Interactive Pill Bottle Caps

Just saw this advertised for patients taking Multaq (dronedarone): interactive pill bottle caps called "GlowCaps:"

GlowCaps^TM is a bottle with built-in wireless communication... When you receive your GlowCap^TM, you program it with your schedule. It will then remind you when it's time to take Multaq by lighting up, playing a melody, or calling your home phone. If you and your physician choose, your GlowCap^TM can also send weekly reminder e-mail to you and a caregiver, send reports to your doctor, and refills can be initiated with the push of a button, if you provide a phone number when registering.

Okay. That's pretty cool.

How It Works

Glowcap^TM, manufactured by Vitality, Inc, has an embedded computer chip that communicates via low frequency RF with a cellular connected nightlight. The nighlight sends information to Vitality via a GE864-QUAD chip, over the AT&T GSM/GPRS network. Hence you must be in an AT&T wireless network area.

But I do worry about alarm fatigue. And how much does this cost? Will patients just ignore their pills or even grow to hate their melodies? And what happens when everyone's pill bottles go off at the symphony? Or what about pill identification: "Doc, it's the one that sounds like a wind-chime." Finally, if I start getting e-mail reports (spam?) from patients regarding their Multaq pills, I really, really won't be happy.

Just because technology can do all these things, doesn't mean it always should.

Still, it shows where technology is taking us in a hurry.

-Wes

Who Should Be Prescribed Dronedarone?

With Sanolfi's release today of their dear doctor letter restricting the use of dronedarone to patients without permanent atrial fibrillation OR atrial flutter, we are left to wonder why paroxysmal atrial fibrillation patient therapy is any safer. (We are also left to ask why the letter is hidden behind MedScape's registration process rather than easily accessible on their website, but that's another matter to take up another day).

Why the quandry? Because of how permanent atrial fibrillation was defined for the study:

Permanent AF was defined by the presence of
AF/atrial flutter (AFL) for at least 6 months prior to randomization and patient/physician decision to allow AF to continue without further efforts to restore sinus rhythm.

Does merely electing to not attempt a cardioversion on a patient with atrial fibrillation or atrial flutter truly define "permanent" atrial fibrillation? Not typically - usually we define permanent atrial fibrillation as someone who fails elective cardioversion long-term. But for the intent and purpose of the PALLAS trial on which the "Dear Doctor" letter is based, it is how the "permanence" of atrial fibrillation was defined.

"Persistent" atrial fibrillation are those patients in atrial fibrillation who CAN be converted to sinus rhythm using cardioversion and whose event lasts more than seven days.

Which leads to the logical question: how many "persistant" afib patients were part of the PALLAS patient population and might "persistant" atrial fibrillation patients be similarly at risk?

It's all as clear as mud.

-Wes

The Clinical Costs of Pharmachologic Post-Market Surveillance

Every drug a doctor prescribes requires an intimate knowledge of the drug's pharmacology, side effects, and possible drug interactions. Nowhere is this more true than antiarrhythic drugs. Concern over side effects with government regulators has reached a fever pitch since there is realization that all the pre-market randomized controlled trials often fail to identify later problems with medications. A classic example of this is dronedarone, initially heralded as a "safer" amiodarone substitute, but was later implicated in rare instances of fulminant hepatic failure.

While post-market surveillance of medications is both necessary and warranted, it is interesting to me how the grunt work of this surveillance (and most other grand regulatory schemes) falls squarely on the backs of physicians rather than the drug companies who manufacture and profit from the medications.

Case in point: the FDA's REMS program. REMS stands for "Risk Evaluation and Mitigation Strategy" and is a program developed by the FDA "to manage known or potential serious risks associated with a drug product. It is required by the Food and Drug Administration (FDA) to ensure that the benefits of a drug outweigh its risks." It covers an increasingly large array of medications.

But what does this grand plan require the drug companies to do?

Drug companies must create a database.

But for doctors who prescribe these antiarrhythmic medications and are board-certified to do so, we now have to perform a "one-time" re-certification that involves filling out a form and agreeing, in writing, to mandated patient appointment frequencies and minimum requirements for patient education that must be conducted during our office visits.

Such is the case with Pfizer's antiarrhythmic medication dofetilide (marketed as Tikosyn). Realize this "re-certification" comes AFTER we have all had to conduct a training regimen and were already registered with the company to prescribe the drug.

The REMS program, begun in 2008, grew more inclusive (and intrusive) after identification of a White House "crisis" involving prescription drug abuse of opioid analgesics that surfaced in April of this year. This edict has now trickled down to the clinical front lines of care with some very significant clinical consequences.

As clinical volumes rise, doctors are finding it increasingly difficult to reach the Utopian vision of frequent patient follow-up for drug surveillance for the pharmaceutical industry. Certainly, if there is clinical reason to do so (marginal renal function, higher-dose therapy, confounding medical issues) we see patients more frequently as needed. But in stable, relatively healthy patients who have a history of safely using these medications, we are left to wonder if the FDA's surveillance program has the potential to limit our ability to see new patients in favor of only managing established patients on chronic medication regimens that require close follow-up.

Clearly, there should be a balance. For many doctors (myself included) we have had to resort to using a nurse practitioner to assist with this requirement to offload the crush of such mandated patient visits. But for doctors in smaller, more rural settings where ancillary care providers are harder to come by, I suspect others will quickly saturate their clinics with regulated patient visits or else just not offer these medications to their patients.

This balance of safety and quality care to the oncoming tsunami of patients sure to hit our door in 2014 is an interesting dilemma not easily solved. Still, innovative ways to avoid top-down regulations that are crushing doctors with mandated (and often clinically unnecessary) care will go a long way to improving the quantity of care we are able to provide our growing population of patients.

-Wes

Multaq's Off Again, On Again, Then Off Again Ride

Today was another tough day for Sanofi's dronedarone antiarrhythmic medication (marketed as Multaq®) after the prospective randomized PALLAS Trial was stopped early. The PALLAS Trial was a trial that studied the safety and efficacy of patients with chronic atrial fibrillation (as opposed to the already-approved patient population with intermittent (or paroxysmal) atrial fibrillation). It seems there was an increased number of "cardiovascular events" in the drug-treatment arm of the trial and was NOT related to problems with hepatic toxicity as previously reported earlier this year.

Patients with intermittent atrial fibrillation already on the drug are encouraged NOT to stop their drug, but rather "consult your treating physician if you have any questions."

But Multaq's path through the drug approval process has been a rocky one. First came the ANDROMEDA Study, a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms. In this study, patients given Multaq had a greater than two-fold increase in mortality. Needless to say the FDA was not too pleased, so the drug failed to gain approval for that indication.

So the drug company decided to try a less sick population and began the ATHENA Trial. The ATHENA trial was the largest anti-arrhythmic drug trial conducted in patients with non-permanent AF/AFL, involving 4,628 patients with a follow-up of 30 months. In this trial, Multaq, on top of standard cardiovascular therapy, significantly reduced cardiovascular hospitalization or death by 24 percent (p<0.001) when compared to placebo, meeting the study’s primary endpoint. So the FDA granted the drug approval for this indication, provided the patients were carefully screened for heart failure (a contraindication to begin therapy).

All seemed right with the world for Sanolfi, at least for a while. Doctors began using the drug but were generally disappointed in its efficacy despite its hype, being an amiodarone cogener and all. Still, plenty of pressure was applied to the writers of our quidelines to make sure this "highly studied" drug was first and foremost of recommended therapies in the latest atrial fibrillation treatment guidelines. In fact, Multaq® is currently available in 32 countries and is recommended as a first line treatment option in the majority of AF patients by BOTH the ESC and ACC/AHA.

Pretty impressive, given its earlier challenges getting approved.

But now we get the news about the PALLAS trial and we have to wonder: if its unsafe for older, sicker patients, why should it be okay for our younger ones?

We really don't know.

But our antennae certainly are at attention now regarding Multaq. I suspect many doctors will now think long and hard before leaping to dronedarone as their "first line" therapy despite the current recommendations of our "guidelines." More likely, this drug will be used when there are no other options (and there are those cases). Truth be told, most of our pharmachologic therapies to manage atrial fibrillation are problematic for many of our patients for one reason or another: either they have significant side effects or else they just don't work. This is largely why the more invasive atrial fibrillation ablation procedure has gained favor.

But ablation is not a cake-walk either.

That is why the current NIH-co-sponsored CABANA trial comparing catheter ablation to drug therapy as first line therapy remains so important to continue.

Then maybe, just maybe, we can learn which therapy really does benefit our patients best long-term.

-Wes

Dronedarone and Liver Failure?

Bad news for Sanolfi Adventis from Larry Husten over at Cardiobrief:

Sanofi-Aventis is about to send a “Dear Doctor” letter to physicians informing them of two cases of fulminant hepatic failure/necrosis resulting in liver transplanation in two patients taking Multaq (dronedarone), CardioBrief has learned. The two patients were women in their 70′s with no other apparent causes of liver injury or known elevations of liver function tests (LFTs) prior to the acute liver failure. Liver failure developed after the women were taking dronedarone for four to six months.

CardioBrief has also learned that Sanofi-Aventis plans to change the drug’s label and will recommend that physicians obtain LFTs at baseline prior to prescribing the drug. The company had previously informed clinical investigators working with the drug about the liver failure cases.

Recall the rocky road that Multaq had to travel to gain FDA approval - it was only approved after patients with congestive heart failure were excluded from the drug's pivotal Athena Trial. Post-approval, it was marketed as a safer alternative to Amiodarone so if true, these cases raise new questions regarding this niche for the treatment of atrial fibrillation.

The specifics of the two affected patients remain unknown to me (did they have a history of CHF?) Still, if true, this drug will certainly no longer be one of the initial recommended therapies for paroxysmal atrial fibrillation management as the new 2011 AF treatment guidelines have suggested, and probably won't be used much at all until the dust settles on this story.

-Wes

Addendum 14 Jan 2011: The released FDA Drug Safety Communication on dronedarone (Multaq) contains this clincial information on the two patients with liver failure:

The two cases of acute hepatic failure requiring transplantation occurred at 4.5 and 6 months after initiation of dronedarone in patients with previously normal hepatic serum enzymes. Both patients were female and approximately 70 years of age. In the first case, the patient had underlying intermittent atrial fibrillation, arterial hypertension and stable coronary artery disease. She was treated with dronedarone for 4.5 months. Two weeks prior to hospitalization she reported increased exhaustion and tiredness. One week prior to admission she discontinued dronedarone, and at the time of admission she was noted to have jaundice, coagulopathy, transaminitis and hyperbilirubinemia, which progressed to hepatic encephalopathy over the next nine days. A pre-transplant workup did not reveal another etiology of liver failure. In the second case, the patient had a medical history of paroxysmal atrial fibrillation and Sjogren's syndrome. Following 6 months of treatment with dronedarone she developed weakness, abdominal pain, coagulopathy, transaminitis and hyperbilirubinemia. She was transplanted 1 month later; no alternative etiology for liver failure was identified in the transplant work-up. In both cases, the explanted liver showed evidence of extensive hepatocellular necrosis.

Addendum 1/16/2011: The distributed Sanolfi Adventis "Dear Doctor" letter.

Basics of Atrial Fibrillation Pharmachologic Management

... nicely reviewed by interventional cardiologist and a fellow physician blogger, Sarah Clarke, MD over at the BCS blog.

-Wes

Mission Impossible

The elevator door opens, and a handsome man wearing dark glasses appears, looking something like a Gentleman's Quarterly magazine model. He makes this way to the swank hotel lobby front desk, and is immediately noticed by the young clerk with the French accent.

“Bon jour, monsieur. May I help syou?”

“I understand there might be a package for me here.” he asks in a hushed tone.

“Ze name?”

“Phelps.”

“Shust a moment, Monsieur Phelps.” She retreats behind the desk and returns, carrying a manilla envelope. “Here you are, monsieur.”

He walks quietly to a corner table at the hotel’s dining room, tipping the waiter to permit him some privacy for a few minutes. He sits, opens the envelope, and removes its contents. A small Bluetooth headset and latest Apple iPhone GS-99 XKE is removed. He deftly assembles them and finds the video play button. A man appears.

“Good morning, Dr. Phelps.”

He smiled slightly. He liked to hear that familiar introduction. The video continued:

“As you know, Sanofi-Aventis, makers of the new drug to treat atrial fibrillation, dronedarone (Multaq), have been actively recruiting doctors to serve as speakers to promote their drug. They are required to speak verbatim from slides housed on a central server using a protected link to the server's flash-player software. No anecdotes can be uttered lest they be terminated. Most remarkably, Interpol has discovered that when recent physician recruits inquired about the cost of the drug as it compares to its competitors, a lawyer stood and claimed that discussing price was illegal. He claimed that because the price would vary from location to location, to discuss price would put the company at liability risk for false advertising.

Your mission, Jim, should you decide to accept it, is to find the price of dronedarone that patients and pharmacy benefit managers will have to pay on the open market. Your unique status as a cardiac rhythm specialist, paired with your unique background, should make it easy to infiltrate the organization. As always, if you or any members of your team are caught and terminated, the Secretary will disavow any of your actions.

Good luck, Jim.

This video will self distruct in five seconds."

Seconds later: Shhhhhhhhhhhhhhhhhhh. Bbbbbzzzaaaappppppppppppp. The iPhone screen went black.

He pondered the mission as he glanced about making sure no one saw the phone screen.

Somehow, the French woman behind the counter seemed the simpler mission.

-Wes

Addendum from Interpol: "Good work, Dr. Phelps."

Prasugrel and Dronedarone: Rough Roads to Approval

This past week or so was the week for the FDA to issue approvals of two drugs with tough paths to approval: prasugrel (marketed by Eli Lilly as "Effient®"), a potent platelet inhibitor used following acute coronary interventions and dronedarone (marketed by Sanofi-Aventis as "Multaq®"), an antiarrhythmic and cogener of amiodarone that does not contain Amiodarone's iodine molecule, which was approved for therapy of atrial flutter and atrial fibrillation is patients without severe congestive heart failure.

Prasugrel (Effient®)

Prasugrel is a thienopyridine — a prodrug that, like clopidogrel, requires conversion to an active metabolite before binding to the platelet P2Y12 receptor to confer antiplatelet activity. In the TRITON TIMI-38, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding while overall mortality did not differ significantly between treatment groups. The trial used a 60-mg loading dose, followed by a 10-mg maintenance dose administered after an acute coronary intervention. It seems that the concerns about bleeding did not escape the FDA's watchful eye, especially in lieu of the controversy surrounding the Cardiovascular and Renal Drugs Advisory Committee's decision to remove Sanjay Kaul, M.D., of Cedars-Sinai Medical Center in Los Angeles, an outspoken critic of the potential bleeding complications of the drug.

Dronedarone (Multaq®)

In 2006, the FDA shot down approval of dronedarone because of its limited effectiveness or safety, we weren't sure. In 2007 additional European data demonstrated efficacy and safety of the drug. In 2008 the drug was granted a reprieve by the FDA after the preliminary results of the Athena Trial that excluded patients with severe CHF were published and demonstrated a reduced incidence of hospitalization due to cardiovascular events or death in patients with atrial fibrillation administered 400 mg twice a day of the medication compared to placebo.

Precisely when these drugs will be available to the general market is uncertain, but I suspect you'll know when meals start showing up in cath labs and offices again.

-Wes

Living With Atrial Fibrillation

I read this recent article by New York Times business writer Duff Wilson regarding his mother's difficulties managing atrial fibrillation: the need for anticoagulation, ineffectiveness of cardioversion, the side effects of the antiarrhythmic drugs, and her indecision regarding future drug or device therapies. For now she has decided leave her rhythm alone and (hopefully) stick with just anticoagulation. For some, doing nothing might just be the best option, provided the heart rate is well-controlled.

Our drugs are just not that effective for atrial fibrillation. Any of them. Even the upcoming dronedarone. Certainly some may work better in some patients than others, but once you fail one drug (especially amiodarone), the odds of having long-term success with another drug is limited (dofetilide might be an exception here, but can only be used in patients with normal or near-normal kidney function).

Sometimes, though, I find its helpful to try to determine what causes some one's fatigue. Is it the rapid heart rate, the irregularity of the heart rhythm, or the loss of mechanical synchronization between the atria (top chambers) and the ventricles (bottom chambers) of the heart.

If the patient complains of racing heart rhythms, then using rate control medications like beta blockers or calcium channel blockers may be all that's needed to improve their symptoms.

If the patient complains that the irregularity of the rhythm is what bothers them, then there is a good chance that a pacemaker might improve their symptoms since their rhythm can be regularized after implanting the pacemaker and then ablating the AV node. While this has the downside of rendering someone pacemaker-dependent for their heart to beat, in the older age group, this therapy has been shown to demonstrate marked improvement in symptoms with only the need for ongoing anticoagulation without the potential side effects and toxicities of antiarrhythmic medications. In the older crowd, this might not be such a bad option.

Finally, if the person's primary complaint centers on fatigue, there are two options: (1) do nothing and continue anticoagulation (since fatigue may be a difficult symptom to resolve) or (2) consider catheter ablation of the atrial fibrillation - provided the risks of the procedure are carefully reviewed. In a small subset of patients, octogenarians were thought to be as safely treated with catheter ablation as younger adults. This study was limited, however, by its retrospective design and limited numbers. What has not been shown yet is a mortality advantage to this approach and certainly there are plenty of risks with this procedure.

Finally, the need for follow-up after any one of these therapies is undertaken might vary and influence which therapy to recommend. The take-home message here is that no two patients' needs are alike and sometimes it's tough to always make the "perfect choice."

Anyway, just some thoughts. It'd be interesting to read what others might recommend.

-Wes

Dronedarone Granted Reprieve

It seems Sanofi-Aventis's amiodarone analog drug, dronedarone (marketed as Multaq®), was granted a stay of execution by the FDA:

Multaq appeared at one stage to have little future, after an early clinical trial showed excess mortality and the drug was rebuffed by regulators.

As we recall:

Dronedarone is structurally similar to amiodarone but lacking the iodine moiety — a feature of amiodarone that has been linked to many non-cardiac side effects (including pulmonary toxicity, ocular effects, thyroid disease, and hepatic dysfunction). The Dronedarone Atrial Fibrillation Study After Electrical Cardioversion (DAFNE) trial demonstrated the efficacy and safety of dronedarone in preventing AF recurrence after cardioversion in 199 patients. In the EURIDIS (European trial in atrial fibrillation or flutter patients receiving dronedarone for the maintenance of sinus rhythm) and ADONIS (American–Australian–African trial with dronedarone in atrial fibrillation or flutter patients for the maintenance of sinus rhythm) trials, dronedarone was effective in preventing AF recurrence and was shown to reduce the ventricular response during AF relapse. There was no evidence of proarrhythmia (including TdP), heart failure exacerbation, or thyroid, pulmonary, or other organ toxicity. The mortality rate was low (1.0%) and not significantly different from placebo (0.7%) during the 12-month follow-up. However, the Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) was stopped prematurely because of a trend towards increased risk of death in the dronedarone group, but this numerical increase in mortality was not statistically significant. In 2006, the United States Food and Drug Administration issued a non-approvable letter based on safety concerns. Consequently, the drug manufacturer withdrew an application for licensing to the European Agency for the Evaluation of Medicinal Products.

But new results from the Athena Trial (ppt) that excluded severe (Class IV) heart failure patients were favorable (except for some problems with a slight decline in renal function) suggesting the drug may become a promising new treatment for atrial fibrillation if approved by the FDA (decision expected in late January, 2009).

-Wes

Dronedarone - A Safer Amiodarone?

Today, the New England Journal of Medicine reports on the safety and efficacy of dronedarone (Sanofi-Adventis (SNY) from the identically-designed EURIDIS and ADONIS (American-Australian-African trial with DronedarONe In atrial fibrillation or flutter patients for the maintenance of Sinus rhythm) trials. Dronedarone was effective at reducing the time to recurrent atrial fibrillation compared to placebo.

From this press release:

The ADONIS study showed that the median time from randomization to a first adjudicated AF/AFL recurrence was 2.7-fold longer in the dronedarone group than in the placebo group. Dronedarone significantly decreased the risk of a first recurrence of AF/AFL within the 12-month study period by 27.5% compared to placebo (log-rank test p=0.0017).

Most initial AF/AFL recurrences were symptomatic in both groups of patients. Overall incidence of adverse events was comparable in the two groups (73% in the placebo arm and 80% in the dronedarone group, (p = ns)) and dronedarone also displayed good cardiac tolerability, with no cases of torsades de pointes.

This trial was so reaffirmed earlier reporting of the trials from 2004 regardings to the long-term efficacy of the drug. As in the earlier 2004 reporting, this trial still demonstrated a disappointing recurrence rate of atrial fibrillation in the treatment group:

At 1 year of follow-up, the risk for AF recurrence in the European arm of the study was 67% with dronedarone, compared with 77% with placebo; in the non-European arm, the risk for AF recurrence was 61% with dronedarone, compared with 73% with placebo.

It was important to note the following about the use of dronedarone in patients with congestive heart failure (from the NEJM article):

A previous study, the Antiarrhythmic Trial with Dronedarone in Moderate to Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA), was discontinued early because an interim safety analysis suggested a potential increase in the risk of death with dronedarone therapy. The discontinued trial involved patients with moderate-to-severe congestive heart failure and ventricular dysfunction, and thus investigated a different (and higher-risk) population than the patients we studied. In our trials, the rates of death from any cause and sudden death in the dronedarone group did not differ significantly from those in the placebo group. Nonetheless, the experience with the ANDROMEDA trial indicates that dronedarone may be associated with an increased risk of death in patients with advanced congestive heart failure and that the drug should not be used in such patients until appropriate data are gathered.

This is an important distinction between dronedarone and its cousin amiodarone (which can be used in these higher risk patients). Still, given the limited number of effective medicines available for treatment of atrial fibrillation these days, the drug may still fill an important niche.

-Wes

References:

Bramah N. Singh, M.D., D.Sc., Stuart J. Connolly, M.D., Harry J.G.M. Crijns, M.D., Denis Roy, M.D., Peter R. Kowey, M.D., Alessandro Capucci, M.D., Ph.D., David Radzik, M.D., Etienne M. Aliot, M.D., Stefan H. Hohnloser, M.D., for the EURIDIS and ADONIS Investigators. "Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter" New Engl J Med, September 6, 2007, 357 (10):987-999.

Medscape (free registration required).