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

Could Potent Antacids Affect The Effectiveness of Antiplatelet Agents?

Today's Journal of the American College of Cardiology reports that omeprazole (Prilosec®), a potent antacid that works by proton pump inhibition and is commonly presribed to prevent gastrointestinal bleeding in patients administered clopidogrel (Plavix®) following coronary interventions, interacts with clopidogrel to reduce its effectiveness as an antiplatelet agent.

The clinical implications of this remain uncertain but clinicians should be aware of this possible interaction following angioplasty or stenting procedures.

-Wes

FDA and Stents: Bet on Aspirin and Plavix

There seems to be a lot of gnashing of teeth about what to recommend for people who have received drug-eluting stents. Should patients continue the anti-platelet (and hence, anti-clotting) drugs, aspirin and clopidogrel (Plavix) indefinitely? Or should these drugs be stopped sometime after one year?

A big, manufacturer-friendly, FDA “advisory panel” will convene on Thursday and Friday in Gaithersburg, Maryland to discuss this topic and review meta-analyses, anecdotal-isms and retrospective registries. No one will have any prospective, randomized data over many years comparing the risk of clot-formation in stents compared to the risk of bleeding from Plavix and aspirin.

It is important to remember that restenosis of bare metal (non- drug-eluting) stents due to the growth of scar-like tissue (called "neointimal hyperplasia") inside the bare stent was a real problem in patients before drug-eluting stents hit the market. Smaller diameter stents were most likely to develop this complication compared to larger diameter stents. But after drug-eluting stents burst into the market, this problem became much less prevalent. Cardiologists stopped seeing the "frequent fliers" for repeat stenting and no longer performed the more complicated brachytherapy (radiation) to prevent restenosis. Cardiologists aren't stupid: they liked this feature of drug eluting stents.

Unfortunately, over the course of time, it was eventually discovered that drug-eluting stents occassionally clot shortly after the Plavix medication was discontinued. This didn't happen all the time, mind you. It happened about 5 percent of the time. But unlike restenosis of bare metal stents that occurs slowly, the clotting seen after stopping Plavix in a drug-eluting stent is often an abrupt, sudden event leading to much larger heart muscle damage.

It became clear that taken together, Plavix and aspirin are important deterrents to the formation of blood clots in stents. But the long-term risks of life-long Plavix, especially it’s risk for developing later bleeding complications, are unknown. And Plavix is expensive. Many cannot afford the drug and Medicare doesn’t cover the drug unless individuals carry a supplemental drug benefit.

The problem now, in my view, is that there are lots and lots of drug-eluting stents in patients already out there. Stents, once deployed, can’t be removed. And we cannot abandon our patients. So the clot-preventing drugs aspirin and Plavix must be continued for at least a year, or better yet, indefinitely unless the risks of bleeding are excessive.

Also, it would not be surprising if the FDA recommended that larger-diameter stents be bare metal, since restenosis risk is lower in these larger-diameter stents. And look for the advisory panel, in the interest of "safety" to require new stents (and new competitors to the panel's companies they represent) to have to submit "more data," delaying approval of the other companies' stents.

Finally, I would not be surprised if the FDA recommends that a registry be developed to track complications (the FDA loves registries: just look at the recent defibrillator recall fiasco). This might permit a later development of data-based guidelines based on probabilities. One such decision support tool that uses retrospective data has recently been deployed in Kansas.

For the non-cardiologist, issues on how to handle non-cardiovascular surgery in patients on Plavix and aspirin still need to be better defined, but I doubt the panel can cover all of this territory in the short two days ahead.

For now, though, a lot of this will be “flying without instruments.” And the weather is still partly cloudy…

-Wes