Skip to content

New AADs for Atrial Fibrillation Trial Data

  • by

Okay so good morning i’m dr. james ray pelton call me university and we’ll be talking about new anti rhythmic rug for atrial fibrillation trial data and considerations with respect to algorithm placement these are my disclosures i show these in all programs that i do and i work with almost every company that’s right out of antiarrhythmic drunkard device but i don’t

Invest in them in my program my presentation is designed to be free of bias there’s been a resurgence of interest in antiarrhythmic drug development during the current decade with a particular focus on the treatment of atrial fibrillation one new agent has reached the marketplace that is true never owned a non-toxic derivative of amiodarone one agent currently

Available for the treatment of angina as preliminary data suggesting efficacy for atrial fibrillation that’s ranolazine and many other agents are under development most of which have been termed atrial selective or atrial specific and one of which is in phase three trials and that’s earn a callant so let’s look at these three as representatives of where the field

Is going trinette our own did many trials in its page 2 and 3 clinical development program they are summarized on this particular slide it was the daphne study which was a dose-ranging efficacy and safety trial in af cardioversion and the maintenance of sinus rhythm it tested 400 600 and 800 milligrams twice a day the results of this trial suggest that only 400

Milligrams vi d would go into further clinical development as the higher doses were not well tolerated due to gi toxicity iridescent adonis two identical trials conducted in different regions of the world those results were pooled were grenadier own versus placebo trials looking at the end point of time to recurrence of atrial fibrillation so this was maintenance

Of sinus rhythm in patients with non permanent atrial fibrillation erato was a trial in permanent afib looking at how much rate control that is ventricular rate would occur with dronedarone nicest was a short trial comparing head to head amiodarone and dronedarone looking at the reduction of recurrent af or premature study drug discontinuation pouring tolerance or

Lack of efficacy athena was a trial in af patients who had high risk markers for events and the primary endpoint was reduction of the combination of cardiovascular hospitalization or death from any cause in this high risk a pip population and the andromeda was a trial specifically for safety in very high risk patients those being pets or heart failure or lesser heart

Failure with recent decompensation this was not specifically in afib trial the results of these files are on this next slide as you can see the daphne trial revealed that only 400 milligrams bi d should be tested in future trials the original adonis experience revealed her at her own to be superior to placebo and along the time to the first recurrence of a trope

Ever atrial flutter both uranus and adonis and erato revealed that dronedarone does reduce the ventricular rate both arrested with exercise usually about 10 to 15 beats per minute that i nicest showed that amiodarone was superior to her nether own in terms of efficacy but that it was less well tolerated and stopped more often for intolerance and toxicity athena

Revealed the true head her own reduced cardiovascular hospitalization including the components of hospitalization dude atrial fibrillation as well as acute coronary syndrome when the trend towards reduced total mortality in the high-risk a fib patients and andromeda the thorn in the side of this development program if you will reveal the draenei terone increased

Hospitalization for heart failure and mortality in a severe heart failure population and it was stopped prematurely consequently in this country brunette around the brand-name multaq received approval to reduce the risk of cardiovascular hospitalization in patients with heiresses more persistent atrial fib reflector with a recent episode meeting non-persistent fib

And one or more of the associated cardiovascular risk factors that were inclusion criteria in the athena trial it did not receive an indication to reduce mortality because that was only a trend in athena the contraindication in this country as well as around the world this class for heart failure or lesser heart failure with recent decompensation and that’s based

On the andromeda study note this indication is not simply for the reduction of atrial fibrillation that approval was obtained in europe where the drug is approved for the reduction of atrial fib and to slow the ventricular rate response but the indication in this country is more specific so here is the wording of the european indication where should we use for

An interim based upon this particular indication well if we think about the 2006 accha esc guidelines then we remember their drug disposition is divided by no heart disease hypertension coronary disease heart failure and we combined our net or owns experience as well as its indication you can see that in noah minimal heart disease turn it around it would appear

To be a reasonable first line choice in those patients who mean its inclusion criteria from athena and it’s indication criteria who do not have heart disease meaning aged over 70 diabetes prior stroke or large left atrium in the hypertensive population than the additional risk factors in the package insert that is the approval package would suggest that either

Hypertension or a reduced ejection fraction would be reasonable criteria to suggest the stroke should be used or slide and that holds true in coronary disease in heart failure as well remembering that in the heart value population it’s contraindicated the class for heart failure or recent decompensation the second drug i want to mention is ranolazine it’s a unique

Agent with had multiple ion channels many of which are the same panels affected by amiodarone it’s approved for the treatment of angina and importantly it has not been associated with any organ toxicity or with pro arrhythmia it has as its most frequent side effects constipation and some vague dizziness but no serious organ toxicity it is electro physiologically

Active ranolazine is an inactivated state sodium channel blocker that is the late sodium channel it has little effect on peak sodium in ventricular myocardium but has a functionally significant effect in atrial myocardium ranolazine also blocks ikr but it prolongs the qt interval only modestly with a mean of six milliseconds because of the beauty prolonging effect

That is the actual potential duration prolonging effect from potassium blockade is offset by the inhibition of the late sodium current inward current ranolazine poland’s a tro refractoriness and decreases its dispersion and prolongs atrial conduction velocity it prevents early after depolarizations in ventricular and atrial tissue and is reduce firing and pulmonary

Vein sleeves all of which may contribute to an anti-fur military effect in the atrium ranolazine has reduced exercise-induced ventricular arrhythmias in patients with coronary disease probably best characterized in its merlin trial and acute coronary syndrome or vernola zeen reduced ventricular ectopy non sustained vt and atrial arrhythmias including new onset afib

And in animal models ranolazine has reduced in disability of atrial fib and pulmonary vein triggers that led dr. david murdock plan to myself to do several small pilot series of afib patients and these have demonstrated that ranolazine can be effective in some patients with new-onset paroxysmal afib or atrial fib that has become refractory to previously effective

Agents as a pill of the pocket / ap determination in those who’ve become refractory to previously effective class 1c agents or cathode wall and to facilitate direct current cardi version after failure off a drug some of that data is on this slide this is our the pocket experience 31 patients with either new or recurrent paroxysmal afib of short duration that is

3 to 48 hours mostly men mean age seventy eighty percent with structural heart disease so this is a population in which we couldn’t use pill in the pocket class 1 c drug we’re given were nosing 2,000 milligrams see there is a single dose or as to 1,000 milligrams doses in close succession 22 were in the hospital five in office or at home and 24 31 converted to

Sinus rhythm within six hours a conversion rate that approximates that scene with class 1 c drugs and remember the placebo conversion rates in all of the class 1 sea trials were half or less than half of the conversion rates of the active drug importantly even in this population with heart disease there were no pro a rhythmic events or no adverse hemodynamic events

And we suggest that this type of experience be carried out in larger trials in patients with prior antiarrhythmic therapy we studied 13 patients who had very frequent paf that it was successfully controlled for at least two years with either a class 1 drug like an ibuprofen own or in a few with a class 3 drug essentially so long then their episodes were occurred

With approximately the same pattern that existed prior to any therapy over a fairly short period of time meaning months they were changed to renault lizzie ranolazine was successful in 10 of the 13th to discontinued side effects none serious in one it did not work and if the ted successfully controlled 8 have remained on the drug with good tolerance three had

No a fit at all with a mean follow-up of eight months to had somewhat greater than 75 percent reduction with tolerable side effects and until the drug was discontinued because of dizziness and constipation so here again we have data that suggests the pronoun lezyne can be effective in at least some e patients and his deserving of larger trials when additional

Experience of milk was a 58 year old woman who gave it we have symptomatic persistent afib for about three years she was managed medically with av nodal agents but a fib recurred after each three separate party version attempts because she felt better with improved exercise tolerance after each party version her rhythm control strategy was adopted history of a

Positive stress test precluded either class 1a or for that matter 1c antiarrhythmics solo was initiated and titrated to 160 milligrams be id which he developed an episode of persistent poor side requiring defibrillation and she was then transferred to our institution columbia university medical center core ablation which was performed with that incident however a

Fib record following pulmonary vein isolation including after a two-month like in period and further left a trill ablation was scheduled all the way to that ablation she was put on renault losing one granby id and party hurted once again after three months including a three-week continuous out patient monitoring period she remained in sinus rhythm and deferred

Repeat ablation this was a slide set i put together two months ago and now at five months she continues to remain in sinus rhythm so again a different line of patients if you will this one being persistent afib suggests that were nosy and be effective where might it fit in our algorithm essentially can be given across the spectrum of heart disease it can fit in

The boxes with no heart disease hypertension coronary disease for which it as an angel indication or lv dysfunction so i think it’s a very promising agent to look at further and finally there are a large list of other agents under development many of which as i suggested earlier were atrial specific agents only some of which are listed on the slide april specific

Agents are an interesting set of compounds because they take advantage of the fact that in the atria there are some channels that are not active in the ventricle the ultra rapid potassium channel and the ik ach channel in the remodeled atrium during fibrillation when action potential duration shortens these early activating channels book dominant in the repolarizing

Mechanism and on the right of this slide you can see the iks and ikr channels are much much less important so that drugs that target these channels which are active in the fibrillating atrium and are not present than the ventricle at least in theory should be able to reduce afib terminated if its present perhaps prevented without the risk of ventricular arrhythmia

And the furthest along is vern a callant originally called rsd 1235 with a proposed trade name of china pit although it is not yet approved it is in class three it isn’t phase three trials it is the frequency in voltage dependent sodium channel blocker it also blocks early activating potassium channels particularly the ik ach channel at his rate enhanced activity

On conduction so it’s more potently effective during the relation it is adriel selective effects on a pd and erp prolongation the activity has been confirmed in several species it has very rare adverse emo dynamic effects intravenously this being developed both iv for conversion and oral for the prevention of afib it’s avi studies to date have included several

Important trials two of them act 1 and act 3 were virtually identical double-blind placebo-controlled phase 3 trials act 1 being somewhat larger than act 3 act 2 is a post-op a fifth study again randomized placebo-controlled double-blind and the results were similar in each of these it was conversion of recent onset afib that is less than seven days in fifty two

Percent of the drug treated patients but only four percent of placebo-treated patients with a median time of eight to eleven minutes if the patients have longer lasting afib that is 32 45 days the conversion rates were 38 to 40 one percent versus three to four percent with placebo interestingly the drug does not work for atrial flutter perhaps because its effects

Are more marked in the left atrium than the right potentially serious adverse events were 1.4 to 2% in these trials vs 0 to 1 percent in the sebo treated patients with no torsades so you can see it appears to be a pretty safe drug in on the right of the slide you can see from the largest of the trials the act one study in white placebo and in magenta burn a comment

You can see the short and long duration af conversion rates compared to placebo and the far right the overall population the most common adverse events have been discussing in paris leashes there have been very rare as significant adverse hemodynamic effects braddock rd and hypotension both less than 1% perhaps vaguely mediated the trials did exclude severe heart

Failure in acute mi and i suspect that any package insert that’s developed will likely exclude symptomatic ischemia or history of heart failure or hypotension there were two ventricular fibrillation one adept in the severe aortic stenosis patient who was a protocol violator should not have received this drug suggesting a risk great about 1.4 per thousand patients

In individuals with prior risk factors and there’s one tour side in the database in which the drug was given subsequent to i butyl i’d which was also a protocol violation and i buta lodgers you know has a significant incidence of tour sod the fda requested an additional trial to be performed it’s anticipated that this will be completed sometime in 2011 or early

2012 and oral studies are also underway and not all of the investigational agents have been successful vasa rod a ht for receptor antagonist zima lied to dis amell of going by the wayside but as you can see from this list there are many many more both a tro selective derivatives of amiodarone the app junction modifiers so stay tuned this is a growing list in an

Exciting field thank you for your attention

Transcribed from video
New AADs for Atrial Fibrillation – Trial Data By JAFIB- Journal of Atrial Fibrillation