Rockville, MD - The US FDA has delayed making a decision on the approval of the new antiplatelet agent prasugrel (Lilly/Daiichi Sankyo) until September.
Prasugrel, which is expected to be the first real competitor to clopidogrel, is awaiting approval for the treatment of ACS patients who are managed with PCI. The approval application, which was filed in January of this year, was given priority status, with the deadline for a decision understood to be this week. Lilly explained that the agency had recently requested additional analyses, which the company has supplied, but this then gives the FDA an extra three months to complete its review, so the new FDA action date for prasugrel is September 26, 2008.
The approval application is based on the TRITON-TIMI 38 trial, which showed significantly reduced ischemic events compared with clopidogrel, but at the expense of an increase in major bleeding in ACS patients scheduled for PCI. The TRITON investigators have highlighted subgroup analyses that they say have identified several groups at higher risk of bleeding, and if these patients were excluded, the benefit of prasugrel appeared to outweigh the risk in the rest of the population.
Many experts have said that being able to clearly identify the patients that gain significant benefit without so much risk will be key to the drug's success, and it appears likely that the FDA will be focusing on this issue. On the basis of these subgroup analyses, it has been suggested that, if approved, prasugrel would likely be contraindicated in patients with a previous stroke, and dose reductions may also be recommended for the elderly and those of lower body weights.
Will TRITON be sufficient?
But clinical-trial guru Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles), is questioning whether the subgroup analyses from TRITON will be sufficient to identify those at highest risk of bleeding with prasugrel.
He commented to heartwire: "The TRITON investigators reported that 'with exclusion of patients with prior stroke/transient ischemic attack and dose reduction in the elderly (>75 years) and those with low body weight (<60 kg), the bleeding risk with prasugrel will be minimized.' But closer scrutiny reveals that while the high-risk subgroup was numerically at a higher risk for bleeding with prasugrel, the between-group difference was not statistically significant. In contrast, the between-group difference in ischemic events was significantly in favor of prasugrel in the non-high-risk subgroup. Thus, the lack of high-risk characteristics identifies patients with improved benefit, not reduced bleeding risk, associated with prasugrel. Combining the efficacy end point (benefit) with the safety end point (risk) into a 'net clinical benefit' end point appears to obscure this subtle, but important, distinction."
Kaul says this has important implications for regulatory approval and clinical practice. "A credible risk minimization or management strategy that reliably identifies patients at high risk of bleeding and mitigates this risk is key for regulatory approval and clinical practice. I am not sure if this has been accomplished based on TRITON data alone. Additional pharmacokinetic or pharmacodynamic studies might be needed to clarify the benefit/risk profile of prasugrel," he suggests.
He adds that another important question relates to the number of patients screened for the trial and the percentage of these patients enrolled. "If a large number of patients were excluded (presumably due to increased bleeding risk), then it has implications for benefit/risk profile of prasugrel in real-world clinical practice," he notes.
In response to these queries, Lilly spokesperson Dr Anthony Ware commented to heartwire: "Daiichi Sankyo and Lilly remain confident in both the prasugrel study results and the overall submission package and will continue working with the FDA and other regulatory agencies to bring prasugrel to market for the benefit of patients with acute coronary syndromes managed with PCI."
TRILOGY ACS trial starts
Daiichi Sankyo and Lilly also announced that the phase 3 TRILOGY trial of prasugrel in medically managed ACS has now begun. TRILOGY ACS will include approximately 10 000 patients at more than 800 hospitals in 35 countries and is comparing prasugrel with clopidogrel in ACS patients who are to be medically managed without a planned PCI.
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June 24, 2008 01:48 (EDT)
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subgroup analysis?
I hope a new medication like prasugrel doesn't get the approval based on "subgroup analysis".
Otherwise, it will again create serious doubts about the FDA ability to protect the public health. |
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June 25, 2008 12:40 (EDT)
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Prasugrel
Juarez made a very valid point. Publishing multiple secondary papers is shifting the attention from the shortcomings of the main TRITON results. To summarize those, clear explanations are needed on the following 10 issues:
1. Almost the entire benefit of prasugrel over clopidogrel has been driven by the reduction (475/620) of non-fatal myocardial infarction (MI). However, phase 2 study (JUMBO, TIMI-26), and TRITON used different MI definitions, which in turn are different from conventional MI definition used in other ACS trials (CURE-PCI, ACUITY, and their own PROVE IT –TIMI 22). Real great start to design the trial!
2. The design of TRITON trial significantly disadvantaged standard of care with clopidogrel. Suboptimal loading dose (300mg), delay of loading (>50% of patients received the drug after the PCI), disallowing clopidogrel pretreatment for 5 days, and lack of protection with platelet GP IIb/IIIa inhibitors in 45% of patients are just few major limitations to be acknowledged.
3. The rates of MI in TRITON are excessive, and 9.7% rate of second MI at 14.5 months follow-up after clopidogrel is unseen, 30% higher than ACUITY rates, and should be independently adjudicated.
4. 88% of prasugrel “benefit” occurs at Day 1, while most bleeding events occur late, making the present prasugrel-dosing regimen not acceptable for chronic human use.
5. All fatal (21/5), and life-threatening (85/56) bleeding events should be included in the primary end point making the difference of 13%, but not 18.2% as reported.
6. Maintenance daily dose of prasugrel 10 mg is about 2.5-2.7 times more potent than conventional 75 mg clopidogrel, cause profound platelet inhibition as observed in the JUMBO platelet study, and confirmed by massive excess bleeding rates in the TRITON trial.
7. Despite the prevention claims for prasugrel, stent thrombosis was not mentioned in the TRITON design paper, or prespecified in the TRITON CRF. If the prasugrel death benefit in patients with stent thrombosis is real (18/29), then clopidogrel have a mortality advantage in the rest 98% of TRITON patients.
8. Based on the PRoFESS trial results, clopidogrel with low dose aspirin will become a standard care for secondary stroke prevention, while prasugrel cause 30% higher combined risk for vascular event, death or major bleeding in the post-stroke/TIA cohort. There is no room for the second thienopyridine, unless a stroke prevention trial will be implemented.
9. Despite the claims that prasugrel dosing is suitable to 80% of all patients, in fact, high screen failure rates, and broad exclusions from TRITON (CABG, clopidogrel pretreatment, high-risk bleedings) suggest that in real life TRITON results may be applicable to no more than 20% post-stent population.
10. Since the real life bleeding risks with clopidogrel+aspirin combination are about 8%, considering the antiplatelet potency of prasugrel, the bleeding with prasugrel on top of aspirin will occur in about 20% of patients. Of course, this picture is a reality not when TIMI major bleedings are counted, but all bleeding events are considered.In turn, this will result in gross non compliance, and ... prasugrel "resistance".
The sad story how overcoming of "clopidogrel resistance" resulted in a totally wrong maintenance dose.
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June 25, 2008 12:08 (EDT)
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will be approved
Any regulatory agency that will allow a poison like Chantix to remain on the market will approve prasugrel ... thats my bet |
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June 25, 2008 12:09 (EDT)
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will be approved
Any regulatory agency that will allow a poison like Chantix to remain on the market will approve prasugrel ... thats my bet |
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June 25, 2008 01:04 (EDT)
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No bets allowed
Joe, bets are no good here. We need to learn from the mistakes in prasugrel development, and do not repeat them in the future |
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June 25, 2008 01:08 (EDT)
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Victor thanks
What a great summary. If Omipatrilat (acenep) couldn't get approved it will surprise me if prasu does. Tough to get by FDA - even cordaptive couldn't do it. |
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June 25, 2008 02:40 (EDT)
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facts not preceptions
Michael, thanks for your kind word. We should stop guessing on FDA decisions.
They are smart and decent people, although sometimes denied to see all the picture, and assess all the facts |
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June 26, 2008 11:01 (EDT)
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So it saves lives in the diabetic subset,
isn't that subset becoming the majority stakeholder in prasugrel?
Off target, Joe, in my area (long term community based internal medicine), Chantix is still the antidote, not the toxin. High success rate, low side effect rate is what I see and hear, particularly from COPD patients. My last patient on Chantix just walked away from smoking, she states without any effort, which totally surprised her. As a group, I don't think smokers are as normal psychiatrically as they were 30 years ago. |
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June 27, 2008 12:23 (EDT)
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Diabetes
Steve, very valid argument that diabetics indeed may yield extra benefit from prasugrel. Diabetic platelets are indeed hyperactive, and may require more aggressive inhibition strategies. |
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June 27, 2008 12:59 (EDT)
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Chantix actually works?
Sorry to burst anyone's bubble, but Dr. Rindone is right. These are not my words, but they work:
"If Chantix is used as a stand-alone quitting aid without ongoing counseling or support, your chances of quitting smoking for one year are probably less than 1 in 11."
As a stand alone agent, Chantix works no better than a placebo or any other stop smoking agent.
It is expensive, and is the only drug that I know that carries both warnings for suicide AND homicide.
If you absolutely want to use a pill, and the patient doesn't have a seizure disorder, use wellbutrin. |
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June 27, 2008 07:51 (EDT)
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Chantix actually works
The odds of quitting cold turkey without any smoking cessation medication is 5% at best.
With Chantix, this moves up to the 50% range. See the recent articles in JAMA and Archives of Internal Medicine.
This has also been my experience. Since the drug was approved in Canada, I have seen scores of patients quit. Don't forget, it's a 12-24 week therapy, and with appropriate counselling and education, they can be warned about the side effects. Having said that, none of my patients have reported any. I have heard nothing but positive comments on Champix, both on this board and in my practice.
Most of the reports of homicide/suicide are uncontrolled. Don't forget that smokers are at inherently higher risk for substance abuse disorders and psychiatric comorbidity. Quitting smoking itself is not without risks in terms of mood, weight gain, and so forth. The fact that a few smokers have killed themselves or others while trying to quit with this drug does not scare me.
Remember, the same thing can easily happen with Wellbutrin - or any SSRI for that matter. When pediatricians stopped using SSRIs, suicide rates skyrocketed. I'm sure it would be the same if Chantix was taken off the market. |
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June 29, 2008 12:08 (EDT)
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Not bursting my bubble, David,
having lost 2 partners to smoking related cancers and 3 patients to metastatic lung cancer this past year and seeing advanced vascular age in smokers and former smokers, gives me a different perspective on the imperitive for smoking cessation.
I agree with you, Dan, when I see a dedicated smoker trying to extract the last nanogram of nicotine from his cigarette before entering the hospital campus no smoking zone, homicide/suicide would be in play if I tried to remove the cigarette from that smoker prematurely.
I am also aware of a 90% success rate in smoking cessation in patients with advanced lung disease with the aid of Chantix as the primary "chemotherapy". The treatment is simple. Stay on Chantix, until the urge is gone, resume the drug if needed. The more dependant patients in this clinic have remained on Chantix for more than 1 year without psychiatric disturbance.
Actually, Joe virtually all the drugs we use are poisons. Look at warfarin, digoxin....., as physicians we just have to dose properly and use risk analysis so that we make decisions favoring our patients health.
To me prasugrel looks to be a sharper scalpel than plavix. We just have to learn how to use it. It seems to have the significant benefits of immediate onset, the absence of drug resistance and absolute event reductions >1% in most endpoints. I think they did include stent thrombosis in the analysis, Victor, with similar benefit. BTW the "supoptimal" dose of Plavix I think was somewhat mandated in the protocol since it was the FDA approved dose.
For now, my hats off to the FDA, as they analyze the truck loads of data and continue to be second guessed by the rest of the world. |
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June 29, 2008 09:35 (EDT)
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Individual responses vary , but it's been a Godsend for so many
My most "hardened" smoker just celebrated his 1 year anniversary for smoking sobriety. Inoperable cicumflex districution disease at age 50, stroke, impotence and emphysema dianoses NEVER were able to motiate him. One month later on Chantix, he was smoke free and continues to be. To him it is a Godsend. One man's poison is another man's Candy, but I'll go with Candy that in a 5000 cohert European based sudy garnered no death,suicide or homicidal ideation. The US experience with any drug that threatens the tobacco industry is destined for class action lawsuits ad nauseum. The success rate as well as side effect profile in our practice has been excellent.
Only when we look at the structure of the nicotine receptor and understand the genetic differences from patient to patient will we then appreciate why Chantix or any drug targeting it doesn't always work for everyone. Then again, even aspirin doesn't, so where is the big suprise?
Melissa |
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June 30, 2008 12:28 (EDT)
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the facts from FDA
there have been over 3000 cases of SERIOUS adverse events reported, more than any other drug by a long shot ... these not only include suicides, but homicidal ideation, psychosis, vision disturbances, seizures, cardiac arrhythmias, falls resulting in fractures, traffic accidents, and the list goes on ... the FAA has prohibited its use in pilots ... the ISMP as recommended that people operating machinery not use it ... I have seen 3 patients get Chantix ... in one it didn't work, one almost commited suicide, and another was ready to commit mass murder ... there, those are my anecdotes ... at my facility we are not using it and our psychiatry dept is thankful for that |
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June 30, 2008 04:50 (EDT)
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interesting
Joe,
why do you suppose that Dr. Tonstadt did not find these adverse events in the 5000 european pts. studied? (initial veranacline trials). The last I heard from her,she was planning a year long study of veranacline and maybe even contemplating longer trials. She gives the impression of being very caring and competent and runs a nicotine addiction clinic with good success.
BTW, most folks who are trying to quit cold turkey profess to wanting to commit mass murder. I saw one patient who became completely psycotic utilizing Nicotine patches ONLY. He requied psychiatric admission and was completely stable before and continues to be stable afterward.
Lung Cancer, myocardial infarction, emphysema....."3000 adverse side effects" pales in comparison. I've certainly not seen those symptoms. Today someone told me their dad had vivid dreams on it. Beats chemo.
Melissa
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June 30, 2008 06:18 (EDT)
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Dr. Tonstadt
Difficult to reconcile what has been reported to FDA and Dr. Tonstadt data. I don't have an explaination other than patients with any mental disorders may be have excluded in the premarketing studies. I've been told this was the case in the US. It would be nice to have some long term data (> 1 year) since cessation rates decline over time. |
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June 30, 2008 06:20 (EDT)
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fear
"these not only include suicides, but homicidal ideation, psychosis, vision disturbances, seizures, cardiac arrhythmias, falls resulting in fractures, traffic accidents, and the list goes on..."
The above list does not suggest a common pathophysiology or mechanism of action for this drug. It sounds like a heightened vigilance to any adverse event occurring as a result of anything in the patient's life who just happens to be on a drug with recent great notoriety.
However I could be wrong and would not have predicted the fiasco with vioxx, valdecoxib, lumaricoxib and celebrex. If this drug gets pulled off the market without solid pharmacovigilance studies, that would be sad in my view. |
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June 30, 2008 09:32 (EDT)
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Amazing shift + Mistake
It seems important how fast the physicians switch from prasugrel to smoking, psychiatry. Sounds like all the "antiplatelet wars" are well beyond the interest of general audience even at our specialized CV site. With regard to my previous statement, para 4 (see above), 88% represents the relative risk, however, the absolute risk at day 1 is 0.8 out of the full absolute benefit 2.3 at the end of the trial. Apologies for misunderstanding. |
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June 30, 2008 11:26 (EDT)
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Just waiting 3 months for the expedited prasugrel review, Victor
So lets clear the smoke, Joe.
Did I not hear that >90% of reported adverse events with Chantix where captured by self reporting by Pfizer, mostly from addiction couselors with only telephone contact to the patient? All medical complaints during the counseling phase were mandatorily reported as adverse events by the addiction counselors (a service provided without charge by PFE to the Chantix patients in order to increase success rate).
This would represent extraordinary postmarketing surveilance, with no comparator group.
Lets give biopharmaceutical development, though somewhat tarnished, but still one of our few remaining crown jewels, a fair chance. |
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Prediction
Victor,
My apologies for my part in the participation of hijacking your post regarding Prasugrel. The FDA approval process is in question and I thought the veranacline comments were pertinent. However, I think the story with prasugrel will not be fully played out unfortunately until this medication is released to large numbers of our population. Let us use our hematologic crystal ball to predict the future: Prasugrel will demonstrate increased bleed rates in the elderly and those with renal failure. We will subsequently be told to reduce the dose in that population. There will be harm in these patients and we will have learned our lesson the hard way unless this drug is released with specific instructions for dosing adjustment. A few years from now, we'll have access to more accurate platelet inhibition studies and be able to put this drug to good use with less harm. Just my humble prediction.
Melissa |
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Thanks Victor
Good summary.
Lilly made a mistake with their dosing on these trials. I don't know what is going to change in 3 months for the FDA.... |
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