial treatment
The plasma renin activity (PRA) assay can help differentiate the etiology of hypertension for individual patients. It costs $30-75 in the United States, and is covered by Medicare. The lab is inaccurate in patients who have not yet ambulated on the day of testing, such as in hospitalized inpatients undergoing a morning blood draw. The test can otherwise be sent at any time of day, and the patient doesn’t need to fast, stop current antihypertensive therapy, or restrict salt intake prior to the test, contrary to prior belief(12).
Recommendations for when to use the plasma renin activity assay vary considerably. Laragh checked the renin activity on the first visit when a patient’s blood pressure is elevated, so that the information was available to help him decide the first antihypertensive drug to prescribe (2). A recent study proposed measuring PRA in those populations with prior probabilities of LREH most approaching 50% (younger black patients and older white patients, using 60 as the age cutoff), but empirically treating other populations based on predicted renin status without using PRA when starting therapy (14). Official guidelines do not make recommendations for ever using plasma renin activity in the routine management of hypertension.
For patients already being treated
There is a small randomized trial suggesting that PRA testing can be helpful in the patient whose hypertension is challenging to control. A small study randomized 39 treated-but-uncontrolled patients to clinical hypertension specialists’ care (CHSC) without the use of PRA, versus 38 patients receiving renin-test guided therapy (RTGT) by those same specialists. Although the rtgt care was provided by specialists, they followed a specific algorithm reproduced in Table 1 of the article, which could easily be used by primary care providers. The study found that blood pressure was controlled in 74% of the rtgt arm vs. 59% in the CHSC arm, although this difference was not statistically significant in this small study. Final numbers of antihypertensive medicatiosn were similar, but the RTGT arm allowed more discontinuation of medications since the RTGT started with more therapies at the time of randomization.
The authors conclude that “the number of [hypertension] specialists is quite insufficient to manage the estimated 17 million treated but uncontrolled hypertensive patients in the US. Accordingly, the RTGT algorithm emerges as a practical and objective biochemical alternative to CHSC that can be used in most clinical settings by a wide range of health-care providers for addressing the public health burden of treated but uncontrolled hypertension.”
Part 2: Antihypertensive medications and trials
Dr. Lindner shared his perspective on a handful of major trials in the treatment of hypertension.
allhat was the major trial in the early 2000s that established diuretics as the primary first-line antihypertensive. However, allhat has been criticized for a design that favored diuretics fro mthe start. Monotherapy failed to treat most patient’s hypertension in the trial, and all patients prescribed a second drug were prescribed beta blockers. A thiazide and beta blocker create a “V/R combo” treatment that is likely more effective for most patients than an “R/R combo” of an ACE inhibitor and beta blocker. Additionally, Dr. Lindner shares concerns in this episode about the excess of metabolic side effects of diuretics that were shown in the trial.
The accomplish trial found that amlodipine performed better than hydrochlorothiazide at reducing cardiovascular events when each was combined with an ACE inhibitor.
ascot-bpla studied English and Scandinavian hypertensive patients with or without diabetes, comparing a calcium channel blocker and ACE inhibitor regimen against a diuretic and beta blocker regimen. It was stopped early due to a decrease in many of cardiovascular complications used as secondary endpoints in the calcium channel blocker and ACE inhibitor group.
accord studied strict versus liberalized blood pressure control in diabetic patients, but the drugs that were used (such as alpha and beta blockers) are no longer considered firstline therapies. It found no benefit to strict control, but it is unclear whether these results would be repeated if current first-line therapies were used. Perhaps outcomes are not just driven by the blood pressure achieved, but by the specific drugs used to achieve that blood pressure.
JNC 7 vs. JNC 8
Pertinent to our discussion in this episode, jnc 8 differed from jnc 7 by recommending less stringent blood pressure targets for certain groups. Language about discontinuing ineffective medications is omitted in JNC 8, so one antihypertensive is added after another until the blood pressure is controlled. jnc 8 was not the official statement of any major society, as support was withdrawn from the individuals publishing the guideline, and a dissenting opinion was also published by other members of the committee.
The Laragh method proposes that hypertension is caused by excess blood volume, excess vasocontriction, or both. By directing treatments at the underlying pathophysiology, it is hypothesized that appropriate blood pressure control may be achieved with fewer drugs, and fewer treatment-related toxicities.
2. Laragh JH, Sealey JE. The plasma renin test reveals the contribution of body sodium-volume content (V) and renin–angiotensin (R) vasoconstriction to long-term blood pressure. American Journal of Hypertension. 2011;24(11):1164–1180.
3. Olson N, DeJongh B, Hough A, Parra D. Plasma renin activity-guided strategy for the management of hypertension. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2012;32(5):446–455.
4. AV C, GL B, HR B, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA. 2003;289(19):2560–2571.
5. Dasgupta K, Quinn RR, Zarnke KB, Rabi DM, Ravani P, Daskalopoulou SS, et al. The 2014 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Canadian Journal of Cardiology. 2014;30(5):485–501.
6. Furberg CD, Alderman MH. JNC 8: Shortcomings in process and treatment recommendations. American Journal of Hypertension. 2014;p. 158.
7. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the eighth joint national committee (JNC 8). JAMA. 2014;311(5):507–520.
8. Krause T, Lovibond K, Caulfield M, McCormack T, Williams B. Management of hypertension: summary of NICE guidance. BMJ. 2011;343.
9. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, et al. Clinical Practice Guidelines for the Management of Hypertension in the Community. The Journal of Clinical Hypertension. 2014;16(1):14–26.
10. Smith SM, Campbell JD. Cost-effectiveness of renin-guided treatment of hypertension. American journal of hypertension. 2013;26(11):1303–1310.
Comparisons of Age/race vs. PRA-guided strategies
11. Dickerson JC, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimisation of antihypertensive treatment by crossover rotation of four major classes. The Lancet. 1999;353(9169):2008–2013.
12. Egan BM, Basile JN, Rehman SU, Davis PB, Grob CH, Riehle JF, et al. Plasma Renin Test–Guided Drug Treatment Algorithm for Correcting Patients With Treated but Uncontrolled Hypertension: A Randomized Controlled Trial. American journal of hypertension. 2009;22(7):792–801.
13. Preston RA, Materson BJ, Reda DJ, Williams DW, Hamburger RJ, Cushman WC, et al. Age-race subgroup compared with renin profile as predictors of blood pressure response to antihypertensive therapy. Jama. 1998;280(13):1168–1172.
14. Schwartz GL, Bailey K, Chapman AB, Boerwinkle E, Turner ST. The role of plasma renin activity, age, and race in selecting effective initial drug therapy for hypertension. American Journal of Hypertension. 2013;p. 957–964.
15. Smith SM, Campbell JD. Cost-Effectiveness of Renin-Guided Treatment of Hypertension. American journal of hypertension. 2013;26(11):1303–1310.
16. Turner ST, Schwartz GL, Chapman AB, Beitelshees AL, Gums JG, Cooper-DeHoff RM, et al. Plasma renin activity predicts blood pressure responses to β-blocker and thiazide diuretic as monotherapy and add-on therapy for hypertension. American journal of hypertension. 2010;23(9):1014–1022.
Criticism of the Laragh method
17. Moser M, Izzo JL. Plasma renin measurement in the management of hypertension: the V and R hypothesis.
The Journal of Clinical Hypertension. 2005;7(s8):32–35.
18. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. The Lancet. 2005;366(9489):895–906.
19. Davis B, Cutler JA, Gordon D, et al. Major outcomes in high risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT). Jama. 2002;288(23):2981–2997.
20. Group AS, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. The New England Journal of Medicine. 2010;362(17):1575.
21. Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. New England Journal of Medicine. 2008;359(23):2417–2428.
23. Laragh JH, Sealey JE. Relevance of the plasma renin hormonal control system that regulates blood pressure and sodium balance for correctly treating hypertension and for evaluating ALLHAT. American Journal of Hypertension. 2003;16(5):407–415. Pressor responses to antihypertensives
Pressor Response to Beta Blockers
24. Alderman MH, Cohen HW, Sealey JE, Laragh JH. Pressor responses to antihypertensive drug types. American
journal of hypertension. 2010;23(9):1031–1037.
Laragh Method Show Notes (PDF)
Laragh Method Transcript (PDF)