Transcript Coaated stents: a new era
The DES controversy and DREAM
Eric J Topol MD Professor of Genetics Case Western Reserve University Cleveland, OH Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC
Thumbs up / Thumbs down – Sept 22, 2006
Evolution of stent technology
Two problems with angioplasty technology
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Abrupt thrombosis at the time of the procedure
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Restenosis Better anticoagulation and the advent of bare-metal stents helped resolve both problems Bare-metal stents reduced symptomatic restenosis by 50% to 75%
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Califf
Drug-eluting stents
Regulatory approval and marketing of drug-eluting stents were based on short-term trials with a straightforward population that excluded more difficult PCI patients The evidence was overwhelming
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No effect on risk of death or nonfatal MI in the 6- to 12-month timeframe
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Additional 70% reduction in restenosis Two main types of drug-eluting stents
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Sirolimus-eluting (Cypher) stents
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Paclitaxel-eluting (Taxus) stents
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Califf
Fantastic data . . . on the surface
The data looked fantastic "Who wouldn't want to sign up for one?" Renu Virmani (Cardiovascular Pathology, Gaithersburg, MD) predicted that there would be a catastrophic problem with the failure to cover the stent with endothelium in a certain percentage of cases Fairly early on there were publications of small series or case reports of late thrombosis
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But the evidence seemed to indicate that it was not much of a problem
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Califf
PREMIER Registry
Funded by a company developing a drug to treat angina People who prematurely stopped clopidogrel had a ninefold increase in the risk of stent thrombosis All acute-coronary-syndrome patients
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Much higher-risk patients than those studied in clinical trials Califf
Spertus JA, et al. Circulation 2006; 113(24):2803-2809. Thumbs up / Thumbs down – Sept 22, 2006
BASKET-LATE
Swiss government – run trial Results were "very concerning, almost frightening" After everyone had stopped taking clopidogrel, there was a significant increase in death and MI in patients randomized to drug-eluting stents vs those randomized to bare-metal stents
Pfisterer ME. American College of Cardiology Annual Scientific Session 2006; March 14, 2006; Atlanta GA. Thumbs up / Thumbs down – Sept 22, 2006
Califf
Signals from Barcelona
The possibility that there is a relatively linear but consistent-over-time incremental risk with drug-eluting stents compared with bare-metal stents The additive effect over two to five years might be highly significant, both clinically and statistically None of the studies were definitive, but they all point in the same direction Dr Salim Yusuf concluded that if we stop putting stents in people who don't need them, this would not be much of a problem
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Califf
SIRTAX
Examining rates of early and late stent thrombosis More than 8000 patients By three years, the rate of stent thrombosis with drug-eluting stents was almost 3% Topol
Wenaweser P. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. Presentation 1012.
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RAVEL: Five-year follow-up
Pristine from the standpoint of restenosis More death with the Cypher stent than with the bare-metal stent: 11.1% vs 7% Not statistically significant, but unexpected
RAVEL: Serruys PW. World Congress of Cardiology 2006; September 6, 2006; Barcelona, Spain. Thumbs up / Thumbs down – Sept 22, 2006
Topol
Meta-analysis
A significant excess of late thrombosis with Cypher stents vs bare-metal stents: 6.3% vs 3.9% Results are consistent with predictions from BASKET "I think it's a pretty significant concern" Topol
Camenzind E. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. Hotline I.
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Courses of action
What advice would you give to a patient who shows up in the cardiologist's office?
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Califf
Not time to panic
Late thrombosis a very-low-frequency event We don't know about the long-term safety of drug eluting stents in some individuals We can't predict who is going to have a late clotting risk
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Some patients never endothelialize the strut of the stent because the drug is so effective
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Some patients have a propensity for thrombosis Tell patients that there is a small risk over extended follow-up
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Topol
Restenosis: A trade-off
The trade-off: the low risk of stent clotting and fatality vs the chance of having a repeat procedure Risk of a repeat procedure is higher with a bare metal stent Restenosis is generally viewed as benign; this might not be entirely true We don't have good data from large, multiyear, randomized trials comparing bare-metal and drug eluting stents
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Topol
Genomics?
Weren't you arguing just last year that we could do small trials with genomics and not have to do large trials?
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Califf
Genomics: The way of the future
If we had DNA for patients who had stent thrombosis and for suitable controls, we could identify the genes involved Stent thrombosis doesn't appear to be a mechanical issue (eg, stent apposition)
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Patients are either not endothelializing well or are prone to thrombosis Eventually, genomics will allow us to get a handle on the problem, but we haven't even started this work yet
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Topol
Clopidogrel or not clopidogrel?
With drug-eluting stents, people are potentially committed to dual antiplatelet therapy for the rest of their lives
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The risk of bleeding
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The expense The possibility of having to stop clopidogrel because of events such as significant dental work, orthopedic procedures, other surgical procedures There are anecdotes of patients developing stent thrombosis days after stopping dual antiplatelet treatment
Thumbs up / Thumbs down – Sept 22, 2006
Topol
Practical advice
If you get a drug-eluting stent, stay on clopidogrel until this is sorted out If you have a patient you don't think can stay on clopidogrel, try not to use a drug eluting stent
Thumbs up / Thumbs down – Sept 22, 2006
Califf
Weighing the risk
Bare-metal stents are preferable for the following people:
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Those who don't take medication reliably
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Those who have issues with the cost Those who might require another significant procedure Until we have data from large, real-world, multiyear trials, we must weigh the risk of restenosis and its complications against the risk of late thrombosis
Thumbs up / Thumbs down – Sept 22, 2006
Topol
FDA reform
The Future of Drug Safety: Promoting and Protecting the Health of the Public
A report on postmarketing FDA issues published by the Institute of Medicine (IOM)
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Califf
Hard-hitting report
A 255-page report that really slammed the FDA The recommendations are extraordinary The IOM got paid $3 million to do it
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"I think the FDA would rather get its money back." It takes on problems with drug-safety leadership
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Topol
FDA takes action
The problem with drug-eluting stents is a postmarketing issue
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There were grounds for their approval The need for monitoring and proper clinical trials is addressed in the report The FDA is convening a special panel to review this issue before year-end
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Topol
The genie's out of the bottle
Drug-eluting stents have been on the market for a number of years They're used in 90% or more of stent procedures in the US Boston Scientific announced today that the use of drug-eluting stents has diminished in recent weeks "It may be that the interventional community is a little spooked about this late thrombosis thing."
Thumbs up / Thumbs down – Sept 22, 2006
Topol
First responders
"I'd have to say the interventional community is one of the most sensitive on earth to clinical-trial findings and clinical research statements" In some other fields, it takes 15 years to integrate results into clinical practice
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Califf
News travels
There wasn't a very good showing of interventional cardiologists from the US at the meetings in Barcelona
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But it did seem to be the story that was highlighted
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Topol
Too many PCIs?
Salim Yusuf's research group (McMaster University, Hamilton ON) continues to turn out trials that are interesting and worthwhile I don't think we are doing too many PCIs, although we might be doing them in the wrong people "I think it's a procedure that has a lot of benefit."
Thumbs up / Thumbs down – Sept 22, 2006
Califf
Attitudes in the US
In the interventional world, no one is allowed to have ischemia, even if they're asymptomatic Yusuf believes that stable angina with occasional angina or even a stress induced functional test is acceptable As long as there has been balloon angioplasty, the attitude has been to stamp out all ischemia Is there a financial incentive to do this?
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Topol
Financial incentive
As long as PCI is rewarded above other activities, people are going to do it when it's a toss-up In this country, the big money's in imaging, it's not in PCI anymore I don't think it's the only factor, but it is part of the culture When you hear there's a blockage and you can open it up, it feels like a good thing
Thumbs up / Thumbs down – Sept 22, 2006
Califf
The debate continues
Drug-eluting stents became commonplace because they got rid of the reoccurrence of blockages "It's a very blockage-centric world we live in in the US." There are no data to show that PCI in stable angina benefits patients, but they do show that it is beneficial in ischemia Echo and nuclear imaging are going to be emphasized with the CT angiography that's popular now
Thumbs up / Thumbs down – Sept 22, 2006
Topol
Worth watching
The FDA hearing will be something worth watching as it goes through these data People should look at the FDA reform report
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Califf
The search for a cure for "diabesity"
People are gaining weight and developing diabetes at relatively young ages and suffering the consequences thereof The pharmaceutical industry has been searching for drugs to prevent the development of diabetes in people who are at risk
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Califf
DPP trial
The Diabetes Prevention Program (DPP) trial
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Looking at whether either diet and exercise or the oral diabetes drug metformin (Glucophage) prevent or delay the onset of type 2 diabetes in people with impaired glucose tolerance Results
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An intensive exercise and diet regimen reduces the time to onset of diabetes diabetes by 60% to 70%
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Califf
ACE inhibitors reduce diabetes
In populations studied for other reasons, ACE inhibitors have been shown to reduce the frequency of diabetes These studies weren't looking specifically at the diabetes end point in a rigorous fashion
Thumbs up / Thumbs down – Sept 22, 2006
Califf
Another class of drug
Thiazolidinediones
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Affect the PPAR system (nuclear-receptor hormones)
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Are widely used without any real outcome data on their effect, other than lowering blood sugar Triglitazone showed a dramatic reduction in time to onset of diabetes
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Unfortunately, it caused liver damage
Thumbs up / Thumbs down – Sept 22, 2006
Califf
The DREAM trial
Factorial randomized design
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1/4 got rosiglitazone
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1/4 got ramipril
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1/4 got both rosiglitazone and ramipril
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1/4 got placebo Patients had impaired fasting glucose levels or impaired glucose tolerance but no diabetes The population was relatively young and at low risk for cardiovascular events DREAM was powered to show a reduction in the onset of diabetes
Thumbs up / Thumbs down – Sept 22, 2006
Califf
DREAM: The ramipril arm
Reduction (about 1%) in onset of diabetes was not statistically significant Fasting glucose levels and the proportion of patients who returned to normal glucose tolerance significantly favored ramipril No significant differences in clinical events Absolutely no difference for the first couple of years, then the curves began to separate but didn't reach significance It could be argued that this was a delayed effect Califf
DREAM trial investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006; 355.
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DREAM: The rosiglitazone arm
Results with rosiglitazone
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A 60% reduction in the onset of diabetes
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Lower blood pressure
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A 2.4-kg increase in weight
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An increase in heart failure
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A trend toward an increase in vascular events Califf
DREAM trial investigators. Effect of rosiglitazone on the frequency of diabetes In patients with impaired glucose tolerance or impaired fasting glucose: A Randomised controlled trial. Lancet 2006.
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A conundrum
ACE inhibitors work but have a much smaller effect than expected Thiazolidinediones clearly reduce diabetes but have an uncertain negative trend in terms of vascular events
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Califf
Why didn't ramipril work?
The ramipril results were really surprising Ramipril worked well in the HOPE trial Other trials of ACE inhibitors showed a pretty consistent reduction in the incidence of diabetes Of course, the DREAM patients didn't have cardiovascular disease
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Topol
DREAM population
The DREAM patients were younger than the HOPE population and not as sick Ramipril did work in the sense that glucose levels were lower, it was just a very weak effect
Thumbs up / Thumbs down – Sept 22, 2006
Califf
Very weak results
For primary outcomes over the 3.5 years, the event curves (combined end point of diabetes and death) are totally superimposable Are you impressed that there was a consistent reduction in the incidence of diabetes with ACE inhibitors in older patients with cardiovascular disease?
Thumbs up / Thumbs down – Sept 22, 2006
Topol
More practical advice
"It's likely that that's true, but there's no way to know for sure." I wouldn't prescribe ramipril just to prevent diabetes, but if I had a reason to give an antihypertensive medicine to someone in a prediabetic state, "it would be a minor additional factor to make me lean in that direction."
Thumbs up / Thumbs down – Sept 22, 2006
Califf
Surprising results
The fact that rosiglitazone was effective for the combined end point (diabetes and death) was a surprise I knew that there would likely be some increase in heart failure, as has been seen with the other glitazones, but I didn't expect it to be as marked
Thumbs up / Thumbs down – Sept 22, 2006
Topol
Drugs doing what they should
"I thought that this would work." These drugs were designed to treat diabetes, so it would be shocking if there wasn't a reduction
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Califf
No benefit
For the clinical outcomes, when mortality was compared with the new incidence of confirmed heart failure, there was no benefit
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Topol
The heart-failure issue
There is likely harm from the thiazolidinediones that comes from fluid retention and a proinflammatory state in some patients We've known about the heart-failure issue for a long time
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Califf
Why two papers?
Rosiglitazone might even be somewhat worse than PYA or other agents in this class Why were these results not incorporated into one paper?
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Topol
Two for one
I presume that one of the advantages of a factorial design is you get two trials for the price of one
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Califf
Two thumbs up
This trial asked a legitimate question "The results are disappointing in that it doesn't really change my view of prescribing ramipril."
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It's a great drug for hypertension and LV dysfunction Ramipril probably somewhat reduced coronary disease events, but I wouldn't prescribe it just to prevent diabetes Rosiglitazone does show that if you have a drug that's highly effective, you might make a dent in the long-term issue of diabetes
Thumbs up / Thumbs down – Sept 22, 2006
Califf
Is it worth the trade-off?
The adverse effects weren't significant, but they weren't far from being significant By inhibiting the development of diabetes, you invite other adverse outcomes
Thumbs up / Thumbs down – Sept 22, 2006
Topol
Needed data on its way
Until we have more outcome data, we should not be prescribing thiazolidinediones to prevent diabetes The good news is that there are several major cardiovascular trials under way that will provide answers
Thumbs up / Thumbs down – Sept 22, 2006
Califf
Another two thumbs up
Aside from the concern about the reporting, it's a two-thumbs-up trial The prevention side of rosiglitazone is something new The adverse outcomes are, at the very least, disquieting Cardiologists don't get to see this population until a decade later
Thumbs up / Thumbs down – Sept 22, 2006
Topol