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Cost and efficacy of myocardial revascularisation in the drug
eluting stent era: how much for how much?
Robert Henderson
Consultant cardiologist, Trent Cardiac Centre, Nottingham University Hospitals, City Hospital
Campus, Nottingham, NG51PB, United Kingdom
56294
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016.
For permissions please email: [email protected].
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Correspondence: Email: [email protected], Phone: +44 (0)115 9691169 ext
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Across Europe, an aging population and improved survival after acute coronary syndrome is
increasing the prevalence of stable coronary artery disease. Large numbers of people
therefore require treatment with long-term anti-anginal and secondary prevention
medication, and may be offered expensive cardiac investigations and myocardial
revascularisation procedures. This use of resources places a substantial economic burden
on healthcare systems and in the United Kingdom it has been estimated that the
management of angina consumes 1% of the total National Health Service budget. 1 More
$177.1 billion and a substantial proportion of these costs were attributable to myocardial
revascularisation procedures. 2 Evidence that this investment represents value for money is
limited, and the review of the published evidence on the cost-effectiveness of myocardial
revascularisation procedures for the treatment of multi-vessel coronary artery disease by
Ariyaratne and colleagues in this issue of the Journal is therefore timely.
Cost-effectiveness is typically assessed with the incremental cost-effectiveness ratio (ICER),
which incorporates differences in clinical efficacy and economic cost between alternative
treatments into a single metric, expressed as the incremental cost per additional unit of
efficacy. The standard metric for assessment of clinical efficacy is the Quality Adjusted Life
Year (QALY), which combines the impact of treatment on quantity and quality of life. A
treatment that is less effective and more expensive than an alternative treatment is not costeffective and would not be recommended. Conversely, treatment that is more effective and
less expensive has a lower ICER, dominates the alternative treatment, and is generally
considered to be the preferred strategy. Health economic analysis is particularly useful,
however, when a treatment increases clinical effectiveness but incurs a higher cost than an
alternative treatment, and in these circumstances the ICER is judged against the amount
that the relevant society is willing to pay per QALY.
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recently in the USA the direct and indirect costs of coronary heart disease were estimated at
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What is the efficacy of alternative myocardial revascularisation procedures?
When Andreas Grüntzig introduced percutaneous transluminal coronary balloon angioplasty
into routine practice nearly 40 years ago, the early clinical results were marred by high rates
of procedure-related coronary occlusion and target lesion restenosis during subsequent
follow-up. Over the ensuing decades these problems have been addressed by iterative
improvements in interventional practice, including the development of bare-metal and drugeluting coronary stents, combined with dual antiplatelet therapy to minimise the risk of stent
thrombosis. As a result, percutaneous coronary intervention is now used to treat many
surgery was previously mandated. Nevertheless, the optimal long-term revascularisation
strategy for most patients with stable multi-vessel coronary artery disease remains
controversial. 3;4
Numerous randomised trials of coronary artery bypass graft surgery versus percutaneous
coronary intervention suggest that both methods of myocardial revascularisation relieve
angina, but have reported inconsistent effects on other major clinical outcomes. Metaanalyses of the trials suggest that coronary artery bypass surgery confers a survival
advantage, particularly in patients with diabetes, 5 but the relevance of this finding to
contemporary practice is limited by wide variation in the percutaneous revascularisation
techniques that were studied in the individual trials.
Two recent randomised trials that assessed the efficacy of percutaneous coronary
intervention using drug-eluting stents are therefore of particular interest. The SYNTAX trial
randomised 1800 patients with multi-vessel coronary disease to coronary artery bypass
surgery or to percutaneous revascularisation using ‘first-generation’ paclitaxel-eluting stents.
Although SYNTAX was designed as a non-inferiority trial, at five years there was a 10%
absolute difference in the rate of the primary endpoint (a composite of all-cause mortality,
stroke, myocardial infarction, and repeat revascularisation), which favoured surgical
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patients with multi-vessel coronary artery disease for whom coronary artery bypass graft
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treatment and exceeded the pre-specified non-inferiority margin. This difference was due to
higher rates of repeat revascularisation and myocardial infarction in the percutaneous
coronary intervention group with no differences in mortality or stroke. 6 The mechanism for
the difference in the rate of myocardial infarction is unclear, but it is plausible that a coronary
bypass graft provides greater protection against the effects of future plaque disruption than
focal treatment with a stent. On the other hand, the difference in the rate of myocardial
infarction might also be explained by ascertainment bias in an open study, and the clinical
impact of myocardial infarction related to interventional coronary procedures varies
substantially, depending on the size of the infarct. 7 Hence, the clinical relevance of the
open to debate. Nevertheless, multiple exploratory subgroup analyses of the primary
endpoint by angiographic risk score and pattern of coronary disease have received
considerable emphasis in SYNTAX trial publications, and have influenced guideline
recommendations, 8 even though such analyses have limited statistical power.
The FREEDOM trial randomised 1900 patients with diabetes and multi-vessel coronary
disease into a trial of coronary artery bypass surgery versus percutaneous revascularisation
using ‘first generation’ sirolimus-eluting coronary stents. At five years the surgical strategy
was associated with a 7.9% absolute reduction in risk of the primary outcome (a composite
of death from any cause, nonfatal myocardial infarction, or nonfatal stroke) and a 5.4%
absolute reduction in mortality. The mortality benefit only appeared after two years and for
the average patient, surgery only extended life by a few months. Moreover stroke was more
frequent in the surgical group, with a 2.8% absolute difference at five years. 9
These randomised trials enrolled selected patients who were considered suitable for both
myocardial revascularisation strategies, and the results may not be generalizable to the
larger population of patients with multi-vessel coronary disease undergoing myocardial
revascularisation in routine practice. Large observational registries may provide additional
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differences in the rates of myocardial infarction and the primary end-point in SYNTAX are
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information, and the ASCERT study of patients with multi-vessel disease reported outcomes
after coronary artery surgery in 86,244 patients and percutaneous revascularisation in
103,549 patients, 78% of whom received a drug-eluting stent. After 4 years propensity-score
adjusted mortality was lower after surgical revascularisation (absolute difference 4.4%), 10
but residual confounding by variables that were not included in multivariable adjustment is
an inherent limitation of this type of analysis. In another registry of 1013 patients undergoing
percutaneous coronary intervention for multi-vessel disease, ineligibility for coronary bypass
surgery in 22% of patients was associated with a six-fold increase in the odds of in-hospital,
and a three-fold increase in the hazard of longer-term mortality. This effect could not be
How much does myocardial revascularisation cost?
Healthcare costs vary widely between different countries and healthcare systems, reflecting
differences in health policy, arrangements for clinical care, and the price of consumables.
Long-term healthcare costs of individual patients with stable coronary artery disease may
also be influenced by cardiovascular risk profile, and low risk patients with longer life
expectancy may incur substantial future healthcare costs. 12
The costs of myocardial revascularisation procedures have evolved over time as new
technologies have become available. In the pre-stent era the cost of a coronary artery
bypass operation was estimated to be nearly twice the cost of a coronary balloon
angioplasty procedure, but this difference attenuated during follow-up, reflecting a greater
requirement for additional revascularisation procedures and medications after percutaneous
treatment. 13 The introduction of bare metal stents narrowed the difference in costs between
the two revascularisation strategies because of the requirement for additional equipment and
medication, and the need to treat late complications including in-stent restenosis. 14 The
development of drug-eluting stents further improved the clinical outcome but also increased
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explained by differences in other known risk factors for adverse outcome. 11
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the costs of percutaneous revascularisation, leading to early restriction in the use of this
technology in many countries.
In the SYNTAX trial the initial procedural costs were lower for coronary artery surgery than
for percutaneous revascularisation, reflecting the high cost of drug-eluting stents, but the
total cost of the initial hospitalisation and estimated life-time costs were higher in the surgical
group. 15 In the FREEDOM trial the total costs of the index hospitalization were also higher
for patients assigned to surgery, but this difference attenuated over 5 years as patients
assigned to percutaneous intervention required more repeat revascularisation procedures
Review of cost-effectiveness studies
Although there is evidence from some recent randomised trials that myocardial
revascularisation by coronary artery bypass surgery confers a modest survival benefit over
percutaneous revascularisation, uncertainty about the optimal choice of revascularisation
strategy for patients with multi-vessel coronary artery disease persists. Moreover, the
estimated costs of revascularisation have varied over time, reflecting rapid advances in
interventional cardiology with the introduction of effective but expensive new technologies.
Against this background reliable estimation of cost-effectiveness of myocardial
revascularisation strategies is challenging.
Ariyaratne et al are therefore to be congratulated on their systematic review of studies
comparing surgical and percutaneous revascularisation procedures in subjects with multivessel disease that also reported health economic analyses. The review identified 16
relevant health economic studies, including 12 that were conducted alongside 11
randomised trials, and 4 that were based on comparison of non-randomised patient cohorts.
This selection process excludes studies comparing coronary bypass surgery and
percutaneous coronary intervention that did not conduct cost effectiveness analyses, which
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and incurred higher medication costs. 16
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potentially biases assessment of the efficacy of the two revascularisation strategies. Patient
characteristics varied between the selected studies, with mean patient ages ranging from 53
to 74 years. Moreover, the studies recruited patients over 18 years (1989 to 2007) and there
was considerable heterogeneity in the revascularisation techniques employed over this time
period. Although most patients were treated by conventional coronary artery bypass surgery,
some patients underwent minimally invasive or ‘off-pump’ surgery. Only five of the studies
included patients treated by percutaneous coronary intervention using drug-eluting stents.
The studies also adopted different analytic approaches with differences in time horizon,
no formal pooled analysis of the data from the selected studies was carried out.
Nevertheless, studies with short time horizons mainly favoured percutaneous
revascularisation, but three recent studies with longer time horizons (SYNTAX, FREEDOM
and ASCERT) reported lifetime ICERs that favoured coronary artery bypass surgery. On this
basis the authors concluded that for patients with multi-vessel disease coronary bypass
surgery is economically more attractive than percutaneous revascularisation.
Other health economic analyses of the same problem have reached different conclusions. In
an economic analysis conducted alongside the development of a clinical guideline on stable
angina, the National Institute of Health and Care Excellence (NICE) concluded that
percutaneous coronary intervention in patients with multi-vessel disease is likely to be costeffective when compared with surgical revascularisation.
17
In another study, 15 randomised
trials of treatment strategies for stable angina that reported cost-effectiveness analyses,
were included in a network meta-analysis. Medical, surgical and percutaneous interventional
strategies had comparable effects on the three year rate of death or myocardial infarction,
but coronary artery bypass surgery was the most costly, and by inference the least costeffective strategy. 18
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health-related utility weights, and modelling methods. The reported ICERs varied widely and
8
Recent developments in the design of drug-eluting stents, including the use of novel alloys
for the metal scaffold and the use of biocompatible and bioabsorbable polymers to deliver
optimal doses of drug, have improved procedural success rates and reduced rates of stent
thrombosis and in-stent restenosis. 19 As yet, no large randomised trials have compared
percutaneous revascularisation using such ‘second generation’ drug-eluting stents with
surgical revascularisation, although use of everolimus-eluting stents in patients with stable
coronary artery disease has been associated with improved survival.
20
Over time, the price
of drug-eluting stents has also declined, partly as a result of competition between
manufacturers, with a beneficial effect on cost-effectiveness. Hence, the cost-effectiveness
moving target.
Perhaps the most important message from the review by Ariyaratne et al is that there are
important gaps in our knowledge about the relative clinical and cost-effectiveness of
alternative myocardial revascularisation strategies for multi-vessel coronary artery disease.
Evidence that one myocardial revascularisation strategy is clinically and economically
superior is lacking, and in this context the choice of strategy for individual patients will
depend on the clinical circumstances, angiographic pattern of disease, local policy and
patient preference. In discussion with patients some clinicians may emphasize potential
survival benefits over other effects of revascularisation but patient expectations of treatment
vary widely. Indeed, some fully informed patients may be willing to trade any long-term
survival advantage from surgical revascularisation for the lower procedural morbidity
(especially stroke) and better short-term quality of life associated with percutaneous
revascularisation. In the SYNTAX trial 50 patients assigned to surgical revascularisation but
only 11 patients assigned to percutaneous revascularisation withdrew consent to the
randomised treatment, suggesting that patient preference influenced patient acceptance of
assigned treatment. 6 Further randomised trials of contemporary revascularisation strategies
in patients with multi-vessel coronary artery disease are required and should take account of
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of treatments for patients with multi-vessel coronary artery disease is likely to remain a
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the patient perspective, and include prospective health economic analyses. Such trials
should also address patients who have been under-represented in previous studies,
including women and older patients, and those with particular anatomical patterns of
coronary artery disease.
In the interim, clinicians, commissioners and purchasers of healthcare should be aware that
the available studies of cost-effectiveness of different myocardial revascularisation strategies
in patients with multi-vessel coronary disease have important limitations, have reported
inconsistent results, and cannot easily be used to support particular health policies.
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References
1.
Stewart S, Murphy N, Walker A, McGuire A, McMurray JJV. The current cost of
angina pectoris to the National Health Service in the UK. Heart 2003; 89:848-853.
2.
Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP et al. 2012
ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and
management of patients with stable ischemic heart disease: A report of the American
Practice Guidelines, and the American College of Physicians, American Association
for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for
Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
Circulation 2012; 126:e354-e471.
3.
Arsalan M, Mack MJ. Coronary artery bypass grafting is currently underutilized.
Circulation 2016; 133:1036-1045.
4.
Fearon WF, Harrington RA. Coronary artery bypass surgery is not underutilized.
Circulation 2016; 133:1027-1035.
5.
Hlatky MA, Boothroyd DB, Bravata DM, Boersma E, Booth J, Brooks MM et al.
Coronary artery bypass surgery compared with percutaneous coronary interventions
for multivessel disease: a collaborative analysis of individual patient data from ten
randomised trials. Lancet 2009; 373:1190-1197.
6.
Mohr FW, Morice MC, Kappetein AP, Feldman TE, Stähle E, Colombo A et al.
Coronary artery bypass graft surgery versus percutaneous coronary intervention in
patients with three-vessel disease and left main coronary disease: 5-year follow-up of
the randomised, clinical SYNTAX trial. Lancet 2013; 381:629-638.
Downloaded from http://ehjqcco.oxfordjournals.org/ by guest on October 25, 2016
College of Cardiology Foundation/American Heart Association Task Force on
11
7.
Cuculi F, Lim CCS, Banning AP. Periprocedural myocardial injury during elective
percutaneous coronary intervention: is it important and how can it be prevented?
Heart 2010; 96:736-740.
8.
Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V et al. 2014 ESC/EACTS
Guidelines on myocardial revascularization. Eur Heart J 2014; 35:2541-2619.
9.
Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G, Mack M et al.
Strategies for multivessel revascularization in patients with diabetes. New Engl J Med
2012; 367:2375-2384.
Zhang Z, Kolm P, Grau-Sepulveda MV, Ponirakis A, O'Brien SM, Klein LW et al.
Cost-effectiveness of revascularization strategies. The ASCERT study. J Am Coll
Cardiol 2015; 65:1-11.
11.
Waldo SW, Secemsky EA, O'Brien C, Kennedy KF, Pomerantsev E, Sundt TM et al.
Surgical ineligibility and mortality among patients with unprotected left main or
multivessel coronary artery disease undergoing percutaneous coronary intervention.
Circulation 2014;130:2295-2301.
12.
Walker S, Asaria M, Manca A, Palmer S, Gale CP, Shah AD et al. Long-term
healthcare use and costs in patients with stable coronary artery disease: a
population-based cohort using linked health records (CALIBER). Europ Heart J Qual
Care Clin Outcomes 2016; 2:125-140.
13.
Henderson RA, Pocock SJ, Sharp SJ, Nanchahal K, Sculpher MJ, Buxton MJ et al.
Long-term results of RITA-1 trial: clinical and cost comparisons of coronary
angioplasty and coronary-artery bypass grafting. Lancet 1998; 352:1419-1425.
Downloaded from http://ehjqcco.oxfordjournals.org/ by guest on October 25, 2016
10.
12
14.
Legrand VMG, Serruys PW, Unger F, van Hout BA, Vrolix MCM, Fransen GMP et al.
Three-year outcome after coronary stenting versus bypass surgery for the treatment
of multivessel disease. Circulation 2004; 109:1114-1120.
15.
Cohen DJ, Osnabrugge RL, Magnuson EA, Wang K, Li H, Chinnakondepalli K et al.
Cost-effectiveness of percutaneous coronary intervention with drug-eluting stents
versus bypass surgery for patients with 3-vessel or left main coronary artery disease.
Final results from the synergy between percutaneous coronary intervention with
TAXUS and cardiac surgery (SYNTAX) trial. Circulation 2014; 130:1146-1157.
Magnuson EA, Farkouh ME, Fuster V, Wang K, Vilain K, Li H et al. Costeffectiveness of percutaneous coronary intervention with drug eluting stents versus
bypass surgery for patients with diabetes mellitus and multivessel coronary artery
disease. Circulation 2013; 127:820-831.
17.
National Institute for Health and Care Excellence. Stable Angina: management.
https://www nice org uk/guidance/cg126.
18.
Caruba T, Katsahian S, Schramm C, Anaïs CN, Durieux P, Bégué D et al. Treatment
for stable coronary artery disease: a network meta-analysis of cost-effectiveness
studies. PLoS ONE 2014; 9:e98371.
19.
Navarese EP, Tandjung K, Claessen B, Andreotti F, Kowalewski M, Kandzari DE et
al. Safety and efficacy outcomes of first and second generation durable polymer drug
eluting stents and biodegradable polymer biolimus eluting stents in clinical practice:
comprehensive network meta-analysis. Br Med J 2013; 347:f6530.
20.
Windecker S, Stortecky S, Stefanini GG, daCosta BR, Rutjes AW, Di Nisio M et al.
Revascularisation versus medical treatment in patients with stable coronary artery
disease: network meta-analysis. Br Med J 2014; 348:g3859.
Downloaded from http://ehjqcco.oxfordjournals.org/ by guest on October 25, 2016
16.