Download Pro_ ACE Inhibitors Should Be Continued Perioperatively and Prior

PRO AND CON
Michelle Capdeville, MD
Section Editors
Pro: ACE Inhibitors Should Be Continued Perioperatively
and Prior to Cardiovascular Operations
Meena Bhatia, MD,* Harendra Arora, MD,*† and Priya A. Kumar, MD*†
D
ECISIONS INVOLVING the initiation or discontinuation
of any medical intervention should be undertaken only
after careful consideration of all available evidence. The risks
and benefits must be evaluated for each individual patient and
circumstance, especially in situations where the evidence is not
as clear as in the question about continuation of perioperative
angiotensin-converting enzyme (ACE) inhibitors. Major medical societies such as the American College of Cardiology and
American Heart Association (ACC/AHA) and European societies recommend continuation of ACE inhibitors in the perioperative period.1,2 Based on currently available evidence, the
authors agree with their recommendation and argue in support
of the continuation of ACE inhibitors prior to cardiovascular operations.
ACE inhibitors were first introduced to the general public in
the early 1980s. Initially, dosing of the pilot drug captopril
proved to be problematic and multiple studies showed profound
hypotension when the drug was initiated.3 As dosing adjustments were made and newer agents like enalapril were
introduced, the real benefit of ACE inhibitors came to light.
The CONSENSUS trial published in 1987 was a doubleblinded study in which 253 patients with severe congestive
heart failure (New York Heart Association [NYHA] functional
Class IV) were randomly assigned to conventional treatment
plus placebo or conventional treatment plus enalapril.4 Mortality after six months was 26% in the enalapril group and 44% in
the placebo group, representing a 40% reduction in mortality.
At 1 year, mortality was reduced 31% in the enalapril group as
compared to the placebo group, and these patients were shown
to have a reduction in left ventricular size and an improvement
in their NYHA classification. Although the CONSENSUS trial
demonstrates the value of ACE inhibitors in patients with
severe heart failure, further studies also have proven their
From the *Department of Anesthesiology, University of North Carolina School of Medicine, Chapel Hill, NC; and †Outcomes Research
Consortium, Cleveland, OH.
Address reprint request to Priya A. Kumar, MD, Department of
Anesthesiology, N2198 University of North Carolina Hospitals, Campus Box 7010, Chapel Hill, NC 27599-7010. E-mail: pkumar@aims.
unc.edu
© 2016 Elsevier Inc. All rights reserved.
1053-0770/2602-0034$36.00/0
http://dx.doi.org/10.1053/j.jvca.2016.04.003
Key words: ACE inhibitors, cardiovascular surgery
816
benefit in patients with less severe disease. In 1992, the SAVE
trial randomized 2,231 patients from multiple centers who had
suffered a myocardial infarction with ejection fractions of 40%
or less and without heart failure symptoms to receive treatment
with either placebo or captopril within 3 to 16 days after their
myocardial infarction.5 All-cause mortality was reduced by
19% in the captopril group. Furthermore, they found a 37% risk
reduction from severe heart failure, a 22% risk reduction in
heart failure requiring hospitalization, and a 25% risk reduction
in recurrent myocardial infarction. Since then, it has been well
established that ACE inhibitors reduce sudden cardiac death in
patients with heart failure and prevent remodeling and dilation
of the left ventricle that can occur after a myocardial infarction.6-9
The beneficial aspects of ACE inhibitors are not limited to
their role in cardiac protection but have also proven to be
advantageous in the diabetic population. Long-term diabetics
are at high risk for developing proteinuria, a decrease in
glomerular filtration rate, and eventual nephropathy.10 There
is evidence that hypertension can accelerate this process and
that the treatment of hypertension can prevent associated
nephropathy.11 ACE inhibitors, while excellent agents for
hypertension, also may protect against the development of
nephropathy in diabetics through their inherent properties.12
Lewis et al looked at patients with insulin-dependent diabetes
with concomitant urinary protein excretion Z500 mg per day
and serum creatinine r2.5 mg per deciliter and randomized
them to either receive captopril treatment or placebo.13 They
found that there was a 48% risk reduction of doubling serum
creatinine in the captopril group, a 76% risk reduction in the
subgroup with a starting serum creatinine 42.0 mg/dL and a
55% risk reduction in the group with a starting creatinine 41.5
mg/dL. Furthermore, the captopril group had a 50% reduction
in the risk of death, need for dialysis, and renal transplantation.
Of note, this study’s results were found to be independent of
blood pressure control. The described renal-protective nature of
ACE inhibitors does not seem to be exclusive to diabetics. The
GISEN group looked at nondiabetic patients with proteinuria
and compared treatment with ramipril versus placebo with both
groups receiving conventional antihypertensive therapy to
achieve diastolic blood pressure o90 mmHg.14 The ramipril
group had a slower rate of decline in glomerular filtration rate
as well as a reduction in the risk of doubling serum creatinine
and eventual end-stage renal failure. Further studies have
substantiated the results of Lewis et al, and many have found
Journal of Cardiothoracic and Vascular Anesthesia, Vol 30, No 3 (June), 2016: pp 816–819
PRO: ACE INHIBITORS
that the renal protective mechanisms against nephropathy
extend to nondiabetics without substantial proteinuria as
well.15,16
While the evidence to support the use of ACE inhibitors in
nonoperative patients is well supported, the decision to
continue them during the perioperative period for cardiovascular surgery remains unclear. The most common argument
against the continuation of ACE inhibitors during cardiac
surgery is the concern for intraoperative hypotension and
vasopressor requirement.17,18 Pigott et al examined the effects
of withholding ACE inhibitors during coronary artery bypass
graft (CABG) surgery.19 They enrolled 40 patients with
preserved left ventricular function who were undergoing
CABG surgery. These patients were randomly assigned to
either withhold or continue their chronic ACE inhibitor the day
before surgery. They found that the group that had omitted
ACE inhibitors had significantly greater arterial pressures
during surgery and required less vasoconstrictor use during
cardiopulmonary bypass (CPB). However, this group also
required significantly more vasodilators secondary to hypertension after separation from CPB and in the postoperative
period. There was no significant difference between the 2
groups in either inotrope or vasopressor use after separation
from CPB and extending up to 2 hours in the early postoperative period. While hypotension after induction may be
more frequent in the ACE inhibitor group, it does not seem to
have any impact once separation from CPB is achieved. On the
other hand, the benefits of ACE inhibitors as antihypertensives
seem to continue well after CPB has been discontinued. This is
further supported in the study by Licker et al where 41 patients
undergoing elective CABG surgery or mitral valve replacement were enrolled.20 All of the enrolled patients had
preserved left ventricular function. These patients were separated into 2 categories: those on chronic ACE inhibitors and
those not on ACE inhibitors. The investigators tested hormonal
responses to norepinephrine and saline challenges in these
subjects. They found that while response to norepinephrine
challenge was attenuated in the ACE inhibitor group, there was
no significant compromise in systemic hemodynamics, fluid
requirements, inotropic, or vasopressor support between the 2
groups. Evidence that chronic ACE inhibitors do not cause
significant hemodynamic compromise is further solidified in
the study by Webb et al, in which 96 patients on the waiting
list for CABG surgery were randomized to receive 6 weeks of
either quinapril therapy or placebo.21 The results found no
significant difference in blood pressure or systemic vascular
resistance during CPB between the 2 groups. Withholding
ACE inhibitors does not appear to offer any advantage and
could potentially diminish the previously described benefits.
Collectively, these studies demonstrate that concern for
intraoperative hypotension from ACE inhibitors may be
grossly overestimated. This is especially true in the cardiac
operating room where close hemodynamic monitoring is
readily available. Any transient hypotensive episode that may
occur during anesthetic induction can promptly be reversed in
the expert hands of the cardiac anesthesiologist.
The debate against continuing perioperative ACE inhibitors
for cardiac surgery is further perpetuated by the belief that ACE
inhibitors cause acute kidney injury after cardiac surgery. Many
817
often cite Miceli et al’s retrospective review, in which they
found that patients taking ACE inhibitors were at a higher risk
of developing postoperative renal dysfunction compared to
others.18 However, patients in the chronic ACE inhibitor group
in this study were more likely to have hypertension, diabetes,
and obesity, all of which are well-established risk factors for
acute kidney injury. After Licker et al’s initial demonstration of
no hemodynamic compromise in the ACE inhibitor group,20
these authors analyzed renal hemodynamics. In their follow-up
study,22 they examined the differences between the group on
ACE inhibitors and placebo undergoing CABG surgery and
whether or not ACE inhibitors affected renal hemodynamics.
Glomerular filtration rate, renal plasma flow, osmolar clearance, and fractional excretion of sodium were measured and
found to be similar in both the ACE inhibitor group and the
control group in all phases of cardiac surgery; prebypass, onbypass, and postbypass. Benedetto et al looked at a cohort of
536 patients in which 281 received preoperative ACE inhibitors.23 Based on propensity score-based analysis, acute kidney
injury (defined as postoperative need for dialysis or 450%
decline in glomerular filtration rate) was found in 6.4% of
patients who received preoperative ACE inhibitors and 12.2%
in patients who did not (p ¼ 0.02). Furthermore, a significantly
lower number of patients in the preoperative ACE inhibitor
group (2.4%) presented with acute kidney injury and need for
dialysis compared to the controls (6.3%). After propensity
score adjustments, ACE inhibitors were found to have a
protective effect on the incidence of acute kidney injury after
CABG surgery (OR ¼ 0.48, p ¼ 0.042). It should also be noted
that this was a large enough cohort of patients as determined by
post hoc analysis that had enough power to detect a significant
difference in acute kidney injury. In yet another study showing
favorable results on renal function, Colson et al looked at 18
patients undergoing routine CABG surgery.24 Patients were
randomized into 2 groups: the treatment group that received
captopril starting 2 days prior to surgery while the control
group received placebo. Effective renal plasma flow and
glomerular filtration rate were decreased in the placebo group
but remained constant in the captopril group. Furthermore the
captopril group had an increased urinary sodium excretion
while on CPB as compared to the placebo group. It appears that
there is no difference in acute kidney injury after continuation
of ACE inhibitors during cardiac surgery, but this data also
suggests that ACE inhibitors may actually be protective in this
patient population.
It is clear from the aforementioned examples that the
literature highlights many contradictions inherent in the argument against perioperative continuation of ACE inhibitors.
There are numerous studies that support the continuation of
ACE inhibitors during cardiac surgery and deserve further
consideration. One example is the effectiveness of ACE
inhibitors as medications used to treat hypertension in cardiac
surgical patients. The mechanism of post-CPB hypertension is
not well understood and likely the byproduct of a number of
factors. Niarchos et al looked at 13 patients with hypertension
after CABG surgery and measured plasma renin levels and
hemodynamics during the peak hypertensive period as well as
15 to 30 minutes after an ACE inhibitor was administered.25
They found that 8 of the 13 patients had increased plasma renin
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BHATIA ET AL
levels and responded to ACE inhibition. The response was
quantified by an increase in cardiac output and stroke volume,
suggesting that the renin-angiotensin system does play an active
role in post-CABG hypertension. It is well established that ACE
inhibitors reduce the sympathetically mediated vasoconstriction
that occurs in peripheral vessels.26 Perondi et al proposed that
vasodilation induced by ACE inhibition also affects the coronary
vasculature.27 These authors looked at 9 patients with coronary
atherosclerosis confirmed by angiography and measured mean
arterial blood pressure, heart rate, coronary sinus blood flow, and
coronary vascular resistance. Coronary vasoconstriction then
was induced through electrical sympathetic stimulation, and
baseline values were compared to values 30 minutes after
captopril administration. The results showed that captopril did
not significantly alter blood pressure or heart rate but did
attenuate the coronary vasoconstriction response after stimulation. The benefit of coronary vasodilation may provide further
evidence in support of continuing of ACE inhibitors in the
perioperative period. Larger randomized controlled trials are
necessary to elicit whether this coronary vasodilation is significant in the setting of cardiac surgery, but the results are
nonetheless intriguing.
The literature examining the use of ACE inhibitors and the
effect on morbidity and mortality after cardiac surgery is
limited but appears to favor the perioperative use of these
medications. In the observational study by Benedetto et al, of
the 481 patients who underwent CABG surgery, 245 received
preoperative ACE inhibitors and 236 patients did not.28
Preoperative ACE inhibitors were associated with statistically
significant lower troponin values postoperatively. There was
also a trend toward lower mortality rates as well as lower rates
of postoperative myocardial infarction in patients on preoperative ACE inhibitors. More recently, Sharafi et al looked
retrospectively at 10,055 patients undergoing CABG surgery,
of which 4,664 received preoperative ACE inhibitors (or
angiotensin receptor blockers).29 Mortality (in-hospital and
30-day) was lower in the ACE inhibitor group (33 deaths) as
compared to the group that did not have preoperative ACE
inhibitors (54 deaths) (OR ¼ 0.628, p ¼ 0.09). Although not
statistically significant, the results are suggestive that ACE
inhibitors may be protective against in-hospital mortality after
CABG surgery. While there are no large randomized trials to
assess the morbidity and mortality associated with ACE
inhibitor use in patients undergoing cardiac surgery, smaller
observational and retrospective studies are encouraging for the
continuation of these drugs.
The controversy surrounding ACE inhibitors is not without
strong opinions on either side. Major medical societies such as
the American College of Cardiology and American Heart
Association (ACC/AHA) state that continuing ACE inhibitors
preoperatively is reasonable (class IIA). This society further
recommends that if ACE inhibitors have been held in the
perioperative period, they should be restarted as soon as
clinically feasible.1 The European Society of Cardiology and
European Society of Anaesthesiology also recommend continuation of ACE inhibitors in patients with stable heart failure
and left ventricular systolic dysfunction.2 This society states
that initiation of ACE inhibitors should be considered for at
least a week prior to surgery in this population. Despite limited
evidence, it is important to note that both recommendations
emphasize that it is “reasonable” to continue ACE inhibitors in
the perioperative period during non-cardiac surgery.1,2 The
most robust argument against the continuation of such drugs is
rooted in the concern for post-induction refractory hypotension.30 However, time and time again, it has been shown that
intraoperative hypotension is not significantly worsened
amongst those on chronic ACE inhibitors.31 It has been shown
that there is no difference in the amount of vasopressor or
inotrope requirement during cardiac surgery.19–21 In fact, as
stated in several studies above, the benefits of ACE inhibitors,
such as control of post-CPB hypertension, coronary artery
vasodilation, renal protection, decreased ventricular dilation,
and increasing cardiac output are well establshed.4,5,14–16,27
Undoubtedly to settle this debate once and for all, large, welldesigned, multi-centered, randomized, controlled trials are
needed. However, based on the literature that currently exists
and the recommendations by the panel of experts in major
medical societies, not only can ACE inhibitors be safely
continued during cardiovascular surgery, but it is also reasonable to say that they should.
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