Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f360 (Published 28 January 2013)
Cite this as: BMJ 2013;346:f360

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Mekani et al have presented an excellent review reinforcing two well-known principles in medicine: firstly, do no harm and secondly, more is not always better. The deleterious effects of dual blockade of the renin-angiotensin system (RAS) on all cause mortality, hypotension and renal failure may in part be mediated by episodes of intravascular volume depletion. Patients complying with sodium restriction and those on diuretics (e.g. heart failure patients and those with nephrotic syndrome) will be at increased risk of volume depletion. While hospitalised patients at risk of volume depletion can be identified and euvolaemia preserved, volume loss frequently arises in the community due to intercurrent illness such as gastroenteritis. There is no consensus on how to ensure early identification of such patients in order to prevent harm. A better understanding of this common clinical phenomenon will help us deliver more balanced treatment regimens in the future, aiming to preserve potential benefits from RAS blockade while minimising harm.

Competing interests: None declared

Catherine Maclean, Specialty Trainee Renal Medicine/ General (Internal) Medicine

Crosshouse Hospital, Kilmarnock Road, Crosshouse, KA2 0BE

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2 March 2013

Drs. Laragh and Sealey made an excellent point and we thoroughly agree that sodium and/or volume depletion increases the risk of adverse events of renin-angiotensin system (RAS) blockade. Indeed, protection against hypotension due to volume depletion is one of the main physiologic functions of the renin angiotensin system in normotensives and hypertensives alike.

As Laragh and Sealey point out, all adverse events of our meta-analysis, i.e., hypotension, hyperkalemia, and renal failure can be explained on the basis of this mechanism. However, it is increasingly clear that we do not need dual RAS blockade to observe these adverse events. Undue hypotension was the most likely cause of excessive risk of death from cardiovascular causes in ROADMAP study in the olmesartan arm.1 Average blood pressure on active therapy was 125.7/74.3 mm Hg, and notably the last blood pressure before an event was lowest and systolic pressure reduction greatest in patients who died.

Even in the non sodium depleted patient Sealey and Laragh seem not to be convinced about the benefits of dual RAS blockade as is obvious from their inherent contradictory statements − “the second renin-angiotensin system blocker adds little benefit to patients whose renin-angiotensin system has already been successfully blocked” and “more patients might benefit from one or even two renin angiotensin system blocking drugs if none of them were sodium depleted with reactively high PRA levels.”

Conceivably, monotherapy with a good dose of a single RAS blocker is all that is needed for vascular protection in sodium replete patients as well as for causing adverse events in sodium depleted ones. Clearly, these risk/benefit considerations argue against dual RAS blockade regardless of the state of sodium depletion.

We greatly appreciate the thoughts of Drs. Franco de Oliveira and Onuigbo.

We also doubt that there is a ”perfect” renal surrogate end point and if there was, it certainly would not be proteinuria/albuminuria.

References
1. Haller H, Ito S, Izzo JL, Jr., Januszewicz A, Katayama S, Menne J, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364(10):907-17.

Competing interests: None declared

Franz H Messerli, Professor of Clinical Medicine

Harikrishna Makani, Sripal Bangalore

St. Luke's Roosevelt Hospital, Columbia University College of Physicians & Surgeons, New York, 1000 Tenth Avenue, New York, New York 10019

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This excellent work from Messerli et al is a laudable effort. Very pertinently, in addition to several other relevant findings, this study had critically demonstrated a 41% increase in the risk of renal failure with dual RAAS blockade, compared to monotherapy (1). The complimentary findings in the ONTARGET trial were very prominently highlighted in this report (1). Moreover, one relevant but neglected finding of the ALLHAT study was that the Lisinopril (ACEI) arm experienced more ESRD compared with the chlorthalidone arm (2). We agree with the authors that there is hardly any evidence-based data to support the so-called total RAAS blockade by the use of dual RAAS blocking strategies. Such an approach very much undermines the very relevance of the RAAS system in the necessary and multifaceted physiologic roles of the maintenance of cardiovascular homeostasis, maintenance of the integrity of glomerulo-tubular balance, the maintenance of several critically important renal tubular transport systems, the maintenance of renal auto-regulation and so on.

Since 2005, we have reported severally on iatrogenic renal failure associated with RAAS blockade in general, including the first reports of the syndrome of late onset renal failure from angiotensin blockade or LORFFAB (3-6). Furthermore, we have demonstrated significant renal salvage following withdrawal of angiotensin inhibition in selected CKD patients (3-6). Subsequent reports from Sheffield Kidney Institute in the United Kingdom by El Nahas et al have further validated our findings (7).

In a recent letter to the Editor of the New England Journal of Medicine, we had raised major concerns about the rampant abuse of untested renal surrogates in the nephrology literature, and this approach, is even further grossly compounded by the rampant and almost reckless use of combinations of these renal surrogate endpoints as if they were independent variables (8). In a recent related report from Messerli et al, again in the BMJ, RCTs reporting surrogate primary outcomes were shown to be more likely to report larger treatment effects than trials reporting final patient relevant primary outcomes and this finding was not explained by differences in the risk of bias or characteristics of the two groups of trials (9). We agree with Messerli et al that renal surrogate use is untested, unproven and potentially dangerous as it appears to hype up RCT outcomes in favor of the test drugs (9,10). Furthermore, and even worse, the excessive use of these untested renal surrogates in combination protocols as so-called “composite end-points”, in our humble submission, is a subterfuge of valid statistical analysis (8). One single major shortcoming of this approach is the employment of such potentially confounding variables, as if they represented independent variables (8). Such practices introduce such phenomena as ecological fallacy and Simpson’s Paradox as it is applied to statistical methodologies (10). Without a doubt, the correct use of combined (renal) surrogate endpoints is only valid if the individual (renal) surrogate factors are indeed independent variables (11). The place of the term “perfect surrogate” has been very much written about in the statistics literature and is very much beyond the scope of this rapid response (12). We here again call for a heightened caution regarding the abuse of such statistical methodologies especially in current nephrology RCTs’ literature.

REFERENCES
1. Makani H, Bangalore S, Desouza KA, Shah A, Franz H Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials. BMJ. 2013; 346: f360.
2. Wright JT Jr, Probstfield JL, Cushman WC, et al; ALLHAT Collaborative Research Group. ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses. Arch Intern Med. 2009;169(9):832-842.
3. Onuigbo MA, Onuigbo NT. Late onset renal failure from angiotensin blockade (LORFFAB): a prospective thirty-month Mayo Health System clinic experience. Med Sci Monit 2005 Oct; 11(10):CR462-9. Epub 2005 Sep 26. PMID:16192897.
4. Onuigbo MA, Onuigbo NT. Late onset azotemia from RAAS blockade in CKD patients with normal renal arteries and no precipitating risk factors. Ren Fail 2008; 30(1):73-80. PMID:18197547. DOI:10.1080/08860220701742161.
5. Onuigbo MA, Onuigbo NT. Late-onset renal failure from angiotensin blockade (LORFFAB) in 100 CKD patients. Int Urol Nephrol 2008; 40(1):233-9. Epub 2008 Jan 15.
6. Onuigbo MA. Can ACE Inhibitors and Angiotensin Receptor Blockers Be Detrimental in CKD Patients? Nephron Clin Pract. 2011 Mar 7;118(4):c407-c419. [Epub ahead of print].
7. Ahmed AK, Kamath NS, El Kossi M, El Nahas AM. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant. 2010 Dec;25(12):3977-82. doi: 10.1093/ndt/gfp511. Epub 2009 Oct 10.
8. Onuigbo MA, Onuigbo NT. Concern about rampant use of combination renal surrogate endpoints in nephrology RCTs. N Eng J Med, 2013 (In Press).
9. Ciani O et al. Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised controlled trials-meta-epidemiological study. BMJ. 2013; 346: f457.
10. Onuigbo MA. Reno-prevention vs. reno-protection: a critical re-appraisal of the evidence-base from the large RAAS blockade trials after ONTARGET--a call for more circumspection. QJM 2009 Mar; 102(3):155-67. Epub 2008 Dec 19.
11. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989 Apr;8(4):431-40.

Competing interests: None declared

Macaulay A. Onuigbo, Nephrologist/Hypertension Specialist

Nnonyelum T.C. Onuigbo MSc

Mayo Clinic, Rochester, MN, USA & Mayo Clinic Health System, Eau Claire, WI, USA, 1221 Whipple Street, Eau Claire, WI

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This detailed, stratified for patients with and without heart failure, meta-analysis of the still very popular dual blockade of the renin-angiotensin-aldosterone system (RAAS) (1) raise insightful issues, that can provide pragmatic clinical strategies for the management of resistant heart failure, hypertension, and diabetic or non-diabetic proteinuric chronic kidney diseases (CKDs) with RAAS blockers.

The evolution of the RAAS point to its emergence 400 million years ago, when cartilage and bony fish diverged(2). Dramatic changes in environment when moving from salt to water (fish), then to combined water and land (amphibians) and to land (reptiles, primates), pressured the evolution to an efficient and sophisticated, circulating and kidney tissular RAAS system to maintain whole body homeostasis(2-4). At these times, angiotensin II was already there as a key volume and blood pressure regulator. When Homo Sapiens appeared about 150.000 years ago(5) and beyond, the RAAS, albeit already fully developed(2,5) started being less demanded. With salt industrialization for food conservation the RAAS changed to become, in most individuals, as a maladaptive state of constant overdrive, causing through its main effector – angiotensin II – salt and volume overload in the body with consequent hypertension, strokes, cardiovascular, and renal diseases(6,7).

The marketing of ACE-Inhibitors (ACE-Is) and a bit later of angiotensin receptor blockers (ARBs) for the treatment of hypertension, heart failure, and proteinuric diabetic and non-diabetic CKDs, a few decades ago, were namely based on hard outcomes data. Conversely, the use of dual RAAS blockade was driven only by “positive results” over lowering of blood pressure and proteinuria/albuminuria, that constitute only meaningless Surrogate markers of diseases, because they were not yet validated by hard outcomes studies under this new therapeutic strategy(8). So, the results of this meta-analysis speak by itself:

Noteworthy, the increase in all-cause mortality found in the combined cohort from the 2 largest prospective randomised clinical trials without heart failure analised: the ONTARGET and the ALTITUDE trials(1) raise the following hypothesis:

Angiotensin II is present in nature, and in human beings, as a defense molecule with a number of diverse functions in processes of health and disease that are key to the maintenance of life. Firstly, angiotensin II is one the major regulators of volume, blood pressure levels, salt and potassium balance, in order to keep them under homeostatic levels. For that, it interacts with a number of other hormonal or local&systemic organ systems like the sympathetic nervous system, modulating systemic sympathetic tonus, and the sympathetic influence on renin release, modulates the adrenal control of aldosterone secretion, and even the tubulo-glomerular feed-back to further influence renal sodium excretium(2-4). Angiotensin II has also a major influence on renal auto-regulation, in order to keep homeostatic levels of renal blood flow and glomerular filtration rate specially under conditions of salt depletion, hypovolemia, and hypotension(9), besides desensitizing the vasodepressor and hypotensive Bezold-Jarish cardiac reflex(10). Angiotensin II has also apoptosis, and wound healing properties in many diverse parts of our body like the skin(11). And these are just a few of the systemic angiotensin II actions(2-4,11).

It is hard to believe that such a vital, complex, systemic, circulating, tissular, and ubiquitous system(2-4,12) could only induce pathophysiologycal damages under the contexts of heart failure, hypertension or proteinuric CKDs, and that just blocking the angiotensin II´s actions as much as possible, without a balanced, and comprehensive approach, it could be done without inducing harms, like hypotension, hyperkalemia, renal failure, and withdrawals for adverse events, to mention the least.

Having said that, it is not surprising that clinical and well conducted observational studies all point in the direction of Harms induced by even single use of just one RAAS blocker like an ACE-I or an ARB in at least special populations in the above mentioned clinical contexts, with an emphasis, but not only, in diabetics or those over 65 years old with CKD, that are progressivelly appearing in the medical literature(13-15).

Indeed, blocking the RAAS can be too much of a good thing, at least for some people, and it can become a really self-dangerous weapon if excessively reducing the circulating or tissular angiotensin II levels.

REFERENCES:
1.Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials. BMJ 2013;346:f360
2.Taylor AA. Comparative physiology of the renin-angiotensin system. 1977 Fed Proc; 36: 1776-1780.
3.Fournier D, Luft FC, Bader M, Ganten D, Andrade-Navarro MA. Emergence and evolution of the renin-angiotensin-aldosterone system. 2012 J Mol Med; 90: 495-508.
4.Kobori H, Nangaku M, Navar LG, Nishiyama A. The Intra-Renal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease. 2007 Pharmacol Rev; 59: 251-287.
5.McDougall I, Brown FH, Fleagle JG. Stratigraphic placement and age of modern humans from Kibish, Ethiopia. 2005 Nature; 433: 733-736.
6.Frisoli TM, Schmieder RE, Grodzicki T, Messerli FH. Salt and Hypertension: Is Salt Dietary Reduction Worth the Effort? 2012 Am J Med; 125: 433-439.
7.Kearney PM, Whealton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worlwide data. 2005 Lancet; 365: 217-223.
8.Yudkin JS, Lipska KJ, Montori VM. The idolatry of the surrogate. BMJ 2011;343:d7995.
9.Hall JE, Guyton AC, Jackson TE, Coleman TG, Lohmeier TE, Trippodo NC. Control of glomerular filtration rate by renin-angiotensin system. 1977 Am J Physiol; 233(5): F366-F372.
10.Mark AL. The Bezold-Jarish Reflex Revisited: Clinical Implications of Inhibitory Reflexes Originating in the Heart. 1983 J Am Coll Cardiol; I: 90-102.
11.Takeda H, Katagata Y, Hozumi Y, Kondo S. Effects of Angiotensin II Receptor Signaling during Skin Wound Healing. 2004 Am J Pathol; 165: 1653-1662.
12.Paul M, Mehr AL, Kreutz R. Physiology of Local Renin-Angiotensin Systems. 2006 Physiol Rev; 86: 747-806.
13.Suissa S, Hutchinson T, Brophy JM, Kezouh A. ACE-inhibitor use and the long-term risk of renal failure in diabetes. 2006 Kidney International; 69: 913-919.
14.Onuigbo MA, Onuigbo NT. Late onset azotemia from RAAS blockade in CKD patients with normal renal arteries and no precipitating risk factors. Ren Fail 2008; 30(1):73-80. PMID:18197547. DOI:10.1080/08860220701742161.
15.Ahmed AK, Kamath NS, El Kossi, El Nahas AM. The impact of stopping inhibitors of the renin-angiotensin system in patients with advanced kidney disease. Nephrol Dial Transplant 2010; 25(12): 3977-3982.

Competing interests: None declared

Jose Mario Franco de Oliveira, Associate Professor of Medicine

Universidade Federal Fluminense, Rua Senador Vergueiro # 2 apt. 202

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Makani et al(1) reported that, irrespective of drug type, adding a second renin-angiotensin system blocker fails to reduce mortality and increases the prevalence of hypotension, hyperkalemia and renal failure in cardiovascular patients. We suspect that is because a few patients in every trial had become excessively sodium depleted by the concurrent use of natriuretic drugs and low salt diets, which put them at risk from renin-angiotensin system blockers.

Sodium depleted patients develop reactively high plasma renin (PRA) levels to vasoconstrict arterioles and protect from undue hypotension(2), to stimulate aldosterone secretion to protect from attendant hyperkalemia(3) and to preferentially vasoconstrict efferent more than afferent renal arterioles to protect from renal failure(4). These were the predominant adverse events reported in the meta-analysis(1).

This explanation is supported by recent reports that cardiovascular patients with high treatment PRA levels die sooner of cardiovascular mortality than do those with low treatment PRA levels, despite taking blockers of the renin-angiotensin system(5-8). We have recently analyzed those reports and found evidence of excessive sodium depletion amongst the highest PRA subgroups(9).

Accordingly, our explanation of differences in efficacy between mono and dual blockade of the renin-angiotensin system in clinical trials is as follows: the first anti-renin-angiotensin system drug blocks the negative effects of the renin-angiotensin system in most patients, but at the same time it increases cardiovascular risk in a lesser number of sodium depleted patients; the net effect is cardiovascular benefit for the group as a whole. Then, the second renin-angiotensin system blocker adds little benefit to patients whose renin-angiotensin system has already been successfully blocked, but it increases risk to those who remain sodium depleted with reactively high PRA levels; the net effect is an increase in cardiovascular risk for the group as a whole.

In sum, the adverse events of hypotension, hyperkalemia and deteriorating renal function are to be expected when the renin-angiotensin system is blocked in sodium depleted patients. However, such adverse events might well be avoided if natriuretic drugs and low salt diets were reduced or withdrawn when PRA levels become elevated during treatment (> 4.5 ng/ml/hr), thereby reducing dependence on an activated circulating renin-angiotensin system. Thus, more patients might benefit from one or even two renin-angiotensin system blocking drugs if none of them were sodium depleted with reactively high PRA levels.

1. Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials. BMJ. 2013;346.
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. Am J Hypertens. 2011;24:1164-80.
3. Sealey JE, Laragh JH. A proposed cybernetic system for sodium and potassium homeostasis: coordination of aldosterone and intrarenal physical factors. Kidney Int. 1974;6:281-90.
4. Hall JE, Guyton AC, Smith MJ, Jr., Coleman TG. Blood pressure and renal function during chronic changes in sodium intake: role of angiotensin. Am J Physiol. 1980;239:F271-80.
5. Masson S, Solomon S, Angelici MS, Latini R, Anand IS, Perscott M, et al. Elevated plasma renin activity predicts adverse outcome in chronic heart failure, independently of pharmacologic therapy: data from the Valsartan Heart Failure Trial (Val-HeFT). J Card Fail. 2010;16:964-70.
6. Verma S, Gupta M, Holmes DT, Xu L, Teoh H, Gupta S, et al. Plasma renin activity predicts cardiovascular mortality in the Heart Outcomes Prevention Evaluation (HOPE) study. Eur Heart J. 2011;32:2135-42.
7. Muhlestein JB, May HT, Bair TL, Prescott MF, Horne BD, White R, et al. Relation of elevated plasma renin activity at baseline to cardiac events in patients with angiographically proven coronary artery disease. Am J Cardiol. 2010;106:764-9.
8. Tomaschitz A, Pilz S, Ritz E, Morganti A, Grammer T, Amrein K, et al. Associations of plasma renin with 10-year cardiovascular mortality, sudden cardiac death, and death due to heart failure. Eur Heart J. 2011;32:2642-9.
9. Sealey JE, Alderman MH, Furberg CD, Laragh JH. Renin-angiotensin system blocking drugs may create more risk than reward for cardiovascular patients who become sodium-volume depleted. American Journal of Hypertension. 2013;In review.

Competing interests: None declared

John H. Laragh, Cardiovascular scientist

Jean E. Sealey

Weill Cornell Medical College, 1300 York Ave, New York NY 10021

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