|Year : 2013 | Volume
| Issue : 1 | Page : 22-28
Management of Coronary Artery Disease in 2013: Recent Insights
Akshyaya Kumar Pradhan
Interventional Cardiologist, Shekhar Heart and Lung Centre, Indira Nagar, Lucknow, Uttar Pradesh, India
|Date of Web Publication||17-Jun-2013|
Akshyaya Kumar Pradhan
Interventional Cardiologist, Shekhar Heart and Lung Centre, Indria Nagar, Lucknow 226 016, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Pradhan AK. Management of Coronary Artery Disease in 2013: Recent Insights. Heart India 2013;1:22-8
| Defining Myocardial Infarction|| |
The recently updated European Society of Cardiology (ESC) consensus statement on "third universal definition of myocardial infarction" released in 2012 has emphasized the central role of cardiac biomarker 6 in diagnosis of acute coronary syndromes.  The term acute MI should be used when there is evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Hence detection of an rise and/or fall of cardiac biomarker values preferably cardiac troponin with at least one value above the 99th percentile upper reference limit needed along with at least one of the following:
- Symptoms of ischemia.
- New or presumed new significant ST-segment-T wave (ST-T) changes or new left bundle branch block.
- Development of pathological Q waves in the electrocardiogram (ECG).
- Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
- Identification of an intracoronary thrombus by angiography or autopsy.
High sensitive troponins
Recently, high-sensitivity or ultrasensitive assays have been introduced that have a 10 to 100-fold lower limit of detection and fulfill the requirements of analytical precision. Therefore, MI can now be detected more frequently and earlier in patients presenting with chest pain. The superiority of these new assays, particularly in the early phase of pain onset, was prospectively demonstrated. , The negative predictive value for MI with a single test on admission is 95% and by including a second sample within 3 h of presentation the sensitivity for MI approaches 100%. The waiting time in Emergency Department can be reduced with a rapid rule put protocol. The new ESC guidelines for the management of ACS in patients presenting without persistent ST-segment elevation, 2011 now recommend a rapid rule-out protocol (0 and 3 h) when highly sensitive troponin tests are available.  The guidelines also emphasize the role for prompt withdrawl of blood for troponins and recommend point-of-care tests for troponins should be implemented when a central laboratory cannot consistently provide test results within 60 min.
Coronary computed tomography (CT) angiography
Multidetector computed tomography (CT) is a promising technique for direct visualization of the coronary arteries. Owing to its high negative predictive value reported in various studies ,, CT angiography, can be useful to exclude ACS or other causes of chest pain. The ESC 2011 guidelines for non ST segment elevation myocardial infarction (NSTEMI) recommend Coronary CT angiography as an alternative to invasive angiography to exclude ACS when there is a low to intermediate likelihood of CAD and when troponins and ECG are inconclusive (Class IIa).
In the CT-STAT trial, Goldstein et al.  randomly assigned patients with acute chest pain in the Emergency Department to Coronary computed tomography angiography (CCTA) and to single-positron emission computed tomography myocardial perfusion imaging (MPI). The CCTA strategy resulted in a 54% reduction in time to diagnosis compared with MPI (2.9 h vs. 6.3 h), and costs of care were 38% lower for the CCTA group. The two strategies showed no difference in freedom from major adverse cardiac events (MACE) at 6 months of follow-up.
Platelet activation and subsequent aggregation play a dominant role in the propagation of arterial thrombosis and consequently are the key therapeutic targets in the management of ACS. New adenosine diphosphate (ADP) receptor blockers prasugrel and ticagrelor have a more rapid onset of action and greater potency and have been proven superior to clopidogrel in large outcome trials.
In the TRITON-TIMI 38 trial,  prasugrel (60 mg loading dose followed by 10 mg) was compared to clopidogrel (300 mg loading dose and then 75 mg daily) in clopidogrel naive patients undergoing percutaneous coronary angioplasty (PCI). The composite primary endpoint (cardiovascular death, non-fatal MI, or stroke) occurred in 11.2% of clopidogrel-treated patients and in 9.3% of prasugrel treated patients (hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.73-0.93; P = 0.002), mostly driven by a significant risk reduction for MI. In the whole cohort, the rate of definite or probable stent thrombosis (as defined by the academic research consortium (ARC)) was significantly reduced in the prasugrel group compared to the clopidogrel group (1.1% vs. 2.4%, respectively; HR 0.48; 95% CI 0.36-0.64; P = 0.001). Prasugrel is contraindicated in patients with prior stroke/transient ischaemic attack. Its use is generally not recommended in patients aged ≥75 years or in patients with lower body weight (<60 kg) as it was not associated with net clinical benefit in these subsets.
In the PLATelet inhibition and patient Outcomes (PLATO) trial,  ticagrelor reduced the composite primary endpoint (cardiovascular death, non-fatal MI, or stroke) and also reduced cardiovascular mortality in clopidogrel naive or pretreated patients with either ST segment elevation myocardial infarction
(STEMI) -(planned for primary PCI) or moderate-to-high risk NSTEMI (planned for either conservative or invasive management). Although there was no significant difference in overall PLATO defined major bleeding rates between the clopidogrel and ticagrelor groups, PLATO-defined and TIMI-defined major bleeding that was unrelated to coronary artery bypass grafting (CABG) surgery was increased with Ticagrelor. The new ESC 2012 guidelines for STEMI recommend prasugrel and ticagrelor as first line ADP receptor blockers.  Clopidogrel should be used preferably when prasugrel or ticagrelor are either not available or contraindicated.
Antithrombotics for PCI
Intravenous unfractionated heparin (UFH) titrated to an appropriate activated clotting remains the mainstay and time tested strategy for anticoagulant therapy at the time of PCI. Enoxaparin and fondaparinux have been studied less extensively in this setting. The ATOLL (acute STEMI treated with Primary PCI and IV enoxaparin or UFH to lower ischemic and bleeding events at short- and long-term follow-up) trial comparing intravenous enoxaparin with UFH for primary PCI failed to meet its primary, composite endpoint. 
Fondaparinux, the only selective activated factor X (factor Xa) inhibitor available for clinical use is inhibits coagulation factor Xa by binding reversibly and non-covalently to antithrombin, with a high affinity. In the OASIS-5 (the fifth organization to assess strategies in acute ischemic syndromes investigators) study, fondaparinux was non inferior to enoxaparin with respect to primary efficacy outcome of death, MI, or refractory ischemia in patients of NSTEMI.  At the same point, major bleeds were halved with fondaparinux (2.2% vs 4.1%). At 6 months the composite endpoint of death, MI, or stroke was significantly lower with fondaparinux vs. enoxaparin (11.3% vs. 12.5%). In the population submitted to PCI, catheter thrombus was observed more frequently with fondaparinux (0.9%) than with enoxaparin (0.4%), but was abolished by injection of an empirically determined bolus of UFH at the time of PCI.
The FUTURA/OASIS-8 trial [ 14] compared a low dose i.v. bolus of UFH (50 IU/kg) and a standard dose UFH, namely 85 IU/kg (reduced to 60 U/kg in the case of the use of GP IIb/IIIa receptor inhibitors), in patients pretreated with fondaparinux, submitted to PCI within 72 h following initiation of therapy. There was no significant difference between the two groups in terms of the primary composite endpoint (major bleeding, minor bleeding, or major vascular access site complications) at 48 h after PCI (4.7% vs. 5.8%, low vs. standard dose group; OR 0.80; 95% CI 0.54-1.19; P = 0.27).
The practical implications of these data are that a standard UFH bolus should be recommended at the time of PCI in patients pre-treated with fondaparinux on the basis of a more favorable net clinical benefit and lower risk of catheter thrombosis compared to low dose UFH. The new ESC guidelines of NSTEMI 2011 list Fondaparinux (2.5 mg subcutaneously daily) as having the most favorable efficacy-safety profile with respect to anticoagulation (Class I recommendation). , If the initial anticoagulant is fondaparinux, a single bolus of UFH (85 IU/kg adapted to ACT, or 60 IU in the case of concomitant use of GP IIb/IIIa receptor inhibitors) should be added at the time of PCI. However it is not recommended in setting of primary PCI for STEMI.
Novel oral anticoagulants
In ATLAS ACS 2-TIMI 51 study,  rivaroxaban in patients with a recent ACS, reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke compared to placebo (hazard ratio in the rivaroxaban group, 0.84; 95% CI, 0.74 to 0.96; P = 0.008). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P = 0.002) and from any cause (2.9% vs. 4.5%, P = 0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. Interestingly, stent thrombosis was reduced by one third. This was associated with 3 fold increase in non-CABG-related major bleeding, and intracranial haemorrhage. However, apixaban in APPRAISE-2,  darexaban in RUBY-1  and dabigatran in REDEEM [ 20] trial, caused dose-dependent increases in major bleeding but no signal of added efficacy when adding anticoagulant therapy to antiplatelet therapy in this setting of ACS. Hence the verdict on novel oral anticoagulants in ACS is still not out, but low dose rivaroxaban reducing mortality in ACS as an add on therapy on aspirin and clopidogrel is interesting.
Glycoprotein IIb/IIIa antagonists
INFUSE-AMI trial showed that local delivery of abciximab reduced the 30-day infarct size, evaluated by magnetic resonance imaging, but did not improve abnormal wall motion score, ST-segment resolution, post-PCI coronary flow or myocardial perfusion. 
The large abciximab intracoronary vs. intravenously drug application 4 (AIDA-STEMI) randomized trial, found no clinical benefit (but also no harm) in this route of administration in terms of the composite of death, reinfarction and heart failure, and found a borderline reduction in the secondary endpoint of heart failure.  Therefore, the intracoronary route may be considered but the i.v. route should remain the standard of care for administration of GP IIb/IIIa inhibitor.
PCI without on site CABG
The Atlantic CPORT investigators randomized,  in a non-inferiority design, nearly 19,000 patients undergoing PCI to a hospital with or without on-site surgery in a ratio of. Six-week mortality was virtually identical (1.0 vs. 0.9%) and 9-month MACE were also similar (11.2 vs. 12.1%); however, target vessel revascularization (TVR) was higher without on-site surgery (6.5 vs. 5.4%, P ¼ 0.01). This difference was seen regardless of the definition of TVR and regardless of stent type and may reflect a more conservative approach or a lower initial success rate without on-site surgery.
Multi vessel disease
The FREEDOM trial randomized 1900 diabetic patients with multi-vessel disease to PCI using drug-eluting stents (DESs) vs. CABG. At 5 years, the primary outcome of death, MI, or cerebrovascular accident occurred more commonly in the PCI group (26.6 vs. 18.7%,P = 0.005). The benefit of CABG was driven by differences in rates of both MI (P < 0.001) and death from any cause (P = 0.049). However, stroke was more frequent in the CABG group (5-year rates of 2.4% in PCI Vs 5.2% with CABG). Hence, patients with diabetes and advanced coronary artery disease, CABG should definitely offered to as a first line therapy. 
In the SYNTAX trial, investigators compared PCI to CABG in patients with left main or three-vessel CAD. The previously reported 1-year results showed similar rates of death and MI with both procedures, more strokes with CABG, and more repeat revascularization procedures with PCI.  The recently presented 5 year results of SYNTAX study demonstrate that outcomes were similar with coronary artery bypass grafting and percutaneous coronary intervention in the lowest tertile of SYNTAX score, whereas CABG outcomes were superior in the highest tertile. Longer follow-up now suggests that CABG beats PCI in the intermediate-risk group as well. 
However, a meta-analysis of 19 randomized trials of over 10,000 patients found a 30-day rate of stroke of 1.2% after CABG and 0.34% after PCI (P = 0.0001). This equates to an excess of seven strokes for every 1000 patients treated with CABG rather than PCI. Similar results were observed after a median follow-up of 1 year and in an analysis of nearly 34,000 patients from 27 observational studies. 
In primary PCI, drug-eluting stents (DES) reduce the risk of repeated TVR, compared with bare-metal stents (BMS).  There have been concerns about increased risks of very late stent thrombosis and reinfarction with DES, compared to BMS. However, HORIZONS AMI a randomized study of DES versus. BMS in STEMI patients, did not reveal any safety concerns, whereas a consistent reduction of restenosis and unplanned repeat revascularization was found after DES implantation even on long-term follow up.  An issue with the routine use of DES in this setting is that it is often difficult to determine reliably the ability of patients to comply with or tolerate the protracted use of dual antiplatelet therapy (DAPT).
The EXAMINATION trial presented at ESC Congress 2012, randomized 1500 patients with STEMI to everolimus DESs and BMSs.  The primary endpoint of death, recurrent MI, or revascularization was similar in the two groups. However, TVR rates were lower with the everolimus stent (3.7 vs. 6.8%), as was sub acute stent thrombosis (SAT) (0.9 vs. 2.5%). Biolimus eluting biodegradable polymer stents were compared the BMS in a 1100-patient randomized COMFORTABLE -AMI trial.  1-year MACE was lower with the biolimus stent, a difference driven mainly by a reduction in re-infarction and TLR. The ESC 2011 guidelines for NSTEMI recommend that owing to the lack of randomized trials in NSTE-ACS, the choice between the use of a BMS or a DES should be based on an individual assessment of benefit versus risk. The new American College of Cardiology/American Heart Association STEMI 2013 guidelines say that lowest rates of stent thrombosis have been reported with cobalt-chromium everolimus-eluting stents. ,
In the setting of stable angina, a meta-analysis of 72 randomized trials (>117, 000 patients) looked at comparative outcomes of different DESs compared with BMSs. Everolimus DESs seemed to have the lowest TVR. Reassuringly, there was no increased risk of any long-term safety outcomes with DESs compared with BMSs; in fact, DESs were associated with reduced MI and SAT rates. 
The RESET trial found that everolimus DES was non inferior sirolimus DES at 1 year for the primary endpoint of TLR (4.3 vs. 5.0%).  The TWENTE trial randomized 1391 patients to zotarolimus (Resolute) versus everolimus (Xience) stents in a non-inferiority design. The primary endpoint of target vessel failure (TVF) was similar in the two groups (8.2 vs. 8.1%), and stent thrombosis rates were low and similar.  SORT OUT IV also compared these two different DESs (sirolimus and everolimus) in a non-inferiority design but with a composite primary endpoint of safety and efficacy. The composite endpoint was similar in the two groups at 9 and 18 months, but definite stent thrombosis was higher at 18 months with the sirolimus stent (0.9 vs. 0.2%).  Even in the subset of left main reduced 1-year MACE, TVF, and restenosis was shown with everolimus DESs. 
In Bern Rotterdam Cohort study, Raber et al. reported that everolimus eluting stent (EES) use is associated with a lower risk of very late stent thrombosis compared to early-generation DESs.  The overall incidence rate of definite stent thrombosis with EES was (1.4 per 100 person-years) compared to SES (2.9; HR, 0.41; P < 0.0001) and PES (4.4; HR, 0.33; P < 0.0001). The incidence rate per 100 person-years of early (0-30 days), late (31 days-1 year), and very late stent thrombosis was significantly lower among everolimus DES-treated patients when compared to sirolimus and paclitaxel eluting DESs. Differences in favor of EES were most pronounced beyond 1 year, with a HR of 0.33 (EES versus SES; P = 0.006) and 0.34 (EES versus PES; P < 0.0001).
In a pooled analysis of ISAR-TEST 3 and 4 and LEADERS trials, the risk of SAT at 4 years with biodegradable polymer DESs was compared with that with a cypher stent (a durable polymer); biodegradable polymer was associated with lower TLR and SAT (HR: 0.56), driven mainly by a reduction in very late SAT.  In a meta-analysis of 50, 000 patients, 1-year SAT was the lowest with everolimus DESs compared with BMSs, zotarolimus, paclitaxel, or sirolimus DESs. 
Duration of dual antiplatelet therapy after PCI
The PRODIGY trial compared a 6 month versus 24-month dual Antiplatelet (DAPT) strategy following a variety of BMSs or DESs implantation.  The study failed to show that prolonging DAPT for 24 months is superior to 6 month duration of therapy in reducing composite primary endpoint of death, MI or stroke in patients receiving 1 st or 2 nd generation DES.
The PROTECT trial compared zotarolimus with sirolimus (cypher) stents in nearly 9,000 patients with duration of DAPT left to the discretion of the operator and showed no difference between the two stents in the primary endpoint of stent thrombosis at 3 years. 
In the EXCELLENT non-inferiority randomized study of 6 months versus 12-month DAPT after DESs, 1-year TVF occurred in 4.8 vs. 4.3%, respectively. A further study of 2000 patients compared 3-12-month DAPT following zotarolimus DESs and found no difference in SAT (0.2 vs. 0.3%) at 1 year. 
Physiological lesion assessment guidance for PCI
The FAME 2 trial assessed fractional flow reserve (FFR) in stable patients and those who had at least one significant lesion (FFR < 0.8) were randomized to FFR-guided PCI or optimal medical therapy (OMT).  The primary endpoint of death, MI, or urgent revascularization was 4.3% in the PCI group and 12.7% in the OMT group (P < 0.001); this difference was due to higher urgent revascularization in the OMT group. The 2011 ACC/AHA Guidelines for PCI recommend FFR to assess angiographic intermediate coronary lesions (50% to 70% diameter stenosis) and to guide revascularization in patients with Stable Ischemic Heart Disease (class IIa). 
The counter-pulsation to reduce infarct size pre-PCI-acute myocardial infarction (CRISP AMI) trial showed no benefit from a routine intra-aortic balloon pump (IABP) in anterior myocardial infarction without shock, and did show increased bleeding, which is consistent with data available regarding the role of IABPs in patients with acute myocardial infarction without cardiogenic shock. 
The IABP-SHOCK II trial showed that the 30 -day mortality was very similar in the two groups (39.7 vs. 41.3%, respectively).  However, in the IABP group, only 13% were inserted pre-PCI. However the 5-year follow data of BCIS-1 trial reported a significant mortality advantage favoring upfront IABP insertion (HR: 0.66, 95% CI: 0.44-0.98, P = 0.039), although the potential mechanisms of this remain unclear. 
Access site for PCI
The STEMI-RADIAL presented at transcatheter therapeutics (TCT) randomized 700 patients to either a radial or femoral approach.  The primary endpoint of bleeding or access-site complications was dramatically lower with the radial approach and MACE was equivalent. Also the radial approach was associated with less contrast use and shorter ICU stay. In the radial versus femoral (RIVAL) access for coronary intervention trial, using radial rather than femoral access actually reduced mortality in the subset of STEMI patients.  Similar findings were also observed in the RIFLE STEACS trial.  In RIVAL there was, however, an interaction between benefit of the radial access route and operator experience, suggesting that the benefit of radial access over femoral depends upon the radial expertise of operators.
High dose statins
Current guidelines suggest early and aggressive low-density lipoprotein (LDL) cholesterol lowering therapy with high dose statins in patients with acute coronary syndrome. ESC guidelines for STEMI 2012 state that, the strongest trial data available so far favors atorvastatin at a dose of 80 mg daily. 
The LUNAR study compared the efficacy of high dose rosuvastatin with that of atorvastatin in decreasing LDL cholesterol in patients with ACS. Results from the LUNAR study show that rosuvastatin 40mg more effectively decreased LDL cholesterol, increased high density lipoproteins (HDL) cholesterol, and improved other blood lipid parameters than atorvastatin 80 mg.  It would not be long before rosuvastatin makes inroads into major guidelines for secondary prevention in ACS.
Bioabsorbable stent promise important theoretical advantages over conventional DES including shorter antiplatelet duration, restored vasomotion and abolished late stent thrombosis risk. The ABSORB B Cohort tested revision 1.1 version of the everolimus-eluting bioabsorbable vascular scaffold (BVS, Abbott vascular) in patients, with up to 2 de novo native coronary artery.  In the first 45 patients of ABSORB Cohort B, in-stent late loss was 0.19 mm at 6-month angiographic follow-up. The 6-month major adverse cardiac event rate (defined as cardiac death, MI, or ischemia-driven TLR) was 4.4%. Furthermore, no stent thrombosis had occurred at 6 months. The everolimus BVS (Absorb) demonstrated a similar neointimal response as the everolimus DES (xience). 
| Conclusion|| |
The management of coronary artery disease is evolving rapidly. The use of high sensitive troponin assays and coronary CT angiography in emergency department promises to be a boon for early and accurate diagnosis of acute MI. With the addition of more powerful ADP receptor antagonists and novel anticoagulant, the medical management of ACS has been revamped. Everolimus DES have been promising with low rates of stent thrombosis and TVR. Biodegradable vascular scaffolds are also now being implanted with ease. In addition a shorter duration of DAPT following PCI is on the anvil. FFR and the Radial route have been positive developments in reducing mortality associated with PCI. Future holds bright for biodegradable vascular scaffolds and gene therapy
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