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Acute coronary syndromes: assessing risk and choosing optimal pharmacological regimens for a superior outcome

Neal Uren
DOI: http://dx.doi.org/10.1093/eurheartj/suq020 D4-D13 First published online: 2 September 2010


Revolutionary strategies for management of acute coronary syndromes (ACSs) have been introduced over the past 15 years. Such innovations have occurred in the area of interventional cardiology (bare metal evolving to drug-eluting stents) as well as in pharmaco-therapy, particularly anti-platelet therapy. Agents including clopidogrel and glycoprotein IIb/IIIa receptor inhibitors have been developed, as adjuncts to aspirin, in order to better target the elevated platelet activity central to the thrombus that underlies ACS. Most importantly, there has been a greater emphasis placed upon a patient's risk for ischaemic complications when determining the overall management strategy including timing of angiography and medications. In the effort to improve outcomes for the most high-risk patients, there has been a continued focus on the development of newer therapies. Research has shown, however, that achieving clinical benefit may not require the formulation of the next generation of anti-platelet agent but may require a more astute awareness of patient risk, and the selection of management strategies that demonstrate the greatest benefit to them.

  • Acute coronary syndrome
  • Non-ST-segment elevation acute coronary syndrome
  • ST-segment elevation myocardial infarction
  • Percutaneous coronary intervention
  • Risk stratification
  • Thienopyridines
  • Glycoprotein IIb/IIIa receptor inhibitors


The preceding 15 years should be regarded as a revolutionary era in the management of patients with acute coronary syndromes (ACSs), namely NSTE-ACS [including unstable angina and non-ST-segment myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI)]. Not since the introduction of the intracoronary stenting have so many new developments been introduced in this area. Improvements in revascularization techniques as well as new agents to address the various components of the acute thrombotic process underlying ACS have resulted in considerable reductions in mortality and adverse outcomes. Still, it should be recognized that there is further work to be done as ischaemic complications remain an important concern, particularly in patients with clinical characteristics placing them at a high risk for clinical events.

Improving outcomes for high-risk ACS patient populations may not necessarily require the formulation of the next-generation anti-platelet agent but may necessitate a more astute awareness of patient risk and the selection of management strategies that have demonstrated the greatest benefit to them. This article will review the global issue of ACS and its underlying pathophysiology, particularly with regard to the role of the platelet. Additionally, it will outline the profile of the high-risk patient and current recommendations as well as practice patterns, with respect to revascularization and pharmacological management.

The global impact of acute coronary syndrome

The global health importance of ACS has been substantiated by several contemporary surveys and registries in recent times. The Global Registry of Acute Coronary Events (GRACE) registry is a continuous compilation of data on patients with ACS (NSTE-ACS and STEMI) since 1999. By 2007, 31 982 patients had been enrolled and suggested in-hospital mortality rates of 2.9 and 6.5% for patients with NSTEMI and STEMI, respectively.1 Cumulative data through 2006 from the US-based CRUSADE registry, including 190 000 patients with NSTE-ACS, cited a 4.9% incidence of in-hospital mortality.2 Similar results were cited from the Euro Heart Survey (EHS) Programme, which were two surveys with data collected for patients with ACS from Europe and the Mediterranean Basin from 2000 to 2001 (EHS-ACS I, n = 10 484) and in 2004 (EHS-ACS II, n = 6385).3 In-hospital and 30-day mortality were significantly lower in EHS-ACS II than it was in EHS-ACS I, at 4.0 and 5.1%, respectively. The US National Registry of Myocardial Infarction (NRMI) registry noted that though the incidence of in-hospital mortality for patients with STEMI has declined between 1990 and 2002, it remains substantial with 4.3 and 4.4% in patients receiving fibrinolytics and primary PCI, respectively.4

The difference in severity between NSTE-ACS and STEMI tends to be evident only with respect to short-term mortality. While in-hospital mortality tends to be higher in patients with STEMI than in those with NSTE-ACS, at 6 months, the rates are similar and at 4 years, mortality is increased two-fold in patients with NSTE-ACS.58 As will be discussed later, the fact that a significant number of patients with NSTE-ACS are older, and have relevant co-morbidities including diabetes and renal insufficiency may be an explanation for this finding.

Pathophysiology of acute coronary syndrome

Acute coronary syndrome is the result of either a partial or complete occlusion of a coronary artery resulting in a significant reduction in blood flow to the myocardium,9,10 with the type and severity of a particular ACS being related to the extent of the coronary occlusion, the presence or absence of myocardial necrosis, and degree of collateralization.1114 An ACS can progress in severity compared with others as a consequence of a more occlusive thrombus and resultant myocardial necrosis.15 All forms of ACS share a similar underlying pathophysiology, primarily the rupture of an atherosclerotic plaque resulting in an intracoronary thrombus.16

The platelet's role in thrombosis

The platelet plays a significant role in the development of the thrombus central to ACS. The initial event in thrombus formation is the adherence of platelets to the disrupted surface of the plaque via the glycoprotein (GP) Ib receptor and von Willebrand factor (vWF).9,10 Adherent platelets become activated and degranulate, resulting in the release of substrates, serotonin, ADP, thromboxane A2, platelet factor-4, P-selectin, vWF, plasminogen activator inhibitor-1, and fibrinogen.9,10 This results in further reduction of blood flow through local vasoconstriction in addition to the developing thrombus. The process of activation involves changes to the shape of the platelet, as well as shape changes (conformational changes) to the GP IIb/IIIa receptors on its surface that are responsible for platelet aggregation. The conformational change to the GP IIb/IIIa receptors results in the exposure of binding sites on the receptors for the circulating protein fibrinogen.17 By binding to active GP IIb/IIIa receptors, fibrinogen cross-links GP IIb/IIIa receptors on adjacent activated platelets, resulting in platelet aggregation. This is referred to as white thrombus. Through activation of the coagulation cascade that triggers the activity of thrombin, fibrinogen is converted to fibrin threads, which further stabilize the thrombus (red thrombus).18

The significance of the platelet in clinical outcomes of acute coronary syndrome

In addition to the physiological function that platelets have in the formation of the thrombotic occlusion in ACS, there has been a suggested relationship between platelet activity and clinical outcome. In a study by Steinhubl et al.19 of patients with STEMI undergoing PCI, higher levels of platelet reactivity were associated with a greater incidence of major adverse cardiac events. An unrelated study in which platelet reactivity was measured before and after treatment in a selected group of patients with STEMI undergoing primary PCI assisted by the systematic use of GP IIb/IIIa inhibitors (GPIs) demonstrated that platelet reactivity both at baseline and after the GP IIb/IIIa inhibitor bolus influenced the angiographic success of the procedure as well as the degree of ST-segment resolution, the extent of myocardial necrosis, and the short- and mid-term clinical outcome.20

The effect of platelets on microcirculatory occlusion in patients with acute coronary syndrome

Though a significant focus is placed on the occlusion of an epicardial vessel, of potentially greater importance is the impaired blood flow within the microcirculation, which is evident in NSTE-ACS and STEMI and often related to reperfusion strategies.21,22 The impact on the microcirculation is quite apparent in situations where blood flow through the infarct-related artery is successfully restored, though myocardial perfusion is still impaired.23

In fact, the most common cause of NSTE-ACS is non-occlusive intracoronary thrombus accompanied by microembolization of platelet aggregates. Platelet aggregation is a major contributor to microcirculatory dysfunction in ACS. Thrombus comprised mostly of platelets tends to be smaller and more likely to embolize distally.24 In addition to their role in microcirculatory occlusion, platelets may induce vasospasm through the release of serotonin, thromboxane A2, and free radicals. The complementary action of these two platelet-driven mechanisms results in impaired myocardial perfusion and ischaemia of the impacted region.22

The high-risk patient with acute coronary syndrome

Unlike STEMI, where the diagnosis is usually obvious and is the key driver of the treatment path, in NSTE-ACS, diagnosis alone does not determine the management strategy. More precisely, an initial and ongoing evaluation of the risk for ischaemic complications is crucial to ensure optimal management of patients diagnosed with NSTE-ACS, as an intensive management approach including early angiography with PCI and triple anti-platelet therapy is of benefit in patients determined to be at high risk for ischaemic complications.2531

Determining a patient's level of risk comprises the patient's medical history, clinical features, laboratory tests, and the electrocardiogram (ECG). In addition to the patient's history and physical exam, risk stratification may be achieved using a formalized risk assessment tool such as the Thrombolysis In Myocardial Infarction (TIMI) Risk Score or the GRACE ACS Risk Model.8 Distinct characteristics including age, certain aspects of the medical history, most notably diabetes and renal insufficiency, cardiac biomarkers, and specific ECG findings have been linked with an increased rate of ischaemic events and, as discussed in the sections below, are therefore considered independent predictors of risk.


Age is a strong predictor of adverse events in ACS.32 A report from the GRACE investigators revealed that even while accounting for other potential confounding factors, the odds for in-hospital mortality increase by 70% for each 10-year increase in age [odds ratio (OR) 1.70, 95% confidence interval (CI), 1.52–1.82].33 As noted by European registries, though the number of patients with ACS over the age of 75 years varies from 27 to 34%, in this patient population, the death rate is at least twice as high as in patients aged <75 years.34

On the basis of retrospective studies, older patients with ACS have more co-morbidities, including pre-existing heart failure, more extensive coronary artery disease, and renal insufficiency.35 Age-related physiological changes may in addition contribute to a higher event rate in this population. Angiographic studies have noted that elderly patients (>75 years) with ACS have more triple-vessel disease, higher left ventricular end-diastolic pressure, and lower left ventricular ejection fractions.36,37 Other mechanisms may come into play, including reduced level of responsiveness to adrenergic stimulation and lowered reactivity in chemoreceptors and baroreceptors.38

Elevated cardiac troponin

Cardiac biomarkers such as troponin and creatine kinase (CK) MB fraction are indicators of myocardial necrosis and become measurable in blood when thrombi that partially or completely occlude coronary arteries and/or the microcirculation result in the death of myocardial cells.39

The TIMI IIIB study established that cardiac troponin I levels provide useful prognostic information and permit the early identification of patients at an increased risk of death. The mortality rate at 42 days was significantly higher in the patients with cardiac troponin I levels ≥0.4 µg/L than in those with troponin I levels <0.4 µg/L (3.7 vs. 1.0%, respectively; P < 0.001). There were statistically significant increases in mortality with increasing levels of cardiac troponin I (P < 0.001). Each increase of 1.0 µg/L in the cardiac troponin I level was associated with a significant increase (P = 0.03) in the risk ratio for death after adjustment for the baseline characteristics that were independently predictive of mortality (ST-segment depression and age ≥65 years).40

Troponins hold a significant advantage over CK-MB with respect to identification of myocardial injury as they are expressed only in myocardial tissue, rendering them cardiac-specific. Troponins are also released from both injured and necrotic myocardial cells, whereas CK is only released from necrotic cells. This results in troponin levels being significantly more sensitive to small amounts of myocardial ischaemia than CK-MB. Finally, troponins will remain in the blood stream for days following a cardiac event, allowing more time for diagnosis. For example, troponin T is released into circulation 4–6 h after onset on injury and remains elevated for 10–14 days. Troponin I is detectable 6 h after onset and remains elevated for 7–10 days.8,39 Though the timing for release of CK-MB is similar to that of troponin, it only remains detectable for 24–72 h.39,41

The guidelines developed by the American College of Cardiology (ACC)/American Heart Association (AHA) and the European Society of Cardiology (ESC) advocate the use of troponin levels in the identification of at-risk patients8,42 and recognize them as the optimal biomarker to predict short-term (30-day) death or myocardial infarction (MI) and with long-term prognostic value (1 year and beyond).8

Electrocardiographic changes

It has been appreciated that in patients with NSTE-ACS, ECG evidence of ST-segment deviation (indicative of myocardial ischaemia) at baseline carries a higher risk for subsequent cardiac events.5,43,44 In a study of patients with unstable coronary artery disease, the 30-day rate of death from MI was 5, 6, 6 and 15% in those with no ST-T changes, isolated T-wave inversion, minor ST-segment elevation, and ST-segment depression, respectively.43 The extent of ST-segment depression was found to have the highest prognostic value for 30-day death, 30-day death or MI, and 1-year death based on an analysis of patients enrolled in GUSTO-IV.44

Additionally, a post hoc analysis of PRISM-PLUS demonstrated that even in patients with low TIMI risk scores, the magnitude of ST-segment deviation was an important predictor of 6-month death or MI.45 In patients with a TIMI risk score of <5, ST-segment deviation of ≥1 mm was found to have the lowest 6-month rate of death or MI (5%) with a two-fold increase in those with an ST-segment deviation of ≥2 mm (13 vs. 5%; P < 0.05). In the subgroup of patients determined as having a ‘low’ TIMI risk score,14 the rate of death or MI at 6 months was markedly increased in those with an ST-segment depression of ≥2 mm when compared with patients without evidence of ST-segment deviation of ≥1 mm (24 vs. 5%; P < 0.001).


There is a longstanding relationship between diabetes and cardiovascular risk. Patients with diabetes and no prior MI have a similar risk of future MI when compared with patients who had already suffered an MI.46 Diabetic patients also have more extensive coronary artery disease and despite modern therapies, experience a higher mortality in ACS.47,48 This was substantiated by means of a pooled subgroup analysis of 62 036 ACS patients (NSTE-ACS and STEMI) with diabetes enrolled in 11 separate TIMI Study Group clinical trials. In patients presenting with NSTE-ACS, mortality at 30 days was significantly higher among patients with diabetes than in those without diabetes (2.1 vs. 1.1%; P < 0.001).48 Additionally, diabetes was associated with a significant mortality risk at 1 year after the diagnosis of NSTE-ACS [hazard ratio (HR), 1.65; 95% CI, 1.30–2.10]. It should also be noted that at 1 year, patients with diabetes who presented with NSTE-ACS had a risk of death approaching non-diabetic patients who presented with STEMI.

Such observations are the likely results of the impact of diabetes on the pathogenesis of thrombosis in ACS. Diabetes is believed to be associated with a hypercoagulable state owing to larger platelet size,49 greater expression of inflammatory markers,50 higher platelet surface density of GP IIb/IIIa receptors,49,51 and higher levels of circulating fibrinogen52 and thrombin–anti-thrombin III complexes53 along with more extensive endothelial dysfunction.54,55

Renal impairment

Impaired renal function has been deemed to be a strong prognostic indicator in patients with ACS. An analysis was conducted encompassing four large ACS trials (GUSTO IIb, GUSTO III, PARAGON, and PURSUIT) comprising 18 621 and 19 304 patients with STEMI and NSTE-ACS, respectively, in which patients were stratified by the presence or absence of abnormal renal function (creatinine clearance <70 mL/min).56 Patients identified as having abnormal renal function demonstrated a higher rate of mortality and higher incidence of death or MI at both 30 and 180 days, irrespective of ST-segment status. Moreover, creatinine clearance was independently linked with mortality risk (HR 0.79 in the STEMI group and 0.81 in the NSTE-ACS group) and with risk of death or MI (HR 0.93) in the NSTE-ACS group at 180 days.

Similarly, results from a study of 2706 consecutive patients with UA or STEMI enrolled from 24 separate hospitals noted that renal insufficiency defined by estimated glomerular function rate (eGFR) was associated with higher odds of death than normal renal function [mild renal insufficiency (GFR 60–89 mL/min/1.73 m2): OR = 1.76; 95% CI, 0.93–3.33; moderate renal insufficiency (GFR 30–59 mL/min/1.73 m2): OR = 2.72; 95% CI, 1.43–5.15; and severe renal insufficiency (GFR <30 mL/min/1.73 m2); OR = 6.18; 95% CI, 3.09–12.36; all compared with normal renal function].57 Renal insufficiency had similar impacts in both the STEMI and UA subgroups (P-value for interaction = 0.45).

Guideline-driven management of high-risk acute coronary syndrome patients

The guidelines developed by both the ACC/AHA and the ESC encourage initial and ongoing risk assessment of all patients presenting with NSTE-ACS, and those deemed as high-risk should be managed with an urgent or early invasive strategy entailing angiography with PCI as appropriate, within 2–72 h, and a more aggressive pharmacological approach.8,42 In the management of STEMI, primary PCI is the ideal revascularization strategy, as long as it can be performed within 120 min of first medical contact as significant delays have been linked with poor outcome.8,5861

Anti-platelet therapy in the management of patients with acute coronary syndrome

As increased platelet activity is an important driver of outcomes in both NSTE-ACS and STEMI, and anti-platelet therapy is a cornerstone of medical management in patients with ACS.

As platelet function is guided by various processes and receptors, the approach to anti-platelet therapy is multi-faceted (Figure 1). This involves the use of combination therapy, particularly those deemed high-risk and thus managed with an invasive strategy. These include agents with complementary mechanisms of action specifically, oral anti-platelet agents (aspirin, thienopyridines/ADP receptor inhibitors, the new cyclo-pentyl-triazolo-pyrimides, and intravenous GPIs.8,62,63

Figure 1

Targets for anti-platelet therapy. Adapted with permission from Meadows and Bhatt.63

Oral anti-platelet therapy

Acetylsalicylic acid (acute coronary syndrome; aspirin)

Aspirin acts promptly to inhibit COX-1 within platelets, thereby preventing the formation of thromboxane A2 and subsequently diminishing the platelet aggregation promoted by this pathway. Aspirin has been demonstrated to be effective across the entire range of ACS. In NSTE-ACS, studies have shown that aspirin used in doses of 74–324 mg daily markedly reduced the risk of vascular events.10,64,65 In the subgroup of patients with NSTE-ACS analysed in the meta-analysis of the Antithrombotic Trialists Collaboration, a 46% odds reduction in vascular events (MI, stroke, or vascular death) was observed (13.3 vs. 8.0%).66 In STEMI, the Second International Study of Infarct Survival (ISIS-2) demonstrated that ASA therapy, started within 12 h of infarction, resulted in a 23% reduction in mortality at 35 days, compared with placebo.67

Adenosine diphosphate receptor inhibitors (clopidogrel, prasugrel, ticagrelor)

Clopidogrel and prasugrel are ADP receptor antagonists that inhibit the adenosine diphosphate (ADP) pathway by specifically blocking the platelet ADP receptor P2Y12. Both are oral pro-drugs requiring metabolism by the hepatic cytochrome P450 enzyme system.68 Ticlopidine was the first of the thienopyridine class, but it is no longer used in contemporary practice.

Clopidogrel was the first thienopyridine to be studied in NSTE-ACS. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial was designed to investigate the addition of clopidogrel to aspirin vs. aspirin alone in 12 562 patients with UA/NSTE-ACS.69 Overall, GPI usage was 6.6% of cases. At 1-year follow-up, there was a 20% reduction in the composite primary endpoint of death/MI/stroke (P < 0.0001), driven by a reduction in MI, 6.7% with aspirin vs. 5.4% with aspirin/clopidogrel (P < 0.01). Thus, treating 1000 patients for 9 months with dual anti-platelet therapy would prevent 28 vascular events, with six individuals requiring transfusion.

The ESC recommends the administration of clopidogrel using loading and maintenance doses in the management of NSTE-ACS and STEMI, specifically those undergoing PCI.8,62 Results from studies such as PCI-CURE, which demonstrated a significant 30% relative risk reduction in the composite of CV death, MI, or urgent TVR at 30 days in patients with NSTE-ACS with a clopidogrel regimen including 300 mg loading and 75 mg maintenance doses in addition to aspirin (6.4 vs. 4.5%; P = 0.03), provide the basis for this recommendation.70

Prasugrel is similar to clopidogrel as it is a pro-drug requiring hepatic cytochrome-dependent metabolism for activity; unlike clopidogrel, prasugrel requires a single- rather than a multiple-step process for activation, giving it a more predictable efficacy in platelet inhibtion.68,71 In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON TIMI)-38 trial, a total of 10 074 patients with UA/NSTE-ACS undergoing PCI, with 55% GPI usage, were randomized to either clopidogrel or prasugrel (60 mg load, 10 mg daily) in addition to aspirin.72 Acknowledging that the majority of patients in the clopidogrel arm did not receive pre-loading as is conventional practice, the prasugrel arm was associated with a 19% reduction in cardiovascular death/MI/stroke at 15 months of follow-up (P < 0.01). An excess of major bleeding was seen in patients over 75 years, those <60 kg in weight, and those with previous TIA/stroke. Thus, treating 1000 patients for 15 months with prasugrel therapy (compared with clopidogrel) prevents 23 MIs, with six individuals having non-CABG major haemorrhage.

The effects of both clopidogrel and prasugrel are slowly reversible, requiring several days for platelet activity to return to normal. In contrast, ticagrelor is a new reversible ADP receptor antagonist that has a faster, greater, and more consistent P2Y12 inhibition than clopidogrel. In the PLATO trial, a total of 18 624 patients with UA/NSTE-ACS/post-STEMI were randomized to either ticagerlor (180 mg load, then 90 mg b.i.d.) or clopidogrel (300–600 mg load, then 75 mg).73 At 12 months, there was a 16% reduction in the composite primary endpoint of cardiovascular death/MI/stroke with ticagrelor vs. clopidogrel dual anti-platelet therapy (P < 0.001). A small increase in non-CABG-related major bleeding was seen with a transient increase in the sensation of dyspnoea. Of considerable interest, there was a reduction in all-cause mortality from 5.9 to 4.5% with ticagrelor (P < 0.001).

Glycoprotein IIb/IIIa receptor inhibitors

An important component of the platelet aggregation pathway is the GP IIb/IIIa receptor. The GP IIb/IIIa receptor binds several substrates, most notably fibrinogen, which forms a bridge between platelets, directly mediating aggregation. GP IIb/IIIa is the most abundant platelet GP with an estimated 40 000–80 000 complexes present on the surface of the resting platelet, and an additional 20 000–40 000 which remain quiescent until activation takes place.74 The GP IIb/IIIa complex is a strong receptor for fibrinogen, but also fibronectin and vWF.17

GPIs selectively block the GP IIb/IIIa receptor on the surface of the platelet, thus preventing the binding of fibrinogen to the receptor.75 They have been regarded as the most potent inhibitors of platelet activity.76

There are three agents in the GPI class: abciximab, eptifibatide, and tirofiban. Abciximab, an irreversible, chimeric human-murine monoclonal antibody Fab fragment (c7E3), was the first agent in this class introduced to clinical practice.77 Unlike abciximab, which binds irreversibly to the receptor, eptifibatide is a synthetic cyclic heptapeptide, and a small-molecule GPI in which the anti-platelet activity is reversible.78 Tirofiban is a non-peptide GPI, and like eptifibatide is a small molecule and reversible.79 The characteristics of the three available GPIs are summarized in Table 1.

View this table:
Table 1

Glycoprotein IIb/IIIa receptor inhibitors

Method of administrationIV: bolus plus infusionIV: bolus plus infusionIV: loading dose plus infusion or bolus plus infusion
Molecule sizeLargeSmallSmall
Molecular structureMonoclonal antibodySynthetic cyclic heptapeptideSynthetic non-peptide
Duration of anti-platelet effectFor the life of platelet4 h after discontinuation8 h after discontinuation
Half-life10–30 min2.5 h2 h

According to the ACC/AHA and ESC guidelines, GPIs are included among the medications recommended for use within the first 24 h of presentation in high-risk patients with NSTE-ACS planned for an early invasive strategy, along with aspirin, beta-blockers, clopidogrel, and anti-thrombotic therapy, such as low-molecular-weight heparin or fondaparinux.8,42 The fact that GPIs block the ability of platelets to aggregate inhibits thrombus formation and reduces the potential for ischaemic complications that may occur in NSTE-ACS patients, particularly those scheduled to undergo PCI.8,42 The ESC explicitly states that triple anti-platelet therapy including a GPI should be used in higher risk patients with NSTE-ACS who have elevated troponins, ST-segment depression, or diabetes.8

Additionally, the authors of the European and US guidelines for the management of STEMI support the use of GPIs in patients being managed with primary PCI, with the ESC designating class IIa and IIb recommendations for the use of abciximab and the small-molecule GPIs (tirofiban/eptifibatide), respectively.62 Likewise, the ACC/AHA advocates initiation of a GPI in selected patients with STEMI at the time of PCI, assigning a class IIa-A to abciximab and IIa-B to tirofiban and eptifibatide.78

Practice trends in acute coronary syndrome management

On the basis of data from registries and surveys including GRACE, the EHS, and CRUSADE, incremental improvements in adherence to guideline-recommended treatment have been observed over time in both patients with NSTE-ACS and STEMI.3,79,80 While this is quite promising, it is not always clear whether these improvements were implemented in those considered at the highest risk for adverse ischaemic events. For example, though the EHS II demonstrated an increase in adherence to guidelines relative to EHS I, the analysis was not designed to stratify by level of risk.3 Other studies, however, provided clear indication that such therapies have remained underused among high-risk patients. An analysis of patients included in the CRUSADE initiative (NSTE-ACS) from January 2001 to September 2003 found that patients determined as being at a high in-hospital mortality risk (including diabetes, renal insufficiency, signs of congestive heart failure, age >75 years) were less likely to receive guideline-recommended acute medications and invasive cardiac procedures as compared with those defined as lower risk (Figure 2).81

Figure 2

Acute treatment patterns by risk category. Adapted with permission from Roe et al.81

A separate analysis of CRUSADE revealed the influence of age on the use of guideline-advocated anti-platelet therapy.82 Age was found to have the most remarkable impact on the use of acute clopidogrel and GPIs. Despite 92% of patients aged ≥85 years exhibiting positive cardiac markers, only 30% were treated with clopidogrel, and 13% received a GPI. In elderly patients managed with an early invasive strategy, the use of clopidogrel and GPIs was significantly lower than their comparably managed younger counterparts.

This disparity may be explained by the multiple co-morbidities often present in the elderly and the increased potential for haemorrhagic events associated with a high-risk status. Essentially, clinicians may be wary of strategies requiring invasive procedures and aggressive platelet inhibition owing to safety concerns in these patients. That said, proper technique, dosing, and monitoring should be utilized in an effort to maintain the balance between efficacy and safety when managing ACS in elderly high-risk patients.


It is evident that patients who exhibit certain characteristics at the diagnosis of an ACS (elevated troponin, ST-segment deviation, increased age, etc.) will indeed be more likely to suffer an adverse event. These patients also respond most favourably to a more aggressive approach to management, including an early invasive strategy and triple anti-platelet therapy. The irony of it all is that studies have shown that it is often the highest risk patients that tend to receive the least aggressive treatment. The guidelines already support the use of early invasive management and triple anti-platelet therapies in patients at the greatest risk for ischaemic events. Though innovation needs to continue in this clinical area, it is critical that clinicians recognize the benefits that can be accomplished at present with more effective risk stratification and suitable management.


Supported by an unrestricted grant from Iroko Cardio, LLC.

Conflict of interest: none declared.


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