Pharmacological cardioversion of atrial fibrillation with vernakalant: evidence in support of the ESC Guidelines.

Pharmacological rhythm control (often including electrical or pharmacological cardioversion) is an integral part of therapy for atrial fibrillation (AF) worldwide. Antiarrhythmic drug strategies would be preferred in many patients provided effective and safe antiarrhythmic agents are available. Also, pharmacological cardioversion could be the preferred option if the limitations of currently available drugs, such as restriction to patients without structural heart disease (flecainide and propafenone), risk of torsade de pointes (ibutilide), and slow onset of action (amiodarone), were overcome. The intravenous formulation of vernakalant (Brinavess, Cardiome) has been approved for pharmacological cardioversion of recent-onset AF (≤7 days) and early (≤3 days) post-operative AF in the European Union, Iceland, and Norway. Vernakalant has a high affinity to ion channels specifically involved in repolarization of atrial tissue and has minimal effects in the ventricles and thus, is thought to have a low proarrhythmic potential. Vernakalant is administered as a 10 min infusion of 3 mg/kg, and if AF persists after 15 min, an additional dose of 2 mg/kg can be given. The efficacy and safety of the drug has been extensively investigated in randomized controlled trials against placebo and an active comparator (amiodarone). The placebo-extracted efficacy of vernakalant is ∼47%. A significant advantage is a rapid effect, with the median to conversion ranging between 8 and 14 min, with the majority of patients (75-82%) converting after the first dose. Vernakalant retained its efficacy in subgroups of patients with associated cardiovascular disease such as hypertension and ischaemic heart disease, but its benefit may be lower and risk of adverse effects is higher in patients with heart failure. In the post-market reports, cardioversion rates with vernakalant are 65-70%. This review focuses on the role of vernakalant in pharmacological cardioversion for AF.

Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention.

Atrial fibrillation (AF) is associated with significant morbidity and mortality. It is also a progressive disease secondary to continuous structural remodelling of the atria due to AF itself, to changes associated with ageing, and to deterioration of underlying heart disease. Current management aims at preventing the recurrence of AF and its consequences (secondary prevention) and includes risk assessment and prevention of stroke, ventricular rate control, and rhythm control therapies including antiarrhythmic drugs and catheter or surgical ablation. The concept of primary prevention of AF with interventions targeting the development of substrate and modifying risk factors for AF has emerged as a result of recent experiments that suggested novel targets for mechanism-based therapies. Upstream therapy refers to the use of non-antiarrhythmic drugs that modify the atrial substrate- or target-specific mechanisms of AF to prevent the occurrence or recurrence of the arrhythmia. Such agents include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), statins, n-3 (ω-3) polyunsaturated fatty acids, and possibly corticosteroids. Animal experiments have compellingly demonstrated the protective effect of these agents against electrical and structural atrial remodelling in association with AF. The key targets of upstream therapy are structural changes in the atria, such as fibrosis, hypertrophy, inflammation, and oxidative stress, but direct and indirect effects on atrial ion channels, gap junctions, and calcium handling are also applied. Although there have been no formal randomized controlled studies (RCTs) in the primary prevention setting, retrospective analyses and reports from the studies in which AF was a pre-specified secondary endpoint have shown a sustained reduction in new-onset AF with ACEIs and ARBs in patients with significant underlying heart disease (e.g. left ventricular dysfunction and hypertrophy), and in the incidence of AF after cardiac surgery in patients treated with statins. In the secondary prevention setting, the results with upstream therapies are significantly less encouraging. Although the results of hypothesis-generating small clinical studies or retrospective analyses in selected patient categories have been positive, larger prospective RCTs have yielded controversial, mostly negative, results. Notably, the controversy exists on whether upstream therapy may impact mortality and major non-fatal cardiovascular events in patients with AF. This has been addressed in retrospective analyses and large prospective RCTs, but the results remain inconclusive pending further reports. This review provides a contemporary evidence-based insight into the role of upstream therapies in primary (Part I) and secondary (Part II) prevention of AF.

Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part II: secondary prevention.

Fundamental research into molecular mechanisms of atrial fibrillation (AF) and improved understanding of processes involved in the initiation and maintenance of AF have transformed the traditional approach to its management by targeting only the electrical aspects, usually with antiarrhythmic drugs and, recently, by ablation. The antiarrhythmic potential of upstream therapies, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (ARBs), statins, and n-3 (ω-3) polyunsaturated fatty acids, extends beyond the benefit of treating underlying heart disease to modifying the atrial substrate and intervening in specific mechanisms of AF. The key target is structural remodelling of the atria, particularly inflammation and fibrosis, although there is evidence to suggest the direct involvement at the ion channel level. Positive clinical reports supported by robust experimental data have suggested that upstream therapies can be valuable strategies for primary prevention of AF in selected patients and have resulted in several class IIA recommendations in the new European guidelines on AF. However, these results have not been consistently replicated in the secondary prevention setting, and several recent randomized controlled studies failed to demonstrate any effect of upstream therapies on AF burden or on major cardiovascular outcomes. Part II of the review summarizes the evidence base for the use of upstream therapies for secondary prevention of AF.

Relative efficacy of antianginal drugs used as add-on therapy in patients with stable angina: A systematic review and meta-analysis.

AIMS: First-line medical management of stable angina generally involves a beta-blocker (BB) or calcium channel blocker (CCB), with other classes of medication being added if symptom control is inadequate. Evidence supporting the appropriate choice of a second-line agent is currently unclear. The objective of this systematic review was to quantify the clinical benefit of BB, CCBs, long-acting nitrates (LANs), ranolazine, trimetazidine, ivabradine or nicorandil added to first-line monotherapy for stable coronary artery disease. METHODS: Randomised controlled trials comparing the efficacy of antianginal therapies in patients with stable angina refractory to first-line therapy were identified from a literature search. Exercise tolerance test (ETT) data and clinical outcomes were extracted and combined in a series of meta-analyses. RESULTS: A total of 46 qualifying studies were identified, evaluating 71 treatment comparisons. The combination of ranolazine added to CCB or BB showed positive outcomes across all outcomes assessed. Other combinations of BB, CCB, LAN and trimetazidine showed significant benefits for most but not all outcomes. Ivabradine demonstrated benefits for ETT assessments but these were not matched in clinical domains. No qualifying studies were identified for nicorandil in an add-on role. CONCLUSION: Across a range of commonly assessed exercise and clinical outcomes, the effectiveness of BB+CCB used in combination is broadly confirmed. Ranolazine used with BB or CCB showed benefits across all outcomes assessed, while LAN and trimetazidine used with BB or CCB have shown benefits across some outcomes. Ivabradine added to BB shows inconsistent effects from a single study, whilst there is no relevant evidence for nicorandil.

Ranolazine in the treatment of atrial fibrillation: Results of the dose-ranging RAFFAELLO (Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion) study.

BACKGROUND: Currently available antiarrhythmic agents for the treatment of atrial fibrillation (AF) have important limitations, leaving an unmet need for safe and effective therapy. Ranolazine is an approved antianginal agent with a favorable safety profile and electrophysiologic properties suggesting a potential role in the treatment of AF. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of ranolazine in the prevention of AF recurrence after successful electrical cardioversion and to ascertain the most appropriate dose of this agent. METHODS: This prospective, multicenter, randomized, double-blind, placebo-control parallel group phase II dose-ranging trial randomized patients with persistent AF (7 days to 6 months) 2 hours after successful electrical cardioversion to placebo, or ranolazine 375 mg, 500 mg, or 750 mg bid. Patients were monitored daily by transtelephonic ECG. The primary end-point was the time to first AF recurrence. RESULTS: Of 241 patients randomized, 238 took at least 1 drug dose. Ranolazine proved to be safe and tolerable. No dose of the drug significantly prolonged time to AF recurrence. AF recurred in 56.4%, 56.9%, 41.7%, and 39.7% of patients in the placebo, ranolazine 375 mg, ranolazine 500 mg, and ranolazine 750 mg groups, respectively. The reduction in overall AF recurrence in the combined 500-mg and 750-mg groups was of borderline significance compared to the placebo group (P = .053) and significant compared to 375-mg group (P = .035). CONCLUSION: No dose of ranolazine significantly prolonged time to AF recurrence. However, the 500-mg and 750 mg-groups combined reduced AF recurrences, suggesting a possible role for this agent in the treatment of AF.

Practical considerations for using novel oral anticoagulants in patients with atrial fibrillation.

Novel oral anticoagulants, including dabigatran, rivaroxaban, and apixaban, represent new options for preventing stroke in patients with atrial fibrillation, as shown by the results from large, randomized phase III trials. Because of their greater specificity, rapid onset of action, and predictable pharmacokinetics, the novel oral anticoagulants (dabigatran, rivaroxaban, and apixaban) address several limitations of warfarin or other vitamin K antagonists in day-to-day clinical practice. However, a range of practical questions relating to the novel oral anticoagulants has emerged, including topics such as patient selection, treatment of patients with renal impairment, risk of myocardial infarction, drug interactions, switching between anticoagulants, and management of bleeding, in addition to use of these agents in patients requiring antiplatelet drug treatment or undergoing cardioversion or percutaneous interventions (eg, ablation). In this review, practical aspects of the use of novel oral anticoagulants in patients with atrial fibrillation are discussed, with reference to available data and guidance from prescribing information.

Primary and secondary prevention of atrial fibrillation with statins and polyunsaturated fatty acids: review of evidence and clinical relevance.

Atrial fibrillation (AF) is an increasingly common arrhythmia that now stands at epidemic proportion, with more than 2.3 million people affected in the USA and over 4.5 million people affected in Western Europe. AF is an expression of underlying heart disease and is increasingly associated with hypertension, congestive heart failure, and ischemic heart disease. It is also a progressive disease secondary to continuous structural remodeling of the atria, which relates to AF itself, to changes associated with aging and to progression of the underlying heart disease. Traditionally, AF has been addressed only after it has already presented with pharmacological and nonpharmacological therapies designed for rhythm or rate control (secondary prevention). Although secondary prevention is the most feasible approach at present, the concept of primary prevention of AF with therapies aimed at preventing the development of substrate and correcting the risk factors for AF has emerged as a strategy, which is likely to produce a larger effect in the general population. Recent experiments provided new insights into AF pathophysiology, which generated background for new mechanism-based therapies. Agents targeting inflammation, oxidative injury, atrial myocyte metabolism, extracellular matrix remodeling, and fibrosis have theoretical advantages as novel therapeutic strategies. In this respect, drugs that are not traditionally antiarrhythmic such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, aldosterone antagonists, statins, and omega-3 polyunsaturated fatty acids have shown an antiarrhythmic potential in addition to any treatment effect on the underlying disease. These agents are thought to have an advantage of targeting both the occurrence and progression of the substrate for AF, thus, providing primary and secondary prevention of the arrhythmia. Although first experimental and hypothesis-generating small clinical studies or retrospective analyses have been encouraging, several larger, properly designed, prospective trials have not confirmed earlier observations. This review provides a contemporary evidence-based insight into the possible preventative and reverse remodeling role of statins and polyunsaturated fatty acids in AF.