Atrial fibrillation clinical trials

Hart RG, Palacio S, Pearce LA. Atrial fibrillation, stroke, and acute antithrombotic therapy. Analysis of randomized clinical trials. Stroke 2002 33 2722-2727. 

Warfarin has not been adequately studied in non-cardioembolic stroke, but it is often recommended in patients after antiplatelet agents fail. One small retrospective study suggests that warfarin is better than aspirin.30 More recent clinical trials have not found oral anticoagulation in those patients without atrial fibrillation or carotid stenosis to be better than antiplatelet therapy. In the majority of patients without atrial fibrillation, antiplatelet therapy is recommended over warfarin. In patients with atrial fibrillation, long-term anticoagulation with warfarin is recommended and is effective in both primary and secondary prevention of stroke.12 The goal International Normalized Ratio (INR) for this indication is 2 to 3. 

Intravenous vernakalant is effective in converting recent-onset atrial fibrillation to normal sinus rhythm in 50% of patients. Approval has been recommended for this purpose. The drug is undergoing clinical trials for maintenance of normal sinus rhythm in patients with paroxysmal or persistent atrial fibrillation. 

A major focus of drug development has been to develop orally active anticoagulants that do not require monitoring. Rivaroxiban is the first oral factor Xa inhibitor to reach phase III clinical trials. The safety and efficacy of rivaroxiban appears to be at least equivalent, and possibly superior, to LMW heparins for prevention of deep vein thrombosis no routine monitoring is required. This drug is also in clinical trials for treatment of deep vein thrombosis and prevention of stroke in atrial fibrillation. 

Quinidine is used for the maintenance of normal sinus rhythm in patients with atrial flutter or fibrillation. It is also used occasionally to treat patients with ventricular tachycardia. Because of its cardiac and extracardiac side effects, its use has decreased considerably in recent years and is now largely restricted to patients with normal (but arrhythmic) hearts. In randomized, controlled clinical trials, quinidine-treated patients are twice as likely to remain in normal sinus rhythm compared with controls. However, drug treatment was associated with a twofold to threefold increase in mortality. 

Atrial fibrillation is increasing in incidence in developed countries and, because of the risk of embolic stroke, most patients require continuous anticoagulation. A large number of patients with atrial fibrillation are currently treated with vitamin K antagonists. Results of clinical trials in patients with atrial fibrillation indicate that oral direct TIs may become potential drugs for the prevention of embolic stroke and may replace warfarin (62,78,79-81). 

Clinical effects A large number of randomized, doubleblind, placebo-controlled trials have shown that the longterm use of (3 blockers improves the clinical status in patients with HF (22-32) (Table 2) and the ACC/AHA guidelines (II) recommend that (3 blockers should be routinely prescribed to all patients with asymptomatic LV dysfunction or stable HF caused by LV systolic dysfunction (unless they have a contraindication or have been shown to be intolerant to treatment with these drugs). (3 blockers should also be used in patients with HF and preserved LV systolic function, particularly when those patients have hypertension, coronary artery disease (CAD) and/or atrial fibrillation. 

Indications for surgical intervention include regurgitation with NYHA lll-IV symptoms or NHYA >11 with atrial fibrillation refractory to conservative treatment. Several surgical techniques are effective, The Alfieri stitch or edge to edge technique is of interest because one of the percutaneous mitral valve repair techniques is based on an equivalent principle (29,30). Currently two methods for transcatheter mitral valve repair are investigated in clinical trials ... 

The book is comprised of five sections with part I covering systemic and endoluminal therapy with an incisive overview of hemostasis and thrombosis part II covers local therapy with several chapters devoted to drug-eluting stents and restenosis therapies part III covers cell therapy and therapeutic angiogenesis and includes chapters on cell transplantation and clinical trials in cellular therapy part IV covers adjunctive pharmacotherapy with chapters devoted to various patient populations including those with heart failure, diabetes, atrial fibrillation, peripheral artery disease,... 

Table 18.5. The baseline clinical characteristics and hemorrhage outcomes of patients randomized to anticoagulation with warfarin in the European Atrial Fibrillation Trial (EAFT) and the Stroke Prevention in Reversible Ischemia Trial (SPIRIT)...

Clinicians are usually most concerned about external validity of trials of potentially dangerous treatments. Complications of medical interventions are a leading cause of death in developed countries. Risks can be overestimated in trials, particularly during the introduction of new treatments when trials are often carried out with patients with very severe disease, but stringent selection of patients, confinement to specialist centers and intensive safety monitoring usually lead to lower risks than in routine clinical practice. Trials of warfarin in non-rheumatic atrial fibrillation are a good example. Prior to 2007, all trials... 

Flecainide slows conduction in all cardiac cells including the anomalous pathways responsible for the Wolff-Parkinson-White (WPW) syndrome. Together with encainide and moricizine, it underwent clinical trials to establish if suppression of asymptomatic premature beats with antiarrhythmic drugs would reduce the risk of death from arrhythmia after myocardial infarction. The study was terminated after preliminary analysis of 1727 patients revealed that mortality in the groups treated with flecainide or encainide was 7.7% compared with 3.0% in controls. The most likely explanation for the result was the induction of lethal ventricular arrhythmias possibly due to ischaemia by flecainide and encainide, i.e. a proarrhythmic effect. In the light of these findings the indications for flecainide are restricted to patients with no evidence of structural heart disease. The most common indication, indeed where it is the drug of choice, is atrioventricular re-entrant tachycardia, such as AV nodal tachycardia or in the tachycardias associated with the WPW syndrome or similar conditions with anomalous pathways. This should be as a prelude to definitive treatment with radiofrequency ablation. Flecainide may also be useful in patients with paroxysmal atrial fibrillation. 

Miller MR, McNamara RL, Segal JB, Kim N, Robinson KA, Goodman SN, Powe NR, Bass EB. Efficacy of agents for pharmacologic conversion of atrial fibrillation and subsequent maintenance of sinus rhythm a metaanalysis of clinical trials. J Earn Pract 2000 49(ll) 1033-46. 

Hypotension, exacerbation or new onset of atrial fibrillation, and dyspnea were infrequently observed in clinical trials (6). Although weight gain and peripheral edema can develop, only one fatal case, compatible with a capillary vascular leak syndrome, has been reported (SEDA-20, 335). 

Hylek EM, D Antonio J, Evans-Molina C, et al. Translating the results of randomized trials into clinical practice the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke 2006 37(4) 1075-80. 

A second fundamental question concerns the role of resynchronization therapy in patients with persistent atrial fibrillation (AF). Atrial fibrillation is common in advanced heart failure (35), but patients with persistent atrial fibrillation were excluded from the majority of randomized clinical trials of resynchronization. Nevertheless, the most recent guidelines classify AF with QRS duration >120 msec to be a Class Ha indication for CRT implantation (1). Three multicenter randomized trials of resynchronization therapy have... 

Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRSd in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003 23 2932-7. 

Digoxin increases the force of cardiac contraction in the failing heart. Thi.s benefit has often Ireen doubted in patients with chronic heart failure in sinus rhythm, but recent clinical trials have shown that digoxin can reduce the symptoms of heart failure in patients who arc already receiving diuretics and ACE inhibitors. Digoxin is particulurly indicated in heart failure caused by atrial fibrillation (Chapter 17). 

In the overall long-term population, 6,841 patients started ximelagatran treatment. The number of patients exposed for 3 months, 6 months, and 15 months were 6,581, 5,987, and 3,630, respectively. The median exposure time in the long-term trials was approximately 1 year. Longest exposure time exceeds 5 years. Data from patients treated for up to 5 years for stroke prevention with nonvalvular atrial fibrillation have been published (AstraZeneca Clinical Trials http //www. astrazenecaclinicaltrials.com/article/527374.aspx). 

Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-in-tensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation Stroke Prevention in Atrial Fibrillation HI randomised clinical trial. Lancet (1996) 348,633-38. 

Atrial fibrillation (Afib) is the most common cardiac arrhythmia in the United States. Persons with Afib are at increased risk of blood clots in the heart that in turn may lead to thromboembolic stroke. The medication warfarin is often prescribed as a preventative measure. While the effectiveness of warfarin in the prevention of thromboembolic stroke is well established, its physiological mechanism of action also puts users at higher risk for other adverse events, for example, bleeding, whose health consequences may be just as devastating. Randomized clinical trials of warfarin have reported favorable results in both effectiveness and safety analyses. However, some clinicians have expressed doubt as to whether these results validly represent the situation in the general Afib patient population. The reason is that typical Afib patients tend to have more comorbidities and may not be as healthy as trial participants. 

Several other trials have also reported favorable results of mHealth in terms of improved medical profile and quality of life, enhanced clinical management, and reduced length of hospitalization [38-39]. Specifically, mHealth technology was used in patients with cardiovascular disease to (a) send a text message on vitals and signals and receive instructions by physicians [38], (b) transmit alerts regarding atrial fibrillation and tachycardia activity for patients with implantable cardioverter-defibrillator [40], and (c) monitor physical activity and diet and receive motivational and educational text messages [39-41]. 

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