NSTEACS versus STEMI: a more complex clinical syndrome
Two-thirds of the hospital admissions with an acute coronary syndrome (ACS) present with-out persistent ST-segment elevation (NSTE) on the electrocardiogram [1]. Compared with patients showing ST-segment elevation (STE), those with NSTEACS are older and more fre-quently female, they have higher incidences of diabetes and chronic kidney dysfunction and they have a longer history of coronary artery disease, including previous myocardial infarc-tions (MI) and coronary revascularizations [1,2]; their coronary arteries reflect these characteris-tics and show a higher prevalence of multivessel disease [2].
In more than 90% of the ST-segment eleva-tion myocardial infarction (STEMI) cases, an acutely occluded major coronary artery is e vident; therefore, immediate reperfu-sion therapy is mandatory, using the fastest available strategy in order to limit irrevers-ible myocardial damage [3]. This strategy has been evidence based for 20 years with fibrin-olytic therapy [4] and became more effective with primary angioplasty [5]. The long-term follow-up of reperfusion studies have consis-tently demonstrated the long-lasting benefit of pharmacological [6] and mechanical single-shot intervention [7]. On the other end, NSTEACS
represent a more complex clinical challenge, and only recently a clear evidence has been proved that an aggressive pharmaco-interven-tional approach provides long-term benefit when applied to higher-risk patients [8–13]. As shown in Box 1, the reasons for this greater c omplexity are multifactorial.
In-hospital mortality of STEMI patients is approximately twice as high as that seen in NSTEACS [1] and it is almost exclusively attributable to ventricular arrhythmias and cardiogenic shock or mechanical complica-tions owing to abrupt coronary occlusion. Improvements in the logistics, pharmacology and techno logy of early reperfusion have led to the recent dramatic reduction in STEMI mortality. For example, in-hospital mortal-ity decreased from 8.4% in 2000 to 4.6% in 2005 in the Global Registry of Acute Coronary Events (GRACE) registry [1], and from 16% in 2002 to 9.5% in 2004 in the Vienna regis-try [14]. On the other hand, owing to the lesser impact of acute c oronary occlusion, in-hospital mortality is lower in NSTEACS (less than 3% in the GRACE registry [1]), but owing to an older age of the patients and the more exten-sive atherosclerotic burden, ischemic recurren-cies and long-term mortality are worse com-pared with STEMI and, so far, have been less s usceptible of s ignificant improvements.
Target populations and relevant therapeutic end points to further improve outcomes in NSTEACS patients
Stefano Savonitto†, Nuccia Morici, Alice Sacco & Silvio Klugmann†Author for correspondence: Dipartimento Cardiologico ‘Angelo De Gasperis’, Ospedale Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy n Tel.: +39 335 605 6565 n Fax: +39 026 444 2458 n [email protected]
An aggressive pharmaco-interventional approach has been shown to improve long-term outcome among high-risk patients with acute coronary syndromes without ST-segment elevation (NSTEACS). However, these patients continue to represent a minority among those enrolled in clinical trials, thus precluding the possibility to further improve therapeutic efficacy. Target populations that are not adequately addressed by the majority of therapeutic trials are mainly the elderly and those with reduced renal function, who all show unfavorable outcome after an episode of NSTEACS. In order to allow comparison among different studies, a prerequisite for the planning of meaningful trials should be a uniform definition of the study end points besides mortality, particularly with reference to recurrent myocardial infarction, and rehospitalization owing to cardiovascular instability or severe bleeding. In addition to trial design issues, improvements in the regulatory rules for drug development and in hospital networking conceal significant opportunities to improve treatment of NSTEACS.
Keywords
n acute coronary syndromes n bleeding n myocardial infarction n outcome n treatment
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Treatment strategies across the broad spectrum of NSTEACS
The NSTEACS encompass a wide spectrum of clinical conditions, ranging from a low-risk 50-year-old woman with minimal ECG changes and normal troponin levels, to a high-risk 80-year-old diabetic man with extensive ST-segment changes indicative of severe c oronary artery disease.
In order to decide the treatment strategy in an individual patient, a prerequisite is to make a clear diagnosis of NSTEACS. The diagno-sis is easy when a patient presents with typical symptoms, unequivocal ECG changes and/or elevated troponin levels. However, when a patient presents after symptoms have subsided, the ECG is normal and troponin is not elevated within 6–12 h of symptoms, then the risk of misdiagnosis is substantial both in the way of not recognizing a patient at risk of impending myocardial infarction or sudden death, and in the opposite of treating as an ACS a patients that has stable coronary artery disease and/or a noncardiac cause of chest pain [12].
After a diagnosis of NSTEACS has been made, the key recommendation of the prac-tice guidelines is that treatment aggressive-ness (both pharmacological and interven-tional) must be tailored to the patient’s risk of adverse ischemic events. It must be empha-sized that this estimate of risk includes both
the severity of acute ischemia, as shown by the ECG changes [15] and enzyme release [16], and the extent of atherosclerotic burden and organ damage, as represented by a history of d iabetes, prior c ardiac events and left ventricu-lar d ysfunction, as well as renal insufficiency and peripheral arterial disease. Thus, the pres-ence of acute ischemia is the key to enter in the ACS population, whereas the amount of isch-emia and myocardial damage and the athero-sclerotic burden define the risk of unfavorable outcome both in the individual patient and in study populations.
There is compelling evidence that an aggres-sive pharmacological approach [17] and system-atic revascularization [9,10] may lead to dramatic improvements in outcome only in high-risk patients. However, since the expected absolute benefit of any acute anti-ischemic intervention is much smaller when the baseline risk is lower, patients at lower ischemic risk should be treated by taking the benefit:risk ratio of any drug and procedure into careful consideration [12]. Finally, and for the first time, the ACC/AHA guidelines clearly state that low-risk patients, especially women, should be treated conser-vatively [13]. A schematic summary of these recommendations is shown in TaBle 1. Thus, in order to further improve outcome in the general population of NSTEACS, future improvements in treatment should be targeted thus:
Box 1. Reasons for NSTEACS complexity.Diagnosis is not always univocaln
Risk of overtreatment (and undue complications) in low-risk patientsn
Immediate clinical benefit of revascularization is evident only in patients with refractory ischemian
Lack of evidence-based approaches in elderly patients and in those with chronic kidney dysfunctionn
Risk of iathrogenic complications in elderly patients and in those with chronic kidney dysfunction: n
need for stabilization and adequate preparation before angiography/revascularization
Multiple competing pharmacological options and risk of untested interactions with n
interventional therapy
‘Culprit’ coronary artery evident only in 50% of cases (vs >90% in STEMI)n
Complex coronary anatomy is more frequent compared to STEMI: coronary artery bypass graft n
indication in 20–30% of the cases; no revascularization option in 30% of cases after angiographyNSTEACS: Non-ST-segment elevation acute coronary syndrome; STEMI: ST-segment elevation myocardial infarction.
Table 1. Treatment strategies in NSTEACS according to baseline ischemic risk.
Baseline ischemic risk* Expected benefit of anti-ischemic intervention
Treatment strategy
Low Minimal Conservative
Intermediate Moderate Carefully estimate benefit vs risk of therapies in individual patients
High Life-saving Aggressive pharmaco-interventional approach
*Risk of ischemic death or myocardial infarction in the short to medium term. NSTEACS: Non-ST-segment elevation acute coronary syndrome.
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To increase the proportion of patients who n
receive timely and effective treatment;
To determine optimal strategies for high-risk n
patient subsets with insufficient evidence of treatment benefit, such as the elderly and patients with chronic kidney dysfunction;
To reduce the early hazard of pharmaco-invasive n
intervention;
To refine the efficacy:safety ratio of long-term n
antithrombotic therapy.
Goal number 1: to increase the proportion of patients who receive timely & effective treatment
Contrary to guideline recommendations, clinical registries in NSTEACS demonstrate that aggres-siveness of treatment depends on cathlab avail-ability rather than on patients’ risk [18–20]. Thus, in clinical practice, a number of low-risk patients admitted to hospitals with cathlab availability are unduly treated aggressively, whereas, and more sadly, many high-risk patients admitted to hospi-tals with no cathlab are denied timely transfer to a cathlab hospital and, thus, a treatment which, in high-risk patients, has been shown to reduce hard cardiovascular end points by 45% [21].
The most recent guidelines of the European Society of Cardiology [12] clearly indicate the clinical characteristics of NSTEACS patients who must undergo an urgent (i.e., as soon as pos-sible) or early (i.e., within 72 h) invasive strategy, and of course these recommendations are valid irrespective of cathlab availability. Candidates sent for urgent angiography (with the intent of revascularization) are a relatively small number of patients with refractory ischemia, haemodynamic instability and life-threatening arrhythmias. Candidates sent for early angiography are a wider number of patients with clear ECG signs of tran-sient ischemia, elevated troponin levels, left ven-tricular dysfunction, prior myocardial infarction or coronary revascularizations, diabetes mellitus and impaired renal function (however, with the
cautions discussed later in this article). Thus, the implementation of regional rules for transferring high-risk patients to hospitals with interventional facilities should be a major t herapeutic goal in NSTEACS. Compared to primary and interhos-pital networks recently implemented for STEMI, referrals for NSTEACS have some r elevant p eculiarities, which are outlined in Box 2.
Goal number 2: to determine optimal strategies for high-risk patient subsets with insufficient evidence of treatment benefit
As a rule, the higher the baseline ischemic risk, the higher the absolute benefit of an early inter-ventional approach. However, there are at least two categories of patients where this rule has so far not been validated. The first and larger patient group are elderly patients, convention-ally defined as those of at least 75 years of age, which represent approximately one-third of the NSTEACS population [20,22]. The Euro Heart Survey 2006 reports the unfavorable outcomes of these patients: compared with patients aged less than 55 years old, the adjusted odds ratio (OR) for in-hospital mortality was 8 for patients aged 75–84 years and as high as 12 for those aged 85 years or older [23]. In addi-tion, according to the GRACE registry, the elderly constitute one third of the NSTEACS population, but contribute more than 50% of hospital mortality owing to this syndrome [24]. Furthermore, a high mortality rate persists in elderly patients after hospital discharge both in trials and in registries [25]: for example in the GRACE registry, whereas mortality does not change from hospital discharge to 30 days in patients younger than 75 years, it increases by a further 1% in patients of between 75 and 84 years and by 3% in those aged 85 years or older [25]. As clearly reported by a recent ad hoc statement from the AHA [25], most of the clini-cal trials comparing treatment strategies in NSTEACS have either excluded elderly patients or included them only as a small minority of the
Box 2. Peculiarities of interhospital transfers in high-risk NSTEACS.
Less urgent time schedule compared to STEMI: more time to evaluate clinical history, blood n
chemistry and left ventricular function
Need for expert cardiological assessmentment: much more complex than in STEMIn
Preangiography antithrombotic therapy should be carefully tailored upon time to angiography, n
probability of CABG, renal function and bleeding risk
Ideal referral to a tertiary care hospital with percutaneous coronary intervention and CABG n
capability (25% of NSTEACS patients need CABG rather than PCI)CABG: Coronary artery bypass graft; NSTEACS: Non-ST-segment elevation acute coronary syndrome; PCI: Percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction.
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study populations (TaBle 2), thus precluding the possibility of evaluating the risk versus benefit of an aggressive strategy, including its pharma-cological background. As shown in TaBle 2, some of these studies suggest that a routine invasive approach may be even more beneficial in the elderly than in younger patients [26]. However, despite the fact that the European Society of Cardiology (ESC) guidelines recommend a rou-tine aggressive approach in elderly patients [12], more evidence needs to be generated in order to support these recommendations [27].
An even more complex population are the patients with chronic kidney dysfunction. The fact that these patients are at very high risk of adverse outcome after an ACS has been clearly demonstrated [28,29]. As an example, in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) registry, in-h ospital mortality was 9.0% among patients with chronic k idney dysfunction (defined as a serum creatinine level >2.0 mg/dl or need for d ialysis) versus 3.6% among those without dysfunc-tion [29]. However, the best course to steer in their management remains to be established. To this regard, although the ESC guidelines state that these patients are at high risk of f urther ischemic events “and therefore should be submitted to invasive evaluation and revas-cularisation whenever possible” [12], the ACC/AHA guidelines more objectively recognize that “unlike in several other high-risk subsets, the value of aggressive therapeutic interventions is less c ertain and should be further studied” [13]. In fact, the uncertainty of the benefit versus risk of an aggressive pharmaco-interventional approach in patients with chronic kidney dys-function derives from the greatly increased risk
of coronary intervention, the need to taylor antithrombotic therapy according to residual renal function and the need of an expert and well equipped clinical team. It should not be for-gotten that all of the guideline-generating trials, both those investigating treatment s trategies and those investigating drugs have excluded patients with significant renal dysfunction.
Goal number 3: to reduce the early hazard of pharmaco-invasive intervention
The long-term follow-up of the Fragmin and Fast Revascularisation during Instability in Coronary artery disease (FRISC)-II study has clearly shown a gradient of efficacy for system-atic angiography (and revascularization, if deemed appropriate) in NSTEACS [10]. In this study, patients were classified as being at high, medium and low risk according to the FRISC score [30]. As shown in Figure 1, the 5-year inci-dence of death and myocardial infarction follow-ing an episode of NSTEACS was 41.6% in high-risk, 20.4 in medium-risk and 8.2% in low-risk patients. Using an invasive approach, this inci-dence was reduced by an absolute value of 8.9% in high-risk, 5.8% in medium-risk, but increased by 2.1% in low-risk patients. In the British Heart Foundation Randomized Intervention Trial of unstable Angina-3 (RITA-3) randomized trial [9], which had a design similar to FRISC-II but enrolled a lower-risk population, the b enefit of an invasive approach at 5-year follow-up was confined to the highest quartile of risk. The meta-ana lysis of Mehta et al. pooled data from 9212 patients enrolled in seven randomized controlled trials (RCTs) comparing the routine versus selective invasive approaches [8]. Overall, the trial populations were at lower risk (particu-larly lower age) compared with clinical practice.
Table 2. Ages of patients in the randomized controlled trials of early treatment strategies in NSTEACS.
Trial Average age (years) % pts ≥75 years Outcome Ref.
TIMI IIIB 59 3 Benefit only >65 years [66]
VANQWISH 61 8 No difference [67]
FRISC II 65 Excluded Benefit only >65 years [10]
RITA 3 63 No age classes reported Not reported by age [9]
TACTICS 62 12.5 39% RR >6556% RR >75
[26]
ICTUS 61 Not reported Trend towards > benefit >65 years
[54]
FRISC: Fragmin and Fast Revascularisation during Instability in Coronary artery disease; ICTUS: Invasive Versus Conservative Treatment in Unstable Coronary Syndromes; NSTEACS: Non-ST-segment elevation acute coronary syndrome; RITA: Randomized Intervention Trial of unstable Angina; RR: Relative risk; TACTICS: Treat Angina With Aggrastat and Determine Cost of Therapy With Invasive or Conservative Strategy; TIMI: Thrombolysis in myocardial infarction; VANQWISH: Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital.
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This meta-analysis confirmed that the long-term benefit of routine invasive strategy is confined to the high-risk patients and had enough power to demonstrate that the lower than expected benefit of revascularization was due, at least in part, to a significantly higher early mortality (1.8 vs 1.1%; p = 0.007) and MI during index hospitalization. They concluded that “future strategies should explore ways to minimize the early hazard and enhance later benefits by focusing on higher-risk patients and opti-mizing timing of intervention and use of proven therapies”.
For a decade it has been known that an aggres-sive antiplatelet therapy reduces the ischemic complications of an early percutaneous coro-nary intervention (PCI) in NSTEACS [31], and the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) trial [17] has reinforced this concept even on contemporary background therapy and in very experienced centers. This randomized, double-blind study compared triple antiplatelet therapy using aspi-rin, clopidogrel and abciximab with double therapy using aspirin, clopidogrel and placebo in NSTEACS patients undergoing PCI. As shown in Figure 2, there was a fourfold differ-ence in the rates at 30 days of death and MI between the patients with elevated troponin levels and those without troponin elevation. Triple therapy reduced the 30-day rate of death and MI in patients with troponin elevations by
28%, but there was no benefit at all in adding abciximab to double therapy in patients with normal t roponin levels.
In patients at intermediate risk, where, as demonstrated by the above mentioned ISAR-REACT 2 data, the early ischemic complica-tions of PCI are much lower, there may be sig-nificant room for improvement by reducing the bleeding risk of an aggressive treatment. The recent studies with fondaparinux and bivaliru-din have opened the way for further develop-ing this concept. The Organization to Assess Strategies for Ischaemic Syndromes (OASIS-5) study [32] has clearly demonstrated that the factor Xa inhibitor fondaparinux may provide similar anti-ischemic protection as enoxaparin during index hospitalization (irrespective of patient risk and treatment strategy), however, reducing the rate of major bleeding during index hospital admission by 50% (4.1–2.1%), and the preven-tion of this iathrogenic complication has been deemed responsible of the reduction in mortality observed at 6-month follow-up (fondaparinux 5.8%, enoxaparin 6.5%, hazard ratio [HR]: 0.89; 95% CI: 0.80–1.0; p = 0.05). The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) study [33] provided evidence that the direct thrombin inhibitor bivalirudin, although providing a slightly lower anti-ischemic protection compared with the combination of heparin and a GP IIb/IIIa receptor blocker in the acute phase, reduced the rate of major bleeding from 5.7 to 3.0% (p < 0.0001) and, at 1-year
Invasive arm
RR 95 CI%
32.7 0.79 0.64–0.97
14.6 0.72 0.55–1.13
Noninvasive arm
41.6
20.4
8.2 10.3 1.26 0.66–2.40
FRISC score 4–7
FRISC score 2–3
FRISC score 0–1
Death and MI at 5 years
Favors invasive Favors noninvasive0.5 1 1.5
FRISC score (sum of*):Age > 70 yearsMale genderDiabetes mellitusPrevious MI
ST-depressionElevated troponinElevated II-6/CRP
Figure 1. Impact of an early invasive versus selective invasive treatment on 5-year outcome of NSTEACS in the FRISC-II study. Patients are grouped according to the baseline risk of death and myocardial infarction calculated using the FRISC score. *Each item counts one in the score. FRISC: Fragmin and Fast Revascularisation during Instability in Coronary artery disease; MI: Myocardial infarction; NSTEACS: Non-ST-segment elevation acute coronary syndrome. Data taken from [10].
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follow-up, bivalirudin-treated patients had a mortality rate superimposable (or slightly lower) to that of patients treated with triple antiplatelet therapy [34]. These data, and a recent meta-analy-sis of the Innovative Stratification of Arrhythmic Risk (ISAR) studies [35] show that bleeding and MI have similar and independent predictive value with regards to long-term ischemic out-comes. Thus, modulating the aggressiveness of antithrombotic therapy on the baseline risk of ischemic and bleeding complications may lead to a reduction in the early hazard of an invasive approach, and perhaps extending its b enefit to lower-risk populations. Unfortunately, as shown in Box 3, most patients categories with high ischemic risk are also at high risk of bleeding, l eaving uncertainty regarding the most efficient treatment in individual patients. The consistent finding across trials is that low-risk patients do not derive benefit from an aggressive acute intervention [8–11] and should be treated using the simplest and least expensive antithrombotic therapy [17,36]. Therefore, in low-risk patients, current guidelines wisely recommend a conser-vative approach in the acute phase followed by an aggressive control of risk factors [12,13].
Goal number 4: to refine the efficacy: safety ratio of long-term antithrombotic therapy for prevention of recurrent ischemic events
Of the ischemic events occurring within 1 year after hospital admission due to a NSTEACS, only one third or a half occur during index admis-sion [1]; recurrencies are at least as frequent and the great majority of these are of thrombotic ori-gin. Therefore, great importance is attributed by current guidelines to long term antithrombotic therapy [12,13]. However, whereas risk stratifica-tion is the rule for acute treatment strategies, after discharge an equally aggressive antithrombotic therapy is recommended, irrespective of risk. This issue deserves consideration in individual patients since the expected benefit of treatment is defi-nitely dependent on patient characteristics, and the same applies to the iathrogenic risk.
Of the two categories of antithrombotic drugs, antiplatelet agents and anticoagulants, so far only antiplatelet agents have been developed for long-term use in secondary prevention of NSTEACS, whereas the use of anticoagulant therapy has been limited by the fact that only vitamin K antago-nists were available, that these agents have a n arrow therapeutic window and, thus, require strict and efficient monitoring, and finally that studies were performed in an era in which high levels of anticoagulation were being used [37,38]. More recently, using more selective agents that do not require specific monitoring, and possibly lower levels of anticoagulation, anticoagulant therapies have been developed that have been shown to be effective in the acute phase of ACS, however with much lower risk of bleeding, and this turned out to reduce long-term mortality [32]. Since increased activation of the coagulation system persist for months after an episode of ACS [39], there is definitely a need for more user-friendly and safer long-term anticoagulants, some of which are under develop ment [40].
The risk versus benefit profile of oral antiplate-let agents is still suboptimal, since any increase in efficacy has so far been payed by a higher risk of bleeding, a finding which has been consistent along the way of antiplatelet drug development. Thus, across the spectrum of cardiovascular disease, a 22% relative reduction in the risk of ischemic events with a single antiplatelet agent (mostly aspirin) compared with placebo in the Antiplatelet Trialist Collaboration meta- analysis was obtained at the cost of a 60% relative increase in major bleeding [41]; similarly, a 20% relative reduction in the risk of ischemic events by adding clopidogrel to aspirin in patients with
20
18
16
14
12
10
8
6
4
2
0Placebon = 474
Abciximabn = 499
Placebon = 536
Abciximabn = 513
TnT - TnT +
p = 0.98
p = 0.02
4.64.6 18.3 13.1
Dea
th o
r M
I at
30 d
ays
(%)
Figure 2. Effect of triple antiplatelet therapy (aspirin + clopidogrel + abciximab) versus double therapy (aspirin + clopidogrel + placebo) according to baseline troponin level in the ISAR-REACT 2 trial. Triple antiplatelet therapy was not useful in patients at low-risk (TnT-), but highly effective in those at high risk (TnT+). ISAR-REACT: Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment. Data taken from [17].
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NSTEACS in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial was achieved at the cost of a 38% relative increase in major bleeding [42]; and, finally, a further 19% relative reduction in the risk of ischemic events in ACS patients candidated to PCI by using a more power ful P2Y
12 receptor prasugrel instead
of clopidogrel was achieved at the cost of a 32% increase in major bleeding [43]. Since major bleeding has been demonstrated to be a power-ful and independent predictor of mortality [44], this tradeoff of anti-ischemic efficacy and bleed-ing risk may be the reason of the null effect of long-term a ntiplatelet therapy on mortality.
The availability of antiplatelet strategies with different risk versus benefit profile (e.g., at present, aspirin alone, aspirin plus clopidogrel, and aspirin plus prasugrel) may offer the opportunity to tailor treatment to the individual patient. In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel – Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38 trial, patients with higher bleeding risk, such as the elderly, those with prior stroke or transient ischemic attack as well as low-weight patients, did not derive any benefit from prasugrel, whereas in those treated by coronary stenting, the benefit of a more powerful anti-platelet therapy was striking [45]. Finally, despite the fact that no eterogeneity of the anti-ischemic effect of clopidogrel based on baseline patient risk has been shown in the CURE study [42], it is clear that the number needed to treat (NNT) to pre-vent a composite ischemic end point (and thus the cost of treatment) is dependent upon the baseline risk of ischemic events.
The duration of dual antiplatelet therapy after an episode of ACS is a still unsettled issue, par-ticularly in patients undergoing stent implanta-tion. Mostly based upon the results of the CURE study [42], both the ESC and the ACC/AHA NSTEACS guidelines recommend that dual antiplatelet therapy using aspirin and clopidogrel be continued for 1 year. Recently, a retrospec-tive cohort study of 3137 patients with ACS discharged from 127 Veterans Affairs hospitals, with posthospital treatment with clopidogrel, demonstrated that rates of death and acute MI were increased, both in patients treated medi-cally and after stenting, during the first 6 months after cessation of clopidogrel [46]. The authors of this important paper suggest that rebound platelet activation may exist following clopi-dogrel withdrawal and an authoritative editorial has commented that “longer duration of clopi-dogrel therapy without interruption seems to be
important for reducing mortality and mortality after ACS” [47]. Since this observation comes from a retrospective ana lysis, and the reason for clopidogrel withdrawal could not be ascer-tained in the study (e.g., bleeding or the need for urgent surgery), more specific (and possibly prospective) data should be generated in order to draw any conclusion on the optimal duration of c lopidogrel treatment after an e pisode of ACS.
Therapeutic end pointsHaving in mind the limitations summarized in Box 1, early intervention on coronary arteries in NSTEACS has traditionally been considered to be at risk of acute ischemic complications, and has become safer only with the use of coronary stents and antithrombotic therapy. The bal-ance of spontaneous versus iathrogenic adverse events has been often unfavorable during index admission for treatments that have been shown to improve long-term outcomes [8,48]. This is particularly true if an aggressive pharmacoin-vasive treatment is applied to high-risk patients (i.e., those who are more likely to derive long-term benefit). In-hospital mortality can be sig-nificantly increased by coronary bypass surgery which, in turn, will show its benefit at long-term follow-up. Even in stable patients where the risk
Box 3. Many of the independent predictors of ischemic outcomes are also independent predictors of bleeding.
Predictors of death and MI in NSTEACS*
Elderlyn
Diabetesn
ST depressionn
Tn elevationn
Renal insufficiency n
Refractory ischemian
Left ventricular dysfunction n
Predictors of bleeding in NSTEACS‡
Elderlyn
Diabetesn
ST depressionn
Tn elevationn
Renal insufficiencyn
Female gender n
Hypertensionn
No prior PCIn
Anemian
MI: Myocardial infarction; NSTEACS: Non-ST-segment elevation acute coronary syndrome; PCI: Percutaneous coronary intervention; Tn: Troponin elevation. *Data taken from [12,13]. ‡Data taken from [48].
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of surgical mortality is below 1%, the reduction in mortality from bypass surgery compared with medical therapy in the Coronary Artery Bypass Graft Surgery Trialists’ Collaboration became evident only after 1 year, with maximum ben-efit not observed until 5–7 years [49]. Similarly, PCI is likely to prevent early catastrophic out-comes only when applied to a small minority of patients with severe ischemic left ventricular dysfunction or extensive ST-segment depression, but it will certainly provoke postprocedural MI in approximately 5–15% of the patients depending on the definition. In addition, an aggressive antithrombotic treatment has been demonstrated to prevent both spontaneous and postprocedural MIs [31]; however, this is at the expense of an increased incidence of bleeding. Both procedural MI and bleeding have been demonstrated to be independent predictors of subsequent mortality [35,50,51]. Finally, despite guideline recommendations for an invasive approach in patients with chronic kidney dys-function (grading IIa-B) [12], post-PCI deteriora-tion of renal function is frequent and has severe prognostic implications [52,53]. Thus, there is still need to pursue better safety of acute treatments in high-risk subgroups.
There is an ongoing debate about whether the study end points should include only efficacy outcomes (such as death, MI and ischemic recur-rencies) or also safety outcomes (such as bleed-ing) [35,54]. In particular, a combined end point of ischemic outcomes and bleeding, defined as net clinical benefit, has been used to evaluate the therapeutic potential of bivalirudin [33,36]. Defendants of the combined efficacy–safety end point indicate that MI and bleeding are equally powerful predictors of long-term mortality and, thus, should both be used in short-term (30-day) studies as surrogates for long-term effect [35,54]. Opposers to this approach maintain that, using an efficacy–safety end point, a drug with little anti-ischemic efficacy, but also low bleeding potential, give results that are equally ‘effective’ compared with a drug that is more effective in preventing ischemic events but also causes more bleeding. Taking into account these divergent positions, in the latest edition of the NSTEACS guidelines [12] the European Society of Cardiology has taken the wise approach of representing the impact of treatment strategies as ischemic outcomes (death and MI), therapeutic efficiency (NNT) and impact on bleeding (reported as TIMI major bleeding [55]); however, without combining anti-ischemic effect and bleeding in a composite end point. Thus, physicians can make up their own
minds in regards to treatment effect (and cost) and select the best treatment according to the patient’s ischemic and bleeding risk.
The importance of end point definitionsThe absolute incidence of a composite end point depends on the absolute incidence of its compo-nents, which in turn depends upon the definitions used. Thus, whereas mortality (total mortality in short-term studies or total and cardio vascular mortality in long-term studies) has a uni-vocal definition, other end points have several d efinitions with very d ifferent incidences.
As far as MI is concerned, its definition has been recently updated by a joint task force of the ESC/ACCF/AHA/WHF [16], but clinical trials have often used different definitions. Thus, whereas the joint task force document defines that any eleva-tion (with a typical curve) in the levels of creatine kinase-MB isoenzyme (CK-MB) or troponin above normal limit, in the context of an ACS or coronary intervention, must be c onsidered an MI, clinical trials have used d ifferent cutoffs (e.g., above mormal limit or above twice the normal limit). Furthermore (and more importantly since most of the MIs occurring during hospital admis-sion for an ACS are postprocedural), although the joint task force document arbitrarily identifies a CKMB elevation of at least three-times above the upper normal limit as representing a post-procedural MI, some trials have used different definitions. As an example, the Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) trial [56] used the same cutoffs (i.e., any CKMB elevation above normal limit) for spontaneous and postprocedural MIs: therefore, the authors of this important study also provided incidences of MI using different cutoffs and defini tions, since this has important implications in evaluating the overall effect of a treatment (see Box 2 of [56]). As far as the ICTUS trial is concerned, despite a number of criticisms the authors have convincingly demonstrated that the overall result of equality between early and selective invasive strategies was consistent across definitions. At least two further points concerning the definition and identification of an MI in ACS studies deserve careful consideration. The first is the recurrence of myocardial infarction during the first 24–48 h of admission, which is problem-atic to discriminate from the index MI owing to the slow kinetics of CKMB: whoever has partici-pated in an event adjudication committee has had experience on how difficult this adjudication is, even with the best possible source documents and even in the few and painstaking studies in whom
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serial CKMB determinations were scheduled by protocol during the first 24–48 h [57,58]. Thus, despite elegant Kaplan-Meier curves showing divarication of the MI curves within the first 24 h after admission, claims that a treatment reduces the incidence of myocardial reinfarction during the 24 h after admission should be regarded with caution [59].
The second issue that deserves consideration is the different threshold for the detection of a myocardial infarction during hospital admis-sion and at follow-up. During index admission, any symptom suggestive of myocardial ischemia and any ischemic changes at serial ECGs prompt CKMB determinations at appropriate timing in order to diagnose an MI. Studies with serial CKMB determinations have demonstrated that in-hospital reinfarctions may occur in 6% of the patients, may be multiple and may have impor-tant prognostic implications [58,60]. However, after discharge it is likely that MIs are detected only in the case of major symptoms, leading to hospital admission and, in the occasional case, of a new Q wave on an ECG: the definition of an MI at follow-up is usually specified in the study protocols. Typically, the Kaplan-Meier curves of MI after an admission for ACS show a steep rise during the first few days (during admission) and then flatten (after discharge)
during follow-up. No doubt, this is biologically plausible but also reflects the above mentioned change in threshold for MI detection. This issue may be particularly relevant in patients with little or atypical ischemic symptoms, such as the elderly and diabetic patients. A more sen-sible detection of postdischarge MI, (which is plausible only in RCTs of secondary prevention) would require the execution of a cardiac mag-netic resonance study, which allows the detec-tion of even small areas of delayed e nhancement, at 1-year follow-up.
The definition of bleeding The definition of bleeding is even subject to variations among trials and the definition used has a significant impact in representing the efficacy:safety ratio of a treatment strategy. Of course, this is particularly true if a combined efficacy–safety end point (‘net clinical benefit’) is used. Several bleeding scales and definitions have been used in trials and registries of ACS and PCI. The definitions of major bleeding used in con-temporary trials are reported in TaBle 3, which also demonstrates how the average incidence of major bleeding may range from 0.5%, using the most severe Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition [61], to 5–8% using the most liberal
Table 3. Definitions of noncoronary artery bypass graft major bleeding in acute coronary syndrome and percutaneous coronary intervention.
Definition Items Average incidence (%) Ref.
TIMI Intracranial hemorrhage or a 5 g/dl decrease in Hb concentration or a 15% absolute decrease in hematocrit (adjusted for transfusion).
1.5–5 [53]
GUSTO Either intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires intervention.
0.5–1.0 [58]
GRACE Life-threatening bleeding requiring transfusion of ≥2 units of PRBC, or resulting in an absolute decrease in haematocrit of ≥10% or death, or hemorrhagic/subdural hematoma.
2.5–5 [59]
STEEPLE Fatal, retroperitoneal, intracranial or intraocular bleeding.Bleeding that causes hemodynamic compromise requiring specific treatment.Bleeding that requires intervention (surgical or endoscopic) or decompression of a closed space to stop or control the event.Clinically overt bleeding requiring any transfusion of ≥1U of PRBC or whole blood.Clinically overt bleeding causing a decrease in Hb of ≥3 g/dl (or, if Hb level not available, a decrease in hematocrit of ≥10%).
1.5–2.5 [63]
OASIS 2 units of blood transfused, decrease of Hb of 3 g/dl, intracranial, fatal, retroperitoneal, intraocular or needing surgical intervention.
2–4 [32]
ACUITY Intracranial or intraocular bleeding.Hemorrhage at the access site requiring intervention.Hematoma with a diameter of at least 5 cm.A reduction in hemoglobin levels of at least 4 g per deciliter without an overt.Bleeding source or at least 3 g per dl with such a source.Reoperation for bleeding or for transfusion of a blood product.
3–8 [33]
ACUITY: Acute Catheterization and Urgent Intervention Triage Strategy; CABG: Coronary artery bypass graft; GRACE: Global Registry of Acute Coronary Events; GUSTO: Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries; Hb: Hemoglobin; OASIS: Organisation to Assess Strategies for Ischaemic Syndromes; PRBC: Packed red blood cells; STEEPLE: The Safety and Efficacy of Enoxaparin in PCI Patients, an International Randomized Evaluation.
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Global Registry of Acute Coronary Events (GRACE) [62,63] and ACUITY [33] definitions. There are specific reasons why the definitions are so different. The GUSTO and thrombolysis in myocardial infarction (TIMI) [55] definitions were developed in the context of thrombolysis trials in STEMI with mortality rates of between 6 and 8%. Thus, in order to compare differences in efficacy and safety between experimental treat-ments, the absolute incidence of severe (or life threatening) bleeding had to be proportionate to an expected difference in mortality of 1.0–1.5%. The remaining definitions were developed in the context of NSTEACS and PCI trials or regis-tries, with no expected differences in mortality between experimental treatments: in these stud-ies, efficacy end points are MI (with incidences of 4–15% based upon baseline ischemic risk) and urgent or unplanned revascularization for i schemia (∼1–2%) during index admission.
Thus, the definitions adopted in a trial depends upon the overall rating of the efficacy:safety ratio of a drug or intervention. The choice of the cut-off points and definitions is conventional and arbitrary because a continuous and independent relationship exists between the level of enzyme elevation (either spontaneous or postprocedural) and subsequent mortality [51,60], and a similar relationship has been shown between any sever-ity of bleeding and long-term ischemic out-comes [44] although the possibility that bleeding represents a marker rather than an independent predictor of mortality has not been ruled out [64]. One possibility, as already discussed for the MI definition adopted in the ICTUS trial, is to show the bleeding rates according to different defini-tions, as already considered in recent papers [33]:
an example is shown in TaBle 4 where the com-parison of bleeding rates between experimental treatments in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial [65] has been represented according to s everal definitions.
Additional end points Additional end points relevant to assess the long-term effect of treatment strategies are being adequately included in contemporary trials. These include hospitalizations for major bleedings, ACS recurrencies, unplanned revascu-larizations, episodes of heart failure and stroke. These end points are likely to capture both spon-taneous events and iathrogenic complications of t reatment strategies.
ConclusionImproving long-term outcomes across the spec-trum of NSTEACS is a complex issue and, so far, has been less successful compared with the strik-ing improvements observed in STEMI. There is evidence base for an aggressive pharmacological and interventional treatment in high-risk patients that should be used irrespective of whether they are initially admitted to a hospital with or without interventional capability. Intermediate risk is ill defined since there is some confusion between the diagnosis of NSTEACS (which implies transient myocardial ischemia with some ECG changes and or some evidence of myocardial damage) and risk stratification (which is to do with the extent of acute ischemia and the underlying burden of atherosclerosis and copathologies); in patients with no high-risk features, the benefit versus risk of any intervention should be carefully
Table 4. 30-day bleeding end points* in the HORIZONS trial.
Thrombolysis in myocardial infarction major 5.0 3.1 0.0020
Thrombolysis in myocardial infarction minor 4.6 2.8 0.0060
Thrombolysis in myocardial infarction major or minor 9.6 5.9 <0.0001
GUSTO life threatening or severe 0.6 0.4 0.4900
GUSTO moderate 5.0 3.1 0.0020
GUSTO life threatening or severe or moderate 5.6 3.5 0.0020*Clinical event committee adjudicated, except protocol minor. ‡Primary end point. HORIZONS: Harmonizing Outcomes with Revascularization and Stents; GUSTO: Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries; UFH: Unfractionated heparin. Data taken from [60].
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Improving outcomes in NSTEACS patients Review
Executive summary
EpidemiologyAmong all hospitalizations for acute coronary syndrome, approximately two-thirds are classified as either unstable angina or non-ST n
segment elevation myocardial infarction (NSTEACS). Compared with the ST-segment elevation myocardial infarction population, these patients are older, more frequently female, with a higher incidence of diabetes and chronic kidney dysfunction and a more complex coronary anatomy.
Clinical presentationThe NSTEACS encompass a wide spectrum of clinical conditions, often without typical symptoms, and with a wide range of risk for n
death or myocardial infarction (MI) at follow-up. The ambiguity of symptoms explains both the delay in seeking early care and the risk of misdiagnosis, especially among older adults with multiple chronic conditions.
Risk assessmentImmediate risk stratification is the first and most important step in order to tailor treatment aggressiveness and it is based on two n
main aspects: – Severity of acute ischemia, as defined by the extent of ECG changes and release of cardiac biomarkers; – Extent of atherosclerotic burden and organ damage, as represented by a history of diabetes, prior cardiac events, left ventricular dysfunction, renal insufficiency and peripheral arterial disease.
Aggressive versus conservative strategyAccording to randomized controlled trials and meta-analyses summarized in the European and American Guidelines published in 2007, n
treatment strategy should be based upon risk stratification: – An early invasive approach with systematic coronary angiography within 72 h of admission (and subsequent revascularization if technically possible), and an aggressive anticoagulant and antiplatelet therapy is recommended in high- and intermediate-risk patients; – A conservative strategy can be applied as first-line treatment in patients at lower risk, with further interventions guided by ischemia recurrence or high-risk stress test despite medical therapy.
Timing of interventionTwo alternatives have emerged for the invasive approach: n
– Urgent (i.e., as soon as possible) in patients with refractory ischemia, hemodynamic instability and life-threatening arrhythmias; – Early (i.e., within 72 h) in the wider number of patients with clear ECG signs of transient ischemia, elevated troponin levels, left ventricular dysfunction, prior MI or coronary revascularizations and diabetes mellitus.
Target population often excluded from clinical trialsOwing to comorbidities and the higher risk of iatrogenic complications, there are at least two categories of patients where general rules n
on NSTEACS patients have not been validated so far and more evidence needs to be generated: – Elderly patients, conventionally defined as those of at least 75 years of age; – Patients with chronic kidney dysfunction.
Efficacy:safety ratioThere is increasing evidence that bleeding is not inconsequential and is associated with recurrence of ischemic events (stroke or MI) and n
a higher risk of death, even when bleeding is not severe enough as to be defined life threatening according to current definitions. Two approaches have emerged in order to balance treatment efficacy and safety: – To modulate the aggressiveness of antithrombotic therapy on the baseline risk of ischemic events; – To resort to antithrombotic therapies with a better safety/efficacy profile, such as bivalirudin and fondaparinux; – Efficacy versus safety on an early aggressive approach has not been established in patient groups at high risk for iathrogenic complications, such as the elderly and those with chronic kidney dysfunction.
Therapeutic end pointsThe most recent ESC guidelines describe the impact of treatment strategies in terms of ischemic outcomes (death and MI), therapeutic n
efficiency (number needed to treat), and impact on bleeding (reported as thrombolysis in MI major bleeding), in order to enable physicians to select the best treatment according to the patient’s ischemic and bleeding risk. This approach seems to be preferable to the alternative of representing treatment effect in terms of a composite of efficacy and safety end point (the so called ‘net clinical benefit’), which is influenced by the definitions of the individual end point components.
Controversial subjectsBoth the ESC and the American College of Cardiology/American Heart Association NSTEACS guidelines recommend that dual n
antiplatelet therapy using aspirin and clopidogrel be continued for 1 year. Recent retrospective analyses have shown clustering of cardiac ischemic events after stopping clopidogrel and raise the hypothesis of a rebound hyperthrombotic period. However, prior to recommending a more prolonged and possibly life-long dual antiplatelet therapy, more (and possibly prospective) data are needed to better understand the pathophysiology of this phenomenon.
ConclusionFuture prospective studies should be planned with adequate power to provide clinically relevant confidence intervals for the n
determination of effect size. To apply uniform definition of the study end points throughout different studies is relevant to allow assessment of the long-term effect of treatment strategies. As far as drug development is concerned, more convincing data should be provided by dose-finding studies before embarking in Phase III trials.
Future Cardiol. (2009) 5(1)38 future science group
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considered. Low-risk patients are usually defined as such based upon their probability of ischemic events in the short term; in these patients the diagnosis of an ACS is often uncertain and they deserve assessment of the atherosclerotic burden and appropriate risk-factor modification.
Study end points have been tailored on expected treatment benefit, which in turn depends on the control incidence of adverse events; the larger the absolute benefit expected from a given treatment, the more solid have been both the efficacy and the safety end points. A more consistent definition of end points should be warranted in order to allow comparisons among trials and pooling of the data, which is often necessary to increase the power to assess treatment effect or iathrogenic hazard in the f requent case of u nderpowered studies.
Future perspectiveOver the last 20 years, there have been striking advances in the treatment of acute coronary artery disease, with a progressive reduction in mortality and risk of recurrencies. However, owing to an increasing life expectancy of the general popula-tion and a more sedentary lifestyle, the numbers of patients with chronic coronary disease are increas-ing, as are the numbers of hospital admissions with acute events. An increasing emphasis on aggressive secondary prevention is being given by the latest editions of the practice guidelines across the spectrum of coronary artery disease, which include NSTEACS, STEMI, PCI and CABG, as well as those specifically dedicated to secondary prevention and risk-factor modifications.
A further improvement in long-term outcomes in NSTEACS can be reasonably expected only by an aggressive treatment of high-risk patients and by the use of safer drugs, though the over-all impact on population health status is likely to be smaller compared with primary preven-tion measures and an aggressive modification of t raditional risk factors.
The development of safer drugs implies that Phase II dose-finding studies must have adequate power in patients with normal and reduced renal function, as well as an adequate representation of elderly patients. These stud-ies must be fully evaluated by independent agencies before embarking in Phase III trials which, in turn, must have adequate sample size. Since most NSTEACS patients require a care-ful assessment of benefit versus risk of drugs therapies, evidence-providing studies, and par-ticularly those of regulatory value, should have adequate power to provide clinically relevant confidence intervals. An ana lysis of current l iterature would easily disclose that Phase II studies of drugs intended for use in large patient populations have unacceptably large confidence intervals to discriminate the most safe/effec-tive dose, and that many Phase III studies have power below 90% and unacceptably large lim-its for noninferiority comparisons. This more r igorous (and costly) process for drug develop-ment would imply negotiation with regard to d uration of p atent p rotection and other p harmaco–economic issues.
The issue of regional networking and plan-ning of coronary revascularization procedures should receive more attention and appropriate-ness of revascularization should be carefully monitored so that high-risk patients receive an adequate treatment and low-risk patients are not unduly treated.
Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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An important paper on the importance of n
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Sabatine MS, Cannon CP, Gibson CM59. et al.: Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 294, 1224–1232 (2005).
www.futuremedicine.com 41future science group
Improving outcomes in NSTEACS patients Review
Savonitto S, Granger CB, Ardissino D60. et al.: The prognostic value of creatine kinase elevations extends across the whole spectrum of the acute coronary syndromes. J. Am. Coll. Cardiol. 39, 22–29 (2002).
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Moscucci M, Fox KA, Cannon CP62. et al.: Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur. Heart J. 24(20), 1815–1823 (2003).
Reference paper on the predictors nn
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AffiliationsStefano Savonitto n
Dipartimento Cardiologico ‘Angelo De Gasperis’, Ospedale Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy Tel.: +39 335 605 6565
