Review
Role of percutaneous coronary intervention in
1
Cardiothoracic Directorate,
Freeman Hospital, Newcastle
Upon Tyne Hospitals NHS
Foundation Trust, Newcastle
Upon Tyne, UK
2
Cardiovascular Diseases of
Vojvodina, Cardiology Clinic,
Sremska Kamenica, Faculty of
Medicine, University of Novi
Sad, Novi Sad, Serbia
3
Department of Internal
Medicine, Division of Cardiology,
Pulmonology and Vascular
Medicine, Nicolaus Copernicus
University in Toruń Ludwik
Rydygier Collegium Medicum in
Bydgoszcz, Bydgoszcz, Poland
4
Klinikum Darmstadt GmbH,
Medizinische Klinik I (Cardiology
and Intensive Care), Darmstadt,
Germany
5
SIRIO MEDICINE Research
Network, Bydgoszcz, Poland
6
Translational and Clinical
Research Institute, Newcastle
University, Newcastle upon
Tyne, UK
Correspondence to
Professor Vijay Kunadian,
Newcastle University
Translational and Clinical
Research Institute, Newcastle
upon Tyne, NE1 7RU, UK;
​vijay.​kunadian@​newcastle.​ac.​uk appropriate patient selection. In this review, we provide
Received 10 November 2022
Accepted 6 March 2023
© Author(s) (or their
employer(s)) 2023. No
commercial re-­use. See rights
and permissions. Published
by BMJ.
To cite: Cartlidge T,
Kovacevic M, Navarese EP,
et al. Heart Epub ahead of
print: [please include Day
Month Year]. doi:10.1136/
heartjnl-2022-321870
the modern-­day management of chronic
coronary syndrome
Timothy Cartlidge,1 Mila Kovacevic,2 Eliano Pio Navarese  ‍ ‍,3,4,5 Gerald Werner,4
Vijay Kunadian  ‍ ‍1,6
ABSTRACT
Contemporary randomised trials of percutaneous
coronary intervention (PCI) in chronic coronary syndrome
(CCS) demonstrate no difference between patients
treated with a conservative or invasive strategy with
respect to all-­cause mortality or myocardial infarction,
although trials lack power to test for individual endpoints
and long-­term follow-­up data are needed. Open-­
label trials consistently show greater improvement in
symptoms and quality of life among patients with stable
angina treated with PCI. Further studies are awaited to
clarify this finding. In patients with severe left ventricular
(LV) systolic dysfunction and obstructive coronary artery
disease in the Revascularization for Ischemic Ventricular
Dysfunction trial, PCI has not been found to improve all-­
cause mortality, heart failure hospitalisation or recovery
of LV function when compared with medical therapy. PCI
was, however, performed without additional hazard and
so remains a treatment option when there are favourable
patient characteristics. The majority of patients reported
no angina, and the low burden of angina in many of the
randomised PCI trials is a widely cited limitation. Despite
contentious evidence, elective PCI for CCS continues
to play a significant role in UK clinical practice. While
PCI for urgent indications has more than doubled since
2006, the rate of elective PCI remains unchanged. PCI
remains an important strategy when symptoms are not
well controlled, and we should maximise its value with
a framework to assist in critical interpretation of findings
from most recent trials and meta-­analysis evidence.
INTRODUCTION
Contrary to patients with acute coronary syndrome
(ACS), the evidence for percutaneous coronary
intervention (PCI) in chronic coronary syndrome
(CCS) is more opaque (table 1). In CCS, the aims
of treatment are to relieve anginal symptoms and
to reduce the risk of important sequelae such
as myocardial infarction (MI), heart failure and
death. Pharmacotherapy has evolved significantly
with the addition of effective antianginal medi-
cations, antiplatelets, renin–angiotensin system
inhibitors, statins and an increasing array of other
lipid-­lowering agents. Modern medical therapy has
beneficial actions throughout the cardiovascular
system and is highly effective in reducing cardio-
vascular risk.1–3 On the other hand, the use of PCI
does not exclude medical therapy, and the synergy
of the two strategies may lead to further outcome
improvement in comparison to medical therapy or
PCI alone.4
Cartlidge T, et al. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321870
While revascularisation is a long established prac-
tice in patients with CCS, this has been challenged
by studies such as Clinical Outcomes Utilizing
Revascularization and Aggressive Drug Evaluation
(COURAGE), International Study of Comparative
Health Effectiveness with Medical and Invasive
Approaches (ISCHEMIA) and Revascularization for
Ischemic Ventricular Dysfunction (REVIVED).5–7
These randomised trials, alongside notable meta-­
analysis on the potential benefit of PCI versus
optimal medical therapy (OMT), are worthy of
discussion. This review provides a summary of
the contemporary randomised trials comparing
PCI versus OMT in the management of CCS and
discusses the limitations of these trials and the role
of PCI in CCS in modern-­day practice. Discussion
relating to optimisation of PCI techniques is beyond
the scope of this article.
PCI VERSUS OMT IN PATIENTS WITH CCS
The COURAGE trial, which compared PCI plus
OMT against OMT alone in patients with CCS,
demonstrated no difference in primary outcome
(death and non-­fatal MI) up to 15 years (table 1).5
The ISCHEMIA open-­ label randomised trial
compared an early invasive strategy (invasive coro-
nary angiography±complete revascularisation
where feasible) added to OMT versus OMT alone.6
ISCHEMIA intended to address perceived limita-
tions of COURAGE (table 2 and figures 1 and 2).8
ISCHEMIA included 5179 patients with stress
testing evidence of moderate or severe ischaemia
with a median follow-­up of 3.2 years. A blinded
CT coronary angiogram was performed to exclude
left main disease (8%) or non-­obstructive disease
(15%). Patients with severe left ventricular (LV)
dysfunction (ejection fraction (EF) <35%), heart
failure with New York Heart Association (NYHA)
functional class 3/4 symptoms, ACS within 12
months, intolerable angina or severe kidney
disease were excluded. The primary endpoint was
a composite of cardiovascular death, MI, admis-
sion with unstable angina or heart failure, or resus-
citated cardiac arrest. The estimated cumulative
event rate for the primary endpoint was 16.4%
in the invasive-­ strategy group and 18.2% in the
conservative-­strategy group (difference −1.8%,
95% CI −4.7 to 1.0). The primary endpoint did
not differ between treatment groups even when
the highest-­risk patients were selected by anatom-
ical complexity of coronary disease or ischaemic
burden. Interestingly, anatomical complexity (as
  1
 Review

Table 1  Trials comparing OMT and revascularisation

Trial Year Patients (n) Age (mean) Female (%) CABG (%) Characteristics Follow-­up Mortality MI Angina relief
ACME-­1 1992 212 62.5 0 0 Stable CCS 3 years → → ↑
ACME-2­ 1997 101 N/A 0 0 Stable CCS 5 years → → ↑
MASS-I­ 1995 144 54–58 42 32 Stable CCS 3 years → → ↑
RITA-­2 2003 1018 58 (median) 18 0 Stable CCS 7 years → → ↑
MASS-­II 2004 408 60 28–33 33 Stable CCS 5 years → → ↑
COURAGE 2007 2287 62 15 0 Stable CCS 4.6 years → → ↑
BARI2D 2009 1605 62.4 30 32 ACS/CCS 5 years → → ↑
Diabetes
FAME 2 2018 888 63.7 22 0 Stable CCS 5 years → → ↑
ORBITA 2018 200 66 27 0 Stable CCS 6 weeks N/A N/A →
ISCHEMIA 2020 5179 64 23 26 Stable CCS 3.3 years → → ↑
REVIVED 2022 700 70 13 0 Stable CCS 3.4 years → → N/A
→ no difference between PCI and OMT; ↑ statistically significant benefit from PCI versus OMT.
ACME-­1, Angioplasty Compared to Medicine 1; ACME-­2, Angioplasty Compared to Medicine 2; ACS, acute coronary syndrome; BARI2D, Bypass Angioplasty Revascularisation
Investigation 2 Diabetes; CABG, coronary artery bypass graft; CCS, chronic coronary syndrome; COURAGE, Clinical Outcomes Utilizing Revascularization and Aggressive Drug
Evaluation; FAME 2, Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2; ISCHEMIA, International Study of Comparative Health Effectiveness with Medical
and Invasive Approaches; MASS-­I, Medicine, Angioplasty or Surgery Study I; MASS-­II, Medicine, Angioplasty or Surgery Study II; MI, myocardial infarction; N/A, not applicable (not
a reported outcome in the study); OMT, optimal medical therapy; ORBITA, Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable
Angina; PCI, percutaneous coronary intervention; REVIVED, Revascularization for Ischemic Ventricular Dysfunction; RITA-­2, Second Randomized Intervention Treatment of Angina.

measured by the modified Duke Prognostic Index) but not isch-
aemic burden was associated with increased risk of MI.9 There
was no difference in primary endpoint when prespecified anal-
yses were performed in patients with diabetes or in the substudy
of patients with severe chronic kidney disease.6 10
Despite a relatively low burden of symptoms at baseline (only
22% of patients reported daily/weekly angina and 34% reported
no angina in the preceding 4 weeks), the invasive-­strategy group
reported greater freedom from angina and improved quality
of life when compared with the conservative-­ strategy group,
and patients with the greatest burden of symptoms derived the
greatest benefit. This is consistent with the results of COURAGE,
though the advantage disappeared after 3–5 years.5
It is important to highlight that patients with significant left
main coronary artery disease were excluded from COURAGE
and ISCHEMIA on account of historical studies demonstrating
increased mortality in patients with severe left main stenosis
and the clear benefit of revascularisation with coronary artery
bypass grafting (CABG).11 On the basis of randomised trials, this
has been extrapolated to broad equivalence of revascularisation
with PCI and CABG for selected patients with severe left main
disease and low anatomical complexity, as supported by guide-
lines (table 3).12–18
The low primary outcome event rates seen in ISCHEMIA
allude to the increasing efficacy of OMT in CCS. In patients with
stable angina and/or evidence of inducible ischaemia (excluding
left main coronary artery (LMCA) disease, severe LV dysfunc-
tion and CCS class 4 angina), a conservative strategy could be
pursued safely, and an invasive strategy should be offered to
those with refractory symptoms without risk of excess harm.
In the Objective Randomized Blinded Investigation With
Optimal Medical Therapy of Angioplasty in Stable Angina
(ORBITA) trial, which randomised 200 patients with ischaemic
symptoms, PCI was compared with a placebo sham procedure in
participants with CCS and at least one severe coronary stenosis
(>70%) amenable to PCI.19 This study showed no significant
difference between groups in the primary endpoint of exercise
time increment (28.4 s vs 11.8 s, p=0.20) or changes in Seattle
Angina Questionnaire physical limitation (7.4 vs 5.0, p=0.42).
However, the PCI group did exhibit greater freedom from
2 Cartlidge T, et al. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321870
angina (49.5% vs 31.5%, p<0.05). Several limitations should be
considered when interpreting the findings of ORBITA (table 2
and figures 1 and 2).15
PCI IN PATIENTS WITH CCS WITH LV DYSFUNCTION
Ischaemic cardiomyopathy is the most common cause of heart
failure and is associated with poor prognosis. The evidence for
revascularisation in patients with LV dysfunction and coronary
disease has been based on trials comparing CABG with medical
therapy, with the Surgical Treatment for Ischaemic Heart Failure
(STICH) trial most prominent.20 Although surgical revasculari-
sation was associated with higher mortality at 30 days (HR 3.12,
95% CI 1.33 to 7.31; p=0.006), a survival benefit emerged at
10 years with reduction in all-­cause death (HR 0.84, 95% CI
0.73 to 0.97; p=0.02).21
In a secondary analysis of ISCHEMIA among patients with
heart failure and/or LV systolic dysfunction (EF 35%–45%), an
invasive strategy was associated with a lower rate of the primary
outcome than a conservative strategy (17.2% vs 29.3%; differ-
ence in 4-­year event rate −12.1% (95% CI −22.6 to −1.6%)),
while among those without heart failure and/or LV systolic
dysfunction, there was no difference between the invasive-­
strategy and conservative-­strategy groups.22 This hints at a posi-
tive role for percutaneous as well as surgical revascularisation in
ischaemic cardiomyopathy.
The REVIVED (REVIVED-­British Cardiovascular Interven-
tion Society 2 (BCIS2)) trial was an open-­label randomised trial
conducted in 700 stable patients with reduced left ventricular
ejection fraction (LVEF) (<35%), significant coronary artery
disease (BCIS Jeopardy score ≥6) and myocardial viability (in
at least four dysfunctional myocardial segments) to compare
PCI plus OMT with OMT alone.7 Patients with decompensated
heart failure, sustained ventricular arrhythmia or recent ACS
were excluded. The primary endpoint was all-­cause death or
hospitalisation for heart failure, with a broad range of secondary
endpoints including LVEF and quality-­of-­life scores.
The median follow-­up was 3.4 years. Mean age was 70 years;
41% had diabetes and 50% had a history of MI. The mean
BCIS Jeopardy score preprocedure was 9.3, and 50%–60%
 Review

Table 2  Strengths and limitations of recent RCTs comparing revascularisation+OMT versus OMT alone
Strengths and Limitations Impact of trial findings on clinical practice
COURAGE
1 Open-­label (unblinded) study design with no cross over in allocated treatment strategy Subject to investigator and participant bias
2 High proportion of patients had mild symptoms: 42% in the PCI cohort had CCS class 1 or 2 Limited scope for symptom improvement and low event rates
angina.
3 Excluded patients with CCS class 4 angina (not controlled with medical therapy) and patients Difficult to determine the benefit of revascularisation among these
with a markedly positive stress test patients
4 Randomisation after angiography (35 539 were screened to enrol 3071) Patients with severe patterns of CAD are likely to have been
excluded.
5 PCI did not reflect contemporary practice with advances in invasive diagnostic assessment Contemporary PCI is suggested to improve outcomes by ~15% (5-­
(pressure wire), intravascular imaging and stent technology (<3% received drug eluting stents) year MACCE in SYNTAX II: 21.5% vs SYNTAX I: 36.4%, p<0.001)
ISCHEMIA
1 Open-­label (unblinded) study design with 21% of patients in conservative group having Subject to investigator and participant bias
revascularisation
2 As a result of recruitment challenges, sample size reduced to 5000 and follow-­up was shorter Power of the study compromised
than expected.
3 As a result of low event rates, the composite endpoint was extended during the trial to include Change in endpoint may affect validity and the addition of
resuscitated cardiac arrest, hospitalisation for unstable angina or heart failure. subjective endpoints may be open to bias.
4 Low burden of angina symptoms: 34% had no angina in the preceding 4 weeks Limited generalisability to patients with severe symptoms
5 Results sensitive to definition of MI: there were either 443 or 593 events, depending on the Further study is required to clarify the prognostic relevance of
definition of procedural MI used different definitions of procedural MI.
ORBITA
1 The sample size was small (n=200) with no crossover in allocated treatment strategy. Subject to type II error
2 Patients in the PCI group began with an exercise time of 528 s (equating to stage 3 of the Mild limitation in effort tolerance and limited scope for
treadmill test) and SAQ physical limitation mean score of 71.3. improvement
3 Objective evidence of inducible ischaemia was not required in the study design. Difficult to determine the impact of revascularisation on ischaemic
segments
4 Patients benefiting from weekly consultant-­delivered care It may be difficult to replicate the intensive medical supervision
provided in the trial run-­in period in the real world.
5 The use of pressure wire assessment to discriminate obstructive lesions is standard practice in 29% of patients had FFR of >0.80 and 32% iFR of >0.89 who
contemporary PCI (class 1A recommendation), but here operators were blinded to data proceeded to PCI; this is not consistent with best practice and may
have attenuated a treatment effect in the PCI group.
REVIVED
1 Open-­label (unblinded) study design with 10.5% in conservative group having unplanned Subject to investigator and participant bias
revascularisation
2 Very low burden of angina: 66% of patients had no angina; 32% had CCS class 1/2 angina; and The paucity of angina symptoms raises questions about the
patients with class 3/4 angina were excluded. prevalence of ischaemia in the study population. Findings cannot be
extrapolated to patients with severe angina.
3 Enrolment after angiography if the local MDT did not recommend CABG and deemed that PCI Selection bias excluding patients with the most severe patterns of
was appropriate CAD and favourable characteristics for surgery; findings cannot be
applied to this group of patients
4 Unclear that extent of CAD accounts for severity of LV dysfunction Await data correlating ischaemia, viability and revascularisation to
establish a causal association of CAD and LV dysfunction and the
effect of PCI
5 Limited duration of follow-­up (3.4 years) Extended follow-­up required to establish whether there is a longer-­
term treatment effect and to allow comparisons with STICH (in
which a survival benefit accrued over 10 years)
CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCS, Canadian Cardiovascular Association; CCS, chronic coronary syndrome; COURAGE, Clinical Outcomes
Utilizing Revascularization and Aggressive Drug Evaluation; FFR, fractional flow reserve; iFR, instantaneous wave-­free ratio; ISCHEMIA, International Study of Comparative Health
Effectiveness with Medical and Invasive Approaches; LV, left ventricular; MACCE, major adverse cardiovascular and cerebrovascular event; MDT, multidisciplinary meeting; MI,
myocardial infarction; OMT, optimal medical therapy; ORBITA, Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina; PCI,
percutaneous coronary intervention; RCT, randomised controlled trial; REVIVED, Revascularization for Ischemic Ventricular Dysfunction; SAQ, Seattle Angina Questionnaire; STICH,
Surgical Treatment for Ischaemic Heart Failure; SYNTAX, Synergy between PCI with Taxus and Cardiac Surgery.

had proximal left anterior descending artery lesions. By way
of symptoms, 71%–77% reported NYHA classes 1 and 2, and
23%–29% reported NYHA class 3 and 4 symptoms. There was a
very low burden of angina, with 66% of patients having no angina,
32% having CCS class 1 and 2 angina and only 2% having class
3 symptoms. Heart failure therapy was robust, with all patients
receiving renin–angiotensin system inhibition, one-­third of those
receiving an angiotensin–neprilysin inhibitor, 54%–57% taking
a mineralocorticoid antagonist, 92%–94% taking a beta-­blocker,
Cartlidge T, et al. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321870
60%–63% taking a diuretic and 85%–88% taking a statin at
2 years. Around one-­ quarter of patients had an implantable
cardioverter defibrillator or cardiac synchronisation therapy
(ICD/CRT-­D) device. PCI was performed in a median of two
vessels and median two lesions, with a mean anatomical revascu-
larisation index of 71%.
The rate of the primary endpoint was comparable between the
PCI group and the OMT group (37.2% vs 38%, p=0.96), and
events were largely driven by all-­cause death (31.7% vs 32.6%).
3
 Review

Figure 1  Factors influencing PCI trials. CAD, coronary artery disease; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT,
randomised controlled trial.

There was no difference in recovery of LVEF (mean difference
0.9%). PCI was performed safely with very little use of haemo-
dynamic support and no increase in mortality. There was a
greater improvement in quality of life scores in the PCI group,
though this disappeared by 24 months. The rate of MI was
similar in the PCI and OMT groups (10.7% vs 10.8%), but after
the expected signal of periprocedural MI, spontaneous MI (18 vs
33 events) and unplanned revascularisation (10 vs 37 events; HR
0.27, 95% CI 0.13 to 0.53) were lower in the PCI group. In the
subset of patients with extensive myocardial viability, there was
a lower rate of activation of ICD/CRT-­D to terminate ventricular
arrhythmia in patients who had been treated with PCI.

Figure 2  Limitations of randomised controlled trials comparing PCI versus OMT. CAD, coronary artery disease; OMT, optimal medical therapy; PCI,
percutaneous coronary intervention.
4 Cartlidge T, et al. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321870
 Review

Table 3  Guideline recommendations for management of CCS Table 4  Questions yet to be answered in Revascularisation for
Guideline recommendations Ischaemic Ventricular Dysfunction
ACC/AHA ESC 1 Correlation of coronary lesions and myocardial ischaemia/viability to consider
in each case whether there was a causal relationship between coronary disease
Diagnosis Assess pretest Assess pretest probability and LV dysfunction or whether these two common conditions simply coexisted
probability
2 The absence of angina in the majority of patients and seeming discordance
Low risk: CAC or ETT CTA /non-­invasive functional test between severity of LV dysfunction and extent of coronary disease make this a
intermediate/high risk: vital point to clarify.
CTA /non-­invasive
3 It will be similarly interesting to appraise procedural data concerning lesion
functional test
characteristics and physiological assessment.
Event risk stratification
4 The aforementioned may help to elucidate whether there are groups of
Health Need to address – patients who could still derive benefit from PCI (such as those with angina and
inequalities disparities in care obstructive proximal coronary disease correlating with a territory of extensive
for women, ethnic ischaemia and viability).
minorities and elderly
LV, left ventricular; PCI, percutaneous coronary intervention.
Treatment – Lifestyle management: smoking,
diet, activity, weight and medication
concordance
it more difficult to demonstrate incremental benefit. Further
– Influenza vaccination
valuable information is still to come from REVIVED (table 4). In
Antiplatelet therapy Pharmacological management
(other pharmacotherapy ► Antianginal therapy.
the meantime, this study underlines the high mortality rates of
not addressed here) ► Antithrombotic therapy. patients who have severe LV systolic dysfunction in the context
► Lipid-­lowering therapy of significant coronary artery disease and the importance of
► RAS inhibitors. evidence-­based medical and device therapy.
Revascularisation Revascularisation
► For prognostic ► For prognostic benefit in high-­risk PCI IN PATIENTS WITH CCS WITH CHRONIC TOTAL
benefit in high-­risk patients or symptom relief.
OCCLUSIONS (CTOS)
patients or symptom ► Individualised, shared decision.
relief. A CTO of a coronary artery supplied by a network of collaterals
► Patient-­centred is the archetype CCS. Despite a collateral supply, this is usually
decision. insufficient to prevent ischaemia during exercise, and there is
► Guided by heart evidence that these lesions are not associated with a benign
team. prognosis.23–26
Heart failure: when Heart failure Optimal Medical Therapy With or Without Stenting for Coro-
patients have LVSD and ► Treat associated LVSD. nary Chronic Total Occlusion was the largest randomised trial
MVD, consider CABG or ► Consider revascularisation.
to date comparing long-­term outcome between CTO–PCI plus
PCI if not suitable
OMT against OMT alone but was hindered by slow enrolment
Surveillance – 3 monthly review for first year then
annual review
and a high number of crossovers (almost 20%).27 Though CTO–
► Clinical assessment, risk PCI was successful in 91%, the trial showed no difference in
stratification and ECG. cardiovascular events between treatment groups (3-­year major
► If ongoing symptoms, non-­invasive adverse cardiovascular events: 22.3% vs 22.4%, p=0.84).
functional test. Notably, ~70% of patients in the OMT group underwent PCI
Special Invasive coronary Consider invasive coronary function to non-­CTO lesions after randomisation (mean number of stents
considerations: function testing testing. per patient 2.0 in the OMT group vs 2.4 in the PCI group), and
angina without recommended
there was equivalent improvement in symptom and quality of
coronary
obstruction life scores in both groups. The Randomized Multicentre Trial
Screening No recommendation Consider screening asymptomatic
to Compare Revascularization With Optimal Medical Therapy
individuals >40 years with risk for the Treatment of Chronic Total Occlusions trial compared
estimation tools and individuals with a impact on symptoms and quality of life in 396 patients treated
strong family history. with either CTO–PCI plus OMT or OMT alone, with appro-
ACC, American College of Cardiology; AHA, American Heart Association; CABG, priate non-­CTO lesions treated before baseline symptom evalu-
coronary artery bypass grafting; CAC, coronary artery calcium score; CCS, chronic ation and randomisation.28 The patients treated with CTO–PCI
coronary syndrome; CTA, CT angiography; ESC, European Society of Cardiology; ETT, reported greater improvement in angina frequency and quality
exercise tolerance test; LVSD, left ventricular systolic dysfunction; MVD, multivessel
of life scores than the OMT group. The smaller Randomized
disease; PCI, percutaneous coronary intervention; RAS, renin–angiotensin system.
Controlled Comparison of Optimal Medical Therapy with
Percutaneous Recanalization of Chronic Total Occlusion recently
Overall, it seems that the beneficial effect of surgical revas- confirmed these findings.29
cularisation in STICH has not been replicated in REVIVED, In a different patient cohort, the Evaluating Xience and Left
although the population in STICH was much larger and survival Ventricular Function in PCI on Occlusions after STEMI trial
benefit accrued over longer follow-­up.7 21 It is likely that patients enrolled patients surviving an ST elevation MI who were found
with severe patterns of coronary disease were not enrolled in to have a CTO as a pre-­existing additional lesion.30 This demon-
REVIVED but referred for surgery on the basis of existing recom- strated no difference in the effect of CTO–PCI versus OMT on
mendations. In addition, the higher standard of evidence-­based LV function at 4 months (44.1%±12.2% vs 44.8%±11.9%,
heart failure therapy used in REVIVED (eg, use of mineralocor- p=0.60), though the procedural success rate was low (73%). The
ticoid receptor antagonist (MRA)s, angiotensin receptor nepri- Randomized Trial to Assess Regional Left Ventricular Function
lysin inhibitor (ARNI)s and implantable devices) will have made after Stent Implantation in Chronic Total Occlusion addressed
Cartlidge T, et al. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321870 5
 Review
the effect of CTO–PCI on regional LV performance in patients
with angina or an abnormal functional test.31 No difference was
observed in LV segmental wall thickening between the groups
treated with CTO–PCI or OMT alone (4.1% vs 6.0%, p=0.57),
though baseline LVEF was actually in the normal range.
As with all randomised trials in the field of PCI, the exclusion
of severely affected patients results in a bias towards enrolling
patients who are less symptomatic. CTO–PCI trials have strug-
gled with patient enrolment due to the large number of partici-
pants required and the limited number of centres with expertise
in CTO–PCI, resulting in extended time periods and termination
before achieving the prespecified recruitment target. This will
remain a challenge in this lesion subset.
While evidence for the prognostic value of PCI in stable coro-
nary disease is lacking, open-­label randomised trials support the
argument that recanalising a CTO alleviates limiting symptoms
and improves quality of life. US guidelines currently recom-
mend that CTO–PCI be considered as second-­ line treatment
for relief of angina in patients with preserved LV function when
they remain symptomatic despite optimal medication.14 A sham-­
procedure control arm in future CTO trials may strengthen our
understanding of symptomatic benefit and the basis for CTO–
PCI in guideline recommendations.
FINDINGS FROM META-ANALYSIS OF CARDIOVASCULAR
OUTCOMES
Following the publication of ISCHEMIA, a meta-­analysis was
performed of 25 randomised trials comprising 19 806 patients
which compared medical therapy with revascularisation in
patients with CCS with an average follow-­up of 5.7 years.4 The
primary endpoint of cardiac mortality was lower in the group
undergoing revascularisation (relative risk (RR) 0.79, 95% CI
0.67 to 0.93; p<0.01) as was the incidence of spontaneous
MI (RR 0.74, 95% CI 0.64 to 0.86; p<0.01). There was no
difference in all-­cause mortality (RR 0.94, 95% CI 0.87 to 1.01;
p=0.11), total MI (combination of procedural and spontaneous
MI) (p=0.14) or stroke (p=0.30). A pivotal finding from this
meta-­analysis is that cardiac mortality reduction was linearly
associated with follow-­ up duration, so that a 19% cardiac
mortality reduction could be expected every 4-­year follow-­up.
By current standards, medical management in older trials was
suboptimal and, it might be argued, may have favoured elec-
tive revascularisation plus medical therapy over medical therapy
alone. Of note, intensity of medical therapy influences not only
the medical therapy arm but also the revascularisation plus
medical therapy arm. This was well illustrated in a pooled anal-
ysis of trials in diabetic patients showing a significant reduction
of the composite of death, MI and stroke with revascularisation
plus medical therapy versus medical therapy alone that accrued
over time.32 In that analysis, the benefit of revascularisation plus
medical therapy was attenuated when lipid-­lowering was subop-
timal. Thus, there is a synergism between revascularisation and
medical therapy, and the combination of both optimal strate-
gies is required to achieve maximal and durable prevention of
adverse events.
The main strength of randomised studies is that study arms
are generally balanced for baseline characteristics (any imbal-
ance should be the result of chance). Similarly, interventions in
study arms other than those under investigation should gener-
ally be balanced during trial follow-­up, as was the case in trials
of revascularisation versus medical therapy alone. Older studies
may have exposed patients to sub-­OMT by current standards,
but this was comparable in both treatment arms, preserving the
6 Cartlidge T, et al. Heart 2023;0:1–7. doi:10.1136/heartjnl-2022-321870
capacity to assess treatment effect of revascularisation on 4-­year
follow-­up in these trials.
The chronological order of studies in the meta-­analysis did not
impact the cardiac death findings. In additional analyses, the per
cent use of any of the most frequently employed drug types, such
as statins, antithrombotic agents, beta blockers or renin–angio-
tensin inhibitors, did not influence cardiac mortality findings nor
explain the heterogeneity of effect across trials. The achieved
power of the meta-­analysis was >90%, the greatest ever in this
setting, by far more than any individual trial or meta-­analysis
comparing revascularisation plus medical therapy versus medical
therapy alone.33 34 The neutral finding for all-­cause mortality
is likely explained by the competing risk of non-­cardiac modes
of death attenuating the estimated true effect between the two
arms. It is also important to note that antianginal medication will
often not eradicate symptoms despite optimal titration and that
patients must endure the potential side effects of taking long-­
term medication. In the correct circumstances, PCI can offer
complete angina relief. In the ISCHEMIA EXTENDED study,
there was no difference in all-­cause mortality with an initial inva-
sive strategy compared with an initial conservative strategy, but
there was lower risk of cardiovascular mortality and higher risk
of non-­cardiovascular mortality with an initial invasive strategy
during a median follow-­up of 5.7 years.35
REAL-WORLD CLINICAL PRACTICE
Despite contentious evidence surrounding the efficacy of PCI in
CCS, it continues to play a major role in UK clinical practice.
Elective PCI for stable coronary disease (34.5% of all PCI proce-
dures) remained relatively constant at 50.7–58.4/100 000 popu-
lation in England and Wales during the period 2006–2019.36
This may represent difficulty in disrupting the long-­held dogma
shared by clinicians and patients that PCI to relieve severe
stenoses in the major epicardial coronary arteries must translate
into clinical benefit. Interventional cardiology practice in the UK
was already aligned with the message of these trials that PCI in
CCS be targeted in those patients with severe symptoms despite
optimised medical therapy.36
FUTURE DIRECTIONS
Older adults are often excluded from research (table 1 and
figure 2). With our population ageing, there is a need to deter-
mine best strategy in older adults with coronary artery disease.37
In addition, female adults are consistently under-­represented in
studies (table 1 and figure 2). Of note, 50%–70% of women
undergoing angiography have ischaemia with non-­obstructive
coronary arteries (INOCA) and require evaluation of the micro-
vascular function and the INOCA endotypes.38–40 Importantly, in
CCS, there is a small rate of plaques with instability criteria (eg,
thin-­cap fibroatheroma) that may rapidly progress.41 Results of
ongoing invasive physiology and intracoronary imaging studies
are awaited.
CONCLUSION
Large randomised trials of a conservative versus invasive
treatment strategy have found no mortality benefit associated
with revascularisation in patients with CCS. It is reasonably
contended that the high proportion of patients with mild angina
in these trials may offset the benefit of revascularisation in those
with severely limiting angina who have higher event rates and
potential for greater symptomatic gain. In patients with CCS,
modifying the atherosclerosis disease process, treating asso-
ciated LV dysfunction and alleviating symptoms with actively

optimised medical therapy should be the foundation of care. PCI
remains an important strategy for those in whom symptoms are
not adequately controlled and potentially improve outcomes at
long term, and we should concentrate its value by maintaining
and refining patient selection.
Twitter Timothy Cartlidge @timcartlidge1 and Vijay Kunadian @VijayKunadian
Contributors  TC, MK and GW wrote the first draft and undertook multiple
revisions. TC, MK, EPN and GW provided critical review. VK conceived the idea and
undertook multiple revisions.
Funding  VK received research funding from the British Heart Foundation
(CS/15/7/31679). The funders had no role in study design, data collection and
analysis, decision to publish or preparation of the manuscript. EPN reports research
grants from Abbott and Amgen and lecture fees/honoraria from Amgen, AstraZeneca,
Bayer, Pfizer and Sanofi-­Regeneron outside the submitted work. GW received
speaker honoraria for Abbott Vascular, ASAHI Intecc, Orbus-­Neich, Philips, Siemens,
Shockwave Medical and Terumo.
Competing interests  VK is an associate editor for Heart.
Patient consent for publication  Not applicable.
Ethics approval  Not applicable.
Provenance and peer review  Commissioned; externally peer reviewed.
ORCID iDs
Eliano Pio Navarese http://orcid.org/0000-0002-2355-4589
Vijay Kunadian http://orcid.org/0000-0003-2975-6971
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