The pharmaceutical pipeline for atrial fibrillation

Figures & data

Table I. Randomized clinical trials of dronedarone.

Characteristics	DAFNE (42)	EURIDIS-ADONIS (43)	ERATO (45)	ANDROMEDA (49)	ATHENA (47)	DIONYSOS (48)
Year	2003	2007	2008	2008	2009	2010
Patients enrolled, n	270	1,244	174	627	4,628	504
Design of the trial	Dronedarone versus placebo	Dronedarone versus placebo	Dronedarone versus placebo	Dronedarone versus placebo	Dronedarone versus placebo	Dronedarone versus amiodarone
Clinical scenario	Persistent AF undergoing CV	SR with at least 1 AF/AFL in the preceding 3 months	Permanent AF	Recent decompensated HF with NYHA class III/IV, LVEF<35%	SR with AF/AFL in the previous 6 months and ≥1 additional risk factor^a	Persistent AF with indication to CV
Primary end-point	Time to first AF	Time to first AF	Ventricular rate during exercise	Death or hospitalization for HF	Death or cardiovascular hospitalizations	Time to first AF or drug discontinuation
Treatment regimen	400–800 mg b.i.d.	400 mg b.i.d.	400 mg b.i.d.	400 mg b.i.d.	400 mg b.i.d.	400 mg b.i.d.(D) versus 600 mg daily for 28 days and 200 mg daily thereafter (A)
Exclusion criteria	Permanent AF, HF with NYHA class III–IV, LVEF<35%	Permanent AF, HF with NYHA class III–IV, renal failure	HF with NYHA class III–IV	Recent MI, acute pulmonary edema	Permanent AF, HF with NYHA class IV, decompensated HF	HF with NYHA class III–IV; unstable angina or recent MI
Follow-up, months	6	12	6	2	21	7
Results	60 days (D) versus 5.3 days (P)	116 days (D) versus 53 days (P)	Reduction of ventricular rate by 25.6 bpm (D) versus 2.2 bpm (P)	Death: 8.1% (D) versus 3.8% (P); Hospitalizations: 22.9% (D) versus 15.7% (P)	Hospitalizations: 36.9% (D) versus 29.3% (P); Death: 5% (D) versus 6% (P)	AF recurrence: 63.5% (D) versus 42% (A); Drug discontinuation: 10.4% (D) versus 13.3% (A)

^aHypertension, diabetes, prior cerebrovascular accident or systemic embolism, left atrium diameter ≥ 50 mm, LVEF < 40%.

AF = atrial fibrillation; AFL = atrial flutter; CV = cardioversion; SR = sinus rhythm; HF = heart failure; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction; MI = myocardial infarction; D = dronedarone; P = placebo; A = amiodarone; b.i.d.= twice daily.

Figure 1. Benefits and risks of dronedarone to prevent the occurrence of atrial fibrillation (AF) or atrial flutter (AFL). The number of AF/AFL events avoided (black squares) and the number dronedarone discontinuations for a serious drug-related adverse event (gray circles) every 1,000 patients treated are plotted against the annual risk of AF recurrence with placebo in each trial. Solid lines indicate linear regressions of treatment effects. Extrapolation of regression lines (dotted lines) toward their intersection suggests that the antiarrhythmic benefits of dronedarone may not outweigh the risks associated with its use when the patients' annual risk of AF recurrence is smaller than 65%–70% (intersection of dotted lines). AEs = adverse events; ADONIS (43) = American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm; EURIDIS (43) = European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm; DAFNE (42) = Dronedarone Atrial Fibrillation Study After Electrical Cardioversion.

Figure 2. Benefits and risks of amiodarone to prevent the occurrence of atrial fibrillation (AF) or atrial flutter (AFL). The number of AF/AFL events avoided (black squares) and the number of amiodarone discontinuations for a serious drug-related adverse event (gray circles) every 1,000 patients treated are plotted against the annual risk of AF recurrence with placebo in each trial. Solid lines indicate linear regressions of treatment effects. Extrapolation of regression lines (dotted lines) does not show intersection, suggesting that the antiarrhythmic benefits of amiodarone outweigh the risks associated with its use across all patient populations. AEs = adverse events; GEFACA (34) = Grupo de Estudio de Fibrilacion Auricular Con Amiodarona; SAFE-T (15) = Sotalol Amiodarone Atrial Fibrillation Efficacy Trial; Kochiadakis et al. (35); Channer et al. (14).

Figure 3. Effects of dronedarone on death or hospitalization for cardiovascular causes in different groups of patients. The number of death or hospitalization events (black squares) avoided (upper panel) or provoked (lower panel) every 1,000 patients treated is plotted against the annual risk of death or hospitalization with placebo in each trial. Solid line indicates linear regression of treatment effect and suggests an inverse relationship between dronedarone-associated benefits and base-line risk of patients, with harm for patients with an annual risk of death or hospitalization greater than 40%–45% (intersection of the regression line with the xaxis). The greatest benefit is observed in patients with low-to-moderate (25%–35%) annual risk of events. EURIDIS (43) = European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm; ADONIS (43) = American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm; ATHENA (47) = A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg b.i.d.for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter; ANDROMEDA (49) = Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease.

Figure 4. Ionic currents involved in the action potential of atrial myocytes. Atrial selective currents are highlighted in gray.

Table II. Summary of atrial selective agents.

Agent	Target	Route	Stage of development	Notes
Vernakalant	Blocker of IKur, Ito, INa, IKr	IV, oral^a	Completed phase III studies; recently approved by the EMEA (only IV route)	High conversion in recent onset AF (<72 h); ineffective in atrial flutter. No data on patients with heart failure
Ranolazine	Blocker of late INa, IKur	IV, oral	Completed phase III studies as anti-ischemic agent; approved as antianginal agent	Reduces the occurrence of AF in subgroup analyses; no randomized trial on AF available
Xention	Blocker of IKur	IV, oral	Phase II	Highly selective IKur blocker but insufficient data
AZD7009	Blocker of IKur, Ito, INa, IKr	IV	Abandoned during phase II	Potent IKr blocker; possible high risk of proarrhythmia
AVE0118	Blocker of IKur, Ito, IACh	IV	Abandoned during phase IIa	Undisclosed reasons for interruption
AVE1231	Blocker of IKur, Ito, IACh	IV, oral	Phase I	Unselective blockade of atrial-selective targets; also blocks IKr, IKs, IKATP, ICaL, INa
NIP-141	Blocker of IKur, Ito, IKACh, ICaL	IV	Phase I	Multichannel blocker with possible anti-remodeling properties

Vernakalant is manufactured by Cardiome; Ranolazine is manufactured by CV Therapeutics.

^aUnder development.

IV = intravenous; AF = atrial fibrillation; AZD = Astra Zeneca; AVE = Sanofi Aventis; NIP = Nissan Pharmaceuticals.

Table III. Randomized clinical trials of vernakalant.

Characteristics	CRAFT (69)	ACT-I (68)	ACT-II (65)	ACT-III (72)	AVRO (70)
Year	2004	2008	2009	Not yet published	Not yet published
Patients enrolled, n	56	336	161	276	254
Design of the trial	Vernakalant versus placebo	Vernakalant versus placebo	Vernakalant versus placebo	Vernakalant versus placebo	Vernakalant versus amiodarone
Clinical scenario	Persistent AF undergoing CV	Persistent AF undergoing CV	Postoperative AF/AFL	Persistent AF/AFL undergoing CV	Persistent AF undergoing CV
Primary end-point	Conversion of AF	Conversion of AF within 90 min of drug initiation	Conversion of AF within 90 min of drug initiation	Conversion of AF within 90 min of drug initiation	Conversion of AF within 90 min of drug initiation
Treatment Regimen	0.5 mg/kg in 10 min followed by 2 mg/kg if no CV or 2 mg/kg in 10 min followed by 3 mg/kg if no CV	3 mg/kg in 10 min followed by 2 mg/kg if no CV	3 mg/kg in 10 min followed by 2 mg/kg if no CV	3 mg/kg in 10 min followed by 2 mg/kg if no CV	3 mg/kg in 10 min followed by 2 mg/kg if no CV
Exclusion criteria	HF	HF with NYHA class IV	HF with NYHA class IV	HF	Not retrievable
Results	At 1 h: 53% (V) versus 5% (P); at 24 h: 79% (V) versus 45% (P)	AF ≤7 days: 51.7% (V) versus 4% (P); AF 8–45 days: 7.9% (V) versus 0% (P)	45% (V) versus 15% (P); no significant CV of AFL to SR	AF ≤7 days: 51.2% (V) versus 3.6% (P); AF 8–45 days: 9.4% (V) versus 2.7% (P); no significant CV of AFL to SR	51.7% (V) versus 5.2% (A)

AF = atrial fibrillation; AFL = atrial flutter; CV = cardioversion; SR = sinus rhythm; HF = heart failure; NYHA = New York Heart Association; V = vernakalant; P = placebo; A = amiodarone.

Figure 5. Indirect comparison of treatment effects of different intravenous antiarrhythmic agents for the acute conversion of atrial fibrillation (AF). SR = sinus rhythm.

Figure 6. Putative molecular effects of upstream therapies for atrial fibrillation. RAA = renin-angiotensin-aldosterone.

Figure 7. Forest plot showing the individual and pooled hazard ratios of postoperative atrial fibrillation comparing therapy with omega-3 fatty acids versus placebo. Square boxes denote hazard ratio; horizontal lines represent 95% confidence interval (CI).

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