Foreword
Advances in the management of patients with acute coronary syndromes (ACS) have evolved dramatically over the past decade and, in many respects, represent a rapidly moving target for the cardiologist or internist who seeks to integrate these recent developments into contemporary clinical practice. Much attention has been directed towards optimizing the diagnosis and management of such patients, particularly in light of the continued evolution of catheter-based interventions and newer pharmacological strategies that afford more complete platelet and thrombin inhibition. Most of the progress in this field stems from the active interaction between basic science and clinical observations generating new hypotheses and research. This supplement, containing the proceedings of a meeting held in Cortona, Italy, in April 2005, stems from the same philosophy: a more efficacious treatment for acute ischaemic syndromes should be targeted at the pathogenetic mechanisms of disease. From this perspective, a group of experts in specific fields came together in Cortona with the goal of sharing knowledge within a discussion format. The impetus of the workshop was the realization that we are entering a new era of therapeutic interventions in ACS. There was no ambition of completeness, exhaustivity, or even balance in choosing topics to discuss. Rather, special attention was devoted to the most elusive or controversial issues of ACS and the most innovative therapeutic approaches. Obviously, many issues remain unsolved. The efforts of participants, both old and new friends who joined us in this venture, provide a snapshot in time that will require continual updating.
The first session, chaired by Diego Ardissino and Bolognese, was devoted to non-ST-elevation (NSTE) ACS. In this subset of patients, Hamm ties recent findings to the new European Society of Cardiology (ESC) guidelines on the use of percutaneous coronary interventions (PCIs), which supplement previous ESC guidelines on ACS with and without ST-elevation. These new guidelines address ACS from the particular view of the interventional cardiologist, providing clarity on the best approach to treatment and the critical importance of risk stratification.
Claudio Cavallini provides a systematic overview of the key role of glycoprotein (GP) receptor IIb/IIIa inhibitors in NSTE-ACS patients. The prime importance of these agents, especially in high-risk patients, is universally agreed on, but the proper timing and the selection of drugs remain in dispute. The best available data indicate a significant benefit of early, upstream use of small-molecule GP IIb/IIIa inhibitors in high-risk patients. Although the current practice in several settings is to use upstream small-molecule GP IIb/IIIa inhibition, a large outcome trial of upstream use compared with targeted use at the time of PCI will be necessary to eliminate debate about this issue. Another lingering unsolved issue concerns which agent should be used and the most appropriate dosage. Patients with ACS may have decreased response to antiplatelet agents, and tirofiban [at the dosage used in TARGET (Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial)] may be less effective in a PCI setting than abciximab within 60 min of administration. Recently, a new dose regimen has been proposed for tirofiban using a bolus of 25 µg/kg (followed by a maintenance infusion of 0.15 µg/kg per minute), which achieves inhibition of platelet aggregation >85% for 60 min.
Bolognese then discusses the prognostic significance and pathophysiological mechanisms underlying post-PCI cardiac enzyme elevations in patients with NSTE-ACS. The few available data suggest that patients with NSTE-ACS who undergo PCI have an increased risk for procedural myocardial damage which, in turn, is associated with an adverse clinical outcome. Although the pathophysiology of post-PCI myocardial damage is multifactorial, embolization of debris or calcified plaque material or exposure of thrombogenic material at intravascular sites seems to play a key role as shown by mechanistic studies that demonstrate a close relationship between post-procedural enzyme release and abnormal tissue perfusion. Finally, Bolognese reviews the available strategies that use antithrombotic therapies aimed at mitigating post-procedural myocardial damage in this setting and discusses also the recently completed EVEREST (Randomized Comparison of Upstream Tirofiban Versus Downstream High Bolus Dose Tirofiban or Abciximab on Tissue-Level Perfusion and Troponin Release in High-risk Acute Coronary Syndromes Treated With Percutaneous Coronary Interventions) trial. This trial compared the effects of upstream tirofiban vs. downstream (in the catheterization laboratory) high-dose bolus tirofiban or abciximab on epicardial and tissue-level perfusion and troponin I release in high-risk NSTE-ACS patients treated with PCI.
Which approach, an interventional, anatomically driven one or a functional, biologically driven one, is preferable for managing ‘vulnerable’ patients (e.g. those with diabetes and the elderly) with NSTE-ACS? Roffi and Liistro address this elusive and controversial issue, which carries important social and health-care implications, in a lucid discussion integrating both evidence-based and real-world perspectives. Dr Roffi points out that diabetic patients with NSTE-ACS are at high risk for subsequent cardiovascular events. At the same time, however, they derive greater benefit than their non-diabetic counterparts from an aggressive acute-phase management based on platelet GP IIb/IIIa receptor antagonists and an early invasive strategy. Despite this, these treatments remain underutilized in this patient population. In his report, Dr Liistro summarizes the key findings of more recent studies in elderly patients with NSTE-ACS, emphasizing how the elderly are significantly under-represented in large randomized trials and frequently undertreated in the real world. Given that people aged >80 have become the fastest growing segment of the population in developed countries, the issues raised by Dr Liistro will become increasingly important. Data from single centre experiences and retrospective analyses of major randomized trials suggest that an early invasive strategy, although underused in elderly NSTE-ACS patients, is feasible, leads to coronary revascularization in the majority of patients, and appears clinically more beneficial than a conservative approach. However, a final decision concerning the best strategy to apply in this subset of patients has yet to be reached, leaving physicians who face this problem on a daily basis with a degree of uncertainty. Dedicated randomized trials are called for in order to provide more definitive data on this emerging clinical issue.
The second session, chaired by Amadeo Betriu and Mario Marzilli, covered new treatment modalities and care strategies for patients presenting with ST-segment elevation myocardial infarction (STEMI). Danzi points out that PCI is now preferred over fibrinolytic therapy, provided the procedure can be carried out promptly by a competent team. However, it has been clear for some time that most patients do not achieve TIMI (thrombolysis in MI) grade 3 flow after an emergency PCI, and the successful reopening of an occluded coronary artery does not necessarily lead to recovery of left ventricular function. Dr Danzi then focuses on promising techniques that are able to measure and quantify both epicardial and microvascular perfusion and on the available therapeutic tools targeted at restoring optimal tissue perfusion, which may be implemented during and shortly after primary PCI. Questions remain about the best adjunctive pharmacological therapy to primary PCI. Dr Danzi makes the case that the new dose regimen of tirofiban may be as effective as abciximab in patients with STEMI who undergo mechanical reperfusion, with better results in terms of bleeding complications. Danzi also touches on the clinical-trial forays into improved interventional approaches, concluding that data from rigorously performed randomized trials are needed before it is possible to suggest that new thrombectomy or distal protection devices and other catheter-based therapeutic approaches will ultimately be considered the standard of care and be used in virtually all patients undergoing an intervention for an acute myocardial infarction (MI).
Given the superiority of primary PCI, the question of whether societies can muster the resources and discipline to develop an organized approach to reperfusion similar to the national trauma systems remains a ‘hot topic’, and the focus of multiple ongoing health technology assessments, especially in the current drug-eluting stent (DES) era. Marco Valgimigli provides an intriguing personal perspective on strategies to implement the liberal use of DES, especially in the primary PCI setting, where the cost-effectiveness profile could be less favourable, without affecting medical expenditure. His analysis is reinforced by the results of the very recent STRATEGY (High-Dose Bolus Tirofiban and Sirolimus Eluting Stent Versus Abciximab and Bare Metal Stent in Acute Myocardial Infarction) trial, which suggest the possibility that, by combining less expensive, but not necessarily less effective, adjunctive antithrombotic therapies with the use of DES, the economic impact of the revascularization strategy could be reduced by absorbing the additional costs of these expensive devices.
Another ‘hot topic’ is the notion of centralization of care and the transfer of the acute MI patient. In addition, a key question needs to be addressed: what are the most appropriate systems for acute MI care regarding transfer and the centralization or regionalization of heart attack centres? van't Hof provides original data on the effect of improving logistics by early infarct diagnosis in the ambulance and subsequent transportation to a PCI centre without visiting a nearby non-PCI clinic in patients included in the On-TIME (Ongoing Tirofiban In Myocardial Infarction Evaluation) study. van't Hof concludes that, for patients who are candidates for primary PCI, pre-hospital infarct diagnosis and triage are associated with shorter time to treatment, a higher initial patency, and better angiographic and clinical outcomes after PCI compared with triage and referral from a non-PCI centre. All efforts should be made, therefore, to implement pre-hospital infarct diagnosis, triage, and therapy in the care of patients with an acute MI.
In summary, we hope that this supplement will provide clinicians with a relevant and timely review of some of the more elusive and controversial aspects of a common syndrome that we face in everyday clinical practice and, at the same time, provide a valuable resource to facilitate and optimize both the management and, more importantly, the clinical outcomes of all patients with ACS.
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