The manifestations of ischemia in non–ST-elevation acute coronary syndrome (ACS), are caused by a severe flow-limiting stenosis or occlusion of a coronary artery. In the majority of cases there are also signs of myocardial infarction (MI), which might be related to thrombotic occlusion of the culprit coronary lesion as well as to downstream embolization of thrombotic material from the lesion. The thrombotic component of the disease can be influenced by treatment with platelet and coagulation inhibition. , Despite such treatment, most often there remains severe coronary stenoses leading to a risk of recurrences after the withdrawal of the initially intense anti-thrombotic treatment. Therefore, there is a rationale for the early use of coronary angiography and revascularization. Elimination or bypassing of the flow-limiting lesions by coronary percutaneous intervention (PCI) or coronary artery bypass grafting (CABG) might be an appropriate complement to medication for rapid as well as long-term stabilization of the condition. The goal is that the early procedure also will contribute to a reduced risk of recurrences of severe angina and MI and thereby also contribute to the avoidance of development of heart failure and improved survival ( Box 27-1 ). Although early revascularization of a flow-limiting coronary lesion often seems an attractive way to solve the problem, still it needs to be emphasized that the treatment strategy needs to be based on the initial response and long-term outcome at the patient level. Thus, the eventual benefits and risks are related not only to lesion characteristics but also to patient characteristics and their impact on the development of the disease and the risks for complications in association with invasive procedures. Furthermore, health economy of the strategy needs to be consideraed: There needs to be an appropriate balance between the increased cost of the early procedures and their eventual compensation of avoiding readmission for recurrent events and late revascularization procedures. The many issues influencing the decision making and recommendations in the selection between an early invasive and a primarily noninvasive treatment strategy in non–ST-elevation acute coronary syndrome are summarized in Box 27-1 . Early invasive procedures are currently not the recommended strategy for all-comers with non–ST-elevation ACS but rather as a selective approach for moderate- to high-risk patients according to the latest international treatment guidelines. Accordingly, in the non–ST-elevation population, currently early angiography is performed in about 65% to 90%, PCI in about 50% to 60%, and CABG in about 5% to 10% before discharge after the index event. The basis for these recommendations is mainly the accumulated results from the large-scale prospective randomized trials comparing an early routine versus a selective ischemia-based invasive treatment approach. The short- and long-term results from these trials will also be the main basis for the current review on for whom, when, and how early revascularization procedures should be performed in non–ST-elevation ACS ( Fig. 27-1 ).
BOX 27-1 Benefits
Survival
Recurrent myocardial infarction
Late revascularization
Late readmission
Recurrent incapacitating angina
Need for anti-anginal medication
Quality of life
Risks
Procedure-related mortality
Procedure-related myocardial infarction
Procedure-related extra-cardiac side effects and morbidity
Restenosis and recurring need for revascularization
Recurrence of angina
Costs
Procedure-related costs
Length of hospital stay
Costs of medication
Costs for sick-leave and retirement pension
Patient selection
Risk indicators and risk scores in relation to benefit, risks, and cost
Optimal revascularization method
Optimal timing of revascularization
For Whom?
Evidence for the Benefit of an Early Invasive Strategy
Three large scale prospective randomized trials (FRISC-2, TACTICS-TIMI-18, and RITA-3) have compared an early routine invasive strategy versus an ischemia-driven conservative strategy with an adequate separation in proportion of early procedures between the two arms in the studies ( Fig. 27-2 ). These were the first three trials where all patients also received most of the currently recommended intense antithrombotic medication and had the majority of revascularization procedures either as PCI with routine stenting or CABG ( Table 27-1 ). All three trials demonstrated the superiority of an early invasive strategy compared with a primarily noninvasive one concerning the composite of death, MI, and recurrent severe angina. Although there was an early hazard with more procedure-related MIs and deaths in association with the procedures while in hospital, in the first two studies (FRISC-2, TACTICS-TIMI-18) there was a reduction in the composite of death and MI already at 6 months. , In the two trials with long-term follow-up to 5 years there was also a maintained reduction in the composite of death and MI and a trend to improved overall survival ( Fig. 27-3A-C ). , Also in meta-analyses there is a support for the overall superiority of the early invasive regimen also when taking into account the more equivocal results of the older TIMI-IIIB, VANQWISH, and smaller MATE, VINO, ISAR-COOL and the latest ICTUS , trials. In the latest performed ICTUS trial there appeared, surprisingly, no advantages when comparing an early invasive approach in all comers with troponin-elevation on admission for non–ST-elevation ACS versus a more selective approach with early revascularization in those with signs of ischemia at rest or exercise ( Fig. 27-3D ). , However, the differing outcome in this trial might mainly be explained by a substantial early crossover of 44% of the noninvasive patients to an invasive regimen (see Table 27-1 , Figs. 27-5 and 27-6 ), and also of an eventual exclusion of the higher risk population sent to early invasive procedures based on the results from the previous trials already available at the start of the ICTUS trial. Much of the difference in outcome between these trials might be explained by the different management finally used in the different arms, as in some trials patients in the invasive arm had less than 50% early revascularization procedures and/or a 35% to 45% early revascularization rate also in the noninvasive arm (see Table 27-1 , Figs. 27-5 and 27-6 ). Therefore it is not surprising that the overall results in a meta-analysis including all these heterogeneous trials only show a modest 16% relative reduction in the composite of death and MI after one year. Only in the study with the largest contrast, 62% in-hospital difference in revascularization procedures, there was a significant improvement in survival by the early invasive approach. Furthermore there was, especially in the trials with a larger contrast in procedure rates between the treatment arms, a substantial reduction in anginal symptoms, exercise tolerance and exercise induced ischemia, readmissions to hospital, and an improved quality of life. The most relevant estimate of the effects of an early invasive versus selective invasive treatment strategy in a contemporary treatment environment might be obtained by including only the seven trials that exclusively randomized patients with a diagnosis of non–ST-elevation ACS and where the currently recommended treatments of thienopyridine and glycoprotein (GP) IIb/IIIa and coronary stents were available for use during PCI. Using such an approach there appeared at 2-year follow-up significant relative reduction of 25% in mortality, 17% in nonfatal reinfarction, and 31% in recurrent unstable angina ( Fig. 27-4A-C ).
| FRISC II | TACTICS | RITA3 | ICTUS | |||||
|---|---|---|---|---|---|---|---|---|
| N | 2457 | 2220 | 1810 | 1200 | ||||
| Time period | 1996-1998 | 1997-1999 | 1997-2001 | 2001-2003 | ||||
| Baseline findings on admission | ||||||||
| Inclusion diagnosis | NSTEMI/UA | NSTEMI/UA | UA | NSTEMI | ||||
| Median age | 65 | 62 | 62 | 62 | ||||
| Female % | 31 | 34 | 38 | 27 | ||||
| Diabetes mellitus | 12 | 28 | 13 | 13 | ||||
| Previous MI | 22 | 39 | 28 | 23 | ||||
| ST-segment depression | 46 | 39 | 37 | 48 | ||||
| Biochemical marker elevation | 57 | 37 | 18 | 82 | ||||
| Ninv | Inv | Ninv | Inv | Ninv | Inv | Ninv | Inv | |
| Angiography | ||||||||
| Before discharge—7 days % | 10 | 96 | 51 | 97 | 16 | 96 | 53 | 98 |
| 6-12 months % | 47 | 98 | 61 | 98 | 48 | 97 | 67 | 99 |
| Extent of CAD (invasive group) | ||||||||
| 0 v.d. % | — | 14 | — | 13 | — | 22 | — | — |
| 1 v.d. % | — | 30 | — | — | — | 33 | — | — |
| 2 v.d. % | — | 26 | — | — | — | 24 | — | — |
| 3 v.d., LMD % | — | 31 | — | 43 | — | 22 | — | — |
| Revascularization | ||||||||
| Before discharge.—10 days % | 9 | 71 | 36 | 60 | 10 | 44 | 40 | 76 |
| Within 6-12 months % | 43 | 78 | 44 | 61 | 28 | 57 | 54 | 79 |
| CABG 6-12 months % | 23 | 37 | 16 | 22 | 12 | 21 | 14 | 18 |
| PCI 6-12 months % | 20 | 41 | 28 | 40 | 16 | 36 | 40 | 61 |
| Non-revasc. with 1-3 v.d. 10 days, % | — | 15 | — | 27 | — | 34 | — | — |
| Non-revasc. with 1-3 v.d. 12 months, % | — | 8 | — | 26 | — | 21 | — | — |
| Outcome 6-12 months | ||||||||
| Death or MI or severe angina % | 42.2 | 13.2 | 19.4 | 15.9 | 14.5 | 9.6 | 21.2 | 22.7 |
| Death or MI in all patients % | 14.1 | 10.4 | 9.5 | 7.3 | 8.3 | 7.6 | — | — |
| Death or MI in men % | 15.8 | 9.6 | — | — | 10.1 | 7.0 | — | — |
| Death or MI in women % | 10.5 | 12.4 | — | — | 5.1 | 8.6 | — | — |
| Death % | 3.9 | 2.2 | 3.5 | 3.3 | 3.9 | 4.6 | 2.5 | 2.5 |
| Spontaneous MI % | 11.3 | 4.2 | — | — | 5.7 | 3.3 | 4.6 | 3.7 |
| Procedure related MI % | 2.1 | 5.4 | — | — | 0.4 | 1.7 | 5.4 | 11.3 |
* Overview of four large randomised trials including more than 1000 patients and were performed over 7 years using baseline treatment with aspirin, heparin, or LMWH and with availability of glycoprotein IIb/IIIa inhibitors and stents followed by thienopyridine.
Cost Effectiveness
Several health economy analyses have demonstrated that the higher initial costs for an early invasive strategy might be partly compensated for by lower costs during longer-term follow-up for length of hospital stay, rehospitalizations, late procedures, outpatient visits, and medical treatment. In the 1-year perspective a strategy of routine catheterization and, if appropriate, revascularization, was, in the FRISC-2 study, associated with higher costs than a strategy of invasive procedures only with severe ischemia or recurrent MI. , However, the costs of the invasive strategy can be reduced by performing invasive procedures earlier, within the first 48 hours, as such an approach results in shorter hospital stay. Using such a strategy in the routine early catheterization arm, and comparing to a nonroutine catheterization strategy with wider indications for early revascularization based on non-invasive risk indicators, there were small differences in costs between these two strategies in the TACTICS trial ( Fig. 27-7 ). Thus, in a setting where revascularization is needed in 40% to 50% of the patients within the next year, as seen both in the FRISC-2 and TACTICS trials, there is only a modest increase in cost, provided that the early routine invasive procedures are performed within the first 48 hours after admission. Therefore, an early invasive strategy might, in the longer term perspective, be cost-effective if the invasive procedures are performed without undue delay. This approach will also be preferred by the patients because the initial hospital stay is shortened and readmissions for recurrent symptoms avoided. Thus, compared with a primarily noninvasive approach, an early invasive strategy in ACS is associated with a trend toward improved late survival, lower morbidity, and improved quality of life at a modest increase in cost for the health care system. These beneficial results in the prospective randomized trials are also supported by similar experiences in adjusted comparisons between patients managed with an early invasive versus a conservative approach in some real life registries or pharmaceutical clinical trials.
Risk Stratification for Selection of Patients for Early Invasive Procedures
As with most other treatments, the risk reduction by an early invasive treatment is larger in patients at higher risk, and symptom relief better in patients with more severe symptoms. Many clinical and laboratory observations are related to the subsequent risk of new events after ACS as summarized in Box 27-2 and presented in previous chapters. Thus, much prognostic information is already available in the patients’ history; that is, the risk is raised by age, male gender, diabetes mellitus, chronic kidney disease, previous MI, previous severe angina, congestive heart failure, or medication for any of these conditions. The severity of the manifestations of the disease (e.g., episodes of chest pain during the last 12 to 24 hours and/or recurrent episodes of pain despite pharmacologic treatment) is associated with higher risk. , Signs of ischemia (ST-segment depression) in an electrocardiograph (ECG) at entry and/or episodes of ST-depression during continuous monitoring are also related to a worse prognosis. Left ventricular dysfunction, as evaluated by elevation of N-terminal prohormone brain natriuretic peptide (NT-proBNP) test or echocardiography, are other observations associated with guarded prognosis. Recently also a moderate renal dysfunction (e.g., glomerular filtration rate (GFR) of less than 90 mL/min, or an elevated cystatin-C level ) have been found associated with worse outcome. The occurrence of elevated biochemical markers of MI, i.e., troponins, is a well established marker of raised risk for subsequent MI as well as mortality. Recently, biochemical markers of inflammatory activity (e.g., C-reactive protein (CRP) and interleukin-6, platelet activity [i.e., CD40-ligand], and of cellular stress and repair [i.e., GDF15] , ) have been shown associated with a worse prognosis. The combination of several of these risk indicators provides a better risk stratification than any marker alone. Thus, the combination of ST-segment depression as a probable indicator of severe coronary stenosis, elevation of troponin as a marker of coronary thrombosis and/or MI, elevation of NT-proBNP as a marker of reduced cardiac performance, reduced creatinine clearance as an indicator of renal dysfunction, elevated CRP as an indicator of inflammatory activity, and elevation of GDF15 as a marker of cellular stress provide better prognostic information than any of these alone. The multivariate analyses of the combination of the patient history, clinical presentation, and several of these laboratory markers have allowed the development of risk scores of key factors containing the most important prognostic information. As most of these variables are easily and rapidly available within a short time after admission, they can also be widely applied as a support for the selection of patients for early invasive treatment in clinical practice ( Fig. 27-8 ).
BOX 27-2
Age (>65 years)
Coronary risk factors—diabetes mellitus, hyperlipidemia, hypertension, smoking
Renal dysfunction (glomerular filtration rate [GFR] <90 mL/min, even higher at <60 mL/min and highest at <30 mL/min)
Previous myocardial infarction, previous angina pectoris
Cardiac dysfunction—elevated NT-proBNP (>300 ng/L, even higher risk at >1000 ng/L)
History of chest pain at rest, or during last 24 hours, or recurrences despite treatment
Myocardial ischemia—ST-segment depression (≥0.1 mV, even higher risk at ≥0.2 mV)
Coronary thrombosis—elevated troponin (troponin T ≥0.01, even higher risk at ≥0.5 µg/L)
Inflammation—elevation of C-reactive protein (>10 mg/L)
Severe coronary artery lesion at coronary angiography
Risk Stratification in Relation to the Effects of Invasive Treatment
The two largest trials randomizing patients to an early invasive versus a selected invasive strategy, FRISC-2 and TACTICS-TIMI-18, have provided a wealth of information on the outcome of an invasive strategy in relation to risk stratification while only limited information is available from the other trials (RITA-3, ICTUS). Therefore the present chapter will mainly use the results from the first two trials as a basis for the currently most appropriate indications for early revascularization.
Both the FRISC-2 and the TACTICS-TIMI-18 trials showed that the absolute risk reduction concerning subsequent coronary events was larger in patients at higher risk according to most of these risk indicators (see Fig. 27-8 .) The invasive treatment was associated with a larger risk in older patients. Still, there was larger relative as well as absolute benefit in patients older than 65 years of age. , Corresponding findings have also been reported from observational trials. , However, the real life experiences show that early revascularization procedures are less often used in the elderly. Likewise, patients with diabetes mellitus have a considerable increased risk for ACS. However, the proportional risk reduction by early revascularization was similar in patients with and without diabetes. Accordingly, the absolute risk reduction in death and MI was larger in patients with diabetes. , Despite these successful results, there is an underutilization of early revascularization procedures in patients with diabetes. , Also patients with left ventricular dysfunction or renal dysfunction were at higher risk but still they had similar relative and thereby a larger absolute risk reduction by the early invasive approach. Patients with signs of severe ischemia as indicated by the degree of ST-segment depression or T-wave changes in ECG at rest had a considerably larger benefit from early invasive procedures than patients without these findings. Both the FRISC-2 and the TACTICS trials indicated that the majority of patients benefiting from an invasive strategy were found in patients with detectable troponin in serum samples at entry. The risk of a subsequent infarction was similar in all patients with any elevation of troponin while there was a linear relation between the level of troponin and mortality. , Thus, in the prioritization of patients for invasive procedures any detectable troponin would suggest an invasive approach, while the urgency of the procedure is raised at higher troponin levels. Patients without any detectable troponin are at very low risk and have little to gain from invasive procedures unless indicated by incapacitating symptoms of angina or the presence of other clinical or biochemical risk indicators. , In relation to the levels of C-reactive protein the relative effects of the invasive approach were similar at all levels and, thereby, the absolute effects are larger in patients with higher levels of these inflammation markers. However, according to the FRISC-2 study results, the initial level of interleukin-6 seemed to be a more specific marker both of raised mortality and the effects of the early invasive treatment. Recently also the presence of elevation of GDF15 has been shown to be an independent indicator of a larger benefit of an early invasive approach in non–ST-elevation ACS. Therefore in the future, a combination of clinical history, signs of ischemia at ECG, and a combination of biochemical markers such as troponin, creatinine clearance, NT-pro-BNP, and GDF15 might provide the best information on the indication for an early invasive treatment strategy in non–ST-elevation ACS. ,
Risk Scores in Relation to the Effects of Early Invasive Treatment
Using combinations of several markers both the FRISC-2 and the TACTICS-TIMI-18 trial demonstrated that the benefits of the invasive strategy seemed confined to patients with a combination of elevated troponin level and ST-segment depression. However, the outcome based on troponin and ST-segment depression was modulated by the other factors such as age, diabetes, renal dysfunction (creatinine clearance), previous MI, left ventricular dysfunction (NT-proBNP), severity of previous and current symptoms of angina, cellular stress (GDF15) and inflammatory activity (CRP, IL6). Using a multivariable approach, it is possible to identify the minimal set of key risk factors needed as components of a risk score for evaluation of prognosis and selection of invasive treatment. , According to these risk scores, the largest benefit of an early invasive treatment was seen at higher scores, that is, in patients with several of the risk indicators (see Fig. 27-8 ). Patients with a high risk score (≥5 risk indicators) had improved survival as well as a lower risk of (re)infarction. At an intermediate risk score (3-4 risk indicators) there was mainly a reduction in (re)infarction. Finally the early invasive treatment, with its inherent risk for peri-procedural complications, did not reduce the risk of death or MI in the low risk score patients (0-2 risk indicators). However, it needs to be emphasized that low-risk as well as high-risk patients with incapacitating symptoms obtain the same symptom relief and improvement in quality of life from the invasive procedures. Thus, in many cases there might, because of symptoms, be reasons to consider invasive procedures even in lower-risk patients. However, the urgency of the procedures is less in such patients because of their lower risk for coronary events while awaiting the procedures. Finally, it needs to be emphasized that all these risk scores have been derived from retrospective analyses and, so far, no risk score has been verified in a prospective randomized trial.
Stress Tests for Risk Stratification
In low-risk patients, a stress test will allow further risk stratification. At these tests a new high-risk category is constituted by either large or multiple areas of exercise-induced myocardial ischemia or low exercise tolerance. A low risk category is defined by an adequate exercise tolerance without any signs of ischemia. In the high-risk category early catheterization and revascularization is indicated. In the low-risk category no early invasive procedures should be performed, as the peri-procedural risks are greater than the potential benefits that can be obtained in this patient category. In the ICTUS trial a strategy with a stepwise decision making with an initial decision for invasive procedures based on clinical presentation and signs of ischemia at rest followed by a second decision for invasive procedures at ischemia at a pre-discharge exercise test was found to provide similar long-term outcome as a direct invasive approach in a troponin positive patient population recruited in centers with an overall high rate of early invasive procedures.
Coronary Angiography for Early Risk Stratification and Selection of Treatment
In many instances the performance of coronary angiography might provide the most reliable information concerning risk stratification and selection of treatment for an individual patient. Not only the culprit lesion and its characteristics are identified but also the extent of coronary artery disease, the existence of collaterals, the myocardial area at risk, and the left ventricular function are elucidated by the catheterization. In patients with a clinical diagnosis of ACS there is about 10% with disease of the left main artery, 25% with three-vessel disease, 25% with two-vessel disease, 25% with one-vessel disease and 15% with no significant coronary artery disease at coronary angiography (see Table 27-1 ). Most of the above outlined risk indicators, i.e., age, male gender, diabetes, previous MI, previous severe angina, renal dysfunction, left ventricular dysfunction (elevated NT-proBNP), ST-segment depression, elevated troponin, elevated GDF15, and higher risk response at a stress test, are associated with a raised occurrence of multivessel- or left main coronary artery disease. However, the correlation between these risk indicators and the extent of coronary artery disease are rather weak. Thus, from the individual patient’s perspective it might be preferable to use the combined results from a coronary angiography and from the noninvasive risk indicators as a basis for a decision of early revascularization. The possible disadvantage of such an approach is that all lesions identified at coronary angiography tend to be dilated and stented at the same session, disregarding the eventual information from other risk indicators. In the invasive arm of the FRISC-2 trial there was no relation between the extent of initial coronary artery disease and subsequent coronary events in the invasive arm, indicating that the early invasive procedures will eliminate the risk for new events associated with severe coronary lesions. These findings support the recommendation of early coronary angiography in the majority of ACS patients in order to identify all severe coronary lesions, the risk of which can be reduced by early revascularization.
Gender and Selection of Invasive Treatment
In the FRISC-2 and the RITA-3 trials there was a significantly better effect of the invasive strategy in men than in women. , This might partly be explained by the lower proportion of women revascularized in the invasive group because of the lower rate of significant lesions in females than males. Another reason might be a raised risk for peri-procedural complications, especially with diabetes mellitus and higher age, in the women with coronary artery bypass surgery. , However, these gender-related differences in the effects of early invasive treatment were observed in neither the TACTICS-TIMI-18 nor the ICTUS trial nor in reports from observational materials. , In a meta-analysis of all published prospective randomized trials there appeared no significant difference between genders in the overall benefit concerning the composite of death, MI and recurrence of severe angina. In women as well as in men the benefits were confined to those at higher risk, that is, with elevated troponin and/or ST-depression in the ECG at rest. In order to properly evaluate women with ACS it seems preferable to use the same indications for diagnostic coronary angiography in both genders, that is, at moderate to high risk of subsequent events according to the risk stratification criteria discussed earlier. However, in the selection of the most appropriate treatment, the better long-term prognosis and the higher peri-procedural risks in women compared to men should be taken into consideration. Finally, because of the uncertainties of the balance between benefits and risks in women new prospective trials comparing an early invasive versus a conservative strategy focusing on women are warranted.
Special Situations
Chronic kidney disease has over the last several years appeared as a very important indicator of raised risk of future events in ACS. Several studies have shown that chronic kidney disease is associated with a more severe atherosclerotic disease, increasing the risk of future events. Additionally, chronic kidney disease also raises the risk of complications for many kinds of medical treatment because of the risk of overdosing at slow rates of excretion. Accordingly chronic kidney disease is a well established risk factor for bleeding both at anticoagulant and antiplatelet treatment both of which are used abundantly in ACS. , The administration of contrast agents at coronary angiograms and PCI procedures also carries a risk of at least temporary impairment of kidney function. Such temporary deterioration of kidney function might be associated with risks of appearance of side effects to previously well accepted medications. Finally chronic kidney disease also carries an increased risk for the need of surgical procedures such as CABG. Despite increased risks of side effects, both individual trials , and meta-analyses indicate that patients with reduced renal function derive the same benefit from early invasive procedures as patients at moderate to high risk based on other risk indicators. Therefore there is little reason not to proceed to early invasive procedures because of reduced creatinine clearance which rather should strengthen the indication unless there are other contraindications.
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