European Heart Journal Supplements - recent issues

Preface

2008-10-31

Antiplatelet strategies in patients undergoing interventions with acute coronary syndrome: introduction

Neumann, J.-F. — 2008-10-31

The evolving science of atherothrombotic disease

Gawaz, M. — 2008-10-31

Atherosclerosis is a systemic inflammatory disease characterized by the accumulation of inflammatory cells in the intima of large arteries. The presence of platelets at the site of inflammation and endothelial injury has been known since the early 1960s. In the following years, it was generally accepted that rupture or erosion of advanced atherosclerotic lesions initiates platelet activation and aggregation on the thrombogenic surface of a disrupted atherosclerotic plaque. Thrombotic vascular occlusion is associated with ischaemic episodes in the retina, brain, heart, and other organs. While it is widely accepted that platelets play a significant role in thromboembolic events generated by atherosclerotic lesions (atherothrombosis), their involvement in the initiation of the atherosclerotic process has not been widely recognized by the scientific community. An expanding body of evidence on the role of platelets in the development of atherosclerotic lesions continues to build. Platelets bind to leukocytes and endothelial cells, and initiate the transformation of monocytes into macrophages. Additionally, platelets internalize oxidized phospholipids and promote foam cell formation, as well as recruit progenitor cells that are able to differentiate into foam or endothelial cells. In total, platelets play a key role in the initiation, development, and total extent of atherosclerotic lesions.

Long-term treatment strategies for atherothrombotic disease: do platelets define the course?

Zimarino, M., De Caterina, R. — 2008-10-31

Atherosclerosis is a slowly progressive disease of the arteries that may undergo a sudden transition to life-threatening conditions following thrombus formation at sites of plaque disruption (atherothrombosis). Platelets play a key role in such late events. This review discusses the evidence supporting the use of oral antiplatelet agents in the long-term prevention of atherothrombotic events.

In ST-elevation acute myocardial infarction and in non-ST elevation acute coronary syndromes, dual antiplatelet therapy with aspirin and clopidogrel has been proved effective in reducing death and myocardial infarction, and prolonged treatment at least up to 1 year is associated with sustained benefit. In some high-risk patients, especially in the setting of urgent percutaneous coronary interventions, adjunctive glycoprotein IIb–IIIa inhibitors confer additional benefit. In chronic coronary artery, cerebrovascular and peripheral arterial disease aspirin reduces the risk of cardiovascular events in both men and women; the adjunctive benefit of clopidogrel is questionable here. In primary prevention, the administration of aspirin is recommended only among patients at high risk.

European perspective on the use of antiplatelet agents in atherothrombotic disease

Sanz-Ruiz, R., Fernandez-Aviles, F. — 2008-10-31

Platelets are components of normal haemostasis, but under certain circumstances, they contribute to coronary occlusion and myocardial ischaemia. Several drugs have been investigated for decades to modulate platelet adhesion and aggregation in coronary artery disease. Although these drugs improve the symptoms and prognosis of millions of patients by reducing arterial thrombosis, they pose a variable risk of haemorrhagic complications. The European Society of Cardiology has published several recommendations on antiplatelet therapy that will be reviewed in this article, together with data from the real-world daily use of these drugs.

Benefits and risks with antiplatelet therapy: how great a problem is bleeding?

Husted, S. — 2008-10-31

Significant advances in treatment strategies for patients with acute coronary syndromes (ACS) have been made over the past 10 years, including the introduction of new antiplatelet therapies. Additionally, modifications have been made in the dosing of these agents, the duration of treatment has been increased, and they are used in dual- and triple-therapeutic regimens. On the basis of a number of large-scale clinical trials, the current guidelines recommend the use of aspirin in combination with clopidogrel as a first-line therapy in patients with ACS. While data show significantly reduced ischaemic events with combination antithrombotic therapy, this is often associated with an increase in major bleeding episodes. Because of these risks, it is important that treatment with antithrombotics follow appropriate guidelines with a risk/benefit ratio calculated for each patient. Additionally, agents with the lowest bleeding risk should be used first. This article reviews the benefits and risks of antiplatelet therapy with emphasis on the potential for serious bleeding episodes.

Duration of antiplatelet therapy following intracoronary stenting: are changes needed?

Byrne, R. A., Kastrati, A. — 2008-10-31

This review addresses the question of whether established guidelines for the duration of dual-antiplatelet therapy (DAT) following intracoronary stenting need to be updated. Current recommendations for the optimal duration of DAT following percutaneous coronary intervention are limited by an inadequate evidence base. While the Percutaneous Coronary Intervention–Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO) studies showed reductions in ischaemic events with prolongation of DAT out to 9–12 months, both the main CURE and CREDO studies showed an excess of major bleeding and are limited in generalizability by study design characteristics. Concerns regarding the rates of delayed acute stent thrombosis following drug-eluting stent (DES) implantation are integral to any debate on the optimal duration of DAT. The most reasonable conclusion from a number of divergent reports is that the evidence for an increased rate of stent thrombosis with DES therapy is conflicting. The Intracoronary Stenting and Antithrombotic Regimen: Safety And eFficacy of a 6-month DAT after drug-Eluting stenting (ISAR-SAFE) trial should help answer whether DAT should be routinely extended beyond 6 months post-DES implantation. Two other studies, ISAR-REBOUND and ISAR-CAUTION, are evaluating the effect of abrupt vs. tapered cessation of clopidogrel therapy on predefined in vitro and clinical endpoints and should shed further light on the existence and clinical significance of a rebound phenomenon following clopidogrel discontinuation.

Clinical implications of the results of recent atherothrombotic trials on patient management

Betriu, A. — 2008-10-31

Significant advances have been made over the last several years in the treatment of patients with acute coronary syndromes including the introduction and approval of new antithrombin and antiplatelet agents. Results from a number of studies have impacted treatment strategies of patients with and without percutaneous coronary intervention. The study design and results of five trials: OASIS-5 PCI, PCI-ACUITY, TRITON–TIMI-38, FINESSE, and CARESS-in-AMI will be reviewed, and implications for clinical practice presented.

Advances in antiplatelet therapy: overview of new P2Y12 receptor antagonists in development

Cattaneo, M. — 2008-10-31

Platelets play an important role in thrombus formation. A number of new antiplatelet agents currently in development are anticipated to improve clinical outcomes and safety benefits in patients with acute coronary syndrome (ACS). This manuscript reviews the pharmacology and clinical development of three of these agents: prasugrel, cangrelor, and AZD6140. Prasugrel, a third-generation, oral thienopyridine, has been shown to be superior to clopidogrel, the current gold standard, in preventing ischaemic events in patients with ACS undergoing percutaneous coronary intervention (PCI), although the bleeding rate was higher. Cangrelor, a chemical analogue of adenosine triphosphate, is a potent direct platelet P2Y₁₂ antagonist. In development as an intravenous agent, cangrelor is currently being evaluated in two phase III studies in patients requiring PCI. AZD6140 is the first of a novel new class of antiplatelet agents that inhibits adenosine diphosphate-induced platelet aggregation at the level of the P2Y₁₂ receptor. AZD6140 was shown to have a good safety profile in phase II studies and is currently being studied in a phase III trial in patients with ACS.

Preface

2008-09-02

Recent advances in the management of atrial fibrillation

Singh, B. N. — 2008-09-02

Prevention of stroke in patients with atrial fibrillation: current strategies and future directions

Hohnloser, S. H., Duray, G. Z., Baber, U., Halperin, J. L. — 2008-09-02

The morbidity and mortality associated with atrial fibrillation (AF) are related mainly to ischaemic stroke, and the prevention of thrombo-embolism is an important component of the patient management. The choice of optimum antithrombotic therapy for a given patient depends on the risk of thrombo-embolism, and the assessment of thrombo-embolic risk using validated stratification schemes, such as the CHADS₂ score, is a critical step. Improved stratification schemes are needed that take into account the risk of intracerebral haemorrhage, which is the most worrisome complication of anticoagulant therapy. The pattern of AF (paroxysmal, persistent, or permanent) should not influence the selection of antithrombotic treatment. Similarly, successful rhythm control is not a sound basis for withdrawing antithrombotic treatment, and whether this situation differs after successful catheter ablation of AF has not been established. At present, oral vitamin K antagonists alone are recommended for patients with AF at moderate-to-high risk of stroke. A combination of anticoagulant and antiplatelet drugs is necessary in patients with AF undergoing percutaneous coronary intervention and stent implantation, but the optimal therapeutic management of these patients has not been defined. The development of new antithrombotic agents that are easier to use and have a superior benefit-to-risk ratio will extend treatment to a greater proportion of the AF population at risk. The large number of phase III trials currently investigating specific inhibitors of thrombin or factor Xa that do not require laboratory monitoring suggests that this goal is within reach.

Upstream therapies to prevent atrial fibrillation

Dorian, P., Singh, B. N. — 2008-09-02

Atrial fibrillation (AF) is the most common sustained arrhythmia in the western world. It is associated with increased morbidity and mortality and decreased quality of life. The absence of a clear benefit of a rhythm-control strategy over a rate-control strategy observed in recent trials may be due to the fact that none of the available membrane-acting antiarrhythmics is entirely satisfactory. In addition, ablative therapy is available only for a small number of patients. Besides research efforts to improve the efficacy and safety of conventional antiarrhythmic agents, therapies directed ‘upstream’ of the electrical aspects of AF, towards the underlying anatomical substrate (atrial remodelling), have emerged as potential new pharmacological therapies. Potential upstream therapies for AF comprise a variety of agents such as those targeting the renin–angiotensin system [angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB)], statins, steroids, and N-3 polyunsaturated fatty acids. On the basis of suggestive experimental data, early phase clinical studies have been conducted and have provided exciting information on the potential of upstream therapy for the prevention of AF across a broad spectrum of cardiovascular patient groups. In some of these groups, such as patients with hypertension or heart failure, data may be considered to be sufficient to support the use of ACEI or ARB, at least in combination with membrane-acting antiarrhythmics. However, in most clinical settings examined, the evidence appears to be insufficient to drive changes in therapy management, and additional data from large-scale, randomized, double-blind, placebo-controlled trials with adequately defined endpoints are still needed. Numerous such trials are ongoing, reflecting the intense scientific interest in this field. The data derived from these trials may add to our understanding of the complex mechanisms that lead to AF and its maintenance, and may provide the necessary substantive evidence clarifying the benefit-to-risk ratio of these new therapeutic approaches.

Controversies in ablation of atrial fibrillation

Aliot, E., Ruskin, J. N. — 2008-09-02

Catheter ablation is increasingly widely used to treat atrial fibrillation (AF) and constantly evolving techniques and protocols have led to improved success rates and lower risks of complications in a broad range of patients. However, long-term clinical trial data are still limited and as a result many questions remain unanswered. Particularly in patients with symptomatic paroxysmal AF, high success rates in restoring sinus rhythm (SR) with a low risk of complications are reported by experienced centres. Nevertheless, the continued suppression of AF over time, particularly with regard to the recurrence of asymptomatic episodes of AF which could influence stroke risk, is not yet adequately documented and therefore the safety of discontinuing oral anticoagulation remains unclear. The risk of silent or subclinical complications associated with ablation procedures, the likelihood of autonomic modulation and the long-term impact of ablation on left atrial mechanical function have not yet been fully determined. Limited clinical trial data suggest that catheter ablation may be particularly beneficial for patients suffering from heart failure (HF) secondary to AF, indicating improved left ventricular function and quality of life with the restoration of SR. However, the processes underlying HF and the co-existing morbidities vary from one patient to another and the factors predicting a successful outcome of ablation have not yet been fully defined. Similarly, the consistently higher rates of AF suppression achieved with catheter ablation vs. antiarrhythmic drug therapy shown in comparative clinical trials encourage consideration of this treatment as a potential first-line treatment in certain patients, but whether this is currently justifiable and if so, in which patient subsets, are open questions. This article reviews current approaches to catheter ablation and attempts to address some of the controversies regarding its use.

Defining endpoints in clinical trials on atrial fibrillation

Camm, A. J., Reiffel, J. A. — 2008-09-02

The major factors influencing the choice of the primary endpoint in any clinical trial in patients with atrial fibrillation (AF) are the purpose of the trial, the specific characteristics of the study population in terms of the class and aetiology of AF concerned, co-morbidities, risk factors, symptom status, and whether the trial is designed for regulatory purposes. Clinically, symptom relief and improvement in quality of life are major therapeutic goals, but they are difficult to measure objectively and an effect of treatment on these parameters is currently insufficient to support drug registration. Hard endpoints such as mortality, stroke, and hospitalization are most relevant to patients with persistent AF and other concomitant morbidities resulting in a high risk of these outcomes; however, their inclusion in an appropriately weighted composite primary endpoint may be necessary in trials including less severely ill patient populations to demonstrate treatment efficacy in a regulatory context. A therapy that reduced AF and improved quality of life but increased mortality, heart failure, or other major morbid events would not be approved in the current era. Time to first AF recurrence has practical advantages as a primary endpoint, but does not accurately reflect clinically important parameters such as the frequency, type, and duration of AF recurrence and the overall AF burden. The clinical relevance of asymptomatic recurrence of AF with regard to prognosis, quality of life, and patient care, including the need for anticoagulation, is increasingly recognized. Improvement in devices enabling more continuous monitoring of cardiac rhythm now permits more accurate assessment of the effect of treatment on asymptomatic AF, representing the majority of episodes recorded in studies employing intensive monitoring procedures. An intention-to-treat analysis is always preferred, but this may not always be possible in clinical trials in patients with AF. Irrespective of the efficacy endpoint chosen, this should ideally be assessed starting from the time steady state is achieved, for drug therapy, or maturation of the lesions in the case of ablation. These time-points may be days to months after randomization. Events occurring during the period from randomization to the pre-defined start of endpoint assessment, known as the blanking period, are not taken into account in the primary efficacy analysis. The longer the blanking period, the further on-therapy analysis departs from true intention-to-treat analysis. However, on-therapy analysis is as essential as intention-to-treat analysis, especially when comparing drug vs. non-drug therapies, as it also takes into account both the frequently high crossover rates and the poor compliance with drug therapy commonly encountered in antiarrhythmic drug (AAD) trials.

EUROPEAN HEART JOURNAL SUPPLEMENTS: Key lessons from morbidity/mortality trials: evidence for benefits of the perindopril/amlodipine combination ESC MUNICH 2008

Ferrari, R. — 2008-09-01

Benefits of perindopril all along the cardiovascular continuum: the level of evidence

Fox, K. — 2008-09-01

Cardiovascular risk factors such as hypertension and diabetes are understood to trigger a sequence of pathological events starting from hypertension and atherosclerosis, which if left unmanaged can ultimately progress to end-stage cardiovascular disease. This chain of events is termed the cardiovascular continuum. The angiotensin-converting enzyme inhibitor, perindopril, has marked restorative effects on endothelial dysfunction and this translates into clinical benefits for patients at all stages of the continuum, making it a highly effective treatment in cardiovascular disease. In hypertensive patients, large-scale clinical trials have shown that perindopril-based treatments reduce morbidity and mortality and reduce the onset of stroke, renal failure, and diabetes when compared with other anti-hypertensive therapies. In patients at more advanced stages of the cardiovascular continuum, the use of perindopril on top of other standard management practices further improves long-term prognosis in coronary artery disease. Perindopril also reduces cardiac remodelling following myocardial infarction and improves patient symptoms and prognosis in diastolic heart failure. Current trial evidence confirms the clinical benefits of perindopril throughout the cardiovascular continuum, thus slowing the progression of cardiovascular disease and improving patient prognosis.

Treatment with angiotensin-converting enzyme inhibitors: insight into perindopril cardiovascular protection

Ferrari, R. — 2008-09-01

Angiotensin-converting enzyme (ACE) inhibitors have an established role in the treatment of patients across the cardiovascular disease continuum, from uncomplicated hypertension to established cardiovascular disease. The first data showing the efficacy of ACE inhibitors for the prevention of cardiovascular events came from the Heart Outcomes Prevention Evaluation trial with ramipril. Since then a number of other large, randomized, controlled trials have confirmed the beneficial effects of ACE inhibitors on cardiovascular outcomes in a variety of patient groups. In addition, evidence suggests that these beneficial effects of ACE inhibitors occur independently of their blood pressure (BP)-lowering effects, a phenomenon that has not been observed for angiotensin receptor blockers. Among the ACE inhibitors, perindopril has the greatest body of evidence for cardiovascular preventive efficacy from major morbidity–mortality trials (e.g. ADVANCE, ASCOT-BPLA, EUROPA, PREAMI, PEP-CHF, PROGRESS). In addition, perindopril may be the treatment of choice in stable coronary artery disease because of its unique anti-apoptotic activity and protective effects on the endothelium. A current major trend in cardiovascular medicine is the increased use of combination therapies. The data reviewed here suggest that any combination therapy for secondary prevention across the continuum of cardiovascular disease should contain an ACE inhibitor.

Selecting a fixed combination to improve morbidity/mortality: the weight of evidence with ASCOT

Poulter, N. R. — 2008-09-01

The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm was designed to compare the effects of a standard combination starting with atenolol and adding a thiazide as needed and a newer combination starting with amlodipine and adding perindopril as needed. Because the newer regimen was associated with a significant reduction in all-cause mortality, the trial was stopped early. Nevertheless, the newer regimen was associated with a significantly superior effect on the primary endpoint excluding silent myocardial infarction, or including revascularization procedures, on total coronary events, cardiovascular (CV) mortality, fatal and non-fatal strokes, unstable angina, total CV events and procedures, new-onset diabetes, and development of renal impairment. The newer regimen was associated with an average blood pressure (BP) which was 2.7/1.9 mmHg lower than that of the standard regimen. Although it seems likely that this BP difference contributed to the superior prevention by the newer regimen, extensive analyses suggested that other advantages of the newer regimen contributed to this superiority. This is in keeping with other findings which suggest that angiotensin-converting enzyme inhibitors may have benefits beyond BP lowering in relation to coronary heart disease events and that calcium channel blockers may have benefits beyond BP lowering in relation to stroke protection.

Which patients would benefit the most from the perindopril-amlodipine combination?

Danchin, N. — 2008-09-01

In the recent Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm trial, the amlodipine ± perindopril strategy resulted in fewer deaths and cardiovascular events than an atenolol ± thiazide strategy. Because of the intrinsic properties of both angiotensin-converting enzyme inhibitors, particularly in terms of secondary prevention of ischaemic heart disease, and calcium-channel blockers, in terms of anti-anginal properties, the combination of amlodipine and perindopril should prove particularly beneficial in patients with coronary artery disease and either hypertension or anginal symptoms. In addition, both classes of medications have a favourable metabolic profile and have been shown to reduce the occurrence of new-onset diabetes mellitus in a variety of clinical situations. Finally, the impact of the amlodipine ± perindopril combination on central aortic pressure suggests a particular relevance in situations of increased central pulse pressure, such as elderly populations or patients with chronic kidney disease. Therefore, the amlodipine ± perindopril combination is likely to offer important clinical benefits in a number of fairly common clinical conditions.