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Treatment of stable coronary artery disease: Pharmacotherapy or InterventionNurcan Arat, MD,
Istanbul Bilim University, Department of Cardiology
Coronary Artery Disease
CAD has decreased by more than 40% during the last two decades.
Half of this decline resulted from prevention and reduction in major risk factors, whereas the other half has been attributed to medical treatment and revascularization.
N Engl J Med 2007;356:2388-2398.
Mortality from stable CAD has not changed significantly over the last decades
Aims Medical management of atherosclerosis ; Alleviate symptoms, Delay or prevent the progression of coronary disease, Prevent adverse outcomes such as death or myocardial infarction retardation of progression of plaque formation, Prevention of plaque rupture, and subsequent events Treatment of the sequelae of the disease.
Revascularization (PCI or CABG) Treatment of flow-limiting coronary stenosis to reduce myocardial ischaemia and its manifestations.
Stable CAD. PharmacotheraphyTreatments aimed at Improving Prognosis
Stable CAD. PharmacotheraphyTreatments aimed at Symptom Relief
Lifestyle Modifications for Patients with CAD
Tobacco cessation
Body mass index goal of 18.5 to 24.9 kg per m2
Moderate-intensity activity for 30 to 60 minutes seven days a week
Alcohol consumption in moderation
Low-sodium diet
Two to three servings of fruit and vegetables each day
Saturated fat less than 10 percent of daily calories
Stable CAD. Pharmacotheraphy
Patients with stable CAD included in the recent ACTION or EUROPA trials, who already received different preventive drugs, had an annual risk of cardiovascular death or MI of about 2.5%.
Revascularization by PCI or CABG
Acute coronary syndrome Clearly shown to improve survival
Chronic stable Angina The role of revascularization of in stable CAD remains
controversial
Randomized trials comparing revascularization with medical treatment
>30 randomized trials, 44 -2368.pts
CABG -13 trials, 6 were performed more than 2 decades ago using predominantly
saphenous vein grafts.
Balloon angioplasty alone 8 studies, use of stents in 9–100%
Drug-eluting stent implantation was negligible except for BARI-2D (35% of patients).
Several trials failed to specify the implemented medical treatment.
Currently recommended aggressive risk factor reduction was not performed
BYPASS SURGERY VS. MEDICAL THERAPY
CASS –(1970s -1980s)
• More patients remained symptom-free after CABG compared to medical therapy
at one year (66 vs 30 %) and five years (63 vs 38 %)
• By 10 years, this difference had disappeared (47 vs 42 %).
• The reoperation rate for recurrent symptoms was 6 to 8 % per year
Relief of angina
95 % of patients have an improvement in
or complete relief of angina immediately
after CABG.
CABGSurvival Benefit?
Better than medical therapy for LM disease ( VA Coop
Study)
3 vessel disease involves proximal
LAD (European Coronary Surgery Study)
3 vessel CAD with low EF (CASS)
Revascularization for Stable CAD.
BYPASS SURGERY VS. MEDICAL THERAPY
Survival advantage as well as a reduced need for repeat intervention at two years For more severe CAD, SYNTAX scores > 22 for 3-vessel
disease and SYNTAX scores > 32 for left main disease
SYNTAX trial
With the exception of left main disease, the survival benefit from CABG compared to medical therapy tends to disappear with prolonged follow-up in these groups
CABGSurvival Benefit?
One year after CABG or PCI 25 to 60% of patients still have ongoing
angina
Many patiens are deemed “inoperable” Anatomy not suitable for PCI or CABG Co-morbidities make procedure too high
risk
The impact of Revascularization on Clinical Outcome
ACIP study, 2 years follow-
up lower risk of death and MI
SWISSI II trial lower rates of ischaemia
improved left-ventricular ejection fraction
absolute reduction in clinical events
(cardiac death, MI, and revascularization) of 6.3% per year in favour of PCI.
Revascularization, more effectively relieves myocardial ischaemia than medical treatment alone
The Impact of Revascularization on Clinical Outcome
DANAMI study
COURAGE
• Better prognosis after revascularization vs.medical therapy alone
• Greater absolute reduction in myocardial ischaemia and more patients exhibited a relevant reduction in ischaemia among those with moderate to severe ischaemia
• Improved event-free survival in patients with significant reduction of ischaemia.
Survival benefit is proportional to the amount of ischaemia
Myocardial perfusion study ,10 627 pts, without prior CAD Increasing survival benefit of revascularization over medical treatment in
patients with moderate to severe ischaemia,
No benefit was apparent in patients with only mild or absence of ischaemia
Circulation 2003;107:2900-2907
Benefit of revascularization in terms of survival is proportional to the amount of ischaemia as assessed by single photon emission computed tomography imaging prior to revascularization.
24 studies, 3088 pts. LV dysfunction (mean LVEF = 32 ± 8%) Viability assessment, 25 months follow up
In patients with myocardial viability, revascularization was associated with an 80% reduction of risk-adjusted mortality compared with medical treatment (16%/year vs. 3%/year).
This benefit was most apparent in patients with impaired left-ventricular function.
No benefit was observed in patients without viability at any level of left-ventricular function. J Am Coll Cardiol 2002; 39: 1151-1158
Mortality reduction is related to viability
FAMEFFR was compared with angiography for guiding PCI in a large-scale randomized trial with 1005 patients
At 1 year, routine measurement of FFR to select lesions requiring PCI (FFR < 80%) was associated with lower rates of death or MI than PCI guided by angiography alone. (7.3 vs. 11.1%, P = 0.04)
Similarly, deferring revascularization in patients with non-significant lesions as determined by FFR appeared safe as shown during the 5 year follow-up of the randomized DEFER study with similar rates of death or MI (<1%/year) among patients treated medically and those undergoing PCI.
The Impact of Revascularization on Prognosis
These findings imply that part of the patients enrolled in previous trials were unlikely to benefit from PCI or CABG if they had no, or limited myocardial ischaemia and suggest that functional assessment of lesions (ischaemia or none) may help to identify those who benefit from revascularization.
LIMITATIONS OF CLINICAL TRIALSBefore the COURAGE
The number of patients entered into the trials was only a small percentage of the number screened and is therefore not reflective of the general population.
Predominantly male patients relatively young preserved left ventricular function focal atherosclerotic coronary disease had not undergone previous revascularization by CABG or PCI.
The majority of patients underwent PTCA alone, without stenting.
For patients in later trials who received a bare-metal stent, current antithrombotic regimens (eg, klopidogrel and glycoprotein IIb/IIIa inhibitors) were not employed.
LIMITATIONS OF CLINICAL TRIALS
Patients were highly selected as randomization was performed following delineation of coronary anatomy by angiography in the vast majority of studies.
The ‘cross-over’ from medical treatment to revascularization was observed in up to half of patients during follow-up.
Accordingly the proportion of patients without revascularization progressively diminished during follow-up, potentially blunting differences between the two strategies.
COURAGE
The largest study comparing PCI with current medical treatment
Kaplan-Meier survival curves.
2287pts, 5 year , minimal or no symptoms
nuclear imaging in a subset of patients was not severe.
The rate of death was similar in the PCI (7.6%) and medical therapy group (8.3%)P = 0.38
Optimal medical therapy was not used in any of the trials prior to COURAGE.
Secondary prevention has proved its worth, with lipid-modulating therapy, lifestyle modification, and the use of aspirin, beta-blockers, and ACE inhibitors.
Patients who are clinically unstable, who have left main CAD, or in whom OMT has failed to control symptoms remain candidates for revascularization.
In the courage trial,, drug-eluting stents that markedly reduce the rate of restenosis and therefore repeat revascularization were used in only 15 percent of patients
Meta-AnalysisThe impact of PCI on survival of patients with stable CAD
Recent meta-analyses have yielded conflicting results
Studies; 1980s - 1990s, balloon angioplasty
Interventional practice has evolved toward the placement of coronary stents
Medical therapy has advanced over the last 20 years as well.
Circulation. 2005;111(22):2906-2912J Am Coll Cardiol. 2008;52(11):894-904.
Prior meta-analyses were based on PCI and medical therapy that do not reflect current interventional practice.
Comparison of PCI vs conservative medical treatment for (A) death, (B) cardiac death or any MI, (C) nonfatal MI, (D) CABG, and (E) PCI during follow-up.
In patients with chronic stable CAD, in the absence of a recent myocardial infarction, PCI does not offer any benefit in terms of death, myocardial infarction, or the need for subsequent revascularization compared with conservative medical treatment.
Circulation 2005;111:2906-2912
A META-ANALYSIS 11 randomized trials
New Meta analysisArch Intern Med. 2012;172(4):312-319
?
INCLUSION CRITERIA
MEDLINE from 1970 to September 2011
Prospective studies, randomized trials
PCI plus medical therapy vs medical therapy alone
Stable CAD
Minimum follow-up of 1 year.
Stent implantation >50% of PCI procedures
ACS were excluded
Stable patients following a completed MI were included.
included regardless of the presence of documented ischemia or any functional assessment of the hemodynamic significance of a coronary stenosis.
only the comparison of medical therapy vs stent implantation was extracted.
Stergiopoulos and Brown. Arch Intern Med. 2012;172(4):312-319.
Comparison of initial stent implantation vs medical management for ;
1.Death
2.Death with 0.5 added to cells with no mortality events reported in the study by hambrecht et al.
3.Nonfatal myocardial infarction;
4.Unplanned revascularization;
5.Persistent angina during follow-up.
Randomized Trials of Stent Implantation vs Medical Therapy in Patients With Stable CAD
Patient Characteristics
Stergiopoulos and Brown. Arch Intern Med. 2012;172(4):312-319.
non fatal MI angina
Meta-analysis of eight contemporary trials (7229 patients, 4.3 years follow-up)
Implantation of a stent for the treatment of stable coronary artery disease
(CAD) does not lower the risk of death, nor does PCI reduce the risk of
nonfatal MI or angina when compared with optimal medical therapy.
Effect of initial stent implantation vs medical management for persistent angina during follow-up
Implications
• The failure of stent implantation to reduce the risk of death or
MI compared with medical therapy reinforces current concepts
of the underlying pathophysiologic characteristics of
atherosclerosis as a diffuse process leading to vulnerable
plaque disruption and subsequent coronary thrombosis, MI,
and death.
• The findings support recommendations that stable CAD
patients should be treated with medical therapy rather than
first undergoing stent implantation.
Chronic Ischemic Heart DiseaseTreatment Gaps
Many patients have relative intolerans to maximum doses of traditional antianginal agents (BB, CCBs, and nitrates)
Patients continue to experience myocardial ischemia
B blockers and many CCBs have similar depressive hemodynamic and electrophysiologic effects
Antianginal drugs without these limitation are needed
Cost efficiency
Secondary prevention of Stable CAD
Statin: 780 $ / year By treating 1000 patients with statins 32 death, 59 revascularization
can be prevented
Beta blocker : 127 $ / year
Aspirin: 30 $ / year
Average cost/ year for a patient with stable angina: 990 $ / year
PCI cost depent on the institution: 2100- 4500 $ / year
J Am Coll Cardiol 2002; 40:603-609Lancet 2005İ 365-1779Circulation 2005; 111: 2906-2911
Revascularization vs Medical Therapy
Initial pharmacological approach to symptom control may be taken in patients not at high risk
Revascularization may be recommended for patients with suitable anatomy who don’t respond adequately to medical therapy, or for the patient who wishes to remain physically active
Optimal secondary preventive medical therapy should be continued in patient after revascularization irrespective of the need for anti-anginal therapy
2006 ESC Guideline
Revascularization to Improve Survival Compared With Medical Therapy
Revascularization to Improve Survival Compared With Medical Therapy
SUMMARY
The basic evidence for CABG and PCI is derived from RCTs and large propensity-matched observational registries; both have important strengths, but also limitations.
By eliminating bias, individual RCTs and their subsequent meta-analyses constitute the highest hierarchical form of evidence-based medicine.
However, their extrapolation to routine clinical practice is complicated by the fact that their patient populations are often not representative of those encountered in normal clinical practice
CONCLUSION
Patients with no or mild symptoms and little ischaemia can safely be treated with medical treatment alone.
Non-invasive (MS-CT, perfusion scintigraphy, or PET-CT) or invasive (FFR) identification of lesions giving rise to extensive ischaemia may further improve outcome in patients submitted to revascularization.
Finally, patient preference must be carefully weighed in the overall treatment selection.
Thank you for your attention
CONCLUSION
Patients with no or mild symptoms and little ischaemia can safely be treated with medical treatment alone.
Non-invasive (MS-CT, perfusion scintigraphy, or PET-CT) or invasive (FFR) identification of lesions giving rise to ischaemia may further improve outcome in patients submitted to revascularization.
Finally, patient preference must be carefully weighed in the overall treatment selection.
Revascularization to Improve Survival Compared With Medical Therapy
Revascularization to Improve Survival Compared With Medical Therapy
While recommendations for coronary intervention by PCI or CABG should be mainly evidence-based, the overall clinical picture (e.g. advanced age, significant co-morbidities, need for dual antiplatelet medication) as well as patient preferences should also be considered.
Myocardial revascularisation in chronic heart failure Patients with (CHF) and systolic (LV) dysfunction,
presenting predominantly with anginal symptoms and regardless of ventricular volumes.
Patients with CHF and no or mild angina Only in the presence of viability and left ventricular end-
systolic volume index (LVESVI) ≤ 60 mL/m2.
Medical Therapy
The numbers needed to treat with drugs depend on the risk for future events of a specific patient group.
To avoid one such event, 175 patients should be treated during 1 year with aspirin (relative risk reduction
23%), 120 patients with a ‘standard dose’ statin (RRR 30%), 200 with an ACE inhibitor or AT2 receptor blocker (RRR 20%), 200 patients with clopidogrel in the first year after ACS (RRR 20%), 240 with high dose statin (RRR 15% when compared with lower statin dose).
In patients at higher risk, the numbers needed to treat are obviously lower, and treatment is more cost-effective.
Chronic Ischemic Heart DiseaseTreatment Gaps
Patients with peripheral artery disease are at increased risk for
periprocedural complications after PCI and CABG.
Higher incidence of a major complication (death, MI, stroke, coma, or
emergency, revascularization) after
PCI (12 versus 8 % for those without PAD)
CABG (21 versus 3 %)
A higher five-year mortality after CABG (14 vs.3 %)
Higher rate of neurologic complications after CABG
ACC/AHA Class I Recommendation for PCI in Stable Chronic Angina
A review compared medical treatment with surgical or percutaneous revascularization
• 13 121 pts. 17 PCI, 6 CABG, and 5 trials using either revascularization strategy
Mortality was lower after revascularization than in the medical therapy group
(7.9 vs. 9.8%, OR = 0.74, 95% CI 0.63–0.88).
These findings remained consistent following exclusion of studies in patients with recent MI
(OR = 0.77, 95% CI 0.65–0.91).
The treatment effect appeared more pronounced in early studies comparing CABG with medical treatment than in the more recent studies comparing PCI with medical treatment
Am J Med 2009;122:152-161
Coronary Angiography for Risk Stratification in Patients With Chronic Stable Angina
RecommendationsClass I
Patients with disabling (Canadian Cardiovascular Society [CCS] classes III and IV) chronic stable angina despite medical therapy. (Level of Evidence: B)
Patients with high-risk criteria on noninvasive testing regardless of anginal severity. (Level of Evidence: B)
Patients with angina who have survived sudden cardiac death or serious ventricular arrhythmia. (Level of Evidence: B)
Patients with angina and symptoms and signs of congestive heart failure. (Level of Evidence: C)
Patients with clinical characteristics that indicate a high likelihood of severe CAD. (Level of Evidence: C)
Class IIa
Patients with significant LV dysfunction (ejection fraction <45%), CCS class I or II angina, and demonstrable ischemia but less than high-risk criteria on noninvasive testing. (Level of Evidence: C)
Patients with inadequate prognostic information after noninvasive testing. (Level of Evidence: C)
Class IIb
Patients with CCS class I or II angina, preserved LV function (ejection fraction >45%), and less than high-risk criteria on noninvasive testing. (Level of Evidence: C)
Class III
Patients with CCS class I or II angina who respond to medical therapy and have no evidence of ischemia on noninvasive testing. (Level of Evidence: C)
Patients who prefer to avoid revascularization. (Level of Evidence: C)
Circulation.1999; 99: 2829-2848
IV. Treatment
Recommendations for Pharmacotherapy to Prevent MI and Death and Reduce SymptomsClass I
Aspirin in the absence of contraindications. (Level of Evidence: A)
ß-Blockers as initial therapy in the absence of contraindications in patients with prior MI. (Level of Evidence: A)
ß-Blockers as initial therapy in the absence of contraindications in patients without prior MI. (Level of Evidence: B)
Calcium antagonists* and/or long-acting nitrates as initial therapy when ß-blockers are contraindicated. (Level of Evidence: B)
Calcium antagonists* and/or long-acting nitrates in combination with ß-blockers when initial treatment with ß-blockers is not successful. (Level of Evidence: B)
Calcium antagonists* and/or long-acting nitrates as a substitute for ß-blockers if initial treatment with ß-blockers leads to unacceptable side effects. (Level of Evidence: C)
Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina. (Level of Evidence: C)
Lipid-lowering therapy in patients with documented or suspected CAD and LDL cholesterol >130 mg/dL with a target LDL of <100 mg/dL. (Level of Evidence: A)
*Short-acting dihydropyridine calcium antagonists should be avoided.
IV. Treatment
Class IIa
Clopidogrel when aspirin is absolutely contraindicated. (Level of Evidence: B)
Long-acting nondihydropyridine calcium antagonists* instead of ß-blockers as initial therapy. (Level of Evidence: B)
Lipid-lowering therapy in patients with documented or suspected CAD and LDL cholesterol 100 to 129 mg/dL, with a target LDL of 100 mg/dL. (Level of Evidence: B)
*Short-acting dihydropyridine calcium antagonists should be avoided.
Class IIbLow-intensity anticoagulation with warfarin in addition to aspirin. (Level of Evidence: B)
Class III
Dipyridamole. (Level of Evidence: B)
Chelation therapy. (Level of Evidence: B)
E. Revascularization for Chronic Stable AnginaRecommendations for Revascularization With PTCA (or Other Catheter-Based Techniques) and CABG in Patients With Stable Angina
Class I
CABG for patients with significant left main coronary disease. (Level of Evidence: A)
CABG for patients with 3-vessel disease. The survival benefit is greater in patients with abnormal LV function (ejection fraction <50%). (Level of Evidence: A)
CABG for patients with 2-vessel disease with significant proximal left anterior descending CAD and either abnormal LV function (ejection fraction <50%) or demonstrable ischemia on noninvasive testing. (Level of Evidence: A)
PTCA for patients with 2- or 3-vessel disease with significant proximal left anterior descending CAD, who have anatomy suitable for catheter-based therapy, normal LV function, and who do not have treated diabetes. (Level of Evidence: B)
PTCA or CABG for patients with 1- or 2-vessel CAD without significant proximal left anterior descending CAD but with a large area of viable myocardium and high-risk criteria on noninvasive testing. (Level of Evidence: B)
CABG for patients with 1- or 2-vessel CAD without significant proximal left anterior descending CAD who have survived sudden cardiac death or sustained ventricular tachycardia. (Level of Evidence: C)
In patients with prior PTCA, CABG or PTCA for recurrent stenosis associated with a large area of viable myocardium and/or high-risk criteria on noninvasive testing. (Level of Evidence: C)
PTCA or CABG for patients who have not been successfully treated (see text) by medical therapy and can undergo revascularization with acceptable risk. (Level of Evidence: B)
lass IIa
Repeat CABG for patients with multiple saphenous vein graft stenoses, especially when there is significant stenosis of a graft supplying the left anterior descending coronary artery. PTCA may be appropriate for focal saphenous vein graft lesions or multiple stenoses in poor candidates for reoperative surgery. (Level of Evidence: C)
PTCA or CABG for patients with 1- or 2-vessel CAD without significant proximal left anterior descending CAD but with a moderate area of viable myocardium and demonstrable ischemia on noninvasive testing. (Level of Evidence: B)
PTCA or CABG for patients with 1-vessel disease with significant proximal left anterior descending CAD. (Level of Evidence: B)
Class IIb
Compared with CABG, PTCA for patients with 3- or 2-vessel disease with significant proximal left anterior descending CAD who have anatomy suitable for catheter-based therapy and who have treated diabetes or abnormal LV function. (Level of Evidence: B)
PTCA for patients with significant left main coronary disease who are not candidates for CABG. (Level of Evidence: C)
PTCA for patients with 1- or 2-vessel CAD without significant proximal left anterior descending CAD who have survived sudden cardiac death or sustained ventricular tachycardia. (Level of Evidence: C)
Class III
PTCA or CABG for patients with 1- or 2-vessel CAD without significant proximal left anterior descending CAD who a. Have mild symptoms that are unlikely due to myocardial ischemia or have not received an adequate trial of medical therapy and
1) Have only a small area of viable myocardium or 2) Have no demonstrable ischemia on noninvasive testing. (Level of Evidence: C)
PTCA or CABG for patients with borderline coronary stenoses (50% to 60% diameter in locations other than the left main) and no demonstrable ischemia on noninvasive testing. (Level of Evidence: C)
PTCA or CABG for patients with insignificant coronary stenosis (<50% diameter). (Level of Evidence: C)
PTCA in patients with significant left main CAD who are candidates for CABG. (Level of Evidence: B)
Note: PTCA is used in these recommendations to indicate PTCA and/or other catheter-based techniques such as stents, atherectomy, and laser therapy.
OMT versus PCI
The effectiveness of PCI (with or without stenting) versus
OMT has been evaluated in many meta-analyses10-15
and in the large, randomised COURAGE trial.16
Most of the meta-analyses reported no difference
in total and cardiovascular mortality, a greater incidence
of non-fatal peri-procedural myocardial infarction,
a reduced need for repeat revascularisation, and
no difference in angina relief in the PCI arm. Only
the meta-analysis of Schömig et al,12 which included
17 RCTs, showed a survival benefit for PCI compared
with OMT alone (respective mortalities 7.4% versus
8.7% over 51 months’ follow up), but this study included
in the revascularisation group patients with a
recent myocardial infarction, as well as patients who
underwent CABG. However, a meta-analysis by Jeremias
et al3 of 28 trials including a total of 13,121 patients
reported lower mortality in the PCI group compared
to OMT alone, over a mean follow-up period
of 3 years (hazard ratio, HR 0.82, 95% confidence interval,
CI: 0.68-0.99).
The COURAGE trial16 randomised 2287 patients
with known stable CAD and objective findings
of myocardial ischaemia to OMT alone, or in
combination with PCI. Over a 4.6-year follow up,
there was no significant difference in the primary
composite endpoint of death, myocardial infarction,
stroke, or rehospitalisation for unstable angina. At
one year, freedom from angina was greater by 12%
in the PCI group; however, at 5 years this benefit had
disappeared, while 21% of the PCI group and 33% of
the OMT group underwent repeat revascularisation
(p<0.001). Thus, this study showed that, in patients
with chronic stable CAD, OMT is comparable to PCI
as regards the risk of death, myocardial infarction or
major adverse cardiovascular events (MACE).
However, in the COURAGE trial16 the severity
of the coronary artery disease was rather moderate—
the incidences of 1-, 2- and 3-vessel disease
being 31%, 39% and 30%, respectively—while only
31% of the patients had disease of the proximal part
of the anterior descending artery. Furthermore, patients
with main stem disease were excluded and most
patients had normal left ventricular function, while
40% of the patients in the medication arm underwent
revascularisation procedures during the follow-up period
because of symptoms that were not controlled by
drug treatment alone.
Altogether, the above data have led guideline
groups to recommend OMT for the initial management
of stable angina, with revascularisation reserved
principally for patients whose symptoms are not satisfactorily
controlled.
Hellenic J Cardiol 2011; 52: 516-524
Balloon angioplasty versus bare-metal stents versusdrug-eluting stents
Brophy et al,17 in a meta-analysis of 29 studies that
included a total of 9918 patients, found no difference
between bare-metal stents (BMS) and PTCA
as regards death, myocardial infarction, or need for
CABG, although there was an absolute reduction of
5% in restenosis rate in the stented group.
Subsequent meta-analyses18 of RCTs that compared
drug-eluting stents (DES) with BMS reported
no differences in the rates of death, cardiac death, or
non-fatal myocardial infarction, although there was a
significantly reduced need for target vessel revascularisation
with the use of DES. In contrast, Kirtane et
al,19 in an unadjusted analysis of 182,901 patients in
34 observational studies of BMS and DES, reported
significantly lower rates of mortality (HR 0.78, 95%
CI: 0.71-0.86) and myocardial infarction (HR 0.87,
95% CI: 0.78-0.97) associated with DES implantation.
However, after multivariable adjustment, the
benefits of DES decreased significantly, and the possibility
cannot be ruled out that their benefit was partly
due to the simultaneous prolonged dual antiplatelet
therapy.
The above findings are reflected in the recent
network meta-analysis by Trikalinos et al13 that in518
• HJC (Hellenic Journal of Cardiology)
E.I. Chatzistamatiou et al
cluded 61 studies, involving a total of 25,388 patients
with chronic CAD, from the earliest use of balloon
angioplasty to the present era of BMS and DES. The
researchers found no difference in terms of risk of
death or myocardial infarction between drug therapy,
PTCA, and PCI with BMS or DES, although there
was a progressive and significant reduction in the
need for repeat revascularisation: BMS vs. PTCA relative
risk (RR) 0.68, 95%CI: 0.60-0.77; DES vs. BMS
RR 0.44, 95% CI 0.35-0.56; DES vs. PTCA RR 0.30,
95% CI 0.17-0.51.
CABG
Hellenic J Cardiol 2011; 52: 516-524
CABG versus drug therapy
The superiority of CABG over medical therapy in
treating certain subgroups of patients with stable
CAD was confirmed persuasively by Jusuf et al20 in
a meta-analysis of seven RCTs that is still the main
legacy for modern CABG. The study revealed a survival
benefit for CABG in patients with main stem or
3-vessel CAD, especially when the proximal segment
of the anterior descending artery was involved. The
benefits were greater in patients with severe symptoms,
with early positive stress tests, and with impaired
left ventricular performance, as well as in diabetic
patients, as shown by the BARI trial.21 The relevance
of these findings to modern practice is being
increasingly questioned, since the medications used
in those studies were significantly inferior to modern
OMT. Indeed, in the recently published STICH
trial22 1212 patients with multi-vessel disease and severely
impaired left ventricular function (ejection
fraction <35%) were randomised to CABG or OMT
to test whether surgical revascularisation would improve
survival. After nearly 5 years’ follow up, allcause
mortality (the primary endpoint) was similar
between the groups, both in the main trial cohort and
in a subgroup with demonstrable myocardial viability.
As the editorialist commented, contemporary OMT
should not be underestimated in the management of
severe CAD.23
However, the recent meta-analysis by Jeremias
et al3 reported a lower risk of death for CABG compared
to OMT (HR 0.63, 95% CI: 0.50-0.77). Moreover,
these findings were confirmed in the recent
BARI-2D trial,24 which included 2368 diabetic type
2 patients (31% with 3-vessel disease). Patients were
stratified as being eligible for either PCI or CABG
and were then randomised to contemporary OMT or
revascularisation. After an average of 5.3 years’ follow
up, rates of all-cause mortality (the primary end
point) were similar for the medical and revascularisation
groups, but in the CABG stratum, patients assigned
to revascularisation had lower cardiovascular
event rates (death, myocardial infarction or stroke)
than patients assigned to OMT.
Isolated disease of the proximal anterior descending
artery
Aziz et al25 and Kapoor et al26 reported two metaanalyses
of more than 3000 patients over a 5-year follow
up, both of which reported no significant differences
in safety endpoints (mortality, myocardial infarction,
stroke) between PCI and CABG. However,
they observed a threefold higher rate of recurrence of
angina and a fivefold higher rate of target vessel revascularisation
in the PCI patients. Similar findings
were reported from a smaller study of 711 patients,
who were treated with minimally invasive direct aortocoronary
bypass or with stenting (predominantly
BMS) and were followed for more than 2 years. The
rates of death and myocardial infarction were similar
in the two groups, apart from revascularisations,
which were significantly fewer in the surgical group.27
Hellenic J Cardiol 2011; 52: 516-524
Multi-vessel coronary artery disease
There are more than 15 studies of PCI versus CABG
in multi-vessel CAD,28 and only one study of OMT
versus CABG (MASS II).29 Most of the patients in
these RCTs had essentially normal left ventricular systolic
performance, with 1- or 2-vessel CAD and without
involvement of the anterior descending artery.
The meta-analysis of these RCTs carried out by
Hlatky et al2 reported that CABG resulted in a fivefold
reduction in the need for re-intervention, with no
or moderate benefit in terms of survival, or a survival
benefit only in patients aged >65 years (HR 0.82)
and in diabetic patients (HR 0.7).
Hueb et al30 recently reported the results from
a 10-year follow up of patients in the MASS II randomised
trial. The unique feature of that study was
the fact that it included an arm with exclusively drug
therapy for the treatment of patients with multi-vessel
CAD. Thus, in one centre 611 patients were randomised
to either CABG (203 patients), PCI with
BMS (205 patients) or OMT alone (203 patients).
These were patients with anatomically severe CAD,
given that 93% had involvement of the proximal an(
Hellenic Journal of Cardiology) HJC • 519
Management
terior descending artery, 58% had 3-vessel disease
and 42% 2-vessel disease. All the patients had a normal
ejection fraction and about 30% were diabetics.
The primary endpoint of the study (a composite
of total deaths, Q-wave myocardial infarction, or refractory
angina requiring revascularisation) occurred
more often in the drug group than in the CABG
group (RR 2.35, 95% CI: 1.78-3.11) and more often
in the PCI group than in the CABG group (RR 1.85,
95% CI: 1.39-2.47). In addition, the 10-year anginafree
rates were 64% for CABG, 59% for PCI, and
43% for drug therapy (p<0.001). The researchers
determined that, compared to CABG, drug therapy
was associated with a higher incidence of myocardial
infarction, higher rates of repeat revascularisation, a
higher rate of cardiac death, and a 2.29 times greater
risk of combined events. PCI was associated with
a greater need for repeat revascularisation, a higher
incidence of myocardial infarction, and a 1.46 times
greater risk of combined events compared to CABG.
Hellenic J Cardiol 2011; 52: 516-524
In addition, CABG proved to be superior to drug
therapy in eliminating anginal symptoms. No statistically
significant difference was found as regards
total mortality among the three therapeutic strategies,
although the study was not designed to show
differences in mortality. The superiority of revascularisation
compared with drug therapy in the MASS
II trial is in conflict with the findings of the COURAGE
trial referred to above. Of course, the difference
could probably be explained by the different patient
populations in the two studies. Indeed, the anatomical
complexity of the CAD was much greater in
the MASS II trial and came close to the anatomical
characteristics of the patients in the SYNTAX trial,
which will be analysed below. In the COURAGE
trial, one third of the patients had 1-vessel disease,
while in the MASS II trial no patient had 1-vessel
disease. Furthermore, only one third of the COURAGE
patients had involvement of the proximal anterior
descending artery, as against 92% in the MASS
II trial.
Coronary main stem disease
CABG is conventionally considered to be the standard
therapeutic strategy in patients with significant
main stem disease who are eligible for surgery, and
the CASS registry reported a mean survival advantage
of 7 years in 912 patients who were treated with
CABG versus medication.34 However, the latest data
from the large SYNTAX trial,35 two more recent
RCTs36,37 and a meta-analysis,38 indicate that PCI offers
equivalent results to CABG, at least in more simple
lesions. None of these trials showed significant
mortality differences between the two revascularisation
strategies, making PCI an option for those patients
unwilling to undergo surgery and prepared to
accept further interventional procedures as necessary.
Hellenic J Cardiol 2011; 52: 516-524
Hellenic J Cardiol 2011; 52: 516-524
Hellenic J Cardiol 2011; 52: 516-524
Recent ESC guidelines
In patients with chronic stable CAD the choice of the
most appropriate therapeutic strategy should be the
result of two components:42
1. Eligibility for revascularisation (Table 1).
2. Relative advantages of CABG and PCI in the
various anatomical and clinical forms of the
disease (Table 2).
The findings we have to hand show that revascularisation
is chosen:
• On an symptomatic basis: in patients with persistent
symptoms (angina or equivalent) despite OMT,
and/or
• On a prognostic basis: in specific anatomical forms
of the disease or if there is a confirmed significant
myocardial mass at risk (even in asymptomatic
patients). Significant main stem disease and/
or significant disease of the proximal part of the
anterior descending artery, especially in the presence
of multi-vessel CAD, are strong indications for
revascularisation. In the more severe forms of stable
CAD, CABG appears to offer a survival benefit as
well as a significant reduction in the need for repeat
revascularisation, despite the greater risk of stroke,
especially in main stem disease.
The impact of revascularization on clinical outcomes
(ACIP) study, 57% of patients treated with revascularization were free of ischaemia at 1 year compared with 31 and 36% in the ischaemia-guided and angina-guided strategies, respectively (P < 0.0001). at 2 years follow-up, the risk of death and MI was
significantly lower among patients undergoing revascularization (4.7%) compared with those receiving ischaemia-guided (8.8%) or angina-guided medical treatment (12.1%, P < 0.04).
SWISSI II trial, patients with silent ischaemia after recent MI
lower rates of ischaemia when allocated to PCI (12%) than medical treatment (29%, P = 0.03), a beneficial effect accompanied by improved left-ventricular ejection fraction (57 vs. 49%, P < 0.001) an absolute reduction in clinical events (cardiac death, MI, and revascularization) of 6.3% per year in favour of PCI.
DANAMI study, Patients with angina or exercise-induced ischaemia early after MI had a better prognosis after revascularization than with medical therapy alone
COURAGE, PCI compared with medical treatment showed a greater absolute reduction in myocardial ischaemia (−2.7 vs. −0.5%, P < 0.0001), and more patients exhibited a relevant reduction in ischaemia (33 vs. 19%, P = 0.0004), particularly among those with moderate to severe ischaemia (78 vs. 52%, P = 0.007)
There was a graded relationship between reduction of ischaemia and subsequent risk of death or MI with improved event-free survival in patients with significant reduction of ischaemia.
Impact of revascularization on mortality in patients with chronic stable coronary artery disease.
Simoons M L , Windecker S Eur Heart J 2010;31:530-541
• CI overlapped widely and an analysis of variance revealed no significant difference between the two revascularization strategies (P = 0.33)
There was no difference in the risk of MI between both groups.
CABGEffects on survival
CABG offered no significant overall mortality benefits compared to medical therapy alone in trials from the 1970s
However, survival was improved in selected patients with severe CAD who were at high risk because a large amount of myocardium was supplied by the diseased vessel or because of significant underlying left ventricular dysfunction.
All patients with stable CAD require medical therapy to prevent disease progression and recurrent cardiovascular events
2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina: J. Am. Coll. Cardiol. 2007;50;2264-2274
All patients with stable CAD require medical therapy to prevent disease progression and recurrent cardiovascular events
An annual influenza vaccination is recommended for patients with cardiovascular disease
2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina: J. Am. Coll. Cardiol. 2007;50;2264-2274
What is the definitive role of PCI in chronic angina and stable CAD?
PCI improves angina and exercise capacity
However, compared to optimal medical therapy,
does PCI
Prolong survival? Reduce risk of subsequent MI? Reduce hospitalization for unstable angina? Decrease need for subsequent CABG? Improve quality of life?
Courtesy of WE Boden, MD
Early Meta-analysisJ Am Coll Cardiol 2008 ;52:894-904
• 17 randomized trials • 7513 pts. • 51 months follow up• PCI 92%
• 43% balloon angioplasty, • 41% stents, • 8% CABG
Overall mortality was significantly reduced by 20% in favour of PCI
MI was similar among both groups
The benefit of revascularization became more pronounced with follow-up periods beyond 5 years.
Meta-analysis No significant reduction in mortality or MI for
PTCA compared with medical therapy, Bare-metal stents compared with PTCA Drug-eluting stents compared with bare-metal stents
The different results of these meta-analyses reflect differences in the analytic methodology and trial selection, but also illustrate that any mortality benefits of PCI are modest at best.
Lancet 2009;373:911-918
Chronic stable coronary artery disease: drugs vs.
revascularization Revascularization and quality of life
Compared with medical therapy, revascularization by PCI or CABG has been consistently shown to more effectively relieve angina, reduce the use of anti-angina drugs, improve exercise capacity and quality of life
Freedom from angina in trials comparing a routine invasive with an initial non-invasive strategy in patients with stable coronary artery disease
Proportion of patients requiring anti-angina drugs in trials comparing a routine invasive with an initial non-invasive strategy in patients with stable coronary artery disease
