Statin Therapy within the Perioperative Period

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DOI: 10.1097/ALN.0b013e318173ef8e · Source: PubMed
CLINICAL CONCEPTS AND COMMENTARY
Bruno Riou, M.D., Ph.D., Editor
Anesthesiology 2008; 108:1141–6 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
Statin Therapy within the Perioperative Period
Yannick Le Manach, M.D.,* Pierre Coriat, M.D., Charles D. Collard, M.D., Bernhard Riedel, M.D., Ph.D.§
STATINS are highly effective in lowering serum cholesterol
concentrations through 3-hydroxy-3-methyl glutaryl coen-
zyme A (HMG-CoA) reductase inhibition and thus are cen-
tral to the primary and secondary prevention of cardiovas-
cular disease. More than 50% of patients undergoing major
vascular surgery and 80% undergoing cardiac surgery are
on chronic statin therapy.
1,2
Statins also exert numerous
lipid-independent or “pleiotropic” effects (effects that were
not expected during drug development) as a result of their
ability to inhibit the inflammatory response, reduce throm-
bosis, enhance fibrinolysis, decrease platelet reactivity, in-
hibit cell growth, reduce ischemia–reperfusion injury, and
restore endothelial function. These beneficial effects result
predominantly from the modulation of the complex inter-
play between the pathologic triad of inflammation, dy-
namic obstruction, and thrombosis.
3
This triad is integral to
the surgical stress response and central to postoperative
outcomes. However, recent reports noted that patients
who undergo postoperative statin withdrawal experience
increased cardiac morbidity when compared with patients
who undergo early postoperative readministration of st-
atins or with patients not treated with statins.
1,4
These facts raise several important questions for the an-
esthesiologist regarding statin therapy during the perioper-
ative period: (1) Do statins modify perioperative risk? (2) Is
continuation or discontinuation of statin therapy during the
perioperative period associated with additional risk? (3) Do
the potential benefits of statin therapy outweigh the poten-
tial risks? This review of the literature explores the risks and
benefits associated with perioperative statin therapy.
Effects of Statins
Lipid-dependent Effects
Low-density lipoprotein (LDL) cholesterol is oxidized by
free radicals and linked to atherothrombosis and its associ-
ated deleterious effects. Reduction of LDL cholesterol con-
centration is one of the primary objectives of chronic
cardiovascular disease prevention. Numerous nonstatin
therapies, such as bile acid sequestrants or fibrates, have
been developed, but few effects have been observed on
mortality. Statins inhibit HMG-CoA, which is central to
cholesterol metabolism, thereby reducing LDL choles-
terol concentrations. As a result, there is a reduction
in mortality when used for primary and secondary
prevention of cardiovascular disease.
5
Nevertheless,
this capacity to reduce LDL cholesterol may not be
comparable between the various statin compounds.
Indeed, a meta-analysis showed a 50% reduction in
LDL cholesterol with 20 mg/day rosuvastatin and a
55% reduction with 80 mg/day atorvastatin, whereas
pravastatin and fluvastatin produced smaller reduc-
tions in LDL cholesterol.
6
Lipid-independent Effects
Randomized trials have consistently shown that statins
induce a greater reduction in the risk of cardiovascular
events than that expected with the magnitude of reduc-
tion in LDL cholesterol alone. The reduction in risk also
occurs earlier than the lowering of LDL cholesterol lev-
els. These beneficial effects of statins are attributed to
the pleiotropic effects—predominantly antiinflamma-
tory, vasodilatory, and antithrombotic effects.
Inhibition of HMG-CoA reductase by statins inhibits the
generation of isoprenoids (geranyl-geranyl pyrophosphate
and farnesyl pyrophosphate) that bind to endogenous Rho
and Ras guanosine triphosphatases, thereby preventing
translocation of these signaling proteins to their active sites.
Rho activates nuclear factor
B, which promotes a number
of inflammatory responses and reduces endothelial nitric
oxide synthetase. Statins, through the inhibition of Rho,
exhibit direct antiinflammatory effects (including a reduc-
tion in acute-phase proteins [C-reactive protein and myelo-
peroxidase], a reduction in inflammatory cytokines [inter-
This article is featured in “This Month in Anesthesiology.”
Please see this issue of ANESTHESIOLOGY, page 5A.
* Associate Professor, Professor and Chairman, Department of Anesthesiol-
ogy and Critical Care, Universite´ Pierre et Marie Curie-Paris 6 and Centre
Hospitalier Universitaire Pitie´-Salpeˆtrie`re, Assistance Publique-Hoˆpitaux de
Paris. Professor, Baylor College of Medicine Division of Cardiovascular
Anesthesiology at the Texas Heart
®
Institute, St. Luke’s Episcopal Hospital,
Houston, Texas. § Professor, Department of Anesthesiology, Vanderbilt Uni-
versity, Nashville, Tennessee.
Received from the Department of Anesthesiology and Critical Care, Groupe
Hospitalier Universitaire Pitie´-Salpeˆtrie`re, Assistance Publique-Hoˆpitaux de Paris,
Paris, France. Submitted for publication May 8, 2007. Accepted for publication
February 15, 2008. Support was provided solely from institutional and/or depart-
mental sources.
James C. Eisenach, M.D., served as Handling Editor for this article. The
illustrations in this article were prepared by Dimitri Karetnikov, 7 Tennyson
Drive, Plainsboro, New Jersey 08536.
Address correspondence to Dr. Le Manach: De´partement d’Anesthe´sie Re´an-
imation, Centre Hospitalier Universitaire Pitie´-Salpeˆtrie`re, 47 Boulevard de
l’Hoˆpital, 75651 Paris cedex 13, France. yannick.le-manach@psl.aphp.fr. This
article may be accessed for personal use at no charge through the Journal Web
site, www.anesthesiology.org.
Anesthesiology, V 108, No 6, Jun 2008 1141
leukins 1, 6, and 8] that activate inflammatory cells and
platelets, and an increase in antiinflammatory cytokines
[e.g., interleukin 10]) and result in the up-regulation of
endothelial nitric oxide synthetase (figs. 1 and 2). The latter
results in improved vasodilatory (reflected in improved
flow-mediated dilatation) properties of the vasculature, me-
diated through a rapid increase in nitric oxide bioavailabil-
ity (observed as early as 3 h after oral administration of
atorvastatin
7
).
Additional vasodilatory effects are mediated through
reduced expression of endothelin and of endothelial
adhesion molecules (e.g., intercellular adhesion mole-
cule 1, E-selectin; fig. 1) and through other vasoprotec-
tive properties, including up-regulation of heme-oxyge-
nase 1 in circulating monocytes/macrophages, inhibition
of angiotensin II–induced reactive oxygen species pro-
duction through down-regulation of angiotensin-1 recep-
tors, and inhibition of activation of Rac, a small G protein
that contributes to nicotinamide adenine dinucleotide
phosphate [NAD(P)H]– oxidase activation.
Statins also exhibit antithrombotic effects, which are me-
diated through both endothelium-dependent and endothe-
lium-independent mechanisms. Statins increase endothelial
thrombomodulin expression and reduce tissue factor ex-
pression on endothelial cells, thus favoring a nonthrom-
botic state of the endothelium (fig. 1). Statins also reduce
the circulating levels of von Willebrand factors and tend to
alter the balance between plasminogen activator inhibitor
Fig. 1. Effects of statin therapy on endothelial abnormalities associated with the postoperative period. Statin therapy reduces the expression of
endothelial adhesion molecules and tissue factor (TF), whereas thrombomodulin (TM) expression is increased. Furthermore, tissue plasmin-
ogen activator (t-PA)/plasminogen activator inhibitor 1 (PAI-1) ratio is normalized, while nitric oxide (NO) bioavailability is restored. All these
effects lead to restoration of the physiologic properties of the endothelium. ET-1 endothelin 1.
1142 LE MANACH ET AL.
Anesthesiology, V 108, No 6, Jun 2008
and tissue plasminogen activator in favor of thrombolysis
(fig. 1). Moreover, statins exhibit systemic effects on coag-
ulation factors V, VII, and XII via poorly understood mech-
anisms
3,8
and have indirect effects on coagulation and
thrombosis through their antiinflammatory actions.
Statins may also play an important role in the repair of
damaged endothelium by accelerating reendothelializa-
tion, mobilization of endothelial progenitor cells, and
increasing cell proliferation. Lastly, statins may exert some
effects that are not mediated through HMG-CoA reductase
inhibition, such as preventing lymphocytes from binding to
endothelial intercellular adhesion molecule 1.
These beneficial pleiotropic effects of statins, including
inhibition of the inflammatory response, reduced thrombo-
sis, enhanced fibrinolysis, decreased platelet reactivity, and
restoration of microcirculation vasoreactivity, culminate in
a protective effect readily evident in the setting of ischemia–
reperfusion injury. In this regard, a number of preclinical
models demonstrate that statins reduce the magnitude of
tissue destruction (infarct volume), tissue dysfunction, and
organ failure in models of myocardial, cerebral, intestinal,
and renal ischemia–reperfusion injury. Interestingly, statins
also protect organs distant to the locus of ischemia–reper-
fusion injury, with statins reducing the severity of acute
lung injury after an intestinal ischemia–reperfusion injury
and reducing coronary dysfunction in a swine model of respi-
ratory infection. Increasing evidence that statins reduce the
incidence and magnitude of myocardial infarction after coro-
nary interventions, decrease the incidence of renal dysfunc-
tion, and improve long-term vasculopathy after transplanta-
tion provides the clinical correlate. These effects may also
increase the stability of the vulnerable atheromatous plaques
and associate with a reduction in risk for periprocedural myo-
cardial infarction, e.g., after coronary intervention.
Adverse Effects
Statin-mediated adverse effects are rare and do not out-
weigh the beneficial effects of statins in the vast majority of
Fig. 2. Withdrawal from chronic statin therapy highly modulates nitric oxide (NO) bioavailability. At baseline, Rho (small guanosine
triphosphatase family) is active (associated to geranylgeranylpyrophosphate [GGPP]). After initiation of statin treatment, formation of
GGPP is interrupted, and Rho is inactive in its cytosolic form, which results in endothelial nitric oxide synthetase (eNOS) up-regulation.
After discontinuation of statin chronic therapy, GGPP becomes available, and Rho is transferred to the membrane, causing
down-regulation of eNOS production below baseline levels.
1143STATIN THERAPY WITHIN THE PERIOPERATIVE PERIOD
Anesthesiology, V 108, No 6, Jun 2008
patients. In fact, the US Food and Drug Administration
reported only 42 deaths attributable to statins (i.e., 1/mil-
lion person years) and only 30 cases of liver failure attrib-
utable to statins (i.e., 1/million person years).
The most serious adverse effect of statins is rhabdomyol-
ysis. This adverse effect is associated with the type of statin
used (primarily cerivastatin) and with factors that increased
serum concentrations of statins (including small body size;
advanced age; renal or hepatic dysfunction; diabetes; hy-
pothyroidism; and use of drugs that interfere with statin
metabolism, such as cyclosporin, antifungal agents, calcium-
channel blockers, and amiodarone). Cerivastatin, which is no
longer available on the market, was the primary drug associ-
ated with this complication (3.16 events/million prescrip-
tions). In contrast, the risk of statin-induced rhabdomyoly-
sis for other commonly used statins ranges only from 0 to
0.19 events/million prescriptions.
9
A recent meta-analysis
10
noted that in the perioperative period, an increase (10
times the upper limit of normal) in creatine kinase activity
occurred only slightly more frequently in patients treated
with statins than in patients who received a placebo (0.17%
vs. 0.13%, respectively).
Do Statins Modify Perioperative Risk?
Poldermans et al.
11
observed that the perioperative
mortality rate among the vascular surgery patient popu-
lation treated with statins was reduced 4.5-fold when
compared with those patients without statin therapy.
Similarly, in a retrospective cohort study of 780,591
patients who underwent noncardiac surgery, Lindenauer
et al.
12
observed that statin therapy was associated with
a reduced risk of postoperative death. In a recent meta-
analysis by Hindler et al.,
13
which reported on 22,300
patients from 12 retrospective and 3 prospective trials,
the authors observed that preoperative statin therapy
compared with no therapy reduced mortality rates by
39%, 59%, and 44% after cardiac surgery (1.9% vs. 3.1%),
vascular surgery (1.7% vs. 6.1%), and surgery of any type
(2.2% vs. 3.2%), respectively. The same meta-analysis
suggested that statins and
-blockers might produce in-
dependent and additive effects on cardiovascular risk.
13
Statin therapy also reduces postoperative morbidity. In
this regard, in a retrospective study of 1,163 patients
undergoing vascular surgery, O’Neil-Callahan et al.
14
re-
ported a protective effect of statins against cardiac mor-
bidity. This finding confirmed that of a prospective ran-
domized study by Durazzo et al.,
15
who reported that
short-term treatment with atorvastatin significantly re-
duced the incidence of major adverse cardiovascular
events after vascular surgery. Statins are also associated
with improved 10-yr freedom from cardiac allograft vas-
culopathy and improved survival after transplantation.
Therefore, patients receiving preoperative statin ther-
apy exhibit 30 –59% lower rates of mortality and of acute
coronary syndromes than do patients who do not take
statins at the time of surgery. However, these findings
are based on observational cohort studies, mostly retro-
spective in design. In most of these studies, dose and
duration of statin use was not reported, and safety data
were not adequately reported. Lindenauer et al.
12
con-
sidered patients who did not receive statins at postop-
erative day 1 as untreated, and thus the deleterious effect
of statin withdrawal might have contributed to the
global detrimental effect observed in patients without
statin therapy. The few randomized studies available,
even pooled together, should be considered as under-
powered in obtaining a definite conclusion.
16
However,
Kapoor et al.
10
concluded in their meta-analysis that it is
reasonable to advocate that statins be started preopera-
tively in patients eligible for statin therapy (for medical
reasons) independent of the proposed operation; how-
ever, they also considered that it is premature to advo-
cate its use for patients who do not have established
coronary artery disease, at least until evidence is avail-
able from an adequately powered randomized study.
Hindler et al.
13
were more cautious, indicating the lim-
itations of such a meta-analysis (i.e., possible publication
bias, poor information on postoperative continuation of
statins, lack of information on the minimum required
duration of preoperative statin therapy, and marked dif-
ferences in pharmacokinetic properties of the available
statins). Therefore, currently there is a strong need for
randomized, controlled studies of perioperative statin
therapy, some of which are now under way. These
studies should shed light on a number of aspects of
perioperative statin therapy: (1) confirm or refute the
benefit of the introduction of a statin before surgery, (2)
stratify the patients that may benefit from preoperative
statin treatment, and (3) determine the optimal dose and
duration of perioperative statin therapy.
Continuation versus Discontinuation of
Statins in the Perioperative Period
The withdrawal of some cardiovascular drugs, such as
-blockers and nitrates, can exert pronounced rebound
symptoms. In vitro, it has been shown that abrupt with-
drawal of statins results in an overshoot translocation
and activation of Rho, causing down-regulation of endo-
thelial nitric oxide synthetase production below baseline
levels (fig. 2). Although improved endothelial function
was noted rapidly after statin dosing, within 1 day of
statin cessation, endothelial-dependent blood flow de-
creased to below baseline values.
17,18
Nitric oxide de-
pendence of this withdrawal effect was demonstrated in
a mouse model where statin withdrawal suppressed en-
dothelial nitric oxide synthetase production within 2
days.
19
A more rapid effect was observed in cultured rat
aortic vascular smooth muscle, where washout of statins
1144 LE MANACH ET AL.
Anesthesiology, V 108, No 6, Jun 2008
produced a rebound increase, above control levels, of
angiotensin II–mediated phosphorylation of extracellu-
lar signal–related kinase 1/2 and p38 mitogen-activated
protein kinase. In knockout mice, it has been shown that
NAD(P)H-oxidase plays a central role in mediating the
statin withdrawal mechanism.
20
In patients, studies have demonstrated that acute statin
withdrawal increase markers of inflammation and oxida-
tive stress, and that statin withdrawal during unstable
periods is associated with an increased risk of adverse
cardiac events.
21
For example, patients with acute cor-
onary syndrome, in whom statins were discontinued,
had an almost threefold higher cardiac event rate than
patients continuing statin therapy.
22
This observation
was more recently confirmed in a large retrospective
study demonstrating a twofold increased mortality rate
among patients with acute coronary syndrome who dis-
continued their statin therapy.
22
Furthermore, in these
patients, statin withdrawal was associated with a higher
rate of complications than in patients who had never
been treated with statins. More recently, some studies
have suggested this potential deleterious effect in other
clinical arenas, such as sepsis
23
and after coronary artery
bypass graft surgery.
4
In contrast, a small study sug-
gested that the short-term discontinuation of statins in
stable cardiac patients was not associated with an in-
creased risk of acute coronary syndromes.
24
Because statins are administered orally and the pleio-
tropic effects of statins are not readily appreciated, statin
withdrawal for several days after surgery is common
practice in the majority of institutions. After considering
recent clinical and experimental reports describing the
adverse effects associated with statin withdrawal, Le
Manach et al.
1
examined a vascular surgery database.
They observed that patients on long-term statin therapy
who experienced statin withdrawal postoperatively
were at increased risk for a postoperative cardiac event,
despite multivariate risk adjustment. Moreover, they spe-
cifically investigated the effect of postoperative statin
withdrawal on postoperative cardiac morbidity and com-
pared this with early readministration or no use of statin
therapy.
1
Using propensity score matching, the odds
ratio associated with the use of statins to predict post-
operative myocardial infarction was 2.1 (95% confidence
interval, 1.1–3.8) in the discontinuation group and 0.38
(95% confidence interval, 0.15– 0.98) in the continuation
group, with a relative risk reduction for postoperative
cardiac morbidity of 5.4 (95% confidence interval, 1.2–
25.3).
1
This finding suggests that postoperative with-
drawal could dramatically reduce the perioperative pro-
tective effect of statins. In contrast, when statins were
resumed early in the postoperative period, a protective
effect against cardiac morbidity was observed compared
with patients not receiving statin therapy. Given the
beneficial effect of long-term statin therapy, we recom-
mend that statin therapy not be interrupted during the
immediate postoperative period.
Given that few treatments are readily available to de-
crease the risk for postoperative cardiovascular complica-
tions (including death); the recent controversial role of
-blockers (Perioperative Ischemic Evaluation [POISE]
study)
25
; the increasing knowledge that it is rather the
proinflammatory and prothrombotic environment after sur-
gery that predominantly contributes to the risk for acute
postoperative cardiac events; and the support from our
data, and that of others, of a myocardial protective effect
(afforded via the vascular effects) by statin therapy, we can
expect an increasing role for perioperative statin therapy.
This is especially true after cardiac and vascular surgery
where extensive tissue trauma and ischemia–reperfusion
injury trigger an inflammatory and prothrombotic response
secondary to platelet activation, increased fibrinogen lev-
els, a temporary shutdown of fibrinolysis, and high circu-
lating levels of catecholamines and stress hormones.
In sum, there is a growing body of evidence that suggests
that statins reduce the incidence of acute adverse cardio-
vascular outcomes, including those that occur after sur-
gery. Recent data obtained from both randomized and
nonrandomized trials of patients undergoing coronary ar-
tery bypass graft surgery, organ transplantation, or noncar-
diac vascular surgery suggest that perioperative statin ther-
apy, independent of its effects on serum cholesterol levels,
is useful for both the primary and secondary prevention of
adverse postoperative outcomes. These beneficial effects
of statin therapy need to be confirmed prospective studies.
In fact, using a pharmacoeconomic analysis of the existing
prospective perioperative studies, Biccard et al.
26
sug-
gested that perioperative
-blockade and statin therapy
could result in cost savings through a reduction in major
perioperative cardiovascular complications in patients with
an expected perioperative major cardiovascular complica-
tion rate exceeding 10% after elective major noncardiac
surgery. They reported a similar number needed to treat
(19) to prevent major cardiovascular complications (includ-
ing death) in high-risk patients for perioperative
-blocker
and statin therapy but cautioned against the potentially
harmful adverse effects of
-blockers in patients with a
lower risk for cardiovascular events.
Statin therapy may thus represent one of the most
effective perioperative therapeutic regimens available
for reducing the risk of postoperative cardiovascular
complications in high-risk surgical patients.
Perioperative Complications of Statins
The most serious potential side effect of statin therapy is
rhabdomyolysis. However, to date, few perioperative stud-
ies have assessed its incidence. In a small, underpowered,
prospective study, Schouten et al.
27
did not observe any
significant increase in the risk of perioperative myopathy in
1145STATIN THERAPY WITHIN THE PERIOPERATIVE PERIOD
Anesthesiology, V 108, No 6, Jun 2008
patients receiving statin therapy. Although no definitive
conclusion can be drawn, this study suggests that findings
obtained outside the perioperative period may not be valid,
because the incidence of increased creatine kinase during the
perioperative period is markedly higher than the rates re-
ported in medical trials. Moreover, because of the low
frequency of statin-induced rhabdomyolysis, very large
studies are required to draw definitive conclusions. Al-
though further randomized trials are needed to evaluate
perioperative statin safety, it would seem that the beneficial
impact of statin therapy on the tremendous socioeconomic
costs of perioperative morbidity and mortality largely out-
weigh the potential risks of statin therapy in the vast ma-
jority of patients.
Conclusions and Perspectives
The use of satins in patients with cardiovascular disease
are increasingly supported by the results of primary and
secondary prevention studies that show a reduction in the
risk of myocardial infarction, stroke, and mortality. In addi-
tion to their lipid-lowering properties, statins have other
beneficial (pleiotropic) effects that include antiinflamma-
tory effects, improved endothelial function, plaque-stabiliz-
ing actions, and antioxidant effects. Moreover, accumulat-
ing data suggest that patients receiving preoperative statin
therapy have a lower risk of postoperative death and acute
coronary syndromes. However, further research is needed
to determine whether untreated high-risk patients present-
ing for surgery should receive perioperative statin therapy.
Furthermore, physicians must be educated about the po-
tential risks associated with discontinuation of statin ther-
apy in the postoperative period, as underlined in the most
recent American College of Cardiology–American Heart
Association recommendations.
28
Finally, although rare, pa-
tients at highest risk for the serious adverse effect of statins
(i.e., rhabdomyolysis) should be more precisely identified
in the future. In the meantime, we urge that serious con-
sideration be given to the incorporation and maintenance
of statin therapy as a perioperative strategy to improve
postoperative outcome in the population of patients at
increased risk of a major adverse cardiovascular event.
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    • "Unfortunately, some of the literature base has questionable scientific validity due to that published by a discredited researcher [59, 60]. A withdrawal effect for statins, with increased risk of postoperative cardiac complications, suggests that patients on chronic statin treatment should continue taking statins in the perioperative period to prevent such adverse outcome [61]. In patients with no history of prior statin use but with multiple cardiac risk factors and elevated levels of inflammatory markers (interleukin-6, and C-reactive protein ) initiation of statin use at least 30 days prior to the planned surgical procedure could be considered [62], however, a shorter duration may be feasible as a rapid physiological effect was demonstrated in a prospective trial where a single oral dose of pravastatin (40 mg) significantly attenuated acetylcholine-mediated vasoconstriction after 24 h [63]. "
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  • [Show abstract] [Hide abstract] ABSTRACT: RESUMEN Objetivo: El objetivo primario es demostrar mediante la valoración preanes-tésica que sirve como factor predictivo de morbimortalidad a los 30 días pos-teriores al procedimiento. El objetivo secundario es identificar los factores de riesgo importantes estadísticamente hablando en la valoración preoperatoria que influyan en la morbimortalidad del paciente con el fin de poder crear una escala de riesgo específica para nuestra población hospitalaria que nos sirva como predictor de morbimortalidad. Material y métodos: Se realizó un estudio de cohortes prospectivo, observacional, único, en UMAE Hospital de Espe-cialidades. Los casos comprenden todo paciente que sea programado para cirugía de urgencia o electiva que requiera valoración preanestésica. Después se realiza el seguimiento vía telefónica del paciente en cuanto a mortalidad y morbilidad a los 30 días. Cada variable tiene una ponderación, que crea una escala de riesgo del -1 a 1 (indeterminado, leve, moderado, severo y alto). Resultados: El total de defunciones fueron cinco, entre el tercer y décimo día postoperatorio; las causas: falla cardíaca, tromboembolia pulmonar y coma diabético (20% para cada etiología). De los sobrevivientes el 82% vivieron sin complicaciones o sin comorbilidades, el 18% restante vive con algún tipo de morbilidad. Conclusiones: Los modelos de regresiones logísticas lineales y la creación del índice de predicción confirman la importancia de estratificar los riesgos previos a una cirugía. El índice arroja una actualización de lo descrito en la literatura que ayuda a predecir y optimizar, con el fin de dar un instrumento útil para iniciar terapéuticas ya estudiadas y analizadas estadísticamente como potentes modificadores de la vida del paciente. Palabras clave: Valoración preoperatoria, escala de riesgo preoperatorio Lagarda-Castellanos.
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