Meta-Analisis de TMO Vs ICP en Angina Estable

10.1161/CIRCULATIONAHA.120.
048194
Routine Revascularization versus Initial Medical Therapy for Stable Ischemic
Heart Disease: A Systematic Review and Meta-Analysis of Randomized Trials
Running Title: Bangalore et al.; Revascularization or Medical Therapy for SIHD
Sripal Bangalore, MD, MHA1; David J. Maron, MD2; Gregg W. Stone, MD3;
Judith S. Hochman, MD1
1
Division of Cardiology, New York University Grossman School of Medicine, New York, NY;
2
Department of Medicine, Stanford University, Stanford, CA;3Division of Cardiology, The Zena
and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New
York and the Cardiovascular Research Foundation, New York, NY

Downloaded from http://ahajournals.org by on June 26, 2020
Address for Correspondence:

Sripal Bangalore, MD, MHA
Professor of Medicine
Director, Cardiac Catheterization Laboratory, Bellevue
Director of Research, Cardiac Catheterization Laboratory
Director, Cardiovascular Outcomes Group
New York University School of Medicine
New York, NY 10016
Tel: 212 263 3540
Fax: 212 263 3988
Email: sripalbangalore@gmail.com
Twitter: @sripalbangalore
1
10.1161/CIRCULATIONAHA.120.048194
Abstract
Background: Revascularization is often performed in patients with stable ischemic heart disease
(SIHD). However, whether revascularization reduces death and other cardiovascular outcomes is
uncertain.
Methods: We conducted PUBMED/EMBASE/CENTRAL searches for randomized trials
comparing routine revascularization versus an initial conservative strategy in patients with SIHD.
The primary outcome was death. Secondary outcomes were cardiovascular death, myocardial
infarction (MI), heart failure, stroke, unstable angina and freedom from angina. Trials were
stratified by percent stent use and by percent statin use to evaluate outcomes in contemporary
trials.
Results: Fourteen RCTs that enrolled 14,877 patients followed up for a weighted mean of 4.5
years with 64,678 patient years of follow-up fulfilled our inclusion criteria. Most trials enrolled
patients with preserved left ventricular systolic function, low symptom burden and excluded
patients with left main disease. Revascularization compared with medical therapy alone was not
associated with a reduced risk of death (RR=0.99, 95% CI 0.90-1.09). Trial sequential analysis
showed that the cumulative z-curve crossed the futility boundary indicating firm evidence for
lack of a 10% or greater reduction in death. Revascularization was associated with a reduced
non-procedural MI (RR=0.76, 95% CI 0.67-0.85) but also with increased procedural MI
(RR=2.48, 95% CI 1.86-3.31) with no difference in overall MI (RR=0.93, 95% CI 0.83-1.03). A
significant reduction in unstable angina (RR=0.64, 95% CI 0.45-0.92) and increase in freedom
from angina (RR=1.10, 95% CI 1.05-1.15) was also observed with revascularization. There were
no treatment-related differences in the risk of heart failure or stroke.
Conclusions: In patients with SIHD, routine revascularization was not associated with improved
survival, but was associated with a lower risk of non-procedural MI and unstable angina with
greater freedom from angina at the expense of higher rates of procedural MI. Longer-term
follow-up of trials is needed to assess whether reduction in these non-fatal spontaneous events
improves long-term survival.
Key Words: medical therapy; revascularization; stable ischemic heart disease
Non-standard Abbreviations and Acronyms

ACS = acute coronary syndromes
CABG = coronary artery bypass graft surgery
CCS = Canadian Cardiovascular Society
CKD = chronic kidney disease
FFR = fractional flow reserve
GDMT = guideline directed medical therapy
MACE = major adverse cardiovascular events
MI = myocardial infarction
PCI = percutaneous coronary intervention
RCT= randomized clinical trial
SIHD = stable ischemic heart disease
2
Clinical Perspective
What is new?
• Cumulative evidence from this meta analysis of randomized trials shows that routine
revascularization was not associated with improved survival, but was associated with a
lower risk of non-procedural MI and unstable angina with greater freedom from angina at
the expense of higher rates of procedural MI.
What are the clinical implications?

• The risk benefits of routine revascularization versus initial medical therapy should be
used in shared decision making for the management of patients with stable ischemic heart
disease
• Longer-term follow-up of trials is needed to assess whether reduction in non-fatal
spontaneous events improves long-term survival.
3
Introduction
In patients with stable ischemic heart disease (SIHD), revascularization by either percutaneous
coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) plus guideline-
directed medical therapy (GDMT) or initial management with GDMT alone are treatment
options. The fundamental goal of such therapies is to make the patients live longer and/or feel
better (relieve angina). In addition, a reduction of nonfatal cardiovascular events that ultimately
result in improved survival and/or quality of life is also a goal. A number of randomized clinical
trials have attempted to determine whether routine revascularization in SIHD improves
prognosis, with varying results. Clinical trials have shown a mortality benefit of routine
revascularization compared with an initial conservative approach in patients with ischemic
cardiomyopathy and in those presenting with acute coronary syndromes (ACS).1, 2 However, the
data to support routine revascularization in patients with SIHD with preserved ejection fraction
has been the subject of intense debate. In the Clinical Outcomes Utilizing Revascularization and
Aggressive Drug Evaluation (COURAGE) trial, PCI added to medical therapy did not reduce the
primary outcome of death or myocardial infarction (MI) compared with initial medical therapy
alone.3 In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial,
revascularization (PCI or CABG) added to medical therapy did not reduce the primary outcome
of death compared with initial medical therapy alone, although revascularization with CABG in
patients with advanced coronary artery disease reduced MI and major adverse cardiovascular
events (MACE).4 In the Fractional Flow Reserve versus Angiography for Multivessel Evaluation
2 (FAME 2) trial, fractional flow reserve (FFR)-guided PCI plus medical therapy significantly
reduced the primary outcome of death, MI, or urgent revascularization, driven by a significant
reduction in urgent revascularization compared with initial medical therapy alone.5 Finally, in the
4
recent International Study of Comparative Health Effectiveness with Medical and Invasive
Approaches (ISCHEMIA) trial, an initial invasive strategy showed an early hazard and late
benefit of invasive strategy with no overall difference in the primary outcome compared with an
initial conservative strategy. Similarly, in the ISCHEMIA-CKD trial, an initial invasive strategy
did not demonstrate a reduced risk of primary outcome (death or MI) in patients with advanced
chronic kidney disease (CKD). No trial to date has shown a reduction in mortality with
revascularization in SIHD. However, individual trials have limited power for the outcome of
mortality, the rates of which are low in most patients with SIHD.
We therefore performed an updated study-level meta-analysis to evaluate the outcomes of a
routine revascularization strategy compared with initial treatment with medical therapy alone in
patients with SIHD.

Methods
The authors declare that all supporting data are available within the article and its online
supplementary files.
Eligibility Criteria
Databases (PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials
(CENTRAL)) were searched, without language restriction, for randomized clinical trials (RCTs)
comparing routine revascularization (PCI, CABG or both) versus initial medical therapy alone in
patients with SIHD using the MeSH search terms as outlined in Table I in the Supplement, until
June 2020 (Week 2). In addition, conference proceedings and abstracts of the following societies
were searched: American Heart Association, American College of Cardiology, Transcatheter
Cardiovascular Therapeutics, Society of Cardiovascular Angiography and Intervention,
5
European Society of Cardiology and EuroPCR. The reference lists of review articles, meta-
analyses, and original studies identified by the electronic searches were checked to find other
eligible trials. The search was kept current by setting up automated reminders from PUBMED
for new publications. Institutional review committee approval was not required given that this is
a meta-analysis of published data.
Inclusion/Exclusion Criteria
The inclusion criterion was RCTs of routine revascularization therapy versus initial medical
therapy in patients with SIHD. Trials that enrolled patients within 48 hours of ACS were
excluded. Similarly, trials that only enrolled post MI patients (such as Arbeitsgemeinschaft
Leitende Kardiologische Krankenhausärzte [ALKK]6 and Swiss Interventional Study on Silent
Ischemia Type II [SWISSI-2]7) were excluded. Contemporary trials were categorized into “no
stent” trials in which <50% of patients in the PCI group received a stent and “stent” trials in
which ≥50% of patients received a stent. Similarly, trials were categorized into “no statin” and
“statin” trials according to whether ≥50% of patients in the medical therapy group received a
statin.
Selection and Risk of Bias Assessment
We assessed trial eligibility, extracted data independently and assessed trial risk of bias using the
components recommended by the Cochrane Collaboration:8 sequence generation of allocation,
allocation concealment, blinding of outcome assessors, incomplete outcome data, selective
outcome reporting, and other sources of bias. Trials with high or unclear risk of bias for any one
of the first three components were considered high-bias risk trials.
Outcomes
Outcomes of interest were: 1) death; 2) cardiovascular death; 3) MI including procedural and
6
non-procedural MI; 4) unstable angina; 5) heart failure; 6) stroke and 7) freedom from angina.
The definitions of each event used by each trial were utilized in this analysis. The events
reported at the longest follow-up time point was abstracted from each of the trials.
Statistical Analyses
The meta-analysis was performed in line with recommendations from the Cochrane
Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) Statement,8, 9 using standard software (Stata 14.0, Stata corporation, Texas).10 For
trials with zero events, constant continuity correction with addition of 0.5 events to both arms
was used. Meta-analysis was performed using both a random-effects model (DerSimonian and
Laird) and a fixed effect model.11 Study weights were from a random-effects model. Statistical
heterogeneity was assessed using the I2 statistic,12 which is the proportion of total variation
observed between the trials attributable to differences between trials rather than sampling error
(chance), with I2 ≥50% considered high. Analyses were stratified by stent vs. no stent” trials to
evaluate outcomes in contemporary versus older trials. We estimated the difference between the
estimates of these subgroups according to test for interaction.13 Pinteraction <0.10 indicates that the
effects of treatment may differ between the tested subgroups. When there were between-
subgroup differences, interpretation was done based on the results from the contemporary trials
(stent era trials or statin era trials subgroup). Small study effect was estimated visually by funnel
plots and using the weighted regression test of Egger.14 Meta-regression analysis was performed
to evaluate the relationship of covariates (year of trial, percent use of sent in the PCI group, and
percent use of statin in the initial medical therapy group) on outcomes, to evaluate whether the
results are different in more recent trials. Finally, the influence of each study on the pooled effect
size was examined by repeating meta-analyses while omitting each study one at a time to
7
evaluate for extreme outliers. Data presented in the results are from a fixed effect model if
heterogeneity I2 <50% or random-effects model if heterogeneity I2 >=50%. P <0.05 was used to
denote statistical significance.
Sensitivity Analysis
Sensitivity analysis was performed categorizing trials into statin vs. no statin trials to evaluate
outcomes in contemporary versus older trials. In addition, to account for different duration of
follow-up among trials, analysis was performed using the incident rate of outcomes per 1000
person-years to obtain the incident rate ratios (IRR) of one treatment relative to another
treatment. Person-years of follow-up were calculated by multiplying the sample size with the
average (mean/median) follow-up duration. Sensitivity analysis was also performed using count
based method and without continuity correction; after including the ALKK and SWISSI-2 trials
and after restricting the analyses to only trials with low risk of bias.
Trial Sequential Analysis
Trial sequential analysis, which is similar to interim analyses in a single trial in which
monitoring boundaries are used to decide whether a trial could be terminated early when a P-
value is sufficiently small to show the anticipated effect or for futility, was performed using
standard software (TSA ver 0.9 Beta)15 for a 5-10% relative risk reduction for death and for MI,
α=5% and 1-β=80% and estimating the required diversity adjusted information size.16, 17 The 5-
10% relative reduction was chosen as this was felt to be the minimal effect size to be clinically
relevant. Trial sequential monitoring boundaries were drawn, similar to interim analysis of
randomized trials and provides information as to whether to continue evaluating for evidence
when the boundary is not crossed or whether sufficient evidence is reached for anticipated effect
8
or for futility when the boundary is crossed. The interpretation is similar to that of DeMets
stopping boundaries for clinical trials.
Results
Study Selection
We included 14 RCTs (Figure 1, Tables 1-2) that randomized a total of 14,877 patients followed
for a weighted mean of 4.5 years (range 1.5 to 6.2 years) with 64,678 patient years of follow-up.
18-37
Baseline Characteristics
Most trials enrolled patients with preserved left ventricular systolic function (ejection fraction
35% or greater), less symptomatic patients (CCS Class I/II) and excluded patients with left main
disease (Table 1). In the revascularization arm, any revascularization was performed in 87.5% of
patients; PCI was the first procedure in 71.3% of patients and CABG was the first procedure in
16.2%. In 8 trials (BARI 2D, COURAGE, MASS-2, TIME, ISCHEMIA, ISCHEMIA-CKD,
FAME 2, JSAP) stents were used in at least 50% of patients undergoing PCI. Drug-eluting stents
were mainly used in 3 trials (FAME 2, ISCHEMIA and ISCHEMIA-CKD). Revascularization
was performed in 31.9% of patients in the medical therapy alone group during 4.5 years mean
follow-up. Background medical therapies, including aspirin and statins were used similarly in
both groups of each trial with the exception of the AVERT trial which randomized patients to
either angioplasty or medical therapy with atorvastatin 80 mg resulting in an imbalance by
design. Statins were used in at least 50% of
patients in 8 trials (BARI 2D, COURAGE, MASS-2, AVERT, ISCHEMIA, ISCHEMIA-CKD,
FAME 2, JSAP).
9
Death
Routine revascularization compared with initial medical therapy was not associated with a
reduced risk of death (RR=0.99, 95% CI 0.90-1.09) with no between trial heterogeneity (I2=0%)
(Figure 2a) or small study effect (Egger’s P=0.07). The results were similar when trials were
analyzed by stent vs. no stent era (Pinteraction= 0.85), and no particular study significantly affected
the summary effects (Figure Ia in the Supplement). In the trial sequential analysis the cumulative
z-curve crossed the futility boundary indicating firm evidence for lack of a 10% or greater
reduction in death with revascularization (Figure 2b). TSA for 5% reduction is shown in Figure
Ib in the Supplement.
No significant difference in cardiovascular death was present between the strategies
(RR=0.92; 95% 0.80-1.06) with no between trial heterogeneity (I2 =0%) (Figure 2c) or small
study effect (Egger’s P=0.94). The results were similar when trials were analyzed by stent era
status (Pinteraction = 0.60), and no particular study significantly affected the summary effects
(Figure IIa in the Supplement).
Myocardial Infarction
Routine revascularization compared with initial medical therapy alone was not associated with a
reduced risk of all MI (RR = 0.93, 95% CI 0.83-1.03) with low between trial heterogeneity
(I2=13.9%) (Figure 3a) and no small study effect (Egger’s P=0.46). However, the estimates
favored revascularization (RR=0.89; 95% 0.80-0.998; P=0.05) in the more contemporary stent
era trials whereas in the older non-stent era trials the estimates favored initial medical therapy
(RR=1.42; 95% 0.97-2.07; P=0.07) (Pinteraction = 0.02). Revascularization was associated with a
reduced risk of non-procedural MI (RR=0.76; 95% CI 0.67-0.85) (Figure 3b) driven by the
results in contemporary stent era trials (Pinteraction = 0.04). Conversely, revascularization was
10
associated with an increased procedural MI (RR=2.48; 95% CI 1.86-3.31) (Figure 3c), with no
between trial heterogeneity (I2 = 0%). No particular study significantly affected the summary
effects (Figures IIb-IId in the supplement). TSA for 5% and 10% reduction in MI is shown in
Figure IIIa and IIIb in the Supplement.
Other Outcomes
Routine revascularization compared with initial medical therapy was associated with similar
risks of heart failure (RR =1.03, 95% CI 0.71-1.49) (Figure 4b) and stroke (RR = 1.26, 95% CI
0.98-1.62) (Figure 4c) but with a reduced the risk of unstable angina (RR = 0.64, 95% CI 0.45-
0.92) (Figure 4a) driven by results from the contemporary stent era trials (RR=0.45, 95% CI
0.29-0.71) (Pinteraction=0.003). Routine revascularization was also associated with greater freedom
from angina (RR=1.10; 95% CI 1.05-1.15). Heterogeneity was high for the outcomes of unstable
angina, heart failure but low for the outcomes of stroke and freedom from angina. There was no
small study effect for any of the above analyses. No particular study significantly affected the
summary effects (Figures IVa-d in the Supplement).
Sensitivity Analysis
Outcomes of the fixed effect and random effect meta-analyses were consistent. Results were
similar in sensitivity analysis stratifying trials by statin use (Table II in the Supplement).
Similarly, the results were consistent in a sensitivity analysis incorporating duration of follow-up
(Table III in the Supplement) or using count based methods (Table IV in the Supplement)
without continuity correction. Similarly, the results were consistent after including the ALKK
and SWISSI-II trials (Table V in the Supplement) and after including only the low risk of bias
trials (Table VI in the Supplement).
11
Meta-regression Analysis
Meta-regression analysis based on year of trial, percent stent use in the PCI group and percent
statin use in the medical therapy group are shown in Figures 5a-5c and Figures V-VII in the
Supplement. There was no statistically significant relationship between the covariates and most
outcomes including death. However, there was greater benefit of routine revascularization for the
outcome of unstable angina (P=0.03) but more heart failure (P=0.02) in contemporary trials
when compared with initial medical therapy.
Discussion
With over 64,000 patient-years of follow-up, the present study is the largest meta-analysis to date
of RCTs of patients with SIHD assigned to either an upfront routine revascularization strategy or
initial medical therapy alone, and importantly includes data from the recently reported
ISCHEMIA and ISCHEMIA-CKD trials. In this analysis, a routine revascularization approach
was not associated with reduced risks of death, cardiovascular death, MI, heart failure or stroke.
The accumulated sample size provides firm evidence for lack of a 10% or greater reduction in
mortality with 80% power at a weighted mean follow-up of 4.5 years. However,
revascularization was associated with reduced risks of non-procedural MI and unstable angina, at
the cost of an increased risk of procedural MI. Finally, freedom from angina was greater with
revascularization. Given the well-established relationship between non-procedural MI and
mortality38 - and the uncertain relationship between procedural MI and subsequent mortalty
based on varying criteria for procedural MI- extended follow-up from clinical trials is warranted
to determine whether the magnitude of the observed reduction in non-procedural MI with routine
revascularization is sufficient to lead to improved long-term survival.
12
The incremental value of routine revascularization when added to initial medical therapy in
reducing cardiovascular events has been intensely debated. Fundamental to the debate is the fact
that studies done in the 1970s showed that although MI can result from flow-limiting lesions,
lesions that are angiographically non-severe greatly outnumber severe stenoses and are the
source of the majority of future MIs.39 However, in the Providing Regional Observations to
Study Predictors of Events in the Coronary Tree (PROSPECT) study in which flow-limiting
lesions were treated with first generation drug-eluting stents, follow-up cardiovascular events
were attributed equally to culprit and angiographically mild non-culprit lesions, suggesting that
revascularization of significant culprit lesions may reduce the risk of cardiovascular events.40
Similar findings were recently reported from the Lipid Rich Placque (LRP) study in which flow-
limiting lesions were treated with second generation drug-eluting stents.41
In patients with SIHD, studies reporting a survival benefit with coronary artery bypass
grafting (CABG) versus no revascularization in patients with largely preserved left ventricular
systolic function are outdated as these trials were conducted in the 1970s with minimal to no
background medical therapy.42-44 Whereas revascularization has been shown to confer a
mortality benefit in patients with acute coronary syndromes (ST-segment elevation MI and high-
risk non-ST-segment elevation MI)45 and in patients with left ventricular ejection fraction
≤35%,2 no contemporary trials have shown a similar survival benefit in patients with SIHD
without heart failure. Most recently, the large-scale ISCHEMIA trial randomized a higher-risk
SIHD cohort with moderate or severe ischemia, with randomization upstream of cardiac
catheterization to avoid potential selection bias in enrollment. This study found no difference in
the primary outcome (composite of cardiovascular death, MI, hospitalization for heart failure,
unstable angina or resuscitated cardiac arrest), key secondary outcome (cardiovascular death or
13
MI) or death between an initial invasive strategy of coronary angiography and revascularization
(if suitable) plus GDMT versus a conservative strategy of GDMT alone with coronary
angiography and revascularization reserved for failure of medical therapy. However, the curves
for the primary and key secondary outcomes crossed at ~2 years such that there was an early
difference in favor of the conservative strategy and a late difference in favor of the invasive
strategy.
The results of the present meta-analysis are clear in demonstrating no evidence of a mortality
benefit with routine revascularization in SIHD. The accumulated sample size of >14,000 patients
and >64,000 patient-years of follow-up provided sufficient power to rule out even a 10%
reduction in death with revascularization compared with medical therapy alone at a mean 4.5
years of follow-up. Whether a difference in mortality might emerge with longer follow-up
(driven by differences in non-fatal endpoints) needs to be studied.

Revascularization was associated with an upfront risk of procedural MI and a late benefit of
reduction in non-procedural (spontaneous) MI. The net effect was no overall reduction in total
MI although significant interaction was noted such that an 11% decrease in total MI was present
in the more contemporary stent trials with a nominal P-value of 0.05. The prognostic importance
of procedural MI vs. spontaneous MI has been intensely debated. Whereas most studies have
shown a positive association of a large elevation in peri-procedural biomarker with mortality,46-52
a few have shown no association of biomarker elevation (especially with troponins) with
prognosis.53, 54 Other studies have found non-procedural MI but not procedural MI to be a
predictor of subsequent mortality.38, 55-57 The relative influence of these effects may explain why
no difference in overall mortality was observed with revascularization. Finally, routine
revascularization was associated with a 36% reduction in unstable angina, a benefit that was
14
especially pronounced (55% reduction in unstable angina) in the contemporary stent era trials,
consistent with the greater reduction in restenosis with stents compared to prior devices.
Greater long-term freedom from angina was observed in patients treated with routine
revascularization compared with intial medical therapy, although the difference was modest.
Revascularization during follow-up was needed in 32% of patients, which occurs most
frequently in those with the greatest severity of angina,58 potentially blunting long-term
differences beween the groups but consistent with appropriate clinical practice. These findings
are consistent with an earlier meta-analysis in which the proportion of angina-free patients with
revascularization compared with intial medical therapy declined over time.59 This is despite the
fact that the majority of trials enrolled less symptomatic patients (CCS Class I/II) with only the
TIME trial enrolling predominantly Class III/IV patients.
Study Limitations
As in other trial level meta-analyses, we did not account for adherence to assigned treatment, or
the type of stent or dosage of medications used which would be best achieved by an individual
patient data meta-analysis. Clinical heterogeneity in the included studies was present, including
differences in trial design, patient population, invasive evaluation arm (initial invasive strategy
vs. revascularization), intensity of medical therapy and the revascularization techniques used
including the proportions of stents and CABG. Of note, the annualized mortality rate in the
initial medical therapy arm in the trials ranged from 0.4% to 10.5%. There was heterogeneity in
the definition of clinical outcomes, especially that for procedural MI (Table 2).
Nonethless,statistical heterogeneity was absent or modest for most of the endpoints. Meta
regression analysis based on covariates such as percent stent use or percent statin use could
15
suffer from ecological bias. Finally, there was variability in the definitions of outcomes,
especially that for MI, used in the trials.
Conclusions
In the present updated systemic review and meta-analysis, routine revascularization was not
associated with improved survival in patients with SIHD over 4.5 years compared with an intial
medical therapy approach. Routine revascularization was associated with reduced non-
procedural MI and unstable angina and increased freedom from angina at the expense of more
procedural MI. In addition, ~1 in 3 patients in the initial medical therapy required
revascularization at a median of 4.5 years of follow-up. These observations should be used in
shared decision-making discussions to determine the initial treatment approach in patients with
SIHD.
Sources of Funding
None
Disclosures
Bangalore: Research grant- NHLBI, Abbott Vascular; Advisory board- Abbott Vascular,
Biotronik, Meril, SMT, Pfizer, Amgen and Reata;
Stone: Speaker or other honoraria from Cook, Terumo, QOOL Therapeutics and Orchestra
Biomed; Consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore,
Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals,
Vectorious, Reva, Matrizyme; Equity/options from Ancora, Qool Therapeutics, Cagent, Applied
Therapeutics, Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success,
16
MedFocus family of funds, Valfix;
Hochman: PI for the ISCHEMIA trial for which, in addition to support by National Heart, Lung,
and Blood Institute grant, there were in-kind donations for participating sites from Abbott
Vascular; Medtronic, Inc.; St. Jude Medical, Inc.; Volcano Corporation; Arbor Pharmaceuticals,
LLC; AstraZeneca Pharmaceuticals, LP; Merck Sharp & Dohme Corp.; Omron Healthcare, Inc.;
and Amgen Inc.; and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca
Pharmaceuticals LP.
Supplemental Materials
Supplemental Tables I-VI
Supplemental Figures I-VII

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22
Table 1. Select baseline characteristics of the included trials
Trial Number of Age Follow Mean Baseline Angina* Statin use ≥50% Stent use Revascularization PCI or Annualized Mortality
Participan (years) up LDL in the medical ≥50% in the in initial medical PTCA/CABG/no Rate in the Initial
ts (years) (mg/dl) therapy group PCI group therapy group revasc in routine Medical Therapy
(%) revasc group (%) Group§ (%/year)
72†
ACME118, 19 212 62
No 3 106
No 43 95/0/5 2.7
99‡
ACME220 101 60
No 5 NR
No 60 100/0/0 4.0
AVERT21 341
Class I/II (82%) 58
Yes 1.5 144
No 12 94/0.6/5.4 0.4
BARI 2D22 2368
Class I/II (70%); 62
Yes 5 96
Yes 42 65/29/6 2.5
Class III/IV (14%)
COURAGE23 2287 62 4.6 101 Class I/II (66%); Yes Yes 31 94/0/6 1.7
Class III (21%)
DEFER24 181 61 5 NR Class I/II (63%); No No 16 100/0/0 1.3
Class III/IV (37%)
FAME 225 888 64 5 NR Class I/II (65%); Yes Yes 51 100/0/0 1.0
Class III/IV (23%)
JSAP26 384 64 3.3 120 Class I/II (85%); Yes Yes 36 100/0/0 1.1
Class III (2.4%)
ISCHEMIA27, 28 5179 64 3.3 83 Class I/II (73.5%); Yes Yes 26 59/21/20 1.6
Class III (4.6%)

ISCHEMIA-CKD 777 63 2.2 83 Class I/II (58.4%); Yes Yes 20 43/7/50 10.5
Class III (4.0%)
MASS-129, 30 214 56 5 151 NR No No 17 51/49/0 1.7
MASS-231, 32 611 60 5 148 Class II/III (81%) Yes Yes 24 47/50/3 3.2
RITA-233, 34 518 58 7 NR Class I/II (60%) No No 35 93/2/5 1.2
Class III/IV (20%)
TIME35 301 80 4 NR Class II (18%); No Yes 47 52/20/28 6.7
Class III/IV (82%)
ACME=Angioplasty Compared to Medicine; ALKK=Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte; AVERT=Atorvastatin versus Revascularization Treatment; BARI
2D=Bypass Angioplasty Revascularization Investigation 2 Diabetes; COURAGE=Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation; FAME 2= Fraction flow
reserve guided PCI versus medical therapy in stable coronary artery disease 2; ISCHEMIA=International Study of Comparative Health Effectiveness with Medical and Invasive Approaches;
ISCHEMIA-CKD=International Study of Comparative Health Effectiveness with Medical and Invasive Approaches- Chronic Kidney Disease trial; JSAP=Japanese Stable Angina Pectoris;
MASS=Medicine, Angioplasty, or Surgery Study; RITA=Randomized Intervention Treatment of Angina; SWISSI II=Swiss Interventional Study on Silent Ischemia Type II; TIME= Trial of
Invasive Versus Medical Therapy in Elderly Patients; NR=Not reported. *Based on Canadian Cardiovascular Society Angina Grade unless otherwise stated. †Based on psychological well-being
score. ‡Based on quality of life score. § Annualized mortality obtained by dividing total number of deaths in the initial medical therapy group over the average follow-up time.
23
Table 2. Select characteristics of included trials
Trial Key Inclusion Criteria Key Exclusion Criteria Definition of MI Risk of Bias Description of medical
Assessment * therapy
ACME118, 19 70-99% stenosis in proximal 2/3rds of Not reported New Q wave on ECG or increase in CK +±±+++ 325 mg Aspirin, Nitrates,
one major coronary artery, stress test level above normal with typical clinical Beta blockers, CCB
with ≥1 mm ST depression in at least 1 signs. Procedural myocardial infarction
lead or filling defect on thallium scan, was defined likewise around the time of
or MI in past 3 months the procedure.
ACME220 History of angina, MI within 3 months, Medically refractory unstable New Q wave (≥0.04-s duration or ≥25% +±++++ Aspirin plus individualized
or ≥3 mm horizontal ST depression on angina, prior PCI, primary cardiac total QRS voltage) in any anterior or therapy of Nitrates, Beta
exercise testing; ≥70% stenosis in diagnosis other than CAD, ≥50% lateral lead or in ≥2 contiguous inferior blockers, and CCB
proximal 2/3rds of 1 or 2 coronary left main stenosis, 3 vessel CAD, leads on a follow-up ECG or hospital
arteries (data for 1 vessel CAD LVEF≤30% admission for CP accompanied by serum
previously presented as ACME-1) biomarker changes meeting local hospital
criteria for MI. Procedural myocardial
infarction was defined likewise around the
time of the procedure.
AVERT21† ≥50% stenosis of at least one coronary Left main disease, 3 vessel CAD, Not reported +±-+++ 80 mg Atorvastatin
artery for which PCI was unstable angina, MI in prior 2
recommended, asymptomatic or with weeks, LVEF<40%

CCS I or II angina, completion of at
least 4 minutes of stress test without
ischemia, LDL≥115 mg/dl, and
triglycerides <500 mg/dl
BARI 2D22† ≥50% stenosis of major coronary artery Need for immediate Spontaneous MI as doubling of cardiac ++++++ Aspirin, Statins, Beta
with positive stress test or ≥70% revascularization, left main biomarkers (CK-MB or troponin) and blockers, and ACEi or
stenosis of major coronary artery with disease, creatinine >2mg/dl, evidence of ischemia ARB; insulin and/or oral
classic angina AND type 2 diabetes HbA1c >13%, class III or IV on the basis of symptoms, ECG or hypoglycemic therapy
heart failure, hepatic dysfunction, imaging; Silent MI as a Q-wave change of
PCI or CABG in previous 12 two grades on routine
months ECG; Procedure related as CKMB
elevation of 3 times and 10 times above
normal for PCI and CABG respectively
DEFER24 Angiography with >50% stenosis in Total occlusion of the target New pathological Q-waves on the ECG or +±++++ Statins, Beta blockers,
native coronary artery and FFR≥0.75, artery, Q-wave infarction, USA, an increase of serum CK levels to > 2 Nitrates
no evidence of reversible ischemia by or small target arteries times the normal value. In-hospital post
noninvasive testing within the previous procedural MI meeting the same definition
2 months were considered procedural MI.
24
COURAGE2 ≥70% stenosis in at least one proximal CCS class IV angina, substantial Clinical presentation consistent with an ++++++ 81-325 mg aspirin and/or 75
3
artery, inducible ischemia on stress ST depression or hypotension ACS and either new abnormal Q waves in mg clopidogrel; long-acting
testing or ST depression or TWI on during Bruce protocol stage 1 ≥ 2 ECG leads or positive results in metoprolol and/or
resting EKG stress testing, refractory heart cardiac biomarkers; Silent as abnormal Q amlodipine and/or nitrates;
failure or cardiogenic shock, waves, confirmed by a core laboratory. lisinopril or losartan;
LVEF <30%, revascularization in Procedural MI was also defined similarly simvastatin alone or with
prior 6 months, coronary anatomy ezetimibe; extended-release
not suitable for PCI niacin and/or fibrates if
needed, lifestyle counseling
FAME 225 Patients with 1) Patients in whom the preferred a. Within 24 hours after randomization or ++++++ Aspirin, statins,
a) stable angina pectoris (Canadian treatment is CABG any PCI antiplatelets, beta blocker,
Cardiovascular Class [CCS] 1, 2, 3) 2) Patients with left main I. CPK-MB above 10 x 99th on a single ACE inhibitor, diabetes
b) or, angina pectoris CCS class 4 coronary artery disease requiring measurement, OR control
subsequently stabilized medically revascularization II. CPK-MB above 5 x 99th percentile
(minimum 7 days) or, 3) Patients with a recent (less than URL determined on a single
c) atypical chest pain or no chest pain 1 Week) STEMI or Non-STEMI measurementPLUS at least one of the
but with documented silent ischemia 4) Prior CABG following:
on non-invasive testing. 6) LVEF < 30% percentile upper reference limit (URL)
2) In whom at least one stenosis is 7) Severe LV hypertrophy determined on a
present of at least 50% in one major single measurement, OR
native epicardial coronary artery with a o new pathological Q waves in at least 2
diameter of at least 2.5 mm and contiguous leads or new persistent non-

supplying viable myocardium rate related LBBB,
o angiographically documented native
coronary artery occlusion,
o imaging evidence of new loss of viable
myocardium
b. More than 24 hours after
randomization:
I. Detection of rise and/or fall of cardiac
biomarkers,CK-MB or toponine with at
least one value above the 99
More than 24 hours after randomization:
the percentile of the URL together with
evidence of myocardial ischemia with at
least one of the following:
o Symptoms of ischemia
o ECG changes indicative of new ischemia
[new ST-T changes or new left bundle
branch block (LBBB)]
25
OR
II. Development of pathological Q waves
(≥ 0.03 seconds in duration and ≥ 1 mm in
depth) in ≥ 2 contiguous precordial leads
or ≥ 2 adjacent limb leads) of the ECG
OR
III. Imaging evidence of loss of viable
myocardium or new regional wall motion
abnormality
ISCHEMIA2 Moderate or severe ischemia, eGFR EF <35%, known unprotected left Primary Definition is based upon the ++++++ High-intensity statins,
7, 28
≥30 main disease, NYHA class III-IV Universal Definition of MI, but relies upon antiplatelets, BP targets,
heart failure, unacceptable level site reported MI decision limits for LDL goals, anti-anginals,
of angina despite maximal troponin (which may or may not be the lifestyle counseling
medical therapy, ACS within the same as the manufacturer 99%URL). Peri-
previous 2 months, PCI or CABG PCI MI requires a rise in CK-MB to >5-
within the previous 2 months fold the ULN (or a rise in troponin to >35
times the MI Decision Limit/ULN, when
CK- MB is unavailable) within 48 hours
post-PCI and at least one of the following:
a) angiographic findings; b) new EKG
changes. Peri-CABG MI requires a rise in
CK-MB to >10-fold the ULN (or a rise in

troponin to >70 times MI Decision
Limit/ULN when
CK-MB is unavailable) within 48 hrs post-
CABG and at least one of the following: a)
substantial wall motion abnormality by
cardiac imaging; b) new pathological Q-
waves or new persistent LBBB.
ISCHEMIA- Moderate or severe ischemia, eGFR EF <35%, known left main Same as ISCHEMIA ++++++ High-intensity statins,
CKD36, 37 <30 or on dialysis disease, NYHA class III-IV heart antiplatelets, BP targets,
failure, Unacceptable level of LDL goals, anti-anginals,
angina despite maximal medical lifestyle counseling
therapy, ACS within the previous
2 months,
PCI or CABG within the previous
2 months
26
JSAP26† ≥75% (or ≥60% on quantitative 3 vessel CAD, left main or ostial New abnormal Q waves in ≥ 2 ECG leads ++++++ Entirely physician-
coronary angiography) 1 or 2 vessel LAD disease, total occlusion, during follow-up, or convincing clinical dependent (majority
CAD, inducible ischemia on stress ACS, LVEF<50%, tendency to history associated with ECG changes received Aspirin or other
testing or ST depression or TWI on bleed, disseminated intravascular compatible with non–Q-wave infarction, anti-platelet, Beta blockers,
resting EKG coagulation, severe pneumonia, and the Nitrates, Statins,
creatinine >1.5 mg/dl, graft serum level of ≥2 cardiac biomarkers ACEi/ARB)
stenosis, low-risk CAD where greater than twice normal
PCI or medical therapy had
already been prescribed
MASS-I29, 30 ≥80% LAD stenosis before takeoff of Total occlusion, lesion length >12 Significant new Q waves in ≥ 2 ECG leads +±±+++ Aspirin, Nitrates, Beta-
first diagonal branch, single vessel mm, involvement of the ostium, or symptoms compatible with a MI blockers
CAD heavy calcification, severe associated with elevation of the
tortuosity, left main disease, CK-MB fraction greater than three times
unstable angina, prior MI, the upper limit of normal.
significant valvular disease,
cardiomyopathy, LV dysfunction,
prior PCI or CABG
MASS-II31, ≥70% proximal multivessel stenosis USA, acute MI requiring Significant new Q waves in ≥ 2 ECG leads +±±+++ Aspirin, Nitrates, Beta-
32
and documented ischemia by stress emergent revascularization, or symptoms compatible with a MI Blockers, CCBs, ACE
testing or CCS II or III ventricular aneurysm requiring associated with elevation of the inhibitors, Statins
surgical repair, LVEF<40%, prior CK-MB fraction greater than three times
PCI or CABG, single vessel the upper limit of normal.

CAD, congenital heart disease,
valvular heart disease,
cardiomyopathy, left main
stenosis ≥50%, unable to comply
with protocol or follow up,
suspected or known pregnancy
RITA-233, 34 Angiography with ≥50% (2 views) or Revascularization necessary for New pathological Q waves (>30 ms in +±++++ Aspirin, Beta blockers,
≥70% (1 view) stenosis in at least 1 symptom relief or prognostic duration) on an ECG within 7 days of any CCB, long acting nitrates at
major artery amenable to PTCA, recent benefit, prior revascularization, myocardial revascularization procedure maximally tolerated doses,
unstable angina at least 7 days before significant left main disease, ACS (procedure-related infarction) or during lipid lowering drugs only as
randomization in the previous 7 days, subsequent follow-up or Typical clinical needed
hemodynamically significant history associated with ECG changes
valve disease, or life threatening compatible with non-Q-wave infarction
non cardiac disease and the serum levels of ≥ 2 cardiac
biomarkers above twice normal
27
TIME35 75 years or older who were referred to

Acute MI within the previous 10 Myocardial infarction was defined as a ++++++ Antianginals, antiaggregants
participating centres in Switzerland for
days; concomitant valvular or clinical event with significant and lipid-lowering drugs
assessment of chest pain refractory to at
other heart disease; congestive electrocardiographic and enzyme changes
least two antianginal drugs
heart failure; lifelimiting and, in context with revascularisation, as
comorbid disease such as cancer, infarct-typical electrocardiographic
severe renal failure; and changes with increases in concentrations of
impossibility of increasing or creatine kinase MB, troponin, or both, of
optimising medical therapy twice the upper limit of normal
See footnote of Table 1 for expansion of trial name; ACEi= Angiotensin converting enzyme inhibitor; ACS=Acute coronary syndrome; ARB=Angiotensin receptor blocker; BMS=Bare
metal stent; CABG=Coronary artery bypass graft; CAD=Coronary artery disease; CCB= Calcium channel blocker; CCS=Canadian Cardiovascular society; CK= Creatinine Kinase;
CP=Chest pain; DES=Drug eluting stent; ECG=Electrocardiogram; HbA1c=Glycosylated hemoglobin; LVEF=Left ventricular ejection fraction; MI=Myocardial infarction;
PCI=Percutaneous coronary intervention; PTCA=Percutaneous transluminal angioplasty; STEMI=ST elevation MI; TWI=T wave inversion; USA=Unstable angina. * Represents risk of
bias based on: sequence generation of allocation; allocation concealment, blinding, incomplete outcome data, selective outcome reporting; and other sources of bias. ‘+’ represents low risk
of bias, ‘-‘high risk of bias and ‘±’ unclear risk of bias. †Additional data from author correspondence.
28
Figure Legends
Figure 1. Study selection. MI = myocardial infarction; RCT = randomized clinical trial.
Figure 2. Meta-analysis of routine revascularization vs. initial medical therapy: a) For the
outcome of death. CI = confidence interval, RR = relative risk. D+L = DerSimonian and Laird; I-
V = Inverse-Variance; b) Trial sequential analysis for the outcome of death; c) For the outcome
of cardiovascular death. CI = confidence interval, RR = relative risk. D+L = DerSimonian and
Laird; I-V = Inverse-Variance.
Figure 3. Routine revascularization vs. initial medical therapy for the outcome of myocardial
infarction: a) Overall myocardial infarction; b) Non procedural myocardial infarction; c)

Procedural myocardial infarction. CI = confidence interval, RR = relative risk. D+L =
DerSimonian and Laird; I-V = Inverse-Variance.
Figure 4. Routine revascularization vs. initial medical therapy for other outcomes: a) Unstable
angina; b) Heart failure; c) Stroke; d)Freedom from angina. CI = confidence interval, RR =
relative risk. D+L = DerSimonian and Laird; I-V = Inverse-Variance.
Figure 5. Relationship of trial publication year on relative risk of outcomes with routine
revascularization vs. initial medical therapy: a) Death; b) Cardiovascular death; c) Non
procedural myocardial infarction
29
Record identified through database search using
MeSH terms for “Coronary artery disease” and
“Revascularization” and limited to RCT (n=580)
Records excluded on the

basis of title and abstract
(n=500)
80 articles retrieved for

detailed evaluation
Trials excluded (n=66)
Outcome of interest not
reported (n=30)
Registry (n=20)
Trial included patient
within 1 week of MI (n=4)
Trials included only
patients with prior MI
(n=2)
Review articles (n=10)
14 articles retrieved for

detailed evaluation
Studies included in
the final meta-
analysis (n=14)

Meta-Analisis de TMO Vs ICP en Angina Estable

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10.1161/CIRCULATIONAHA.120.

Routine Revascularization versus Initial Medical Therapy for Stable Ischemic

Heart Disease: A Systematic Review and Meta-Analysis of Randomized Trials

Running Title: Bangalore et al.; Revascularization or Medical Therapy for SIHD

Judith S. Hochman, MD1

York and the Cardiovascular Research Foundation, New York, NY

Address for Correspondence:

Key Words: medical therapy; revascularization; stable ischemic heart disease

Non-standard Abbreviations and Acronyms

What are the clinical implications?

trials have attempted to determine whether routine revascularization in SIHD improves

revascularization compared with an initial conservative approach in patients with ischemic

We therefore performed an updated study-level meta-analysis to evaluate the outcomes of a

patients with SIHD.

Databases (PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials

were searched: American Heart Association, American College of Cardiology, Transcatheter

Cardiovascular Therapeutics, Society of Cardiovascular Angiography and Intervention,

a meta-analysis of published data.

Leitende Kardiologische Krankenhausärzte [ALKK]6 and Swiss Interventional Study on Silent

Selection and Risk of Bias Assessment

components recommended by the Cochrane Collaboration:8 sequence generation of allocation,

allocation concealment, blinding of outcome assessors, incomplete outcome data, selective

of the first three components were considered high-bias risk trials.

Outcomes of interest were: 1) death; 2) cardiovascular death; 3) MI including procedural and

heterogeneity I2 <50% or random-effects model if heterogeneity I2 >=50%. P <0.05 was used to

denote statistical significance.

Trial Sequential Analysis

stopping boundaries for clinical trials.

16.2%. In 8 trials (BARI 2D, COURAGE, MASS-2, TIME, ISCHEMIA, ISCHEMIA-CKD,

were mainly used in 3 trials (FAME 2, ISCHEMIA and ISCHEMIA-CKD). Revascularization

either angioplasty or medical therapy with atorvastatin 80 mg resulting in an imbalance by

design. Statins were used in at least 50% of

patients in 8 trials (BARI 2D, COURAGE, MASS-2, AVERT, ISCHEMIA, ISCHEMIA-CKD,

No significant difference in cardiovascular death was present between the strategies

(Figure IIa in the Supplement).

Figure IIIa and IIIb in the Supplement.

summary effects (Figures IVa-d in the Supplement).

trials (Table VI in the Supplement).

when compared with initial medical therapy.

ISCHEMIA and ISCHEMIA-CKD trials. In this analysis, a routine revascularization approach

revascularization. Given the well-established relationship between non-procedural MI and

revascularization is sufficient to lead to improved long-term survival.

limiting lesions were treated with second generation drug-eluting stents.41

background medical therapy.42-44 Whereas revascularization has been shown to confer a

(driven by differences in non-fatal endpoints) needs to be studied.

shown a positive association of a large elevation in peri-procedural biomarker with mortality,46-52

prognosis.53, 54 Other studies have found non-procedural MI but not procedural MI to be a

no difference in overall mortality was observed with revascularization. Finally, routine

TIME trial enrolling predominantly Class III/IV patients.

especially that for MI, used in the trials.

procedural MI. In addition, ~1 in 3 patients in the initial medical therapy required

revascularization at a median of 4.5 years of follow-up. These observations should be used in

Biotronik, Meril, SMT, Pfizer, Amgen and Reata;

Biomed; Consultant to Valfix, TherOx, Vascular Dynamics, Robocath, HeartFlow, Gore,

Ablative Solutions, Miracor, Neovasc, V-Wave, Abiomed, Ancora, MAIA Pharmaceuticals,

MedFocus family of funds, Valfix;

Supplemental Tables I-VI

Supplemental Figures I-VII

study of the arbeitsgemeinschaft leitende kardiologische krankenhausarzte. Circulation.

randomized controlled clinical trial of 3 therapeutic strategies for multivessel coronary

predicting mid-term mortality. The American journal of cardiology. 2004;93:18-23.

to revascularization within 12 months of randomization to optimal medical therapy in the

Table 1. Select baseline characteristics of the included trials