Hold the ACEi and ARBs? What is the evidence?tsa.org/handouts/Hold_the_ACE_or_ARB.pdfLv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GF. Antihypertensive agents for preventing

Hold the ACEi and ARBs? What is the evidence?

Davide Cattano, MD, PhD, FASA, CMQ Professor, Department of Anesthesiology

McGovern Medical School

The University of Texas Medical School at Houston

Medical Director, Preoperative Anesthesia Clinic

Anesthesia Service Chief Head and Neck Surgery

Memorial Hermann Hospital

Between Myth and Reality

Evidences and Doubts

TSA 2018, Lost Pines Sept 6th-9th

I did not receive any honoraria, don’t

own any royalties, or gained other

benefits for this presentation.

I do not hold significant “interest”

that needs to be disclosed, related to

the presentation.

Disclosures

Learning Objectives

• 1. Define physiology of blood pressure control by Angiotensin, identify current pharmacology strategies to control hypertension and compare anesthesiology preoperative guidelines.

• 2. Analyze the risk factors for intraoperative hypotension (IOH) and identify current mortality and morbidity related to IOH.

• 3. Discuss optimal perioperative clinical strategies based on evidence based medicine.

Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GF.

Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst

Rev. 2012 Dec 12;12:CD004136. doi: 10.1002/14651858.CD004136.pub3.

ACEIs were found to prevent new onset DKD and death in normo-albuminuric people with diabetes, and could therefore be used in this population.

Xue H, Lu Z, Tang WL, Pang LW, Wang GM, Wong GW, Wright JM.

First-line drugs inhibiting the renin angiotensin system versus other first-line

antihypertensive drug classes for hypertension. Cochrane Database Syst Rev. 2015 Jan

11;1:CD008170. doi: 10.1002/14651858.CD008170.pub2.

• First-line thiazides caused less HF and stroke than

first-line RAS inhibitors.

• Compared with first-line CCBs, first-line RAS inhibitors

reduced HF but increased stroke. The magnitude of the

reduction in HF exceeded the increase in stroke.

We found predominantly moderate quality evidence that all-cause mortality is similar when first-line RAS inhibitors are compared to

other first-line antihypertensive agents.

1. What are the current guidelines regarding ACEI/ARBs use in the perioperative period?

2. What are the dangers to using them during this period?

3. What do we know about these dangers?

4. Are the current “practice” guidelines appropriately addressing these matters? Is there enough evidence to justify them?

Clinical Questions and Dilemmas

• IOH (Intraoperative hypotension)

• AKI (Acute Kidney Injury)

• MINS (Myocardial Injury after Non cardiac Surgery)

• Others? (Stroke, IscOptNeu, “POCD/Delirium”)

Fleisher, LA, Fleischmann, KE, Auerbach, AD, Barnason, SA, Beckman, JA, Bozkurt, B, Davila-

Roman, VG, Gerhard-Herman, MD, Holly, TA, Kane, GC, Marine, JE, Nelson, MT, Spencer, CC,

Thompson, A, Ting, HH, Uretsky, BF, Wijeysundera, DN

2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of

patients undergoing noncardiac surgery: Executive summary: A report of the American

College of Cardiology/American Heart Association Task Force on Practice Guidelines.

Circulation. (2014). 130 2215–45

ACEIs or ARBs

• Continuation of ACEIs or ARBs is reasonable perioperatively.

IIa, B

• If ACEIs or ARBs are held before surgery, it is reasonable to restart it PO as soon as clinically feasible.

IIa, C

We recommend withholding ACEI/ARB starting 24 hours before noncardiac surgery in patients

treated chronically with an ACEI/ARB (Strong Recommendation; Low-Quality Evidence).

• Substantial increase in the risk of IOH associated with perioperative continuation of ACEI/ARB therapy.

• Because the risk of hypotension is greatest within 24 hours of surgery, physicians should consider

restarting ACEI/ARB on day 2 after surgery in patients receiving chronic ACEI/ARB therapy, if the

patient is hemodynamically stable.

Emmanuelle Duceppe, MD,a,b,c Joel Parlow, MD, MSc (Co-chair),d Paul MacDonald, MD,e Kristin Lyons, MDCM,f Michael McMullen, MD,d Sadeesh Srinathan,MD, MSc,g Michelle Graham, MD,h Vikas Tandon,MD,I Kim Styles,MD,j Amal Bessissow,MD,MSc,k Daniell. Sessler, MD,l Gregory Bryson,MD,MSc,m,n and P.J. Devereaux, MD, PhD (Co-chair)b,c,i. Canadian Cardiovascular Society Guidelines on Perioperative Cardiac Risk Assessment and Management for Patients Who Undergo Noncardiac Surgery. http://www.onlinecjc.ca/article/S0828-282X(16)30980-1/pdf

Roshanov, PS, Rochwerg, B, Patel, A, Salehian, O, Duceppe, E, Belley-Côté, EP, Guyatt, GH, Sessler, DI, Le

Manach, Y, Borges, FK, Tandon, V, Worster, A, Thompson, A, Koshy, M, Devereaux, B, Spencer, FA,

Sanders, RD, Sloan, EN, Morley, EE, Paul, J, Raymer, KE, Punthakee, Z, Devereaux, PJ.

Withholding versus Continuing Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor

Blockers before Noncardiac Surgery: An Analysis of the Vascular events In noncardiac Surgery

patients cohort evaluation Prospective Cohort. Anesthesiology. 2017 Jan;126(1):16-27.

Recommendation: consider withholding ACEI/ARBs

24 h before surgery.

A large randomized trial is needed to confirm this finding.

• Patients who withheld their ACEI/ARB in the 24 h before surgery were

less likely to suffer of all-cause death, stroke, or myocardial injury

after noncardiac surgery at 30 days compared to the ones who did not.

(150/1,245 [12.0%] vs. 459/3,557 [12.9%]; adjusted relative risk, 0.82; 95% CI, 0.70 to 0.96; P =

0.01); Adjusted relative risk, 0.80; 95% CI, 0.72 to 0.93; P < 0.001; respectively).

• The risk of PO hypotension was similar between the two groups.

(adjusted relative risk, 0.92; 95% CI, 0.77 to 1.10; P = 0.36). Results were consistent across the

range of preoperative blood pressures.

Botto F1, Alonso-Coello P, Chan MT, Villar JC, Xavier D, Srinathan S, Guyatt G, Cruz P, Graham M, Wang CY, Berwanger O, Pearse RM, Biccard BM,

Abraham V, Malaga G, Hillis GS, Rodseth RN, Cook D, Polanczyk CA, Szczeklik W, Sessler DI, Sheth T, Ackland GL, Leuwer M, Garg AX, Lemanach Y,

Pettit S, Heels-Ansdell D, Luratibuse G, Walsh M, Sapsford R, Schünemann HJ, Kurz A, Thomas S, Mrkobrada M, Thabane L, Gerstein H, Paniagua P,

Nagele P, Raina P, Yusuf S, Devereaux PJ, Devereaux PJ, Sessler DI, Walsh M, Guyatt G, McQueen MJ, Bhandari M, Cook D, Bosch J, Buckley N, Yusuf

S, Chow CK, Hillis GS, Halliwell R, Li S, Lee VW, Mooney J, Polanczyk CA, Furtado MV, Berwanger O, Suzumura E, Santucci E, Leite K, Santo JA,

Jardim CA, Cavalcanti AB, Guimaraes HP, Jacka MJ, Graham M, McAlister F, McMurtry S, Townsend D, Pannu N, Bagshaw S, Bessissow A, Bhandari M,

Duceppe E, Eikelboom J, Ganame J, Hankinson J, Hill S, Jolly S, Lamy A, Ling E, Magloire P, Pare G, Reddy D, Szalay D, Tittley J, Weitz J, Whitlock R,

Darvish-Kazim S, Debeer J, Kavsak P, Kearon C, Mizera R, O'Donnell M, McQueen M, Pinthus J, Ribas S, Simunovic M, Tandon V, Vanhelder T,

Winemaker M, Gerstein H, McDonald S, O'Bryne P, Patel A, Paul J, Punthakee Z, Raymer K, Salehian O, Spencer F, Walter S, Worster A, Adili A, Clase

C, Cook D, Crowther M, Douketis J, Gangji A, Jackson P, Lim W, Lovrics P, Mazzadi S, Orovan W, Rudkowski J, Soth M, Tiboni M, Acedillo R, Garg A,

Hildebrand A, Lam N, Macneil D, Mrkobrada M, Roshanov PS, Srinathan SK, Ramsey C, John PS, Thorlacius L, Siddiqui FS, Grocott HP, McKay A, Lee

TW, Amadeo R, Funk D, McDonald H, Zacharias J, Villar JC, Cortés OL, Chaparro MS, Vásquez S, Castañeda A, Ferreira S, Coriat P, Monneret D,

Goarin JP, Esteve CI, Royer C, Daas G, Chan MT, Choi GY, Gin T, Lit LC, Xavier D, Sigamani A, Faruqui A, Dhanpal R, Almeida S, Cherian J, Furruqh S,

Abraham V, Afzal L, George P, Mala S, Schünemann H, Muti P, Vizza E, Wang CY, Ong GS, Mansor M, Tan AS, Shariffuddin II, Vasanthan V, Hashim

NH, Undok AW, Ki U, Lai HY, Ahmad WA, Razack AH, Malaga G, Valderrama-Victoria V, Loza-Herrera JD, De Los Angeles Lazo M, Rotta-Rotta A,

Szczeklik W, Sokolowska B, Musial J, Gorka J, Iwaszczuk P, Kozka M, Chwala M, Raczek M, Mrowiecki T, Kaczmarek B, Biccard B, Cassimjee H,

Gopalan D, Kisten T, Mugabi A, Naidoo P, Naidoo R, Rodseth R, Skinner D, Torborg A, Paniagua P, Urrutia G, Maestre ML, Santaló M, Gonzalez R, Font

A, Martínez C, Pelaez X, De Antonio M, Villamor JM, García JA, Ferré MJ, Popova E, Alonso-Coello P, Garutti I, Cruz P, Fernández C, Palencia M, Díaz

S, Del Castillo T, Varela A, de Miguel A, Muñoz M, Piñeiro P, Cusati G, Del Barrio M, Membrillo MJ, Orozco D, Reyes F, Sapsford RJ, Barth J, Scott J,

Hall A, Howell S, Lobley M, Woods J, Howard S, Fletcher J, Dewhirst N, Williams C, Rushton A, Welters I, Leuwer M, Pearse R, Ackland G, Khan A,

Niebrzegowska E, Benton S, Wragg A, Archbold A, Smith A, McAlees E, Ramballi C, Macdonald N, Januszewska M, Stephens R, Reyes A, Paredes LG,

Sultan P, Cain D, Whittle J, Del Arroyo AG, Sessler DI, Kurz A, Sun Z, Finnegan PS, Egan C, Honar H, Shahinyan A, Panjasawatwong K, Fu AY, Wang S,

Reineks E, Nagele P, Blood J, Kalin M, Gibson D, Wildes T; Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Writing Group, on

behalf of The Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) Investigators; Appendix 1. The Vascular events In noncardiac

Surgery patIents cOhort evaluatioN (VISION) Study Investigators Writing Group; Appendix 2. The Vascular events In noncardiac Surgery patIents cOhort

evaluatioN Operations Committee; Vascular events In noncardiac Surgery patIents cOhort evaluatioN VISION Study Investigators.

Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic

criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology. 2014 Mar;120(3):564-78.

Among adults undergoing noncardiac surgery, MINS

is common and associated with substantial mortality.

• The VISION study, given its large sample size and complex multinational logistics, it was not

designed to capture extensive physiologic data. Because of this, the hypotension variables

were limited to a categorical response (yes/no) although the total duration of the episodes

was captured. Unfortunately, neither medication use after surgery nor renal outcomes were

systematically captured.

• Although ACEI/ARB use was associated with intraoperative hypotension and was

correlated with progressively longer total duration, it was not associated with the primary

outcome. Postoperative hypotension was associated with the primary outcome but not with

ACEI/ARB use.

• An acute elevation of creatinine can be precipitated by hypovolemia, sepsis, hemodynamic

instability due to new or worsening dysrhythmias, and so forth. Thus, it is tempting to

speculate that patients with deteriorating renal function were given their ACEIs/ARBs

inappropriately, leading to higher risk of adverse perioperative outcomes associated with

either chronic preoperative or acute perioperative renal injury.

London MJ.

Preoperative Administration of Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor

Blockers: Do We Have Enough "VISION" to Stop It? . Anesthesiology. 2017 Jan;126(1):1-3.

There is contradicting information here

?

In patients with moderate renal insufficiency undergoing cardiac catheterization, withholding ACEI/ARB resulted in a non-significant reduction in contrast-induced

AKI and a significant reduction in post-procedural rise of creatinine.

Bainey KR1, Rahim S2, Etherington K2, Rokoss ML2, Natarajan MK2, Velianou JL2, Brons S2, Mehta SR3;

Captain investigators.

Effects of withdrawing vs continuing renin-angiotensin blockers on incidence of acute kidney injury in

patients with renal insufficiency undergoing cardiac catheterization: Results from the Angiotensin

Converting Enzyme Inhibitor/Angiotensin Receptor Blocker and Contrast Induced Nephropathy in

Patients Receiving Cardiac Catheterization (CAPTAIN) trial. Am Heart J. 2015 Jul;170(1):110-6.

Coca SG, Garg AX, Swaminathan M, Garwood S, Hong K, Thiessen-Philbrook H, Passik C, Koyner JL, Parikh

CR; TRIBE-AKI Consortium.

Preoperative angiotensin-converting enzyme inhibitors and angiotensin receptor blocker use and

acute kidney injury in patients undergoing cardiac surgery. Nephrol Dial Transplant. 2013

Nov;28(11):2787-99. doi: 10.1093/ndt/gft405. Epub 2013 Sep 29.

• Preoperative ACEI/ARB usage was associated with functional but not structural acute kidney injury.

• As AKI from ACEI/ARB in this setting is unclear. ?

• Many different definitions of IOH were found and resulted in different

IOH incidences.

• Any episode of SBP < 80 mmHg was found in 41% of the patients,

whereas 93% of the patients had at least one episode of SBP > 20%

below baseline. Both definitions are frequently used in the literature.

There is no widely accepted definition of

IOH.

Salmasi V, Maheshwari K, Yang D, Mascha EJ, Singh A, Sessler DI, Kurz A.

Relationship between Intraoperative Hypotension, Defined by Either Reduction from Baseline or

Absolute Thresholds, and Acute Kidney and Myocardial Injury after Noncardiac Surgery: A

Retrospective Cohort Analysis. Anesthesiology. 2017 Jan;126(1):47-65.

Anesthetic management can thus be based on IO pressures without regard to preoperative pressure.

• MAP below absolute thresholds of 65 mmHg or relative thresholds

of 20% were progressively related to both myocardial and kidney

injury. They both had comparable ability to detect these outcomes.

• At any given threshold, prolonged exposure was associated with

increased odds.

• Preoperative BP did not have important interactions with the

outcomes studied at MAP < 65 mmHg

Walsh M, Devereaux PJ, Garg AX, Kurz A, Turan A, Rodseth RN, Cywinski J, Thabane L, Sessler DI.

Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an

empirical definition of hypotension. Anesthesiology. 2013 Sep;119(3):507-15. doi: 10.1097/ALN.0b013e3182a10e26.

• The MAP threshold where the risk for AKI or Myocardial injury

increased was < 55 mmHg.

• Compared with never developing a MAP < 55 mmHg, those with a

MAP < 55 mmHg for 1-5, 6-10, 11-20, and >20 min had graded

increases in their risk of the two outcomes. (AKI: 1.18 [95% CI, 1.06-1.31],

1.19 [1.03-1.39], 1.32 [1.11-1.56], and 1.51 [1.24-1.84], respectively; myocardial injury 1.30

[1.06-1.5], 1.47 [1.13-1.93], 1.79 [1.33-2.39], and 1.82 [1.31-2.55], respectively].

Even short durations of an IO MAP < 55 mmHg are associated with

AKI and myocardial injury.

Randomized trials are required to determine whether outcomes improve with

interventions that maintain an IO MAP of at least 55 mmHg.

Sessler DI, Meyhoff CS, Zimmerman NM, Mao G, Leslie K, Vásquez SM, Balaji P, Alvarez-Garcia J,

Cavalcanti AB, Parlow JL, Rahate PV, Seeberger MD, Gossetti B, Walker SA, Premchand RK, Dahl RM,

Duceppe E, Rodseth R, Botto F, Devereaux PJ.

Period-dependent Associations between Hypotension during and for Four Days after Noncardiac

Surgery and a Composite of Myocardial Infarction and Death: A Substudy of the POISE-2 Trial.

Anesthesiology. 2018 Feb;128(2):317-327.

• Clinically important hypotension was defined as SBP < 90 mmHg

requiring treatment.

• IO, the estimated average relative effect across MI and mortality per 10-

min increase in hypotension duration was 1.08 (98.3% CI, 1.03, 1.12; P < 0.001).

• For the remaining day of surgery, the OR per 10-min increase in

hypotension duration was 1.03 (98.3% CI, 1.01, 1.05; P < 0.001).

• The average relative effect OR in patients with hypotension during the

subsequent 4 days of hospitalization was 2.83 (98.3% CI, 1.26, 6.35; P = 0.002).

Clinically important hypotension was significantly associated with a

composite of MI and death during each of the perioperative periods

van Waes JA, van Klei WA, Wijeysundera DN, van Wolfswinkel L, Lindsay TF, Beattie WS.

Association between Intraoperative Hypotension and Myocardial Injury after Vascular

Surgery. Anesthesiology. 2016 Jan;124(1):35-44.

• Depending on the definition, IOH occurred in 12-81% of the patients.

• 40% decrease from the pre-induction MAP with a cumulative duration

> 30 min was associated with PO myocardial injury. (relative risk, 1.8; 99% CI, 1.2 to 2.6, P < 0.001).

• PO MI and death within 30 days occurred in 26 (6%) and 17 (4%)

patients with IOH as defined by a < 60 mmHg, compared with 12 (3%;

P = 0.08) and 15 (3%; P = 0.77) patients without IOH, respectively.

Gu WJ, Hou BL, Kwong JSW, Tian X, Qian Y, Cui Y, Hao J, Li JC, Ma ZL, Gu XP.

Association between intraoperative hypotension and 30-day mortality, major adverse cardiac events,

and acute kidney injury after non-cardiac surgery: A meta-analysis of cohort studies. Int J Cardiol.

2018 Feb 2. pii: S0167-5273(17)35125-2.

• Meta-analysis of 14 cohort studies that were heterogeneous in terms

of definition of IOH.

• IOH alone was associated with increased risk of 30-day mortality,

MACEs, especially myocardial injury, and AKI. (OR 1.29 [95% CI, 1.19-

1.41]), (OR 1.59 [95% CI, 1.23-2.05]), (OR 1.67 [95% CI, 1.31-2.13]), (OR 1.39 [95%

CI, 1.09-1.77]); respectively.

• Triple low (IOH coincident with low bispectral index and low MAC) also

predicts increased risk of 30-day mortality (OR 1.32 [95% CI, 1.03-1.68]).

ACEIs/ARBs can be

continued perioperatively

if hemodynamically stable,

good renal function and

normal electrolytes.

Steely AM1, Callas PW1, Bertges DJ2; Vascular Study Group of New England.

Renin-angiotensin-aldosterone-system inhibition is safe in the preoperative period

surrounding carotid endarterectomy. J Vasc Surg. 2016 Mar;63(3):715-21.

• Preoperative ACEI/ARB use was associated with marginally

increased use of IV BP med for HTN but not for hypotension,

and was not associated with increased MACE, stroke, or death.

• The use of preoperative ACEI/ARB appears safe before CEA.

Vijay A, Grover A, Coulson TG, Myles PS

Perioperative management of patients treated with angiotensin-converting enzyme inhibitors and

angiotensin II receptor blockers: a quality improvement audit. Anaesth Intensive Care. 2016

May;44(3):346-52.

Problems:

• Possibility of confounding

• Possibility of Insufficient

sample size.

Future prospective randomized

clinical trials are required

No significant differences in measured outcomes between the

continued or withheld ACEI/ARB groups were found.

There was no statistically significant difference between the continued or

withheld groups in:

• Vasopressor or IV fluid administration ((metaraminol use 3.5 [1.5-8.3] mg Vs. 3.5

[1.5-8.5] mg, P=0.67) (1000 ml [800-1500] ml Vs. 1000 [800-1500] ml, P=0.096) respectively).

• Rates of PO AKI or AFib ((13% vs 18%, P=0.25)(15% versus 18%, P=0.71) respectively).

Seshadri C. Mudumbai, MD, MS , Steven Takemoto, PhD, Brian A. Cason, MD, Selwyn Au, MS, Anjali Upadhyay, MS, Arthur W. Wallace, MD, PhD Thirty‐day mortality risk associated with the postoperative non-resumption of angiotensin‐converting enzyme inhibitors: A retrospective study of the veterans affairs healthcare system. J. Hosp. Med. 2014 May;9(5):289-296.

Restarting of an ACE‐I within PO day 0 to 14 is associated with

a decreased 30‐day mortality.

• Patients were classified into groups based upon the timing of PO

resumption of an ACEIs (PO days 0 to 14 and 15 to 30).

• Nonresumption of an ACEI in PO days 0 to 14 was independently

associated with increased 30‐day mortality compared to the restart

group. (hazard ratio: 3.44; 95% CI: 3.30‐3.60; P < 0.001) Sensitivity analyses

maintained this relationship.

• ACEIs and ARBs are safe to use preoperatively.

• Withholding them for the IO period and restarting them as soon as clinically possible, might be the best course of action to prevent intra and postoperative hypotension and based on current evidences, HYPOTHETICALLY reduce adverse outcomes.

• Large scale randomized trials are still needed to find the right answer.

Conclusions

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