A new and exciting ‘journey’ in interventional cardiology began more than 20 years ago with the introduction of intracoronary stenting.

Introduction

Developments along the way have included better patient selection, improved peri-procedural management of patients and, with newer-generation drugs and devices, better results. Recent hurdles have been confronted, including left main stem disease, complex bifurcation lesions and total chronic occlusions. Similarly, primary percutaneous coronary intervention (PCI) has become the treatment of choice in acute myocardial infarction. Challenges remain, however, including restenosis. The fine balance between thrombosis and haemostasis demands that we provide more effective and predictable antiplatelet strategies to optimise risk reduction.

Newer approaches are being developed, including stents made of biological materials and biodegradable stents, along with refinements and adjuncts in pharmacology, to provide more potent and selective inhibition of the many pathways of platelet activation and aggregation. We may also be entering an era of routine genotyping and point-of-care platelet function testing. Exciting times! The purpose of this supplement is to review the “state of the art” and see where the journey has brought us, and also to look a little at what may lie ahead. In this first section we will review newer terms and definitions, and we will move on to look in detail at some of the remaining clinical challenges such as coronary artery disease in patients with diabetes.

New terms and approaches to risk management

Acute coronary syndrome (ACS) is now the label which describes a range of symptoms extending from unstable angina to myocardial infarction. As more sensitive and specific serological biomarkers and more precise imaging techniques have developed, ever smaller amounts of myocardial necrosis are now detectable. Therefore previous definitions of myocardial infarction have been re-evaluated, a process which has implications for clinicians for risk-stratifying high- versus low-risk groups; for health care delivery systems for future planning and resource utilisation; and also for design and analysis of clinical trials.

A universal definition of myocardial infarction was developed by a joint European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation (ESC/ACCF/AHA/WHF) task force.¹ Now, the term myocardial infarction should be used when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischaemia. Criteria include detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischaemia with at least one of the following:

• Symptoms of ischaemia
• ECG changes indicative of new ischaemia (new ST-T changes or new left bundle branch block)
• Development of pathological Q waves in
  the ECG
• Imaging evidence of new loss of viable myocardium or new regional wall
  motion abnormality.

The preferred biomarkers are troponin T or I, which have nearly absolute myocardial tissue specificity as well as high clinical sensitivity, reflecting even microscopic zones of myocardial necrosis.¹

Acute ST-segment elevation myocardial infarction (STEMI) is associated with coronary artery occlusion and progressive necrosis of the myocardial tissue. In non-ST segment elevation myocardial infarction (NSTEMI), thrombus does not occlude the lumen completely, or perhaps blocks it intermittently.² Some myocardial necrosis occurs in these circumstances also. But when myocardial ischaemia is present without myocardial necrosis (normal serum troponin level), the clinical syndrome is termed unstable angina. The ESC definition of ACS is illustrated in figure 1.³

Although mortality from myocardial infarction has declined in recent years in the UK, the number of people admitted to hospital with unstable angina and NSTEMI (NSTE-ACS) has shown less of a decline. Although STEMI historically was considered to produce worse outcomes, we now know that six-month mortality from NSTE-ACS is comparable to that of STEMI patients.³ Indeed, data suggest that six-month mortality may be worse in NSTEMI.⁴ The management of these patients, therefore, remains a high priority, particularly in face of worrying trends in the incidence of obesity and diabetes. Patients with ACS also have widely varying risks of mortality and other cardiovascular events, both in-hospital and after discharge.² Many factors have been shown to be predictive of adverse outcome during ACS, including advancing age, raised heart rate, the magnitude in rise of biomarkers of myocardial injury, and diabetes mellitus.²

A single risk factor may not provide a reliable assessment of outcome. In clinical practice there has been a tendency to use serum troponin levels for patient risk stratification but “serum troponin does not accurately measure risk in individual patients, particularly when used as a dichotomous outcome”.² A number of risk scoring systems have been developed to predict outcome in ACS patients. Many are derived from clinical trial populations (such as PURSUIT⁵ and PREDICT⁶), which have generally excluded patients at highest risk; others (such as GRACE⁷) have been derived from large patient databases in an attempt to obtain a population with a broader spectrum of risk. None of these risk models is clearly superior, according to the National Institute for Health and Clinical Excellence (NICE) 2010 guideline. ² The same document continues: “Clinical assessment alone may not accurately reflect the patient’s risk. There is potential for a systematic approach to risk assessment (that would) result in more accurate estimation of risk and more appropriate intervention”².

References

1. Thygesen K, Alpert JS, White HD on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J 2007; 28:2525–38.

2. The National Institute for Health and Clinical Excellence (NICE). Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. Clinical guideline CG94. London: NICE, 2010.

3. Guidelines for the diagnosis and treatment of non-ST elevation acute coronary syndromes. Task Force for diagnosis and treatment of non-ST elevation acute coronary syndromes of the European Society of Cardiology. Bassand JP, Hamm CW, Ardissino D et al. Eur Heart J 2007;28:1598–660.

4. Nair SB, Chacko SM, Dixit A et al. Comparisons of patients’ demographics, in-hospital and three-year mortality rates and independent predictors of death in ST-elevation versus non-ST-elevation myocardial infarction. An interventional centre experience. Heart 2010;96(suppl 1):A71–A72.

5. Boersma E, Pieper KS, Steyerberg EW et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation 2000;101:2557–67.

6. Jacobs DR, Kroenke C, Crow R et al. PREDICT: A simple risk score for clinical severity and long-term prognosis after hospitalization for acute myocardial infarction or unstable angina: the Minnesota heart survey. Circulation 1999;100:599–607.

7. Fox KA, Dabbous OH, Goldberg RJ et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndromes: prospective multinational observational study (GRACE). BMJ 2006;333:1091.

Treatment options in ACS include optimised medical therapy, intervention and surgical revascularisation.

Introduction

While primary PCI, rather than thrombolysis, is now the reperfusion treatment of choice for STEMI, the majority of patients coming for revascularisation in the UK have stable coronary disease or NSTE-ACS. In the treatment of NSTE-ACS, first principles involve the selection of patients for diagnostic angiography followed by either PCI or coronary artery bypass grafting (CABG). Rates of PCI are increasing annually in the UK, which, in part, is a reflection of greater awareness of coronary artery disease, its earlier diagnosis and treatment in the ageing population.

This section looks at coronary intervention in general, how PCI activity in the UK compares with other European countries, and trends in the mode of vascular access. We also look at outcomes following PCI compared with CABG and latest UK guidance in this area.

Percutaneous coronary intervention statistics in the UK

Audit returns data from the British Cardiovascular Intervention Society (BCIS)¹ show the current state of PCI in the UK. It is becoming an increasingly common procedure: latest data from 2008 show that 105 centres in the UK performed percutaneous coronary intervention (PCI).¹ PCIs were performed in five NHS and one private facility in Scotland; in 76 NHS and 16 private facilities in England; in three hospitals in Northern Ireland; and in two in Wales.¹ The total number of PCIs for the UK for 2008 was 80,331: the vast majority (78,077) in NHS hospitals and 2,254 in the private sector.¹ Figure 1 expresses BCIS data showing that both the number of PCIs performed and the number of PCIs performed per million population are gradually increasing each year. In addition, 54 of the 87 NHS units now perform day-case PCI.¹

Figure 2 shows the indications for PCI during 2008.¹ The “other” indications include bailout and hybrid procedures.

In all, 11,784 PCIs were performed for STEMI, most of them (n=9,224) primary PCI and the others rescue PCI.¹ This gives an overall primary PCI rate of 150 per million population in the UK, a lower figure than those from many European countries (figure 3).¹

Compared to 2007, interventionists made increasing use of thrombectomy, laser, rotablation, intravascular ultrasound and pressure wires but decreasing use of cutting balloons and distal protection.¹

Femoral and radial access routes for PCI: take-up and results

Historically PCI has been carried out using femoral artery access. Over the years, the mode of vascular access in PCI has changed to reduce procedural complications. BCIS data for 2008 show how radial artery access for PCI is slowly becoming more widespread in the UK.¹ It was used for 28.1% of cases in 2007 and 34.61% of cases in 2008, in roughly one third of patients presenting with stable coronary syndromes, acute coronary syndromes (not STEMI) and those who underwent primary PCI.¹ Fewer complications were reported after use of the radial route compared to the femoral route, see figure 4.¹ BCIS also reports that there appears to be no significant difference in door-to-balloon (DTB) time between the two routes. The mean DTB time for the 2,511 procedures using femoral artery access was 66.02 minutes, compared to 63.16 minutes for the 976 procedures using the radial artery (p=0.08).

The patient pathway

Symptomatic patients who receive PCI may already be in hospital. More often, they will be admitted from the community, either directly to a PCI centre or having first been admitted to a non-PCI centre and then transferred. Data indicate that the time to PCI is shorter when the patient is admitted directly to a PCI centre. Thus, for NSTEMI/unstable angina and convalescent STEMI, the median door to PCI time is 2.96 days. In contrast, it is 4.2 days in total for patients who follow the latter route: this is composed of 3.2 days for door 1 (non-PCI centre) to door 2 (PCI centre) and 1.0 days for door 2 to PCI.¹ (These figures may be compared with NICE clinical guideline 94, which recommends that coronary angiography [with follow-up PCI if indicated] should be offered within 96 hours of first admission to hospital to patients at intermediate or higher risk of adverse cardiovascular events.)²

Outcomes of PCI

For 2008, BCIS reports there was a 91.8% procedure success rate for all PCIs.¹ Adverse outcomes include death (overall mean in-hospital mortality rate 1.03%), cerebrovascular accident (0.08%) and need for emergency CABG (0.07%).¹

Table 1 shows an analysis of outcomes for 2008 for PCIs performed for NSTEMI, STEMI, primary PCI and rescue PCI.¹ It can be seen that success rates are very high—over 93% for NSTEMI, unstable angina and STEMI in the absence of shock, and over 91% for primary and rescue PCI. The mortality may be risk-stratified by syndrome. The overall in-hospital mortality rate is 1.03% but the mortality is far lower among those with an elective PCI (0.13%), low in those treated by PCI for unstable angina or NSTEMI (0.62%), and higher in those treated with primary or rescue PCI (4.1% and 4.7%, respectively).¹

There are also gender differences in in-hospital mortality: overall mortality is higher among women (1.36% versus 0.95%). The percentage mortality is similar between men and women for those with elective procedures but again is higher in women for those with STEMI (5.44% versus 3.58%).¹ This highlights that the difference in outcome between genders is greater in the higher-risk procedures.

The mortality for primary PCI varies with the number of interventions performed. Figure 5 illustrates the mortality versus volume funnel, showing that while there were no worrying ‘outliers’, and that there is wide variation in reported mortality between centres, there appears to be a trend of lower complications at higher volumes.¹ This has led to calls for PCI to be carried out in higher volume specialist centres.

Primary PCI as routine treatment for STEMI

With the introduction of specialist centres has come national policy to promote primary PCI rather than thrombolysis as a treatment of choice for STEMI.³ 2008 BCIS data show there were either daytime-only or round-the-clock primary PCI in 50 NHS centres and round-the-clock in 28 NHS centres.¹ For patients admitted directly to PCI units, the mean door-to-balloon (DTB) time was 53.8 minutes, with 81.3% of all patients having a DTB time below 90 minutes. For this same group of patients, the mean call-to-balloon time (CTB) was 116.6 minutes, with 78.8% of all patients having a CTB time below 150 minutes.¹

These figures may be compared with international figures.⁴ Data from 5,170 patients with STEMI enrolled in GRACE from 2003 to 2007 were examined. The median elapsed time from first hospital presentation to primary PCI was 86 minutes (interquartile range 53-135 minutes), with no significant changes in delay times to treatment over the years under study. The strongest predictors of prolonged delay time were geographic location and patient transfer.

Crossroads decision: PCI versus CABG in NSTE-ACS

For non-STEMI patients, cardiologists now have to decide on optimum treatment and which pathway to follow.

Guidance for NSTE-ACS was published in March 2010 in the UK by the National Institute for Health and Clinical Excellence (NICE).² The guideline was developed by the National Clinical Guideline Centre of the Royal College of Physicians on behalf of NICE. Part of this guidance considered PCI versus CABG and concluded that current evidence supports the use of both revascularisation strategies – the selection of which procedure to use in an individual patient will depend on factors such as the extent and severity of coronary disease (which presently would require diagnostic coronary angiography), left ventricular function, estimated risk, co-morbidity and patient choice. Multi-disciplinary meetings may be used to help determine this. Comparative cost-effectiveness of the two procedures is uncertain given the lack of outcome data: it will need to take into consideration any survival advantage and the need for repeat procedures (including drug intervention to prevent re-stenosis).

This guidance was based on the results from four randomised trials in which patients with unstable angina or NSTEMI were randomised to PCI or CABG: ERACI-II,⁵ AWESOME,⁶ SoS⁷ and ARTS⁸.

In ERACI-II, 450 patients with NSTE-ACS were randomised: at 30 days, CABG patients had higher rates of death, acute myocardial infarction and major adverse cardiac and cerebrovascular events.⁵ The difference in mortality rates persisted to 33 months but was non-significant at five years. Those who underwent PCI initially had a higher rate of further revascularisation procedures during follow-up. In the AWESOME trial,⁶ there was no difference in survival between the PCI and CABG groups but more from the PCI group required further revascularisation procedures. A subgroup analysis of SoS,⁷ and similarly of ARTS,⁸ showed a non-significant difference in death rates (lower with CABG) after one year, and those in the PCI group had a higher need for repeat revascularisation. All these trials involved only placement of bare-metal stents, which are known to have a higher risk of restenosis than drug-eluting stents. The most significant difference observed in these trials between the two treatment approaches – the difference in need for repeat revascularisation – may therefore over-estimate the advantage of CABG given the increased use of drug-eluting stents.

Caveats to the guidance included the fact that many of the trial data are derived from patients with stable angina; the elderly and those at highest risk may be excluded from trials; and, as surgical techniques and adjunctive therapy have advanced, so the populations of patients considered suitable for either PCI or CABG have changed.

There are still treatment dilemmas. CABG is the obvious choice for a patient with diffuse triple vessel disease or left main stem disease, for example, as shown in the SYNTAX trial.⁹ In this trial, 1,800 patients with three-vessel or left main coronary disease were randomly assigned to undergo CABG or PCI. Rates of death and myocardial infarction at one year were similar between the two treatment groups; the rate of stroke was increased in the CABG group and the rate of repeat revascularisation was increased in the PCI group. Patients with low or intermediate SYNTAX scores had similar rates of major adverse cardiac or cerebrovascular events; among patients with high SYNTAX scores, the event rate was significantly increased in the PCI group. It is challenging to work out the patient group equally suitable for treatment with either PCI or CABG. NICE recommends that research be conducted into the efficacy and cost-effectiveness of CABG versus PCI in the management of patients with NSTE-ACS.

Early invasive versus conservative management strategies

In order to be considered for PCI or CABG, patients with NSTE-ACS need to be referred for diagnostic angiography. Patients who do not stabilise on optimal medical management, including beta blockers, low molecular weight heparin, plus antiplatelet therapy (conventionally, aspirin and clopidogrel) clearly warrant referral. Many patients, however, settle on medical therapy and historically have been successfully discharged home without any PCI – the “conservative” approach to treatment. Yet, there is evidence that even those who do initially become symptom-free on medical therapy might benefit from revascularisation – the “invasive” approach.

The NICE 2010 guideline considered five trials from the coronary stent era that compared early invasive with conservative strategies for management of NSTE-ACS (FRISC II, TACTICS-TIMI 18, VINO, RITA-3 and ICTUS).^10-14 An invasive strategy was found to significantly decrease the composite of death and myocardial infarction at 6-12 months’ follow-up and to reduce the long-term rate of re-hospitalisation. Procedure-related myocardial infarction was significantly increased in the invasive arm. There was no difference in mortality according to whether angiography was performed less than 24 hours or more than 48 hours from randomisation.

Data from FRISC II¹⁰ and RITA-3¹³ suggest that the benefit of an invasive strategy is mostly in higher-risk people. ICTUS¹⁴ suggested that an early invasive strategy did not confer benefit but in this trial the conservative arm had a high rate of early angiography and revascularisation. Appropriate use of GP IIb/IIIa inhibitors reduced in-hospital mortality when added to an invasive strategy (TACTICS-TIMI 18 and ICTUS trial data).^11,14 People randomised to an early invasive strategy had better quality of life scores at six and 12 month follow-up (FRISC II and RITA-3).^10,13

NICE recommendations made are: ²

• patients with a predicted six-month mortality of 3% or less should be managed conservatively, without early coronary angiography, but ischaemia testing should be considered before discharge
• patients who are unstable and those at high ischaemic risk should have an angiogram as
  soon as possible after admission
• those who have an intermediate or higher
  risk of cardiac events (predicted six-month mortality > 3.0%) should be offered angiography/PCI within 96 hours in the
  absence of contra-indications

References

1. BCIS audit returns for the year 2008, presented by Peter F Ludman, BCIS National Audit Lead. Available online as: BCIS%20Audit%202008%20for%20web%2016-10-09%20version%201.pdf

2. NICE. Unstable angina and NSTEMI: the early management of unstable angina and NSTEMI. Clinical guideline CG94. London: NICE, 2010.

3. McLenachan JM, Marley C, Machin S. Heart improvement. A guide to improving primary angioplasty. NHS improvement 2009. www.improvement.nhs/uk/heart/reperfusion

4. Spencer FA, Montalescot G, Fox KAA et al; GRACE Investigators. Delay to reperfusion in patients with acute myocardial infarction presenting to acute care hospitals: an international perspective. Eur Heart J 2010;31:1328–36.

5. Rodriguez AE. Five-year follow-up of the Argentine randomized trial of coronary angioplasty with stenting versus coronary artery bypass surgery in patients with multiple vessel disease (ERACI II). J Am Coll Cardiol 2005;46:582–8.

6. Morrison DA, Sethi G, Sacks J et al. Percutaneous coronary intervention versus coronary artery bypass graft surgery for patients with medically refractory myocardial ischemia and risk factors for adverse outcomes with bypass: a multicenter randomized trial. J Am Coll Cardiol 2001;38:143–9.

7. Zhang Z, Spertus JA, Mahoney EM et al. The impact of acute coronary syndrome on clinical, economic and cardiac-specific health status after coronary artery bypass surgery versus stent-assisted percutaneous coronary intervention: 1-year results from the Stent or Surgery (SoS) trial. Am Heart J 2005;150:175–81.

8. De Feyter PJ, Serruys PW, Unger F et al. Bypass surgery versus stenting for the treatment of multivessel disease in patients with unstable angina compared with stable angina. Circulation 2002;105:2367–72.

9. Serruys PW, Morice M-C, Kappetein P et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961–72.

10. Anon. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomized multicentre study. Lancet 1999;354:708–15.

11. Cannon CP, Weintraub WS, Demopoulos LA et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the GP IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879–97.

12. Spacek R, Widimsky P, Straka Z et al. Value of first-day angiography/angioplasty in evolving non-ST segment elevation MI; an open multicentre randomized trial. The VINO study. Eur Heart J 2002;23:130–8.

13. Fox KA, Poole-Wilson PA, Henderson RA et al. Interventional versus conservative treatment for patients with unstable angina or NSTEMI; the British Heart Foundation RITA 3 randomised trial. Lancet 2002;360:743–51.

14. De Winter R, Windhausen F, Cornel JH et al. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005;353:1095–104.

The first widely used antiplatelet agent, aspirin, continues to be standard therapy in ACS patients. The meta-analysis of the Antithrombotic Trialists’ Collaboration showed a 40% reduction in the rate of vascular events with aspirin.¹

Introduction

The discovery of the thienopyridines, or ADP receptor antagonists, led to the development of more effective oral antiplatelet agents. Trials assessed dual antiplatelet therapy in high-risk patients versus aspirin alone and the significant benefits observed have resulted in dual antiplatelet therapy becoming a mainstay of treatment. As expected with more potent dual therapy, there is always a fine balance between prevention of thrombosis and bleeding risk.

There are still many challenges to overcome. Many patients, such as those with diabetes or with a previous stent thrombosis, are at high risk for further infarction, indicating the need for improvements in existing treatments. Considerable interest has also emerged regarding resistance to existing antiplatelet treatments and recent trials have shed much light on this, particularly the extent to which the variability of the effectiveness of antiplatelet agents is genetically determined. It has also been seen that some high-risk groups may not respond optimally to existing therapies.

Potential new therapeutic options are addressed in this section, including the recent introduction of prasugrel, a thienopyridine with different characteristics to clopidogrel.

Drug treatment of ACS – updated recommendations

Many international guidelines for ACS predate advances in antiplatelet treatment. The European Society of Cardiology (ESC) together with the European Association of Cardio-Thoracic Surgery (EACTS) has recently published new guidance on myocardial revascularisation.² In the UK, NICE³ has recently updated its guidance on the early management of unstable angina and NSTEMI, which replaced previous guidance including the technology appraisal for clopidogrel. The thienopyridine prasugrel was also the subject of a NICE technology appraisal⁴ and was not considered further for the 2010 NICE guidance on unstable angina/NSTEMI.

Recommendations made for clopidogrel covered dosage and timing of administration. The two approaches to timing are to start treatment early (upstream) or to wait until coronary anatomy has been defined by catheterisation. The former approach has the potential to reduce early ischaemic events but also the potential for increased bleeding in patients who go on to early CABG. Also considered were the benefits of different loading doses of clopidogrel, 300 mg and 600 mg (NICE notes the higher dose is not currently licensed in the UK),³ and the benefits of clopidogrel with and without GP IIb/IIIa inhibitors on a background of aspirin therapy.

The NICE guideline recommends that once the risk of adverse cardiovascular events has been assessed, a loading dose of clopidogrel
300 mg plus aspirin should be offered to patients with a predicted six-month mortality risk >1.5% and no contra-indications.³

For particular groups of patients, NICE recommends the use of prasugrel with aspirin for patients who have diabetes or who have had a stent thrombosis on clopidogrel treatment (in addition to STEMI patients undergoing primary PCI).⁴

The ESC/EACTS guidelines² recommend that (excluding patients with higher bleeding risk), prasugrel offers significant benefit over clopidogrel; that it confers a significant advantage in diabetic patients presenting with ACS; and that it should be used in patients who present with stent thrombosis while taking clopidogrel.²

In patients going on to CABG, discontinuation of clopidogrel may be considered five days before surgery if the risk of adverse events is considered low. For patients at intermediate or higher risk, it will be necessary to balance the individual risks of ischaemia and bleeding.

Length of antiplatelet therapy

NICE recommends that clopidogrel plus aspirin be continued for 12 months after the most recent episode of NSTE-ACS.³ Clinical review is advised before discontinuation of treatment: there are concerns that management facilitated by automated software programmes carry the danger of discontinuation without review. Some patients, such as those who have had a drug-eluting stent as part of complex PCI or those who have had late stent thrombosis, may be advised to remain indefinitely on dual antiplatelet treatment.

The ESC/EACTS guidelines concur that dual antiplatelet therapy should be given to all patients after ACS for one year, irrespective of revascularisation strategy. Certain patient populations, such as those at high risk of thromboembolic events, may benefit from more prolonged dual antiplatelet therapy.²

Premature discontinuation of dual antiplatelet therapy greatly increases the risk of stent thrombosis, MI and death:⁵ this American Science Advisory stresses the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent.

Concomitant therapy

Concomitant therapies, such as glycoprotein (GP) IIb/IIIa inhibitors, can be given alongside single or dual antiplatelet therapy. Some give a drug from this class routinely when the ACS patient arrives in hospital on the grounds that a treatment benefit exists whether or not the patient goes on to PCI. Other doctors discount clinical benefit upstream of PCI and wait for angiography results before considering their use.

The Boersma (2002) meta-analysis of six trials (PRISM, PRISM-PLUS, PARAGON-A, PARAGON-B, PURSUIT and GUSTO-IV ACS) compared GP IIb/IIIa inhibitors with placebo or control in NSTE-ACS patients not routinely scheduled for early revascularisation.⁶ The active treatment group had a significantly decreased chance of death or myocardial infarction (MI) at 30 days but also a significantly increased chance of major bleeding at 30 days. Another meta-analysis of the same six trials⁷ suggested that the benefit depended on the revascularisation strategy. The greatest benefit among patients not routinely scheduled for early revascularisation was seen in patients who underwent PCI during GPIIb/IIIa inhibitor infusion; the benefit was less marked in those who underwent PCI after drug discontinuation.

An analysis of the ACUITY TIMING and EARLY ACS trials published in the NICE 2010 guideline³ states that, compared with deferred use, upstream use significantly decreases the risk of MI and unplanned revascularisation at 30 days but at the expense of increased TIMI major and minor bleeding. In the ISAR-COOL trial,⁸ prolonged anti-thrombotic treatment (3–5 days) was compared with early intervention (<6 hours) in NSTE-ACS patients undergoing cardiac catheterisation. Those randomised to prolonged anti-thrombotic treatment had a significantly increased risk of death or non-fatal MI at 30 days.

Use of the GPIIb/IIIa inhibitors has decreased in the UK as clopidogrel has become more widely used.³ NICE felt that the evidence is less convincing for routine use of the former class of drugs in the medical management of patients with NSTE-ACS, especially with the increased use of early angiography and revascularisation. There maybe a place for IV eptifibatide or tirofiban as part of early management of patients at intermediate or higher risk of adverse cardiovascular events who are scheduled for angiography within 96 hours of hospital admission (this is a recommendation for off-label use).

Triple therapy with clopidogrel, GP IIb/IIIa inhibitors and aspirin is another area of interest although not licensed in the UK.

Maximising the consistency of antiplatelet response

Inter-individual variability of platelet inhibition with clopidogrel leads to a potential risk for recurrent atherothrombotic events.⁹ Other agents, such as the thienopyridine, prasugrel, appear to give a more consistent antiplatelet response.

In a review, Campo¹⁰ states that about 20% of patients who receive clopidogrel are either non-responders or poor responders. These patients have an increased risk of death, reinfarction and stent thrombosis.¹⁰ Poor/non-responsiveness is poorly defined and the literature reports variation between 5 and 56%.¹¹ The mechanisms leading to poor responsiveness may include genetic factors (see below), accelerated platelet turnover, high baseline platelet reactivity, under-dosing and poor compliance. Switching to a different thienopyridine, re-evaluation of existing therapies and improved patient education are all potentially useful strategies in maximising the antiplatelet response.

Pharmacokinetics and response variability in antiplatelet agents

A two-way cross-over study¹² found that prasugrel 60 mg results in more rapid, potent and consistent inhibition of platelet function than clopidogrel 300 mg in healthy individuals (see figure 1). In all, 68 healthy volunteers received one of the two thienopyridines orally for the initial dosing period and then crossed over to the other agent after a two-week washout period. Prasugrel 60 mg was associated with significant inhibition of platelet aggregation (IPA) in response to ADP as early as 15 minutes after treatment compared to baseline (p=0.0014); the level of IPA was significantly higher with prasugrel throughout the 24 hours after drug administration; the peak IPA was nearly twice as high with prasugrel; and there was a more consistent response between subjects in the magnitude of IPA received. The authors conclude that pharmacokinetic differences may account for the different effects of the two drugs, and that the rapid and consistent response may be of value both during urgent intervention and during long-term maintenance therapy.

Greater exposure to prasugrel’s active metabolite may result in a more favourable risk:benefit ratio. A study by Payne,⁹ in healthy volunteers, compared the level of platelet inhibition and the degree of response variability achieved by prasugrel (60 mg loading dose and 10 mg maintenance dose) against those achieved by clopidogrel (300 mg and 75 mg). At 30 minutes after the loading dose, prasugrel achieved greater mean inhibition of platelet aggregation (IPA) to 20 mM ADP than clopidogrel. During the maintenance phase, the mean IPA to 20 mM ADP exceeded 75% with prasugrel and was higher than that achieved with clopidogrel. The IPA was also less variable with prasugrel.

In this study, 39% of subjects could be classified as poor responders (IPA <20% at four hours or <25% at 24 hours) to clopidogrel 300 mg but all subjects responded to the loading dose of prasugrel. During the maintenance phase, all subjects taking prasugrel could be classified as responders whereas 9% were poor responders to clopidogrel. The active metabolites of prasugrel and clopidogrel are equally potent but, in vivo, a proportion of clopidogrel is hydrolysed in the intestine and/or liver to an inactive metabolite and then converted to its active metabolite by CYP enzymes. These steps limit both the rate and extent
of active metabolite formation in comparison to prasugrel.

The JUMBO-TIMI 26 trial¹³ was a dose-ranging study designed to assess the safety of prasugrel and clopidogrel when given at the time of PCI, in particular to establish whether the more powerful and consistent effects of prasugrel resulted in an unacceptable risk of bleeding. The study randomised 905 patients who were candidates for elective or urgent PCI. Subjects were randomised to three different loading and maintenance doses of prasugrel or to clopidogrel, with randomisation stratified by the investigators’ decision to use a GP IIb/IIIa inhibitor during PCI. All subjects received aspirin and UFH, and were monitored for 30 days. The primary end point was TIMI major plus minor non-CABG-related bleeding in the treatment groups. Bleeding rates were low: 0.7% experienced major bleeding, 1.1% minor bleeding and 2.4% minimal bleeding, with two thirds of episodes related to instrumentation. There was no significant difference between patients treated with prasugrel and those treated with clopidogrel (1.7% versus 1.2%, hazard ratio 1.42). In prasugrel-treated patients, there were numerically lower incidences of the primary efficacy composite end point (30-day major adverse cardiac events) and of the secondary end points MI, recurrent ischaemia and clinical target vessel thrombosis. The results of this trial were the foundation of the large phase III trial of prasugrel, TRITON-TIMI 38.¹⁴

Essentials of TRITON-TIMI 38

The Trial to assess Improvement in Therapeutic Outcomes by Optimising Platelet Inhibition with Prasugrel vs. Thrombolysis In Myocardial Infarction (TRITON-TIMI 38)¹⁴ was a landmark phase III trial assessing prasugrel and clopidogrel. It involved patients with ACS and scheduled PCI, and suggested that faster, greater and more consistent platelet inhibition is associated with reduced rates of ischaemic events.

The trial enrolled 13,608 patients, three quarters with moderate-to-high risk unstable angina or NSTEMI and one quarter with STEMI. Patients received a loading dose of 60 mg prasugrel or 300 mg clopidogrel, and maintenance doses of prasugrel 10 mg or clopidogrel 75 mg daily. All patients also received aspirin, and the median duration of therapy was 14.5 months. Ninety-four percent of patients received at least one intracoronary stent, and 14% of patients had multi-vessel PCI. The primary efficacy end point was a composite of rate of death from cardiovascular causes, non-fatal MI or non-fatal stroke during the follow-up period. Key safety end points were TIMI major bleeding or TIMI life-threatening bleeding not related to CABG, and TIMI major or minor bleeding.

Prasugrel demonstrated a 2.2% absolute reduction and a significant 19% relative risk reduction in the primary efficacy end point compared to clopidogrel (12.1% of clopidogrel patients vs. 9.9% of patients receiving prasugrel) (see figure 2). Rates of ischaemic events were also reduced in the prasugrel group, with a 2.3% absolute reduction and a 24% relative reduction in MI. A significant reduction in the primary end point was seen by the first pre-specified time point, three days (5.6% clopidogrel group vs. 4.7% prasugrel group, p=0.01), which persisted throughout the follow-up period. This difference was driven largely by the greater reduction in MI in the prasugrel group (9.7% in the clopidogrel group vs. 7.4% in the prasugrel group, HR 0.76, p<0.001) throughout the study. Subgroup analysis showed the need for urgent target vessel revascularisation was also reduced by 34% in the prasugrel group (3.7% vs. 2.5%, p<0.001), while stent thrombosis was reduced by 51% (2.4% vs. 1.1%, p<0.001).

All patients received aspirin. Bleeding rates were higher in patients treated with prasugrel than in patients treated with clopidogrel. Major bleeding occurred in 2.4% and 1.8%, respectively (HR 1.32, p=0.03); the rate of life-threatening bleeding was also greater with prasugrel (1.4% vs. 0.9%, p=0.01).

A pre-specified analysis of the trial which examined net clinical benefit, i.e. rates of death from any cause, non-fatal MI, non-fatal stroke and TIMI major haemorrhage showed that the net benefit significantly favoured prasugrel. However, three patient groups were identified who did not have a net clinical benefit with prasugrel treatment. Patients with a previous stroke or transient ischaemic attack had net harm from prasugrel; patients aged 75 years and above had no net benefit; and patients weighing less than 60kg had no net benefit. Patients with at least one of these three risk factors had higher rates of bleeding than those without them. The risks of intensive bleeding appear to be enhanced in these patients, and additional caution is required in their management. The summary of product characteristics should be consulted for further information.

Antiplatelet treatment and stent thrombosis

Findings from the sub-analysis of TRITON-TIMI 38 show that of 13,608 patients randomised into TRITON-TIMI 38, a total of 12,844 received a stent: 6,461 received a bare-metal stent and 5,743 had a drug-eluting stent.¹⁵ Overall, a 19% reduction in the primary end point was recorded with prasugrel compared with clopidogrel among patients who had a stent (9.7% vs. 11.9%, p=0.0001). The net clinical benefit significantly favoured prasugrel treatment (12.0% vs. 13.7%, p=0.002). There was a 51% reduction in stent thrombosis with prasugrel between day 0 and day 3; definite or probable stent thrombosis (ARC designations) were reduced by 59% within 30 days of stent placement. The analysis confirmed the adverse relationship between stent thrombosis and clinical outcomes, with 22% of such patients dying and 89% experiencing a non-fatal MI or dying. Figure 3 shows the relative risk reduction for early and late stent thrombosis in the TRITON-TIMI 38 study.

ACS in the patient with diabetes

Cardiovascular mortality risk increases continuously with blood glucose levels: elevated blood glucose, diabetes or both contribute to three million cardiovascular deaths globally a year.¹⁶ In the United States, nearly two thirds of individuals with diabetes die from cardiovascular disease.¹⁷ Diabetes confers an adverse prognosis in ACS.

The recently reported Euro Heart Survey¹⁸ on diabetes and the heart showed that abnormal glucose regulation was more common than normal glucose regulation in patients with coronary artery disease (CAD). In the study of 4,196 patients, 31% had diabetes. Looking at the subgroup of those with acute CAD without known diabetes, 36% had impaired glucose regulation and 22% newly detected diabetes. In the stable group, these proportions were 37% and 14%, respectively.

In the Donahoe study,¹⁷ patients with ACS were pooled from 11 TIMI studies from 1997 to 2006, giving a cohort of 62,036 patients. Of these patients, a total of 46,577 had STEMI, 15,459 NSTEMI and 10,613 (17.1%) had diabetes. Coronary angiography data were available for 25.1% of patients. Among this subset, patients with diabetes were more likely to have multi-vessel coronary disease (62.0% vs. 48.1%, p<0.001). At 30 days, mortality was significantly higher among patients with diabetes compared to those without diabetes following either unstable angina/NSTEMI (2.1% vs. 1.1%; p<0.001) or STEMI (8.5% vs. 5.4%; p<0.001). At one year, diabetes remained a significant independent factor associated with all-cause mortality for patients presenting with unstable angina/NSTEMI (HR 1.65) and for patients presenting with STEMI (HR 1.22). By one year, the mortality of patients with diabetes presenting with unstable angina/NSTEMI approached that of patients without diabetes but with STEMI.

Platelet aggregation and activation are increased in subjects with diabetes compared to those without:¹⁹ in this study, there were also higher numbers of clopidogrel non-responders among patients with diabetes. This suggests that decreased sensitivity to antiplatelet drugs may contribute to the increased antithrombotic risk observed in diabetes. A further study by Angiolillo²⁰ confirmed that patients with type 2 diabetes have higher platelet reactivity compared to those without, and found that high platelet reactivity was associated with atherothrombotic complications even in patients taking dual antiplatelet therapy. It was the strongest predictor of major adverse cardiac events over two-year follow-up, with a three-fold increase in event rates. The authors suggest that there is a need for tailored anti-thrombotic regimens in these high-risk patients. This is considered in more detail later.

Antiplatelet treatment for diabetes patients

A pre-specified subgroup analysis of TRITON-TIMI 38 with patients stratified by diabetes status showed that subjects with diabetes tended to have a greater net treatment benefit, with prasugrel compared to clopidogrel (figure 4).²¹ There was a greater reduction in ischaemic events without an observed increased in TIMI major bleeding. Of the 13,608 patients randomised into TRITON-TIMI 38, a total of 3,146 (23%) had diabetes and 776 (6%) were on insulin treatment. There were some differences between patients with diabetes and those without: those with diabetes were more likely to have unstable angina or NSTEMI, to be older, to be female, and to have a higher median body mass index (BMI). They were also more likely to have had a previous MI or CABG. Patients with diabetes were also more likely to have multivessel intervention and at least one drug-eluting stent.

Rates of thrombotic events such as MI, cerebrovascular accident and stent thrombosis were higher among patients with diabetes than among those without diabetes. After controlling for baseline demographic and treatment differences, diabetes was an independent predictor of ischaemic outcomes, including the primary end point of the trial (cardiovascular death/non-fatal MI/non-fatal stroke), MI, stent thrombosis and net clinical benefit. Prasugrel was more effective than clopidogrel in reducing events among patients with diabetes. A 14% reduction in the primary efficacy end point was seen with prasugrel treatment among patients without diabetes (p=0.02), while among those with diabetes, the primary end point was reduced by 30% (p<0.001). The NNT to prevent one primary end point event among subjects with diabetes was 21.

The reduction in the primary end point was largely driven by a lower incidence of MI (an 18% reduction in subjects without diabetes compared to a 40% reduction in subjects with diabetes). Interestingly, in this study subjects with diabetes had similar non-CABG-related TIMI major bleeding rates regardless of treatment with prasugrel or clopidogrel (2.5% and 2.6%, respectively, at 15 months). The greater effect of prasugrel compared to clopidogrel in this analysis supports the theory that greater platelet inhibition results in better outcomes among patients with diabetes. Prasugrel was more effective than clopidogrel both in patients who were taking and those who were not taking a GP IIb/IIIa inhibitor.

Results of this trial led to the licensing of prasugrel in the UK and and the NICE technology appraisal of prasugrel,⁴ which said that that it was appropriate to consider prasugrel for treatment of people with diabetes having PCI, since diabetes mellitus represents an important and definable risk factor for more severe cardiovascular disease and greater risk of cardiovascular events during and after PCI. It concluded that use of prasugrel for patients with diabetes undergoing PCI could be considered a cost-effective use of NHS resources and should be recommended as an option.

More recent findings on platelet reactivity

The platelet substudy of TRITON-TIMI 38 shows that prasugrel results in greater inhibition of ADP-mediated platelet function than clopidogrel in patients with ACS.²² In this substudy, 125 patients were prospectively enrolled to evaluate ADP-attenuated phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) and 31 patients to evaluate ADP-stimulated platelet aggregation. VASP platelet reactivity index was lower in patients treated with prasugrel than in patients treated with clopidogrel both one to two hours after PCI and at 30 days. Maximal platelet aggregation was lower in patients treated with prasugrel than in patients treated with clopidogrel both hours after PCI and at 30 days (p<0.001). Similarly, thienopyridine hyporesponsiveness was more frequent in patients treated with clopidogrel than patients treated with prasugrel at the shorter and longer measurement times. These findings would tie in with the observations of fewer ischaemic events and more bleeding early and late following PCI in patients treated with prasugrel.

Fast inhibition of platelet aggregation is important within the setting of ACS and PCI: interestingly, it appears that slow response to clopidogrel within the first hour is a reliable marker of low response at 24 hours and high post-treatment platelet reactivity.²³ This study was a post-hoc analysis of the ALBION²⁴ study: kinetic profiles of maximal platelet aggregation (MPA) and change in MPA were studied at eight time points after clopidogrel loading in patients with NSTE-ACS. Inflammatory markers (PAC-1 and P-selectin) and VASP were also measured.

Fifty-five percent of patients were slow responders. Non-current smoking and body mass index 25kg/m² or above were associated with lower and slower responses. High post-treatment platelet reactivity was more frequent in slow responders, and there was a dose-response relationship of clopidogrel on change in MPA. Slow responders also had a slower and lower decrease in inflammatory markers and a higher VASP index at six hours.

A maintenance dose (MD) of prasugrel 10 mg has recently been shown, in ACS patients, to result in significantly greater platelet inhibition than clopidogrel given at a higher than usual maintenance dose and after a 900 mg loading dose (LD)²⁵ (300 mg is the licensed LD in the UK for ACS-PCI). Patients with NSTE-ACS (n=56), treated with aspirin and clopidogrel 900 mg LD, were randomised to receive a maintenance dose of either prasugrel 10 mg or clopidogrel 150 mg. After 14 days, subjects were switched to the comparator drug for a further 14 days. Prasugrel reduced maximum platelet aggregation (MPA) from the LD level (41.2% to 29.1%, p=0.003). Poor response was 0-6% for the prasugrel MD and 4-34% for the clopidogrel MD, indicating a more complete and consistent response with prasugrel.

Platelet function tests can now help the physician to identify within minutes those who are likely to be clopidogrel non-responders.

Pharmacogenetics of clopidogrel

There is some evidence that the antiplatelet effects of clopidogrel are determined by genetic factors, and that this may have a bearing on cardiovascular events.²⁶ Clopidogrel is transformed into its active metabolite by cytochrome P-450 (CYP) enzymes; the genes encoding CYP enzymes are polymorphic.

Mega and colleagues²⁶ compared carriers and non-carriers of a reduced-function CYP2C19 allele among 16 healthy subjects and among 1,477 subjects with acute coronary syndromes within TRITON-TIMI 38. Among the healthy subjects, carriers of at least one reduced-function allele had reduced plasma exposure to the active metabolite of clopidogrel and an absolute reduction in maximal platelet aggregation in response to clopidogrel (both p<0.001). Among TRITON-TIMI 38 subjects, carriers of this allele had a relative increase of 53% in the composite primary efficacy outcome (12.1% vs. 8.0%, p=0.01) and treble the risk of stent thrombosis (2.6% vs. 0.8%, p=0.02).

Simon and colleagues enrolled 2,208 patients presenting with an acute myocardial infarction to a nationwide French registry;²⁷ these patients received clopidogrel and were followed up for one year. The relationship of genetic polymorphisms affecting clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19) and biological activity (P2RY12 and ITGB3) to risk of all-cause death, non-fatal stroke and myocardial infarction was examined.

The single nucleotide polymorphisms (SNPs) CYP3A5, P2RY12 and ITGB3 were not associated with risk of adverse outcome. However, patients with two variant alleles of ABCB1 had a higher rate of cardiovascular events at one year than those with the wild-type genotype (15.5% vs. 10.7%). Patients carrying any two CYP2C19 loss-of-function alleles had a higher event rate compared to those with none (21.1% versus 13.3%). The rate of cardiovascular events was 3.58 times higher among the 1,535 patients with two loss-of-function alleles who underwent PCI during hospitalisation.

Carriers of the loss-of-function mutant allele of CYP2C19 also have higher risk of stent thrombosis compared with wild-type allele carriers after PCI. Sibbing and colleagues²⁸ followed for 30 days 2,485 consecutive patients undergoing coronary stent placement after pre-treatment with clopidogrel 600mg (an off-licence dose). The incidence of stent thrombosis was 3.8 times higher in loss-of-function allele carriers (1.5% versus 0.4%, p=0.007). The risk was highest (2.1%) among patients homozygous for the loss-of-function allele.

High on-treatment platelet reactivity (HTPR) after a clopidogrel loading dose predicts the risk of thrombotic events after PCI.²⁹ In a prospective study of patients undergoing PCI, body mass index (p=0.01), diabetes (p=0.03) and acute coronary syndrome (p=0.02) were clinical predictors of HTPR, and the mutant *2 allele CYP2C19 polymorphism was also significantly associated. In most cases, dose adjustment with platelet reactivity monitoring improves the HTPR: BMI was the only predictor of failed dose adjustment in this study.

Genetic testing to identify carriers of this allele can now be done at the bedside before the patient is taken to the catheter lab.

Conclusion

Looking ahead, while other products are under investigation and until such time as they are licensed, reviewed by NICE and widely adopted, physicians should optimise therapy with the currently available options.

It is clear that there is no single treatment for all patients in ACS. Physicians must choose the right evidence-based treatment for patients on an individual basis. With the increasing evidence base in this area, we are now on the brink of entering a new era of personalised treatment for this common disease.

References

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