Про дронедарон

[thorn]

Сообщение от Nastydoc

Dronedarone Trial Suspended Due to CV Events in Permanent AF
[Ссылки доступны только зарегистрированным пользователям ]

The PALLAS trial was testing the drug in patients with permanent atrial fibrillation (AF) and at least one other cardiovascular disease risk factor; at present, dronedarone is approved in patients with nonpermanent AF.

Не понимаю, зачем при перманентной фибрилляции предсердий дронедарон? Кто пояснит? Для rate control?
Вот это понравилось:

"For patients who are currently on dronedarone and who have nonpermanent AF, I would say that it's reasonable to stay on the drug, and I don't think they should be worried."

Это после вот такого пассажа:

co-primary investigator Dr Stuart Connolly (McMaster University, Hamilton, ON) said he could not provide details on the types of cardiovascular events seen. "Suffice it to say . . . there was a significant increase in major cardiovascular events, and in our study that was defined as a composite of stroke, MI, systemic embolism, or cardiovascular death. . . . These were pretty important events."

Прекрасно...

[Nastydoc]

ну дак написано, что пациентов с непостоянной формой просят не волоновацо, таблетки принимать. что такого-то? повышение рисков ведь зафиксировано в исследовании постоянной формы. Проясняют для обывателей, чтобы не запутались.

[Gilarov]

Сообщение от thorn

Не понимаю, зачем при перманентной фибрилляции предсердий дронедарон? Кто пояснит? Для rate control?

Ну, типа, да. Идея была такая: 1) дронедарон неплохо урежает ЧСС и 2) в исследовании ATHENA отмечено было снижение смертности и частоты госпитализаций вне зависимости от эффективности контроля ритма дронедароном. Отсюда и PALLAS. Только результаты совсем неожиданные. Как в ANDROMEDA...

[Chevychelov]

А что урежать-то. Урежать-то практически нечего:
Класс III – нет пользы
1. Лечение, чтобы достигнуть строгого контроля частоты сердечных сокращений (ЧСС) (< 80 уд в мин в покое или
< 110 уд в мин во время 6-минутной прогулки), не полезно по сравнению с достижением ЧСС в покое < 110 уд в мин у пациентов с персисстирующей ФП, которые имеют стабильную желудочковую функцию (фракция выброса левого желудочка > 0.40) и не имеют или имеют приемлемые симптомы связанные с аритмией, хотя неконтролируемая тахикардия может в течение долгого времени ассоциироваться с обратимым снижением
желудочковой работы.3 (Уровень доказанности: B)
[Ссылки доступны только зарегистрированным пользователям ]

[Gilarov]

А что, у всех пациентов с ФП ЧСС менее 110 и ФВ более 40? Опять же как Вы выражаетесь, не все имеют приемлемые симптомы, связанные с аритмией. Некоторые имеют неприемлемые. Или не имеют приемлемые. Не знаю, как правильно.

[Chevychelov]

Сообщение от Gilarov

А что, у всех пациентов с ФП ЧСС менее 110 и ФВ более 40? Опять же как Вы выражаетесь, не все имеют приемлемые симптомы, связанные с аритмией. Некоторые имеют неприемлемые. Или не имеют приемлемые. Не знаю, как правильно.

Класс III- Вред
1. Дронедарон не должен назначаться пациентам с классом IV
сердечной недостаточности или пациентам, которые имели
эпизод декомпенсированной сердечной недостаточности за последние 4 недели, особенно если у них сниженная левожелудочковая функция (фракция выброса левого желудочка ≤35 %). 30 (Уровень доказанности: B)

[Gilarov]

Увы, но Ваша цитата на мой первый вопрос не отвечает. Тем не менее,опять спрошу, а что не бывает ХСН II ФК при ФВ 30%?

[Chevychelov]

Бывает... Да я и не спорю. Я к тому, что трайлы и даже гайды оставляют простор клиницисту для принятия решения. Я вот кордароном практически никогда не урежаю при хронической ФП. Пользуюсь в основном бисопрололом и дигоксином и хватает. А другие пользются. Наверное также будет и с дронедароном... Теперь вот можно при ЧСС 100 не суетиться.

[BMB]

при ФВ 30% я бы предпочел не назначать дронедарон, даже если не было эпизода декомпенсированной сердечной недостаточности не только за последние 4 недели, а и вобще не было, и ф. класс только I - II. Тем более - для урежения ритма.

[Gilarov]

Сообщение от BMB

при ФВ 30% я бы предпочел не назначать дронедарон

У Вас для этого есть какие-то аргументы? М. б. личный негативный опыт?

[BMB]

Сообщение от Gilarov

У Вас для этого есть какие-то аргументы? М. б. личный негативный опыт?

Нет, личного опыта такого нет. Просто осторожность, возможно, в данном случае иррациональная. Предпочитаю подождать накопления большего объёма данных, посмотреть на чужой опыт в подобных ситуациях.

[thorn]

подробности... [Ссылки доступны только зарегистрированным пользователям ]
CV death, MI, stroke, systemic embolism Hazard ratio 2.3 p=0.009

The FDA announcement notes that while the PALLAS data are still considered preliminary, it will be important to address the "critical question" of "whether and how the unfavorable results of the PALLAS study . . . apply to patients who use Multaq for the approved indications."

[Chevychelov]

WASHINGTON -- The FDA confirmed Thursday that it is reviewing safety data from a clinical trial of dronedarone (Multaq) that was halted when the data monitoring committee discovered a twofold increase in death among atrial fibrillation patients treated with the drug.

In the trial of more than 3,000 patients, there were 32 deaths in the dronedarone arm versus 14 in the placebo group (P=0.009), and for the combined endpoint of death or unplanned hospitalization, the difference was also highly significant, at 118 versus 81 (P=0.006).

There were 17 strokes in the dronedarone arm versus seven in the controls (P=0.047).

In January, sanofi-aventis, the drug's maker, and the FDA warned that reports of acute liver injury associated with the drug had been received.

Then, earlier this month sanofi-aventis, announced that it had halted its Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study. The study enrolled patients with permanent atrial fibrillation and randomized them to dronedarone or placebo on top of standard therapy.

At the time that it was halted, PALLAS, which is a phase IIIb study, had enrolled 3,148 patients with permanent afib, with 70% showing symptoms for more than two years.

Dronedarone is currently approved for paroxysmal afib and atrial flutter, but is not approved for permanent atrial fibrillation.

The FDA said a critical question, which it is reviewing, is whether "and how the unfavorable results of the PALLAS study, obtained in patients with permanent atrial fibrillation, apply to patients who use Multaq for the approved indications."

Currently more than 240,000 Americans are taking dronedarone.

In addition to the FDA action, HealthCanada also announced Thursday that it is reviewing Multaq's safety; the Canadian government health agency said it would "take appropriate regulatory action as necessary once the review is complete."

[Chevychelov]

Europe Eyes Afib Drug Restriction

By Chris Kaiser, Cardiology Editor, September 22, 2011

Review

The European Medicines Agency (EMA) today recommended restricting the use of the antiarrhythmic drug dronedarone (Multaq) because of its adverse event profile.

The drug has been associated with an increased risk of liver, lung, and cardiovascular adverse events.

The EMA's Committee for Medicinal Products for Human Use (CHMP) said dronedarone should be prescribed only for maintaining sinus rhythm after successful cardioversion in patients with paroxysmal or persistent atrial fibrillation or after alternative treatment options have been considered and rejected.

In January, the FDA said it would require a warning about the potential for liver injury added to the drug's label.

Then in July, drugmaker sanofi-aventis pulled the plug on the PALLAS trial because of an increase in cardiovascular events. PALLAS was testing dronedarone in patients with permanent atrial fibrillation, for which it is not approved.

The EMA committee initiated its review of the drug following reports of severe liver injury and the discontinuation of the PALLAS trial.

The committee acknowledged, however, that dronedarone remains a useful treatment option for some patients.

It also cautioned that the drug must not be used in patients with permanent atrial fibrillation, heart failure, or left ventricular systolic dysfunction and that doctors should consider discontinuation of treatment if atrial fibrillation reoccurs.

Patients on amiodarone should have regular monitoring of lung and liver function and heart rhythm. It's especially important to monitor liver function closely during the first few weeks of treatment, according to the committee.

The European Commission will consider the committee's recommendation.

[Chevychelov]

Dronedarone Hazardous in Permanent Afib

By Crystal Phend, Senior Staff Writer,
November 14, 2011

Action Points
Note that in a previous study (ATHENA) dronedarone (a modified amiodarone, with presumably reduced toxicity) was associated wiht reduced hosptalization for cardiovascular causes and cardiovascular death as well as reduced stroke rates in atrial fibrillation.


Note however that in the present study (PALLAS) dronedarone was associated with increased stroke, MI, and cardiovascular death in patients with permanent atrial fibrillation necessitating stoppage of the study for safety reasons leading to recommendations that the drug should not be used in patients with permanent atrial fibrillation.
Review

ORLANDO -- Dronedarone (Multaq) shouldn't be used in permanent atrial fibrillation due to cerebrovascular, cardiovascular, and mortality risks, researchers warned.

Analysis of the halted PALLAS trial turned up a 2.29-fold excess in stroke, myocardial infarction, systemic embolism, and death from cardiovascular causes combined among patients on the rhythm control drug (P=0.002).

Hospitalization for heart failure also was elevated a relative 81% compared with placebo (P=0.02), Stuart Connolly, MD, of McMaster University in Hamilton, Ontario, and colleagues reported online in the New England Journal of Medicine.

These results from the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) were also presented here at the American Heart Association meeting.

Despite low absolute numbers of events in the permanent atrial fibrillation patients with vascular event risk factors, the message for clinical practice was clear, the investigators noted.

"Our data show that dronedarone is hazardous in such patients," they wrote.

The European Medicines Agency agreed.

After drugmaker sanofi-aventis announced termination of the trial in July over safety concerns, the regulatory agency recommended restricting use to only paroxysmal or persistent atrial fibrillation or after other options had been considered.

The FDA also has an ongoing safety review of the data, looking at implications for the drug's approved indications.

The strikingly negative results of PALLAS caught many by surprise, noted Stanley Nattel, MD, of the Montreal Heart Institute and University of Montreal, in an accompanying editorial.

Dronedarone, a modified version of amiodarone (Cordarone, Pacerone), had not only reduced hospitalization for cardiovascular causes and cardiovascular death in the ATHENA trial, but was also the first antiarrhythmic to reduce stroke rates in atrial fibrillation.

But there had been signs of trouble in the earlier ANDROMEDA study, which had to be stopped due to increased mortality with dronedarone in an atrial fibrillation population with advanced heart failure and recent hospitalization for decompensation.

Notably, PALLAS' population of 3,236 patients 65 and older with at least six months of permanent atrial fibrillation and risk factors for major vascular events was closer to ANDROMEDA than ATHENA in prevalence of heart failure and digoxin use.

The list of risk factors that would qualify a patient for enrollment in PALLAS included symptomatic heart failure, which was present in two-thirds.

And 88% were on a rate-control medication -- digoxin in one-third.

Those two factors may partially explain the negative results of the trial, the researchers suggested.

Dronedarone raises digoxin levels -- by an average 33% in PALLAS to an average 1.2 ng/mL, above which digoxin toxicity has been linked to cardiovascular death.

Digoxin use in ANDROMEDA was similar to that in PALLAS, but with only around 30% of patients on the medication, "it is hard to see how digitalis toxicity could explain the increased rates of stroke and heart failure," the editorialists argued.

They noted that heart failure has a clear association with potentially fatal effects of antiarrhythmic drugs.

But both groups concluded that they couldn't really determine what the cause of the negative findings was.

The researchers warned that early termination of the study substantially reduced its statistical power, potentially biasing the results toward finding higher risk with dronedarone.

The primary broad composite endpoint comparison was based on only 43 versus 19 events, while the co-primary of unplanned cardiovascular hospitalization or death occurred in 127 and 67 patients, for a 95% higher risk with dronedarone (P<0.001).

Other measures also came up statistically significant for a higher risk with dronedarone:
All-cause mortality (25 versus 13 events, hazard ratio 1.94, P=0.049)
Cardiovascular mortality (21 versus 10, HR 2.11, P=0.046)
Arrhythmia-related death (13 versus 4, HR 3.26, P=0.03)
Stroke (23 versus 10, HR 2.32, P=0.02)
Unplanned hospitalization for cardiovascular causes (113 versus 59, HR 1.97, P<0.001)


Whatever the reason for these results, it's reasonable to avoid dronedarone in heart failure and other advanced cardiovascular disease, particularly when in the setting of permanent atrial fibrillation, the researchers suggested.

The editorialists agreed that permanent atrial fibrillation patients have no reason to receive antiarrhythmic drugs, and certainly should not receive dronedarone.

"In light of the poorly understood adverse outcomes in PALLAS and previous observations in ANDROMEDA, it will be necessary to reexamine guidelines for the management of atrial fibrillation and to reserve dronedarone for selected low-risk patients with persistent or paroxysmal atrial fibrillation, possibly those in whom other antiarrhythmic drugs have failed," they concluded.