What do we need to indicate CTO PCI?

Tony Gershlick
Professor Interventional Cardiology
University Hospitals of Leicester UK
EURO CTO 2017
“What do we need to indicate CTO PCI?”
Who and why ?
Leicester Cardiovascular Biomedical Research Centre

Chronic total occlusion
What is it ?
complete vessel occlusion withTIMI 0 flow within the occluded segment and an
estimated occlusion duration of ≥3 months
How common is it
In consecutive series of patients recent myocardial infarction, who underwent
angiography, totally occluded vessels were observed in 15- 25% of cases
Christofferson RD,. Effect of chronic total coronary occlusion on treatment strategy. Am
J Cardiol 2005;95(9):1088–1091.
Fefer P,. Current perspectives on coronary chronic total occlusions: the Canadian
MulticenterChronicTotal Occlusions Registry. J Am Coll Cardiol 2012;59:991–997.
Jeroudi OM, Prevalence and management of coronary chronic total occlusions in a
tertiaryVeterans Affairs hospital. Catheter Cardiovasc Interv 2014;84:637–643.

Patients with CTO
o underwent PCI less frequently than those without CTO
(11% vs. 36%, respectively; P , 0.0001)
o but were more frequently assigned to CABG or medical therapy
Christofferson RD, Effect of chronic total coronary occlusion on treatment
strategy. Am J Cardiol 2005;95(9):1088–1091.

How do we get right this ?
Patient selection
Best procedural outcomes
Proof of value
Education of colleagues

DATA
NEED for evidence based practice
While several observational studies (and now randomised trial) demonstrate successful
CTO better CV outcome and improved QoL
clinical benefit continues to be debated
PERCEPTION
⓿CTO intervention is considered to be a cumbersome and costly procedure
⓿Associated with a higher rate of complications, when compared with non-CTO lesions.
⓿ Not seen as being necessary procedure

Both European and American guidelines have assigned a
class IIa (level of evidence B) recommendation for CTO PCI

APPROPRIATENESS
(it is needed by the patient)

“Treatment of CTOs should be considered in the presence of symptoms or objective
evidence of viability/ischaemia in the territory of the occluded artery
Given the usually high procedural contrast volume, the potential long-term risk of
radiation exposure and contrast-induced nephropathy should be considered”

 CTO- pre-requisites –
i. Symptoms
ii. Viabiltiy
iii.Evidence of reversible ischaemia
iv.Useful collaterals

Stress echo can be very accurate - Report pre angiogram :

Symptoms despite “adequate” medical therapy
Evidence reversible ischaemia
Viable heart muscle
Dead heart muscle (Gadolinium CMR) doesn’t
need treating !!

Galass1 AR EHJ 2016 37 2692 – 700

1. Symptom relief:
Study FU
months
No. with
successful PCI
% symptom relief at
FU
Holmes et al JACC 1984 7 13 10 (77)
Keriakes et al JACC 1985 7 40 30 (75)
Serruys et al EHJ 1985 7 28 18 (64)
DiSciascio et al AHJ 1986 8 29 16 (55)
Melchior et al AJC 1987 8 49 40 (82)
Finci et al AJC 1990 24 100 57 (57)
Warren et al AHJ 1990 31 20 16 (80)
Bell et al Circulation 1992 32 234 178 (76)
Ruocco et al AJC 1992 24 160 110 (69)
Ivanhoe et al Circulation 1992 48 286 196 (69)
Stewart et al JACC 1993 14 45 31 (69)
Total 1004 702 (70%)
Why treat CTOs ?

identified a baseline ischaemic burden of 12.5% as an
optimal cut-off to identify patients most likely to have a
significant decrease in ischaemic burden post-CTO PCI

Continue to standardise procedure
according to patient
Kit Approach

Need to understand and
communicate to colleagues
what are the likely
outcomes/benefits of successful
CTO procedure
=
DATA
Convince non CTO colleagues
(which) patients benefit from
appropriate CTO procedure !!

Randomized (n = 1,800) and nested PCI (n
= 198) and CABG (n = 649) registries, 4-
year clinical outcomes were compared in
groups, with and without angiographicCR,
in the PCI and CABG arms
Conclusions
Within the PCI and CABG arms of the all-
comers SYNTAX trial, angiographically
determined ICR has a detrimental impact
on long-term clinical outcomes, including
mortality.This effect remained consistent
in patients with and withoutTOs.
Patients with CTO do worse

Prognostic impact of a chronic total
occlusion in a non-infarct-related
artery in patients with ST-segment
elevation myocardial infarction: 3-
year results from the HORIZONS-
AMI trial.
Claessen BE
Eur Heart J. 2012 Mar;33(6):768-75.

10-center prospective PCI registry
including Seattle Angina
Questionnaire (SAQ) assessment at
the time of PCI and in follow-up
propensity matched attempted CTO
PCIs with up to 10 non-CTO PCIs.
3,303 patients enrolled, 167 single-
vessel CTOs were attempted; 147
(88%) were matched with 1,616 non-
CTO PCI
The primary analysis compared changes between
baseline and 6 months in SAQ Physical Limitation (PL),
Quality of Life (QoL); Angina Frequency (AF) scores as
well as the Rose Dyspnea scores (RDS) and the EQ5D
VisualAnalogue Scale (VAS)

Formal noninferiority testing demonstrated that CTO PCI was
not inferior to non-CTO PCI (P ≤ 0.02 for all

Requirement for CABG
FU
(months)
CTO success
(% CABG)
CTO failure
(% CABG)
Bell et al 1992 32 18% 58% <0.001
Ivanhoe et al 1992 36 13% 36% <0.0001
Noguchi et al 2000 52 7% 28% <0.001
Oliviari et al 2002 12 2.5% 16% <0.0001

Methods
• Analysis of the UK Central Cardiac Audit Database
• Procedures between Jan 1st 2005 – Dec 31st 2009
• on 13 443 patients
• Mortality data from the Medical Research Information Service
(MRIS)

Successful revascularisation is associated with reduced mortality
15 492 elective CTO procedures

Jose Henrigues et al
RANDOMISED
STUDIES

1. Viability of myocardium subtended by the occluded non-culprit artery was not
assessed in all patients prior to inclusion in the study
2. Optimal timing of non-culprit PCI in STEMI patients has so far not been
clearly defined
a. Trials (PRAMI , CvLPRIT) excluded patients with non-culprit artery CTO
b. performing CTO PCI within 7 days of primary PCI may have biased the
results
3. LV functional improvement in STEMI patients impacted on by success of
primary PCI
a. predictors of LV recovery beyond post-procedural TIMI flow in the infarct-
related artery, e.g. MVO not taken into account
CRITIQUE

CRITIQUE
o Slow/low recruitment
o 1 large recruiting centre (bias)
o High success rates suggest lesser significant/complex lesions
o the lack of clarity regarding how many patients had
symptoms/ischemia after revascularization of non-CTO lesions
o 70% of OMT patients received some kind of PCI
o whether myocardial territories supplied by the CTO were viable at the
outset
o the almost 20% rate of crossover from the medical therapy arm to PCI,
and the trial’s early termination, which limits the power of the results
Interpretation:
“The results of this trial indicate that routine CTO-PCI + OMT is
not superior to OMT alone in reducing cardiovascular
outcomes among patients with at least one CTO”
o Non Inferiority only on ITT
o Numerically superior on per treated analysis

A Randomized Multicentre Trial to
Evaluate the Utilization of
Revascularization or Optimal Medical
Therapy for the Treatment of Chronic
Total Coronary Occlusions
Gerald S. Werner, MD PhD
on behalf of the
EURO CTO trial investigators
TRIAL 3

Changes in CCS class during follow-up
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Baseline Follow-up Baseline Follow-up
CCS 1 CCS 2 CCS 3 CCS 4
OMT PCI
P<0.001

Data
1. Right patients in right hands enjoy improved outcomes better quality of life reduced angina
[? Mortality …UK Registry suggest need a trial >10 000]
2. Essential that any trial data is robust if we are to make our case !!!
3. Such benefits should not be under-estimated or dismissed as not being worthy
4. CTO success can be as good as non CTO PCI (>90%) with low complications
BUT ONLY WORKS IF :
the myocardium sub tended by the CTO is viable and ischaemic
AND FINALLY

What do we need to do ?
o Ensure appropriate patients are treated
 On treatment Symptoms , ischaemia, viability)
o Optimize success rates
o Minimize complications (including CIN Radiation exposure)
o Manage expectations re outcomes no trial will demonstrate mortality
benefit
o But continue to produce meaningful robust quality data
o Educate … be humble about it

CTO success
(n=248)
CTO failure
(N=60) P value
No Angina 220 (88.7%) 45 (75%) 0.008
ETT
performed 210 (84.7%) 42 (70%) 0.01
Maximal ETT 155 (62.5%) 20(33%) 0.0001
Negative ETT 181(73%) 28 (46.7%) 0.0001
TOAST-GISE
390 CTOs 1999-2000, 1 year follow up
Oliviari, JACC. 41, 2003:1672-8

Effect on LV Function
LV angiography
Echo
Stress Echo
MPS
MRI

WallThickening(%)HyperaemicMBF(ml/g/min)
Cheng et al. JACC Cardiovasc Interventions, 2008
MRI Demonstrates Improved Myocardial Blood Flow And
Wall Thickening Post CTO and Non CTO PCI
Base 24h 6/12

Survival advantage – Registry data

Suero, J. A. et al. J Am Coll Cardiol 2001;38:409-414
Cumulative 10-year survival, 2,007 CTO
patients

The procedural success rate is lower for PCI of CTO than for non-CTO lesions, with a
similar rate of complications.746,747 In a meta-analysis of 13 studies encompassing
7288 patients, recanalization was successful in 69% of cases (ranging from 51–
74%).743 Success rates are strongly dependent on operator skills, experience with
specific procedural techniques, and the availability of dedicated equipment
(specialized guide wires and catheters or very low profile CTO balloons). Bilateral
angiography and IVUS can be very helpful, as can special techniques such as guide-
anchoring, various retrograde approaches, and specific wiring manipulation
techniques, including parallel or anchoring wire.748 A retrograde approach via
collateral pathways offers an additional possibility of success after failure of
antegrade crossing, especially for right coronary artery and LAD occlusions.749 In
general, this technique is not regarded as a first-line approach and is generally
reserved for previous failed attempts.The overall success rate with the retrograde
approach in a multicentre registry of 175 patients was 83.4%.750

Observational studies suggest that successfully revascularized CTOs confer a long-term survival
advantage over failed revascularization.740–742,743,744 In addition, better relief of angina and
functional status was observed after successful CTO recanalization.745 In the post hoc analysis of 4-
year results of the SYNTAX trial, the presence of CTO was the strongest independent predictor of
incomplete revascularization (46.6% in the PCI arm), and had an adverse effect on clinical
outcomes, including mortality.594

High rates of success and low rates of complications are now
achieved by expert operators, even in complex cases

In a meta-analysis of 13 studies encompassing 7288 patients,
recanalization was successful in 69% of cases (ranging from
51–74%).743

The presence of well-developed collaterals often underlies the
reluctance of clinicians to offer PCI in patients affected by
CTOs. However, although the presence of collateral circulation
has been associated with improved survival,36 the collateral
flow was sufficient to preserve ventricular function in only 5%
of CTO patients.37
Werner GS, Surber R, Ferrari M, Fritzenwanger M,
Figulla HR.The functional reserve of collaterals supplying long-
term chronic total coronary occlusions in patients without prior
myocardial infarction. Eur Heart J 2006;27:2406–2412.

A meta-analysis by Joyal et al.40 demonstrated a survival
benefit for patients who underwent CTO recanalization (odds
ratio [OR] 0.56), and a reduction of the need for subsequent
coronary artery bypass graft (CABG) (OR 0.22) and
residual/recurrent angina (OR 0.45). A more recent meta-
analysis also confirmed that successfulCTO PCI was also
associated with reduced mortality in comparison with failed
procedures (OR 0.52).41
Joyal D, Afilalo J, Rinfret S. Effectiveness of recanalization of
chronic total occlusions: a systematic review and meta-
analysis. Am Heart J 2010;160:179–187.
Hoebers LP, Claessen BE, Elias J, Dangas GD, Mehran R,
Henriques JP. Meta-analysis on the impact of percutaneous
coronary intervention of chronic total occlusions on left
ventricular function and clinical outcome. Int J Cardiol
2015;187:90–96.

Despite observational data in favour of CTO PCI from .20 000 patients, the physiological
evidence, and the steady increase in PCI success rates in CTOs to a range similar to complex
non-occlusive lesions, there is a major need for randomized trials to support the treatment
option.At least three major randomized trials are under way.The EURO-CTO trial
(NCT01760083), supported by the EuroCTO club, is examining the impact of PCI on the QOL
parameters as assessed by standardized questionnaires in patients with a CTO when compared
with optimal medical therapy alone within 12 months of treatment. Furthermore, the safety of
the interventional approach is being assessed by comparing clinical endpoints at 3 years.
Unfortunately, the results of this latter trial will not be available before 2016. Another group
from Korea is currently randomizing patients with CTOs and stable angina to PCI vs. medical
therapy [DECISION-CTO (NCT01078051)] to assess the impact of the intervention on cardiac
mortality and MI during a follow-up of 5 years.The ongoing EXPLORE trial is a randomized
clinical trial powered to investigate whether recanalization of a CTO in a noninfarct-related
artery after primary PCI for STEMI in 300 patients randomized to either elective PCI of the CTO
within 7 days or standard medical treatment.The primary endpoints are LVEF and left
ventricular dimensions, as determined by magnetic resonance imaging. Enrolment has been
completed and results are anticipated during 2015

Chronic total occlusion revascularization and quality of life

In the presence of a CTO lesion, the decision-making process
leading to revascularization passes through three steps: the
evaluation of symptoms, the assessment of ischaemic burden,
and the demonstration of viability.47

Patients affected by CTOs sometimes show atypical
symptoms; shortness of breath and exercise limitation are
more frequently observed than typical angina.10 Grantham et
al.45 showed that successfulCTO recanalization was
associated with angina relief, improved physical function, and
enhanced QOL only in symptomatic patients at baseline.
Grantham JA, Jones PG, Cannon L, Spertus JA.
Quantifying the early health status benefits of successful
chronic total occlusion recanalization: results from the
FlowCardia's Approach to ChronicTotal Occlusion
Recanalization (FACTOR) trial. Circ Cardiovasc Qual Outcomes
2010;3:284–290.

The decision about appropriateness was based on the relative
benefits (symptoms, functional status, and/or QOL) and risks
of revascularization using currently available literature and
expert opinion.The main factors considered include symptom
severity on maximal medical therapy, stress testing, extent of
coronary disease, and anatomical location

The AUC revascularization for CTO has been critically
examined in several recent articles.10,55,56 Several aspects of
the UAC methodology have been questioned.55The AUC also
do not consider patient preferences, tolerance to medical
therapy, or the expertise of the CTO PCI operator, which is a
particularly important determinant of both the success rate
and complications in complex CTO cases. An even more
fundamental issue with the current AUC revascularization
ratings is whether CTOs should be regarded as a separate
entity from non-CTO lesions.

It is worthwhile to note that the statement supporting the
recommendation considers the different clinical scenarios
associated with CTO lesions and emphasizes that CTO PCI
should be performed ‘in patients with appropriate clinical
indications’. However, the remainder of the statement is rather
vague, particularly since the definition for ‘suitable anatomy’
or ‘appropriate operator expertise’ is not specified and remains
evolving concepts. Since the publication of these guidelines,
CTO PCI in the USA (as well as around the world) has
undergone drastic improvements with success rates
consistently above 90% and major complication rates around
2% reported in several expert CTO sites.62,63

Conclusion
Although several observational studies have demonstrated
that CTO PCI can improve cardiovascular outcomes and
enhance QOL, its prognostic impact remains under debate. As
a result, the recommendations for CTO PCI are downgraded in
the current guidelines of myocardial revascularization, when
compared with non-CTO lesions. Such a downgrade may not
be justified based on data and in light of current developments
in CTO PCI. In addition to the development of dedicated
equipment and the high success rates achieved among
different interventionalists' communities, the expected results
of randomized trials might hopefully remove remaining doubts
about the efficacy and safety of CTO PCI and therefore expand
its indications. Rational patients' selection and operator's
experience will remain key factors to ensure procedural
success and optimal outcomes.

In Europe, there are no AUC separated from the guidelines.
The decision for individual patients is left to the HeartTeam,
overcoming some of the limitations highlighted above, such
as, for instance, the expertise of the PCI operator. Chronic total
occlusion is included among the anatomical factors to be
considered in the selection of the modality of
revascularization, but the only factors mandating the need for
a HeartTeam discussion are the presence of proximal left
anterior descending (LAD) involvement (if absent PCI can be
performed when technically feasible without the HeartTeam
discussion) and the Syntax Score (when ≥22 CABG can be
performed without the HeartTeam discussion in patients at
low surgical risk). Obviously, the weight given to the presence
of a CTO in the calculation of the SYNTAX score is such that
very few patients with multivessel disease and a CTO will
qualify for PCI, because a complex LAD CTO will almost be
sufficient by itself to reach the surgical threshold of 23 (or 33 if
the left main is involved).

The cut-off of 22 for three-vessel disease without left main
involvement, and 33 for patients with left main disease stems
from the SYNTAX (Synergy between PCI withTaxus and
Cardiac Surgery) trial, can be considered a clear bias against
CTO recanalization. In lesions with stenosis severity between
50 and 99%, the weight of each segment is multiplied by 2.
However, a factor of 5 is used for CTO lesions, so that a
proximal LAD (weight 3.50) occlusion alone with CTO criteria
of risk-adding points (e.g. absence of stump, bridging
collaterals, and calcification) nearly reaches the critical 22
threshold.

Despite the paucity of randomized trials, one question arises
in light of the recent technical advances in CTO
revascularization, why should the indication to treat a CTO by
an expert operator should be considered any different from
the one to treat other nonCTO lesions in stable angina, when
symptoms and/or ischaemia are present?We can at least say
that there is no evidence to support that a CTO is less relevant
with regard to clinical outcomes than for non-occlusive
lesions

The essence of this talk
► Provided patients are selected CTO-PCI can be justified
► CTO results are variable
► How can we improve outcomes
► Novel techniques and approaches to CTO

ׄ Route and course of CTO – distal segment well visualised
– assess quality of distal vessel
ׄ Length and diameter distal without foreshortening
ׄ Best angio view ?
ׄ Presence calcification
ׄNo bridging septal collaterals

Why do them ?
Why do them successfully ?

Patient characteristics
• Mean age 63.5 years
• 78.8% male (p=0.026)
• 96% had angina
• 37% previous MI
• 10% previous CABG

Results
• 10,199 procedures successful (70.6%)
– Revascularisation of at least one vessel
• 751 deaths (5.6%)
– 20.4 per 1000 person years of follow up
• Median follow up 2.56 years (IQR 1.59-3.83)

Multivariate predictors of death
Hazard Ratio
0.1 1 10 100
Renal disease (3.05, 2.26-4.13)
No renal disease
LV ejection fraction <30% (2.24, 1.68-2.97)
LV ejection fraction 30-50% (1.27, 1.02-1.58)
LV ejection fractions >50%
Current smoker (1.67, 1.30-2.14)
Ex-smoker (1.28, 1.09-1.49)
Never smoked
DM - insulin (1.84, 1.38-2.45)
DM - oral agents (1.13, 0.89-1.43)
DM - diet only (1.06, 0.76-1.48)
No DM
NHYA pre PCI IV (2.45, 1.46-4.12)
NHYA pre PCI III (1.40, 1.13-1.75)
NHYA pre PCI II (1.16, 0.97-1.39)
NHYA pre PCI I
Angina pre-PCI Grade 4 (0.50, 0.30-0.84)
No angina pre-PCI
Age 80+ (9.28, 6.31-13.67)
Age 70-<80 (3.94, 2.74-5.66)
Age 60-<70 (2.28, 1.59-3.28)
Age 50-<60 (1.02, 0.68-1.52)
Age <50
Successful revascularisation (0.72, 0.62-0.83)
Failed revascularisation

Mortality is not related to the identity of the occluded coronary artery
0%
2%
4%
6%
8%
10%
Cumulativepercentage
5446 4404 3106 1983 944RCA
1947 1590 1125 699 343CFX
3213 2693 1934 1276 666LAD
0 .5 1 1.5 2 2.5 3 3.5 4
Follow-up time (years)
LAD
CFX
RCA
CFX vs. RCA p= 0.98
LAD vs. RCA p= 0.054

After successful revascularisation, mortality is independent of the identity of the target
vessel
0%
2%
4%
6%
8%
10%
Cumulativepercentage
3484 3013 2117 1352 661RCA
1427 1210 859 529 263CFX
2332 2045 1483 973 504LAD
0 .5 1 1.5 2 2.5 3 3.5 4
LAD
CFX
RCA

Conclusions
• Successful PCI to CTO associated with increased survival
• Complete revascularisation seems to confer advantage
• No significant difference between target epicardial vessels

Study FU
months
No. with
successful PCI
% symptom relief
at FU
Holmes et al JACC 1984 7 13 10 (77)
Keriakes et al JACC 1985 7 40 30 (75)
Serruys et al EHJ 1985 7 28 18 (64)
DiSciascio et al AHJ 1986 8 29 16 (55)
Melchior et al AJC 1987 8 49 40 (82)
Finci et al AJC 1990 24 100 57 (57)
Warren et al AHJ 1990 31 20 16 (80)
Bell et al Circulation 1992 32 234 178 (76)
Ruocco et al AJC 1992 24 160 110 (69)
Ivanhoe et al Circulation 1992 48 286 196 (69)
Stewart et al JACC 1993 14 45 31 (69)
Total 1004 702 (70%)
………REGISTRY
REGISTRY DATA SUGGEST SYMPTOM RELIEF
What data are there on
CTO ?

Requirement for CABG (%)
FU
(months)
CTO success CTO failure
Bell et al 1992 32 18% 58% <0.001
Ivanhoe et al 1992 36 13% 36% <0.0001
Noguchi et al 2000 52 7% 28% <0.001
Oliviari et al 2002 12 2.5% 16% <0.0001

Long term follow up of 14 439
chronic total occlusion angioplasty
cases from the United Kingdom
central cardiac audit database
NICOR
National Institute for Cardiovasular Outcomes Research
Sudhakar George, MRCP; James Cockburn, MD, MRCP; Tim C Clayton, MSc; Peter LudmanMA, MD, FRCP;
James Cotton MD, FRCP; James Spratt MA, FRCP; Simon Redwood MD, FRCP; Mark de Belder MA, MD,
FRCP; Adam de Belder MD, FRCP; Jonathan Hill MA, MRCP; Angela Hoye MB ChB, PhD, FRCP; Nick Palmer
MD, FRCP; Sudhir Rathore MD, MRCP; Anthony Gershlick FRCP; Carlo Di Mario MD, PhD, FRCP; David
Hildick-Smith, MD, FRCP.
14 439 elective CTO procedures on 13 443 patients
4 year follow up
2009

0%
2%
4%
6%
8%
10%
Cumulativemortality
9647 8825 6465 4229 2181Success
3796 3108 2261 1489 727Failure
0 .5 1 1.5 2 2.5 3 3.5 4
All attempted CTOs failed
At least 1 CTO successful
Successful revascularisation is associated with improved survival
p<0.001

Multivariate predictors of death

Prognostic impact of a chronic total
occlusion in a non-infarct-related
artery in patients with ST-segment
elevation myocardial infarction: 3-
year results from the HORIZONS-
AMI trial
Eur Heart J. 2012;33(6):768-775
Prognostic impact of a chronic total occlusion in a non-infarct-related artery in
patients with ST-segment elevation myocardial infarction: 3-year results from the
HORIZONS-AMI trial
Bimmer E. Claessen, George D. Dangas Giora Weisz et al
TREATING CTO IN
THE CONTEXT OF
STEMI

What do we need to indicate CTO PCI?

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