European Heart Journal Advance Access originally published online on March 15, 2005
European Heart Journal 2005 26(8):804-847; doi:10.1093/eurheartj/ehi138
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Guidelines for Percutaneous Coronary Interventions
The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology
Authors/Task Force Members,* Corresponding author. Chairperson: Prof. Sigmund Silber, MD, FACC, FESC, Kardiologische Praxis und Praxisklinik, Am Isarkanal 36, 81379 München, Germany. Tel: +49 89 742 15130; fax: +49 89 742 151 31. E-mail address: sigmund{at}silber.com
ESC Committee for Practice Guidelines (CPG): Silvia G. Priori (Chairperson) (Italy), Maria Angeles Alonso Garcia (Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica Dean (France), Jaap Deckers (The Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindahl (Sweden), Gianfranco Mazzotta (Italy), Keith McGregor (France), João Morais (Portugal), Ali Oto (Turkey), Otto A. Smiseth (Norway)
Document Reviewers: Jaap Deckers (CPG Review Coordinator) (The Netherlands), Jean-Pierre Bassand (France), Alexander Battler (Israel), Michel Bertrand (France), Amadeo Gibert Betriu (Spain), Dennis Cokkinos (Greece), Nicolas Danchin (France), Carlo Di Mario (Italy), Pim de Feyter (The Netherlands), Kim Fox (UK), Ciro Indolfi (Italy), Karl Karsch (UK), Manfred Niederberger (Austria), Philippe Gabriel Steg (France), Michal Tendera (Poland), Frans Van de Werf (Belgium), Freek W.A. Verheugt (The Netherlands), Petr Widimski (Czech Republic)
In patients with stable CAD, PCI can be considered a valuable initial mode of revascularization in all patients with objective large ischaemia in the presence of almost every lesion subset, with only one exception: chronic total occlusions that cannot be crossed. In early studies, there was a small survival advantage with CABG surgery compared with PCI without stenting. The addition of stents and newer adjunctive medications improved the outcome for PCI. The decision to recommend PCI or CABG surgery will be guided by technical improvements in cardiology or surgery, local expertise, and patients' preference. However, until proved otherwise, PCI should be used only with reservation in diabetics with multi-vessel disease and in patients with unprotected left main stenosis. The use of drug-eluting stents might change this situation.
Patients presenting with NSTE-ACS (UA or NSTEMI) have to be stratified first for their risk of acute thrombotic complications. A clear benefit from early angiography (<48 h) and, when needed, PCI or CABG surgery has been reported only in the high-risk groups. Deferral of intervention does not improve outcome. Routine stenting is recommended on the basis of the predictability of the result and its immediate safety.
In patients with STEMI, primary PCI should be the treatment of choice in patients presenting in a hospital with PCI facility and an experienced team. Patients with contra-indications to thrombolysis should be immediately transferred for primary PCI, because this might be their only chance for quickly opening the coronary artery. In cardiogenic shock, emergency PCI for complete revascularization may be life-saving and should be considered at an early stage. Compared with thrombolysis, randomized trials that transferred the patients for primary PCI to a ‘heart attack centre’ observed a better clinical outcome, despite transport times leading to a significantly longer delay between randomization and start of the treatment. The superiority of primary PCI over thrombolysis seems to be especially clinically relevant for the time interval between 3 and 12 h after onset of chest pain or other symptoms on the basis of its superior preservation of myocardium. Furthermore, with increasing time to presentation, major-adverse-cardiac-event rates increase after thrombolysis, but appear to remain relatively stable after primary PCI. Within the first 3 h after onset of chest pain or other symptoms, both reperfusion strategies seem equally effective in reducing infarct size and mortality. Therefore, thrombolysis is still a viable alternative to primary PCI, if it can be delivered within 3 h after onset of chest pain or other symptoms. Primary PCI compared with thrombolysis significantly reduced stroke. Overall, we prefer primary PCI over thrombolysis in the first 3 h of chest pain to prevent stroke, and in patients presenting 3–12 h after the onset of chest pain, to salvage myocardium and also to prevent stroke. At the moment, there is no evidence to recommend facilitated PCI. Rescue PCI is recommended, if thrombolysis failed within 45–60 min after starting the administration. After successful thrombolysis, the use of routine coronary angiography within 24 h and PCI, if applicable, is recommended even in asymptomatic patients without demonstrable ischaemia to improve patients' outcome. If a PCI centre is not available within 24 h, patients who have received successful thrombolysis with evidence of spontaneous or inducible ischaemia before discharge should be referred to coronary angiography and revascularized accordingly—independent of ‘maximal’ medical therapy.
Guidelines and Expert Consensus documents aim to present all the relevant evidence on a particular issue in order to help physicians to weigh the benefits and risks of a particular diagnostic or therapeutic procedure. They should be helpful in everyday clinical decision-making.
A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) and by different organizations and other related societies. This profusion can put at stake the authority and validity of guidelines, which can only be guaranteed if they have been developed by an unquestionable decision-making process. This is one of the reasons why the ESC and others have issued recommendations for formulating and issuing Guidelines and Expert Consensus Documents.
In spite of the fact that standards for issuing good quality Guidelines and Expert Consensus Documents are well defined, recent surveys of Guidelines and Expert Consensus Documents published in peer-reviewed journals between 1985 and 1998 have shown that methodological standards were not complied with in the vast majority of cases. It is therefore of great importance that guidelines and recommendations are presented in formats that are easily interpreted. Subsequently, their implementation programmes must also be well conducted. Attempts have been made to determine whether guidelines improve the quality of clinical practice and the utilization of health resources.
The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups, or consensus panels. The chosen experts in these writing panels are asked to provide disclosure statements of all relationships they may have which might be perceived as real or potential conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. The Committee is also responsible for the endorsement of these Guidelines and Expert Consensus Documents or statements.
The Task Force has classified and ranked the usefulness or efficacy of the recommended procedure and/or treatments and the Level of Evidence as indicated in the tables that follow:
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1. Introduction and definitions
With the tremendous increase in publications available, guidelines become more and more important to make available to clinicians the most relevant information while simultaneously improving patient care on the basis of evidence.1,2 Furthermore, guidelines are increasingly used by health care providers and politicians to assess the ‘appropriate use’ and develop disease management programmes. The European Society of Cardiology (ESC) has a tradition—initiated in 1992—of publishing annual reports and analyses regarding interventional cardiology.3 ESC Guidelines for percutaneous coronary interventions (PCI), however, have not been established. It is the purpose of these guidelines to give practically oriented recommendations on when to perform PCI on the basis of currently available published data derived from randomized and nonrandomized clinical studies.
1.1. Method of review
A literature review was performed using Medline (PubMed) for peer-reviewed published literature. The use of abstracts should be avoided in guidelines. According to the ESC recommendations for task force creation and report production, clinical trials presented at a major cardiology meeting were included for decision-making on the condition that the authors provided a draft of the final document to be submitted for publication.4
1.2. Definition of levels of recommendation
The levels of recommendations were graded on the basis of the ESC recommendations.4 In contrast to the ACC/AHA levels of recommendations,5 class III (‘conditions for which there is evidence and/or general agreement that the procedure is not useful/effective and in some cases may be harmful’) is discouraged by the ESC4 (Table on Classes of recommendations). Consensus could be achieved for all recommendations on the basis of evidence (Table on Levels of evidence). To verify the applicability of the recommendations to a specific area, the expert panel emphasized the importance of the primary endpoint for the randomized trials, giving high priority to the importance of significantly improving patients' outcome as the primary endpoint investigated in an adequately powered sample size.
2. Indications for PCI
2.1. Indications for PCI in stable coronary artery disease
2.1.1. General indications for PCI in stable coronary artery disease
2.1.1.1. PCI vs. medical therapy
Three randomized studies compared PCI with medical treatment. The ACME study6,7 was designed to evaluate whether PCI was superior to optimized medical therapy in relieving angina in patients with single and double-vessel disease. PCI offered earlier and more complete relief of angina than medical therapy and was associated with a better exercise tolerance and/or less ischaemia during exercise testing.6 Some of the early benefits from PCI in patients with single-vessel disease are sustained, making it an attractive therapeutic option for these patients.7 The ACIP trial8 focused on patients with severe daily-life ischaemia. Patients had both stress-inducible ischaemia and at least one episode of silent ischaemia on 48 h Holter monitoring (Table 1). Two years after randomization, the total mortality was significantly reduced from 6.6% in the angina-guided to 4.4% in the ischaemia-guided and to 1.1% in the revascularization strategy.9 (Recommendation for PCI to treat objective large ischaemia: I A).
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In patients with no or mild symptoms, however, the scenario is different and unlikely to be improved by PCI, as shown by the AVERT trial.10,11 At 18 months, 13% of the patients who received aggressive lipid lowering had ischaemic events, compared with 21% of the patients who underwent PCI as planned. This difference was initially statistically significant, but lost its significance after being adjusted for interim analysis. There are two major limitations in AVERT: (i) it is not a fair comparison of medical treatment with PCI because a more aggressive lipid-lowering treatment was used in the medical arm; stenting was used in only 30% and restenosis requiring re-intervention is more likely to happen in the PCI than in the conservative group. (ii) AVERT did not show the anti-ischaemic effect of statins, but it did show that statins may prevent acute coronary events. RITA-2 was a randomized trial comparing the long-term effects of PCI with conservative (medical) care in patients with CAD considered suitable for either treatment option.12 After a median follow-up of 2.7 years, death or definite myocardial infarction occurred in 6.3% treated with PCI and in 3.3% with medical care (P=0.02). On the other hand, PCI was associated with greater symptomatic improvement, especially in patients with more severe angina. RITA-2, however, cannot be applied to today's modern PCI. Only 7.6% of the patients received stents. Ticlopidine, clopidogrel, or GP IIb/IIIa inhibitors were not even mentioned in the study.
A meta-analysis of randomized controlled trials found that PCI may lead to a greater reduction in angina compared with medical treatment, although the trials have not included enough patients for informative estimates of the effect of PCI on myocardial infarction, death, or subsequent revascularization.13 Regardless of assignment to invasive or medical treatment (TIME study14) and medication with at least two antianginal drugs, long-term survival was similar in patients aged 75 years or older presenting with Canadian Cardiac Society (CCS) class II or greater angina. The benefits of both treatments in angina relief and improvement in quality of life were maintained, but nonfatal events occurred more frequently in patients assigned to medical treatment. Irrespective of whether patients were catheterized initially or only after drug therapy failure, their survival rates were better if they were revascularized within the first year.14 Costs should not be an argument against invasive management of elderly patients with chronic angina.15
2.1.1.2. PCI vs. CABG surgery
Data comparing PCI with coronary artery bypass graft (CABG) surgery are derived from 13 trials, randomizing 7964 patients between 1987 and 1999. For a follow-up period of 8 years, there was no statistically significant risk difference for death between the two revascularization strategies at 1, 3, or 8 years (except at year 5).16 The use of stents plays a major role: in early trials without stents, there was a trend favouring CABG surgery over PCI at 3 years that was no longer present in more recent trials with stents.16 The trend in favour of CABG surgery disappeared despite a reduction in mortality in the CABG surgery arm from 5.2% in trials without stents to 3.5% in the more recent trials with stents.16 Stenting halved the risk difference for repeat revascularization.16 Both PCI and CABG surgery provided good symptom relief.
2.1.2. Indications for PCI in special subsets of stable patients
2.1.2.1. Chronic total occlusions
Chronic total occlusion (CTO) still represents the anatomical subset associated with the lowest technical success rates with PCI. When the occlusion can be crossed with a guide wire and the distal lumen has been reached, satisfactory results are obtainable with stent implantation, as shown by several trials with primarily angiographic primary endpoints (GISSOC,17 PRISON,18 SARECCO,19 SICCO,20 SPACTO,21 STOP,22 and TOSCA23), albeit at the expense of a high restenosis rate ranging from 32 to 55%. The value of drug-eluting stents in this respect is currently under evaluation. In the PACTO study, the treatment of CTOs with the Taxus stent considerably reduced major adverse cardiac events (MACE) and restenosis and almost eliminated reocclusion—all typically frequent occurrences with bare metal stents.24 First results from a Cypher stent registry were encouraging.25 Before approaching CTOs, one has to keep in mind the possibly increased risk of side branch occlusion or perforation. (Recommendation for PCI in patients with chronic total occlusion: IIa C).
2.1.2.2. PCI in high surgical risk patients
The AWESOME trial26 tested the hypothesis that PCI is a safe and effective alternative to CABG surgery for patients with refractory ischaemia and high risk of adverse outcomes. In a subgroup analysis of patients with prior CABG surgery, the repeat CABG and PCI 3-year survival rates were 73 and 76%, respectively.27 Patients with severely depressed left ventricular function seem to benefit from revascularization by PCI, in particular when there is evidence for residual viability of the dysfunctional myocardium. The ‘patient choice registry’ revealed that PCI is preferable to CABG surgery for many post-CABG patients.27 The conclusions of the AWESOME randomized trial and registry are also applicable to the subset of patients with low left ventricular ejection fractions (LVEFs).28 (Recommendation for PCI in patients at high surgical risk: IIa B).
2.1.2.3. PCI in patients with multi-vessel disease and/or diabetes mellitus
In patients with multi-vessel CAD and many high-risk characteristics, CABG was associated with better survival than PCI after adjustment for risk profile.29 Early differences in cost and quality of life between CABG and PCI, however, were no longer significant at 10–12 years of follow-up in patients with multi-vessel disease.30 The decision to perform either culprit vessel or complete revascularization can be made on an individual basis.31
Although a formal trial evaluating the value of PCI vs. CABG surgery in diabetics is not yet available, every subgroup or post hoc analysis has invariably shown that the outcome for diabetics was worse following PCI than after CABG surgery. In the ARTS trial32,33 comparing PCI with surgery in patients with multi-vessel disease, the outcome for diabetics was poor in both treatment arms, but even more so following PCI. After 3 years, mortality was 7.1% in the PCI and 4.2% in the CABG group with a still significant difference in event-free survival of 52.7% in the PCI group and 81.3% in the CABG surgery group.33 In patients with multi-vessel disease, PCI in those with one or two haemodynamically significant lesions as identified by an FFR <0.75 (see section 4.6.2) yielded a similar favourable outcome as CABG in those with three or more culprit lesions despite a similar angiographic extent of disease.34 (Recommendation for PCI in patients with multi-vessel disease and/or diabetes mellitus: IIb C). Upcoming data on the use of drug-eluting stents in patients with multi-vessel disease and/or diabetes mellitus may change this situation.
2.1.2.4. PCI of unprotected left main disease
The presence of a left main (LM) coronary artery stenosis identifies an anatomic subset still requiring bypass surgery for revascularization. PCI of protected left main disease (i.e. partially bypass protected) can be performed, although a 1-year MACE of 25% is still rather high, which may reflect an increased mortality in patients with severe CAD who have previously undergone CABG surgery.35,36 The 2% periprocedural mortality and 95% 1-year survival for protected LM stenting appear comparable to outcomes for a repeat coronary bypass surgery while avoiding potential morbidity associated with a repeat operation.36
Stenting for unprotected LM disease should only be considered in the absence of other revascularization options.36 Therefore, PCI can be recommended in these subsets when bypass surgery has a very high perioperative risk (e.g. EuroSCORE>10%). Initial data on the use of drug-eluting stents in unprotected LM disease seem promising.37,38 (Recommendation for PCI in patients with unprotected left main stenosis in the absence of other revascularization options: IIb C).
2.1.3. Provisional or elective stenting in stable CAD?
There is no doubt that stents are a valuable tool in dissections with threatening vessel closure or insufficient results after balloon angioplasty. In general, stents are superior to balloons (BENESTENT-I,39 STRESS,40 REST,41 and others42–45 for the following reasons:
- Plaque fracture and dissection caused by balloon angioplasty often result in a pseudo-successful procedure and limited luminal enlargement is obtained.
- While abrupt closure within 48 h following balloon treatment is not uncommon (up to 15% in the presence of severe residual dissection), the treated lesion shows greater acute and subacute stability after stenting.
- The angiographic results that can be obtained after stenting are predictable irrespective of the stenotic complexity.
- In the medium-long term, stent implantation results in fewer vessel occlusions or reocclusions and lower rates of clinical restenosis.
In a meta-analysis of 29 trials involving 9918 patients, coronary stenting, compared with balloon angioplasty, reduced the rate of restenosis and the need for repeated PCI for about 50%.46 A recent meta-analysis47 showed that stenting is associated with reduced mortality compared with balloon angioplasty and patients who underwent stent placement had a significantly lower risk of MACE when target revascularization is included as an endpoint.48 The benefit of routine stenting is even more evident in smaller coronary arteries.49 A similar benefit could be shown in saphenous venous bypass grafts (SAVED,50 VENESTENT51). After bare metal stent implantation, the 5-year clinical outcome is related to disease progression in segments other than the stented lesion, which itself remains relatively stable.52,53 (Recommendation for routine stenting of de novo lesions in native coronary arteries or venous bypass grafts in patients with stable CAD: I A).
2.1.4. Troponin elevation after PCI in stable CAD
Troponin release is relatively common after PCI in stable CAD and associated with procedural complications, including side branch occlusions, thrombus formations, sapheneous vein graft interventions, multi-stent use, and glycoprotein IIb/IIIa use.54,55 In patients without acute myocardial infarction, troponin I elevation after PCI did not predict mortality56 and a post-PCI elevation of more than three times the normal limit had no incremental risk of adverse 8 months clinical outcomes.57 A meta-analysis of 2605 patients suggested that the use of low cutoff concentrations after PCI does not correlate with an increased incidence of composite adverse events (cardiac death, myocardial infarction bypass surgery, or repeat PCI of the target vessel) and some multiple of the cutoff may be more appropriate for the prediction of adverse events.58 In a recent study, even troponin-I elevations five times above the upper limit of normal did not predict events after hospital discharge.59 Therefore, with respect to periprocedural elevations of cardiac markers, increasing evidence exists that only an increase in CK-MB of more than five times normal (and not any level of troponin I elevation) is associated with a higher mortality at follow-up, whereas mild (one to five times normal) CK-MB elevation is increasingly regarded as a common procedure-related event with little prognostic relevance.56
In summary, PCI can be considered a valuable initial mode of revascularization in all patients with stable CAD and objective large ischaemia in the presence of almost every lesion subset, with only one exception: CTO that cannot be crossed. In early studies, there was a small survival advantage with CABG surgery compared with PCI without stenting. The addition of stents and newer adjunctive medications improved the outcome for PCI. The decision to recommend PCI or CABG surgery will be guided by technical improvements in cardiology or surgery, local expertise, and patients' preference. However, until proved otherwise, PCI should be used only with reservation in diabetics with multi-vessel disease and in patients with unprotected LM stenosis. The use of drug-eluting stents might change this situation.
2.2. Indications for PCI in acute coronary syndromes without ST-segment elevation
The ESC recently published guidelines for the general management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation.60 The present guidelines focus on PCI to optimize the management of patients presenting with NSTE-ACS. Patients demonstrating elevated serum markers [troponin (Tn)-I, Tn-T, or CK-MB] will be subsequently considered to have non-ST-segment elevation myocardial infarction (NSTEMI).
2.2.1. Risk stratification in NSTE-ACS
The importance of stratifying patients with unstable angina (UA) or NSTEMI in high-risk vs. low-risk groups applies to the fact that a clear benefit of early angiography and, when needed, PCI, has been reported only in high-risk groups.61–65
According to the ESC NSTE-ACS guidelines,60 the characteristics of patients at high risk for rapid progression to myocardial infarction or death who should undergo coronary angiography within 48 h are given in Table 2.66–76
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Furthermore, the following markers of severe underlying disease, i.e. a high long-term risk, might also be helpful for risk assessment in NSTE-ACS:63–73,77–80
- age >65–70 years,
- history of known CAD, previous MI, prior PCI, or CABG,
- congestive heart failure, pulmonary oedema, new mitral regurgitation murmur,
- elevated inflammatory markers (i.e. CRP, Fibrinogen, IL 6),
- BNP or NT-proBNP in upper quartiles,
- renal insufficiency.
2.2.2. Conservative, early invasive, or immediately invasive?
Recently published surveys revealed that less than 50% of the patients with NSTE-ACS are undergoing invasive procedures (GRACE82 and CRUSADE83). Proponents of a conservative strategy in the management of UA and NSTEMI base their suggestions on the results of the TIMI IIIB trial,84 the MATE trial,85 and the VANQWISH trial.86 Several methodological flaws arise in these studies (high crossover rates, no or minimal usage of stenting, no usage of GP IIb/IIIa inhibitors), making their conclusions not contemporary. In GUSTO IV-ACS, revascularization within 30 days was associated with an improved prognosis.87 The relative high mortality in medically treated patients might have been related in part to patient selection.
Besides two smaller European studies (TRUCS88 and VINO89), the preference for an early invasive vs. an initially conservative approach is based on the results of 6487 patients in three trials: FRISC II,90 TACTICS-TIMI 18,91 and RITA-392 (Tables 3 and 4 and Figure 1). (Recommendation for early PCI in patients with high-risk NSTE-ACS: I A).
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Although caution is needed in interpretation, gender differences may exist.93 There are more studies underway (e.g. ICTUS) that include a more potent antiplatelet regime and therefore may challenge the currently recommended invasive strategy. ISAR-COOL94 compared a medical (‘cooling’) strategy vs. immediate PCI in patients at high risk with either ST-segment depression (65%) or elevated troponin T (67%). The median time to catheterization was 86 h in the cooling off group and 2.4 h in the immediate group. Only 5.8% of the deferred group had to be catheterized earlier. The primary endpoint, defined as death from any cause and large nonfatal MI at 30 days, occurred in 11.6% of patients randomized to the cooling-off group (‘prolonged antithrombotic pre-treatment’) vs. 5.9% of patients randomized to the immediate invasive strategy (P=0.04). This outcome was attributable to events occurring before catheterization. The investigators concluded that in patients with NSTE-ACS at high risk, deferral of intervention does not improve outcome and antithrombotic pre-treatment should be kept to the minimum duration required to organize cardiac catheterization and revascularization. (Recommendation for immediate, i.e. <2.5 h PCI in patients with high-risk NSTE-ACS: IIa B).
In most of the studies utilizing PCI in UA or NSTEMI, stenting was the most frequently applied final treatment. (Recommendation for routine stenting in de novo lesions of patients with high-risk NSTE-ACS: I C).
In summary, patients presenting with NSTE-ACS (UA or NSTEMI) have to be first stratified for their risk of acute thrombotic complications. A clear benefit from early angiography (<48 h) and, when needed, PCI or CABG surgery has been reported only in the high-risk groups. Deferral of intervention does not improve outcome. Routine stenting is recommended on the basis of the predictability of the result and its immediate safety.
2.3. Indications for PCI in ACS with ST-segment elevation
The ESC recently published guidelines for the general management of patients presenting with STEMI, i.e. patients with history of chest pain/discomfort associated with persistent ST-segment elevation or (presumed) new bundle-branch block.95 The present guidelines focus more specifically on the use of PCI in this condition (Figure 2).
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PCI for STEMI requires an experienced team of interventional cardiologists working together with a skilled support staff. This means that only hospitals with an established interventional programme should use PCI for STEMI instead of intravenous thrombolysis. Most of the trials comparing thrombolysis vs. primary PCI were carried out in high-volume centres by experienced operators with short response times. Therefore, the results do not necessarily apply in other settings. Large variations between individual institutions have been documented.96–104 In general, for primary PCI, a higher level of experience and patient volume is required than for PCI in patients with stable coronary artery disease.104 In patients with multi-vessel disease, primary PCI should be directed only at the infarct-related coronary artery (culprit vessel), with decisions about PCI of non-culprit lesions guided by objective evidence of residual ischaemia at later follow-up.105
Fortunately, the implementation of guidelines for patients with acute MI has shown to improve the quality of care.106 In one study, patients treated during off-hours had a higher incidence of failed angioplasty and consequently a worse clinical outcome than patients treated during routine duty hours.107 In another study, patients who underwent primary PCI during off-peak hours achieved rates of TIMI grade 3 flow, 30-day and 1-year mortality and improvement in ejection fraction and regional wall motion similar to those presenting on weekdays.108
2.3.1. Primary PCI
Primary PCI is defined as intervention in the culprit vessel within 12 h after the onset of chest pain or other symptoms, without prior (full or concomitant) thrombolytic or other clot-dissolving therapy. Primary PCI was first performed in 1979,109 i.e. only 2 years after the introduction of PCI.110 Ever since, many randomized controlled trials have documented that primary PCI is superior to intravenous thrombolysis for the immediate treatment of STEMI (more effective restoration of coronary patency, less recurrent myocardial ischaemia, less coronary reocclusion, less recurrent MI, improved residual left ventricular function, and better clinical outcome including strokes). It seems that women111 and elderly patients112 particularly benefit from primary PCI vs. thrombolysis.
A meta-analysis of 23 randomized trials,113 which together assigned 7739 thrombolytic-eligible patients with STEMI to either primary PCI or thrombolytic medication, revealed the following findings: primary PCI was better than thrombolytic therapy at reducing overall short-term (defined as 4–6 weeks) death (9.3 vs. 7.0%, P=0.0002), non-fatal re-infarction (6.8 vs. 2.5%, P<0.0001), total stroke (2.0 vs. 1.0%, P=0.0004), and the combined endpoint of death, non-fatal re-infarction, and stroke (14.5 vs. 8.2%, P<0.0001). During long-term follow-up (6–18 months), the results seen with primary PCI remained better than those seen with thrombolytic therapy with 12.8 vs. 9.6% for death, 10.0 vs. 4.8% for non-fatal MI, and 19 vs. 12% for the combined endpoint of death, non-fatal re-infarction, and stroke.113–116
The most impressive difference between thrombolysis and primary PCI was the significant reduction of recurrent ischaemia from 21% with thrombolysis to 6% following primary PCI during short-term (P<0.0001), and also during long-term follow-up (39 vs. 22%, P<0.0001).113 (Recommendation for primary PCI in STEMI: I A).
The pivotal studies contributing to level of evidence A for primary PCI were PAMI,117 GUSTO-IIb,118 C-PORT,119 PRAGUE-1,120 PRAGUE-2,121 and DANAMI-2122 (Table 7).
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2.3.1.1. Transfer of patients for primary PCI
There is no doubt that patients presenting within 12 h after onset of chest pain or other symptoms in hospitals without PCI facilities and having contra-indications to thrombolysis should be immediately transferred for coronary angiography and, if applicable, primary PCI in another hospital, because PCI might be their only chance for quickly opening the coronary artery. Absolute contra-indications to thrombolysis are the following conditions: aortic dissection, status post haemorrhagic stroke, recent major trauma/surgery, GI bleeding within the last month or a known bleeding disorder.95 Patients with a contra-indication to thrombolysis are known to have a higher morbidity and mortality than those who are eligible.123 Primary PCI has not been formally evaluated by a randomized controlled trial in this subset of patients, but it has been shown to be safely feasible in a large majority of cases.124 (Recommendation for primary PCI in patients with contra-indications to thrombolysis: I C).
The decision for transferring a patient to a PCI facility will also depend on the individual clinical risk assessment. The choice between PCI and thrombolysis is often dictated by logistic constraints and transport delays.125 The trials that have investigated the possible superiority of primary PCI despite the need for patient transfer from a non-PCI hospital to a PCI hospital are Limburg (LIMI),126 PRAGUE-1,120 PRAGUE-2,121 Air-PAMI,127 and DANAMI-2.122 Their details are listed in Table 5.
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The DANAMI-2 trial122 was the first to show a significant reduction in the primary endpoint of death, re-infarction, and stroke after 30 days with primary PCI, despite the transfer-induced delays (Table 5). The PRAGUE-2 trial121 was prematurely stopped because of a 2.5-fold excess mortality in the thrombolysis group among patients treated after >3 h from symptom onset. In patients randomized >3 h after the onset of symptoms, the mortality of the thrombolysis group reached 15.3% compared with 6% in the PCI group (P<0.02). Patients randomized within <3 h of symptom onset had no difference in mortality whether treated by thrombolysis (7.4%) or transferred to primary PCI (7.3%). Approximately two-thirds of the patients were randomized within <3 h after onset of chest pain, so PRAGUE-2 had no chance of reaching the primary endpoint.
Within the first 3 h after onset of chest pain, thrombolysis is a viable alternative as indicated by PRAGUE-2,121 STOPAMI-1 and -2,128 MITRA, and MIR129 as well as CAPTIM130 with pre-hospital thrombolysis131 (Figure 2). Therefore, within the first 3 h after onset of chest pain, both reperfusion strategies seem equally effective in reducing infarct size and mortality. This questioned superiority of primary PCI vs. thrombolysis within the first 3 h can be additionally addressed by a combined analysis from STOPAMI-1 and -2.128 However, the ‘myocardial salvation index’ was not statistically different between thrombolysis and primary PCI within the first 165 min (0.45 vs. 0.56); it showed a highly significant superiority of primary PCI after 165–280 min (0.29 vs. 0.57, P=0.003) and after 280 min (0.20 vs. 0.57). This time-dependent superiority of primary PCI compared with thrombolysis (i.e. with increasing time to presentation, MACE rates increase after thrombolysis but appear to remain relatively stable after PCI) has also been previously observed in the PCAT meta-analysis of 2635 patients132 and in patients with a pre-hospital delay of >3 h (MITRA and MIR registries129). Thus, ‘late is perhaps not too late’.133
The major reason why one could possibly prefer primary PCI over thrombolysis even within the first 3 h after onset of chest pain is stroke prevention. The meta-analysis of 23 randomized trials113 showed that primary PCI as compared with thrombolysis significantly reduced total stroke (2.0 vs. 1.0%). According to the PCAT132 meta-analysis, the advantage of stroke reduction by primary PCI vs. thrombolysis is 0.7% in patients presenting within 2 h, 1.2% in patients presenting 2–4 h, and 0.7% in patients presenting 4–12 h between onset of chest pain and presentation. These data are consistent with the CAPTIM study, with 1% (4/419) strokes in the thrombolysis and 0% (0/421) in the primary PCI group.130 A meta-analysis focusing on the transfer trials revealed a significant 1.2% reduction of stroke from 1.88% (thrombolysis) to 0.64% (primary PCI).134 Therefore, the major rationale for preference of primary PCI over thrombolysis for patients presenting 3–12 h after onset of chest pain is not only to salvage myocardium but also prevent stroke. (Recommendation for primary PCI in patients presenting within 3–12 h after onset of chest pain: I C).
The PRAGUE-2 and DANAMI-2 trials are especially important as they show that primary PCI for STEMI can be applied in large areas of partly urbanized Europe with good results.135 Primary PCI in high-risk STEMI patients at hospitals with no cardiac surgery on-site appears to be safe and effective.136,137
2.3.1.2. Routine stenting in STEMI
One trial has suggested that direct stenting (without prior balloon dilatation) is associated with a more complete ST-segment resolution.138 Three studies have documented the usefulness of stenting in patients with STEMI: Zwolle,139 Stent-PAMI,140 and CADILLAC.141 (Recommendation for routine stenting in patients with STEMI: I A).
2.3.2. Facilitated PCI
Facilitated PCI is defined as planned intervention within 12 h after onset of chest pain or symptoms, soon after clot-dissolving medication to bridge the delay between first medical contact and primary PCI. However, the term ‘facilitated PCI’ is not uniformly used for identical settings: it should be used as initially planned PCI, following shortly after initiating thrombolysis and/or GP IIb/IIIa inhibitors. Therefore, in randomized studies testing the concept of facilitated PCI, all patients (with or without pre-treatment) should undergo planned primary PCI.
2.3.2.1. Thrombolysis-facilitated primary PCI
Facilitated PCI was tested in smaller subgroups of PRAGUE-1 study120 and SPEED (GUSTO-4 Pilot142). Newer concepts with administration of a half dose of t-PA prior to systematic primary PCI have shown to be associated with improved TIMI-3 flow rates upon arrival at the catheterization laboratory, but this did not translate into a relevant clinical benefit (PACT study143). In BRAVE,144 randomizing to either half dose reteplase plus abciximab or abciximab alone before they were transferred for planned PCI with stenting, early administration of reteplase plus abciximab did not lead to a reduction of infarct size compared with abciximab alone. Although the concept of ‘low-dose thrombolysis’145 combined with clopidogrel and GP IIb/IIIa inhibitors shortly before stenting in STEMI is an interesting one, the studies dedicated to facilitated PCI suggest no benefit and even potential harm.116 More data will be available from the currently ongoing ASSENT-4 trial (randomizing TNK-facilitated primary PCI vs. primary PCI with GP IIb/IIIa inhibitor as needed) and from FINESSE146 (randomizing reteplase-facilitated vs. abciximab-facilitated vs. un-facilitated primary PCI). But at the moment, there is no evidence for the recommendation of thrombolysis-facilitated PCI.
2.3.2.2. GP IIb/IIIa inhibitor-facilitated primary PCI
In the ADMIRAL study,147 the analysis of the pre-specified subgroup that received abciximab in the emergency department or in the ambulance showed better outcomes than the group of patients receiving the drug later, suggesting an advantage of ‘facilitation’. In the ON-TIME trial,148 patients were prospectively randomized to early, pre-hospital initiation of tirofiban (early) or to initiation in the catheterization laboratory (late). At initial angiography, TIMI 3 flow was present in 19% of the early group and in 15% of the late group (not significant). No beneficial effect on post-PCI angiographic or clinical outcome was found. Although the TIGER-PA149 pilot and the BRIDGING150 studies suggested that early administration of tirofiban or abciximab improves angiographic outcomes in patients undergoing primary PCI and although in a meta-analysis of six randomized trials151 early administration of GP IIb/IIIa inhibitors in STEMI appeared to improve coronary patency with favourable trends for clinical outcomes, no evidence-based recommendation for GP IIb/IIIa inhibitor-facilitated primary PCI can be made at the present time to improve patients' outcome.
2.3.3. Rescue PCI after failed thrombolysis
Rescue PCI is defined as PCI in a coronary artery that remains occluded despite thrombolytic therapy. Failed thrombolysis is generally suspected when persistent chest pain and non-resolution of ST-segment elevation are evident 45–60 min after starting the administration. It is then confirmed angiographically (significant epicardial coronary lesion together with impaired flow<TIMI 3). A Cleveland Clinic Study investigated the value of rescue PCI after failed thrombolysis.152 The patients were randomized to ASA, heparin, and coronary vasodilators (conservative therapy) or to the same medical therapy and PCI. The occurrence of the primary endpoint (either death or severe heart failure) was significantly reduced by rescue PCI from 17 to 6%. A meta-analysis from the RESCUE I, RESCUE II, and other clinical experiences suggested a probable benefit of rescue PCI.153 On the other hand, in the MERLIN trial,154 rescue PCI did not improve survival by 30 days, but improved event-free survival almost completely due to a reduction in subsequent revascularization. The most serious limitation of MERLIN, however, was that it was considerably underpowered.155 The recently finished REACT trial156 (enrolling patients who, after a 90-min ECG, failed to achieve a >50% resolution of ST changes) indicates that rescue PCI is superior to repeat thrombolysis or conservative treatment in patients who failed to achieve reperfusion after thrombolysis. At 6 months, the incidence of any event was reduced by almost half in the rescue PCI group, compared with either the repeat lysis or conservative therapy groups (death: 18 vs. 9%). As compared with MERLIN, the use of GP IIb/IIIa inhibitors and stents was higher; and in REACT, the time delays for rescue PCI were shorter. As in primary PCI, stenting is superior to balloon-only angioplasty in rescue PCI.157 (Recommendation for rescue PCI in patients with failed thrombolysis: I B).
2.3.4. Emergency PCI in cardiogenic shock
Cardiogenic shock is a clinical state of hypoperfusion characterized by a systolic blood pressure <90 mmHg and a capillary wedge pressure >20 mmHg or a cardiac index <1.8 l/min m2 (ESC Guidelines on STEMI95). Emergency PCI or surgery may be life-saving and should be considered at an early stage.95 If neither PCI nor surgery is available or can only be provided after a long delay, thrombolytic therapy should be given.95 Women have a higher mortality than men, regardless of the treatment received.
Two randomized, controlled trials (SHOCK158,159 and SMASH160) have evaluated early revascularization (PCI or CABG surgery) in patients with shock because of left ventricular dysfunction following STEMI. PCI in patients with cardiogenic shock is characterized by two differences in comparison to ‘normal’ STEMI patients: the usually recommended time window of 12 h after onset of chest pain is wider161 and multi-vessel PCI should be strongly considered. All trials of primary PCI have evaluated a strategy of limiting the acute revascularization procedure to the culprit vessel. Only in the setting of cardiogenic shock is there a consensus for attempting multi-vessel PCI in selected patients with multiple critical lesions. The use of intra-aortic balloon pump (IABP) should be strongly considered. If the multi-vessel disease is not amenable to relatively complete percutaneous revascularization, surgery should be considered in these patients.161 In the Benchmark Counterpulsation Outcomes Registry (25 136 patients), in-hospital mortality was higher in patients who received only medical interventions (32.5%) than in those who underwent percutaneous (18.8%) and surgical (19.2%) interventions.162 One should keep in mind that patients with cardiogenic shock and NSTEMI have an in-hospital mortality similar to shock patients with STEMI.163 In-hospital mortality in patients with acute MI complicated by cardiogenic shock remains high, even with early PCI.164 Among patients older than 75 years with MI complicated by cardiogenic shock, outcomes may be better than previously believed when early revascularization is performed. In this population, 56% of patients survived to be discharged from the hospital, and of the hospital survivors, 75% were alive at 1 year.165 Within the last few years, an increase in revascularization of patients with acute MI complicated for cardiogenic shock was observed, probably due to more frequent admission of eligible patients to hospitals capable of this service.166 (Recommendation for emergency PCI in patients with cardiogenic shock: I C).
2.3.5. Routine angiography early post thrombolysis
The ALKK study167 randomized 300 patients (initially planned were 800) to either PCI or medical therapy. Before randomization, 63% of the PCI and 57% of the medical group received thrombolysis. PCI was performed at a mean of 24 days after STEMI. The event-free survival at 1 year showed a trend in favour of PCI (90 vs. 82%). This difference was mainly due to the difference in the need for (re)interventions (5.4 vs. 13.2%, P=0.03). A multi-level analysis of patients in ASSENT-2 showed a lower mortality in the countries with the highest rates of PCI after thrombolytic treatment.168 A meta-analysis of 20 101 patients from the TIMI 4, 9, and 10B and InTIME-II trials revealed that PCI during hospitalization was associated with a lower rate of in-hospital recurrent MI (4.5 vs. 1.6%, P<0.001) and a lower 2-year mortality (11.6 vs. 5.6%, P<0.001).169 A prospective cohort study from the Swedish National Cause of Death registry supported the use of an invasive approach early after an acute myocardial infarction.170 In GUSTO-I, the rates of cardiac catheterization and revascularization during the index hospitalization among US patients were more than twice those among Canadian patients.171 The 5-year mortality rate was 19.6% among US patients and 21.4% among Canadian patients (P=0.02). Thus, a more conservative pattern of care with regard to early revascularization had a detrimental effect on long-term survival.171
Four randomized studies have contributed to recommend routine coronary angiography and—if applicable—PCI early post-thrombolysis: SIAM III,172 GRACIA-1,173 CAPITAL-AMI,174 and the Leipzig Prehospital Lysis Study (LPLS175). The details of these four studies are listed in Table 6.
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Thus, SIAM III, GRACIA-1, and CAPITAL-AMI together with LPLS, the ALKK study, the ASSENT-2 analysis, the meta-analysis of the TIMI 4, 9, and 10B, and InTIME-II trials as well as GUSTO-I have contributed to the solution of an old but still pivotal problem: the incidence of re-infarction, the ‘Achilles' heel’ of thrombolysis. Thus, thrombolysis, even if successful, should not be considered as the final treatment: ‘lyse now, stent later’.176 (Recommendation of routine coronary angiography and PCI, if applicable, in patients after successful thrombolysis: I A).
2.3.6. Ischaemia-driven PCI after thrombolysis
The DANAMI-1 trial177 was the first and only prospective, randomized study comparing an invasive strategy of PCI/CABG surgery with a conservative strategy in patients with pre-discharge inducible myocardial ischaemia after thrombolytic treatment for a first STEMI. The occurrences of the primary endpoint (mortality, re-infarction, and admission with unstable angina) were significantly reduced with 15.4 vs. 29.5% at 1 year, 23.5 vs. 36.6% at 2 years, and 31.7 vs. 44.0% at 4 years. Thus, patients who have received treatment with thrombolytics for their first STEMI with inducible ischaemia before discharge should be referred to coronary angiography and revascularized accordingly—independent of maximal medical therapy. (Recommendation for ischaemia-driven PCI after successful thrombolysis: I B).
2.3.7. PCI for patients not having received reperfusion within the first 12 h
Patients often seek medical attention too late and either do not receive reperfusion therapy or reperfusion therapy fails to successfully recanalize the artery. Late reperfusion therapy is defined as thrombolysis or PCI starting >12 h after onset of symptoms (for late PCI in cardiogenic shock please see section 2.3.4.). Thrombolytic therapy for the late treatment of patients with STEMI does not reduce infarct size or preserve left ventricular function, probably because it is ineffective in establishing coronary patency.178
Cautious interpretation of PCAT,132 PRAGUE-2,121 and CAPTIM130 might consider a possible beneficial effect of late PCI. This, however, is inconsistent with the smaller TOAT trial,179 with late PCI having an adverse effect on LV remodelling. In DECOPI,180 212 patients with a first Q-wave MI and an occluded infarct vessel were randomized to PCI, carried out 2–15 days after symptom onset or medical therapy. The primary endpoint was a composite of cardiac death, non-fatal MI, or ventricular tachyarrhythmia. Although at 6 months, LV-EF was significantly higher (5%) in the invasive compared with the medical group and significantly more patients had a patent artery (82.8 vs 34.2%), at a mean of 34 months of follow-up, the occurrence of the primary endpoint was similar in the medical and PCI groups (8.7 vs. 7.3%, respectively). Because recruitment and event rates were lower than planned, the study is markedly underpowered. Thus, although the ‘late open artery hypothesis’ seems appealing,181 we will have to wait for the results of the OAT trial. Currently, there is no agreement on treatment recommendations for this group of patients.
2.3.8. Minimization of time delays
For all forms of PCI in STEMI (Table 7) there is unanimous agreement that every effort must be made to minimize any delays between onset of chest pain/other symptoms and the initiation of a safe and effective reperfusion strategy in patients with STEMI.182,183 Shortening the total ischaemic time is pivotal, not only for thrombolytic therapy but also for primary PCI.184 (Figure 3). Minimizing presentation and treatment delays significantly improves clinical outcome, whereas prolonged symptom-to-treatment times are associated with impaired myocardial perfusion independent of epicardial flow.185 The effort starts with patient education and includes improvements in organization of ambulance services as well as optimizing procedures within the hospital or private practice (Figure 3). As far as primary PCI is concerned, all efforts should be made to keep the average time between first medical contact and PCI below 90 min, including door to balloon time. Skipping the emergency room and directly transferring STEMI patients to the cath lab additionally reduces door to balloon times. However, patients with longer delays should also be treated by primary PCI even when presenting 3 h after onset of symptoms. Only when a substantial delay (e.g. >2–3 h) in initiating primary PCI is likely, reperfusion therapy with second or third-generation fibrinolytic agents should be considered.186
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In summary, primary PCI should be the treatment of choice in patients presenting with STEMI in a hospital with PCI facility and an experienced team. Patients with contra-indications to thrombolysis should be immediately transferred for primary PCI, because this might be their only chance for quickly opening the coronary artery. In cardiogenic shock, emergency PCI for complete revascularization may be life-saving and should be considered at an early stage. Compared with thrombolysis, randomized trials that transferred the patients for primary PCI to a ‘heart attack centre’, observed a better clinical outcome, despite transport times leading to a significantly longer delay between randomization and start of the treatment. The superiority of primary PCI over thrombolysis seems to be especially clinically relevant for the time interval between 3 and 12 h after onset of chest pain or other symptoms on the basis of its superior preservation of myocardium. Furthermore, with increasing time to presentation, MACE rates increase after thrombolysis, but appear to remain relatively stable after primary PCI.
Within the first 3 h after onset of chest pain or other symptoms, both reperfusion strategies seem equally effective in reducing infarct size and mortality. Therefore, thrombolysis is still a viable alternative to primary PCI, if it can be delivered within 3 h after onset of chest pain or other symptoms. Primary PCI compared with thrombolysis significantly reduced stroke. Overall, we prefer primary PCI over thrombolysis in the first 3 h of chest pain to prevent stroke and, in patients presenting 3–12 h after the onset of chest pain, to salvage myocardium and also prevent stroke. At the moment, there is no evidence to recommend facilitated PCI.
Rescue PCI is recommended, if thrombolysis failed within 45–60 min after starting the administration. After successful thrombolysis, the use of routine coronary angiography within 24 h and PCI, if applicable, is recommended even in asymptomatic patients without demonstrable ischaemia to improve outcomes. If a PCI centre is not available within 24 h, patients who have received successful thrombolysis with evidence of spontaneous or inducible ischaemia before discharge should be referred to coronary angiography and revascularized accordingly—independent of maximal medical therapy.
3. Adjunctive medications for PCI
A routine pre-treatment with an intracoronary bolus of nitroglycerin (NTG) is recommended to unmask vasospasm, to assess the true vessel size, and to reduce the risk of vasospastic reactions during the procedure (Recommendation for NTG: I C). The bolus may be repeated during and at the end of the procedure, depending on the blood pressure. In the rare case of spasm resistant to NTG, verapamil is a useful alternative.
In the setting of ‘no/slow reflow’ (see 4.5.), many reports investigated the intracoronary application of verapamil and adenosine in various dosages.187 The direct nitric oxide donor nitroprusside (NPN) seems also to be an effective and safe treatment of reduced blood flow or no-reflow associated with PCI.188,189 In addition, IABP might be helpful. The combination of adenosine and nitroprusside provided an improvement in coronary flow that was better than the improvement with intracoronary adenosine alone.190 (Recommendation for adenosine, verapamil and NPN for no/slow reflow: IIa C).
3.1. Acetylsalicylic acid
Since the beginning of interventional cardiology, antiplatelet drugs are a cornerstone of the adjunctive medication because the trauma induced by PCI to the endothelium and deeper layers of the vessel wall regularly results in platelet activation. The basic pharmacology and general clinical application of antiplatelet agents in patients with atherosclerotic cardiovascular disease have been recently elaborated in an ESC consensus document.191 The PCI guidelines address their indications more specifically to the setting of PCI.
3.1.1. Acetylsalicylic acid in stable CAD
In the ‘Antithrombotic Trialists' Collaboration meta-analysis, acetylsalicylic acid (ASA) reduced vascular death, MI, or stroke among all patients who were at high risk for vascular events in 22% as compared with placebo.192 M-HEART II193 was the only placebo-controlled PCI study with ASA alone showing a significant improvement of clinical outcome in comparison to placebo (30 vs. 41%). MI was significantly reduced by ASA from 5.7 to 1.2%. Today, ASA continues to play an important role in reducing ischaemic complications related to PCI. If patients are not chronically pre-treated or when there is doubt about medication compliance, a loading dose of 500 mg orally should be given more than 3 h prior or at least 300 mg intravenously directly prior to the procedure. Only in patients with known allergy against ASA, should it be omitted. As pointed out in the ESC consensus document, for chronic use, there is no need for doses higher than 100 mg daily.191 (Recommendation for ASA in PCI for stable CAD: I B).
3.1.2. ASA in NSTE-ACS
The ‘Antithrombotic Trialists' Collaboration meta-analysis revealed a 46% reduction of vascular death, MI, or stroke (from 13.3 to 8.0%).192 Although these studies were performed before the widespread use of PCI, they have led to the universal recommendation of ASA as standard therapy in NSTE-ACS with and without PCI. (Recommendation for ASA in PCI for NSTE-ACS: I C).
3.1.3. ASA in STE-ACS (STEMI)
ASA has proved its efficacy compared with placebo in the ISIS-2 trial, showing ASA to be almost as effective as Streptokinase.194 The administration of both drugs was additive. Despite the limitations and side effects of ASA, it should be given to all patients with STEMI (if clinically justifiable) as soon as possible after the diagnosis is established.95 (Recommendation for ASA in PCI for STEMI: I B).
Recently, the problem of ‘aspirin resistance’ has arisen.195 However, more prospective studies are needed to correlate ASA non-responsiveness to adverse clinical events.
3.2. Ticlopidine and clopidogrel
3.2.1. Thienopyridines (ticlopidine/clopidogrel) in stable CAD
Ticlopidine and clopidogrel are potent antiplatelet compounds. There is a compelling evidence that for a reduction in acute and sub-acute stent thrombosis following PCI with stent implantation, the combination therapy of a thienopyridine plus ASA is superior to ASA alone or ASA plus an oral anticoagulant (Milan/Tokyo,196 ISAR,197 STARS,198 FANTASTIC,199 and MATTIS200). According to three randomized, controlled studies (CLASSICS,201 TOPPS,202 Bad Krozingen,203) and several registries and meta-analyses,204–209 clopidogrel seems to be at least as effective as ticlopidine. Compared with ticlopidine, clopidogrel has fewer side-effects and is better tolerated. (Recommendation for 3–4 weeks of ticlopidine or clopidogrel in addition to ASA after bare metal stent implantation in stable CAD: I A).
At present, as the vast majority of PCI procedures eventually conclude with stent implantation, every patient scheduled for PCI should be considered for pre-treatment with clopidogrel, regardless of whether stent implantation is intended or not.210 A pre-treatment with 300 mg within 2.5 h, however, may not be sufficient.211 To ensure full antiplatelet activity, clopidogrel should be initiated at least 6 h prior to the procedure with a loading dose of 300 mg, ideally administered the day before a planned PCI (CREDO trial212 and TARGET analysis213). If this is not possible, a loading dose of 600 mg should be administered at least 2 h before PCI, but no fully published (ARMYDA-2-study) randomized data exist.94,214–216 If diagnostic angiography is negative or no stenting was performed, or if early heart surgery is indicated, clopidogrel can be stopped. Patients unable to be pre-treated with clopidogrel should receive the (possibly higher) loading dose immediately following the procedure. (Recommendation for pre-treatment with 300 mg clopidogrel at least 6 h before PCI: I C).
After stenting, there is no need to recommend prolonged (>4 weeks) treatment in patients with stable angina—except after brachytherapy or after implantation of a drug-eluting stent (Table 8, see also Chapter 5). (Recommendation for clopidogrel administration after brachytherapy for 12 months or drug-eluting stents for 6–12 months: I C).
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3.2.2. Clopidogrel in NSTE-ACS
The optimal time for initiating clopidogrel therapy in patients with NSTE-ACS is a matter of discussion: on the one hand, the CURE trial217 revealed that the frequency of adverse events was significantly reduced within the first hours of entry into the trial.218 On the other hand, in patients referred to cardiac surgery while on clopidogrel, perioperative blood loss during surgery is a concern. In CURE, no overall significant excess of major bleeding episodes occurred after CABG surgery (1.3 vs. 1.1%). In the patients who did not stop study medication until 5 days before surgery, the rate of major bleeding was higher in the clopidogrel group (9.6 vs. 6.3%).217 Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks even among those who proceed to CABG surgery during the initial hospitalization.219 In several cases, platelets have to be substituted. A clear increase in bleeding risk occurred as the dose of ASA increased from 100 to 100–200 mg or
200 mg in patients treated with both ASA alone (1.9, 2.8, 3.7% major bleedings) and ASA plus clopidogrel (3.0, 3.4, 4.9%).220 The available data suggest that in patients treated for NSTE-ACS, a daily dose of ASA in the range of 75–100 mg may be optimal.220 According to the ACC/AHA guidelines for the management of patients with NSTE-ACS,221 in many hospitals in which patients with UA or NSTEMI undergo diagnostic catheterization within 24–36 h of admission, clopidogrel should not be started until it is clear that CABG surgery will not be scheduled within the next several days. Today's preference for an early invasive strategy, combined with stenting and GP IIb/IIIa inhibitors, lowers the likelihood of urgent bypass surgery for the majority of these high-risk patients. On the basis of the very early positive effects of clopidogrel218 we therefore recommend initiating clopidogrel administration as soon as possible, if clinically justifiable. (Recommendation for the immediate clopidogrel administration in NSTE-ACS: I B).
After the acute phase of NSTE-ACS, the continuation of ASA plus clopidogrel over 9–12 months is beneficial (CURE,217 PCI-CURE222). (Recommendation for prolonged clopidogrel administration for 9–12 months after NSTE-ACS: I B).
3.2.3. Clopidogrel in STE-ACS (STEMI)
Although not being PCI-studies, CLARITY (loading dose: 300 mg) and COMMIT/CCS-2 (no loading dose) showed that ASA+clopidogrel was more effective in STEMI than ASA alone. With primary PCI and stenting in STEMI, clopidogrel will be additionally administered in these patients, preferably with a loading dose of 600 mg. Regarding the duration of clopidogrel prescription, the results from NSTE-ACS may be extrapolated to STE-ACS, but this has yet to be scientifically proven.
Some initial laboratory findings warned of the combination of clopidogrel with statins metabolized in the liver, especially atorvastatin,223 but it does not seem to play a clinical role.224 The emerging question about possible clopidogrel resistance requires more investigation.225,226
In summary, the ‘double’ antiplatelet therapy with ASA and clopidogrel is standard for the pre-treatment of patients with stable CAD undergoing PCI—with or without planned stent implantation. After implantation of a bare metal stent, clopidogrel must be continued for 3–4 weeks and ASA lifelong. In patients presenting with NSTE-ACS, ASA and, if clinically justifiable, immediate administration of clopidogrel, is the basic standard antiplatelet regimen. After the acute phase, the continuation of 100 mg/d ASA+clopidogrel 75 mg/d over 9–12 months is beneficial. ASA should be given i.v. to all patients with STEMI as soon as possible after the diagnosis is established, if clinically justifiable. With the concept of primary PCI and primary stenting in STEMI, clopidogrel will be additionally administered in these patients. After brachytherapy, clopidogrel should be administered in addition to ASA for 12 months and after drug-eluting stents for 6–12 months to avoid late vessel thrombosis.
3.3. Unfractionated heparin
3.3.1. Unfractionated heparin for PCI in stable CAD
Since the beginning of PCI, unfractionated heparin (UFH) has been used to prevent thrombosis on the instrumentarium and to minimize thrombus formation at the site of iatrogenic vessel wall injury/plaque rupture. There are obviously no placebo-controlled trials specifically addressed to PCI, as the omission of anticoagulation would be prohibitive in the setting of any coronary interventions. UFH is given as an i.v. bolus either under activated clotting time (ACT) guidance (ACT in the range of 250–350 s or 200–250 s, if GP IIb/IIIa receptor inhibitor is given) or in a weight-adjusted manner (usually 100 IU/kg or 
50–60 IU/kg, if GP IIb/IIIa receptor inhibitor is given). Because of marked variability in UFH bio-availability, ACT-guided dosing is advocated, especially for prolonged procedures when additional bolus (-es) may be required. The therapeutic response to UFH in general is difficult to predict. There is evidence that its benefit is linked to an effective dose, although low doses (5000 IU or lower) have been used in routine procedures.227 Continued heparinization after completion of the procedure, either preceding or following arterial sheath removal is not recommended.
3.3.2. UFH for PCI in NSTE-ACS
Adding UFH as a standard regimen is usually recommended on the basis of a meta-analysis of six smaller randomized trials showing a 7.9% rate of death/MI in patients with unstable angina treated with ASA plus heparin compared with 10.3% in those treated with ASA alone.228 Discontinuation of UFH in patients with unstable angina carries the inherent risk of a rebound effect.229
3.3.3. UFH for PCI in STE-ACS (STEMI)
UFH is the standard therapy in patients with STEMI, especially for those undergoing primary PCI. UFH served as control for many studies investigating LMWHs (see 3.4.3.) or bivalirudin. (