ACC: Drug-Eluting Stent Safety for Acute MI Seen in Real World Practice

By Crystal Phend
CHICAGO, March 31 -- For acute MI patients, drug-eluting stents hold no more risk than bare-metal devices, researchers said here.
An observational study of all acute MI patients in Massachusetts for 18 months revealed only benefits at two years in rates of mortality, heart attack, and revascularization for drug-eluting stents compared with bare-metal devices, reported Laura Mauri, M.D., of Brigham and Women's Hospital in Boston, and colleagues, at the American College of Cardiology meeting.
The findings may help settle some of the disagreements over the appropriate choice of stents for acute MI, she said. "In particular in ST-elevation MI, there have been concerns that the presence of thrombus might impact outcomes related to drug-eluting stents."
The reassuring results may also increase use of drug-eluting stents in acute MI from the relatively low 40% penetration, said William Knopf, M.D., of Saint Joseph's Hospital in Atlanta, who moderated a press conference at which the findings were discussed.
However, it may be too early to make the jump from bare-metal stents, said Bruce R. Brodie, M.D., of the Moses Cone Heart and Vascular Center in Greensboro, N.C., who was a discussant for the study at a late-breaking clinical trials session.
Healing may be inhibited by stents in patients with ruptured versus stable plaques, he said. "We should wait for HORIZONS AMI."
Early outcomes from that trial made waves at the Transcatheter Cardiovascular Therapeutics meeting last October by showing bivalirudin (Angiomax), a direct thrombin inhibitor, improved major cardiovascular adverse events over abciximab (ReoPro) and heparin (See: HORIZONS AMI Verdict: Bivalirudin (Angiomax) a Winner).
But that trial also randomized patients to drug-eluting or bare-metal stents, an ongoing component that could provide more guidance in acute MI.
Aside from HORIZONS AMI, acute MI patients have typically been excluded from randomized trials comparing stent types, Dr. Mauri said.
So to expand the evidence, her group studied outcomes for all patients who had two years of follow-up after percutaneous coronary intervention for ST- or non-ST-segment elevation MI in Massachusetts hospitals from April 2003 through September 2004.
Overall, 3,200 patients were given bare-metal stents while 4,016 patients had drug-eluting stents, 2,849 of them sirolimus (Rapamune)-eluting stents.
There was a clear selection bias, Dr. Mauri said. Those with more complex lesions were more likely to get drug-eluting stents, whereas those with more comorbidities tended to get bare-metal stents.
So for analysis of thrombosis outcomes, the researchers used propensity matching on 63 patient, procedural, and hospital variables to select 2,629 pairs of patients with similar risk factors.
Dr. Mauri said her group set out to see whether there was a signal of harm from drug-eluting stents but was surprised to find that all outcomes favored drug-eluting stents in the matched MI patient groups at two years.
In the overall cohort, mortality risk was 2.7% lower with drug-eluting than bare-metal stents (10.6% versus 13.4%, P=0.002) while recurrent MI tended to be 1.5% less common with drug-eluting stents (P=0.08).
STEMI patients had an even greater benefit in mortality with drug-eluting versus bare-metal stents (3.1% lower risk, P=0.009), whereas non-STEMI patients had a lesser benefit which was not significant (1.9% lower risk, P=0.18).
Recurrent MI tended to be less common among drug-eluting stent patients compared with bare-metal stent patients (risk difference -1.5% overall, -2.4% for non-STEMI, and -1.6% for STEMI, P=NS for all).
The largest benefits, though, were a reduction in need for revascularization or target-vessel revascularization (5.3% and 3.6% lower risk with drug-eluting stents overall, respectively, both P<0.001). Both STEMI and non-STEMI patient subgroups had significant advantages as well.
The reduction in revascularization "to us means that the randomized trial benefits that have been documented for drug-eluting stents in preventing restenosis translate into actual benefits in practice," Dr. Mauri said.
She said the group plans to continue to follow this cohort of patients. Monitoring late-stent thrombosis will be important, Dr. Brodie said. Data are needed on early and late subacute thrombosis as well, Dr. Knopf said.
Dr. Mauri reported receiving honoraria from Abbott, Boston Scientific, Cordis, and Medtronic. Co-authors reported employment or research funding from the Massachusetts Department of Public Health. Dr. Knopf reported no conflicts of interest. Dr. Brodie provided no information on conflicts of interest.
Primary source: American College of Cardiology meetingSource reference:Mauri L, et al "Long-term clinical outcomes following drug-eluting and bare-metal stenting for acute myocardial infarction in Massachusetts" ACC meeting 2008; Abstract 2404-2.

FDA Wants Longer Studies and Harder Endpoints for Drug-Eluting Stent Approvals

By Peggy Peck
ROCKVILLE, Md., March 26 -- The FDA proposed today that new drug-eluting stents accumulate at least 12 months of data, with twice that experience for a substantial number of patients, before the devices are submitted for approval.
Moreover, novel drug-eluting stents should be required to submit clinical data from at least one study that used a hard clinical endpoint from a study "appropriately powered for statistical demonstration of superiority or non-inferiority against an appropriate control." The preferred control should be a drug-eluting stent or a bare-metal device plus a drug-eluting stent.
Those recommendations, not unexpected, were included in a draft document that contains the FDA's new guidance to industry on the approval process for drug-eluting stents. The agency said it would consider comments on the proposal for the next 120 days.
The requirement for at least 12 months of clinical data is an increase from the nine months of data that were the basis of the FDA approval for the sirolimus-eluting stent (Cypher) and the paclitaxel-eluting stent (Taxus).
A zotarolimus-eluting stent (Endeavor) was approved last month, but all patients in clinical trials of that stent had at least one-year follow-up and the average follow-up was four years (See: FDA Approves Third Drug-Eluting Coronary Stent).
The FDA has been working on changes to the approval process since late 2006 when it convened a two-day advisory panel to review drug-eluting stent safety following a series of reports linking them to an increased risk of stent thrombosis (See: FDA Stent Panel Agrees that Benefits of On-Label Use Outweigh Risk).
The new document addresses several of the safety issues raised at the safety-panel meetings: reliance on angiographic endpoints rather than hard clinical endpoints, duration of dual antiplatelet therapy, trial design -- both pre- and post-approval -- and independent oversight of trials.
Among the new FDA recommendations:
Although nonclinical imaging endpoints such as late lumen loss and percent diameter stenosis are "potentially powerful effectiveness endpoints," they can only be used as the sole primary endpoint for iterative modifications of already-approved drug-eluting stents.
Angiography and IV ultrasound should "be captured in a study separate from the pivotal trial," or protocol-mandated angiography should be conducted after the 12-month clinical visit.
Secondary endpoints can include quantitative coronary angiography.
When using an unstudied drug with a drug-eluting stent, the sponsor should include liver enzyme values pre- and post-procedure, white blood cell counts, information on hypersensitivity reactions, ECG parameters, ECG changes (especially QT invervals), and data on concomitant medications.
The use of data-monitoring committees for all DES studies, called a strong recommendation, and when sponsors are conducting multiple studies the same data monitoring committee should monitor all studies.
The FDA also recommended standard post-marketing studies similar to the five-year follow-up it required when it approved the zotarolimus-eluting stent.

AHA-ATVB: No Early Benefit Seen to Drug-Eluting Stents Over CABG

Drug-eluting stents may not offer the early advantage over coronary artery bypass grafts (CABG) seen with bare-metal devices, researchers reported here.
In a single-center observational study, drug-eluting stents and CABG had similar 30-day and three-year outcomes for coronary patients, said James M. Wilson, M.D., of the Texas Heart Institute at St. Luke's Episcopal Hospital in Houston, and colleagues.
The study, presented at the American Heart Association's Conference on Arteriosclerosis, Thrombosis, and Vascular Biology here, represented one of the first reports on outcomes of drug-eluting stents versus bypass grafting.
In previous studies, bare-metal stents had better outcomes at one year that then eroded to equivalence at three years and disadvantage compared with CABG at long-term follow-up, Dr. Wilson said.
"It's a little worrisome that we don't have that early advantage we had with the bare-metal stents," he said. "This surprised us."
Dr. Wilson and colleagues looked at in-hospital and three-year follow-up data from 1,598 unselected coronary-artery patients who underwent isolated primary revascularization by drug-eluting stents or CABG.
Patients were case matched by procedure propensity score to ensure similar patient characteristics between groups. For both, the average age was 64, about 7% had an urgent procedure, about 30% had diabetes, and about 75% had more than one diseased vessel.
Early, 30-day major adverse cardiac and cerebrovascular event findings were:
Similar overall (3.78% CABG versus 5.01% DES, P=NS).
Not significantly different for myocardial infarction between groups (1.67% versus 2.22%, P=NS).
Significantly lower stroke rate with drug eluting stents (1.11% versus 0.11%, P<0.01).
Similar for 30-day mortality (1.67% versus 2.22%, P=NS).
Identical target vessel and target lesion revascularization rates by CABG (0.11% versus 0.11%, P=NS).
Significantly different target vessel and target lesion revascularization rates by drug eluting stents between groups (0.00% versus 1.78%, P<0.01).
For mid-term outcomes, the researchers looked at mortality at three years post-revascularization. They found no statistically significant difference between CABG and drug eluting stents (6.6% versus 9.0%, P=NS).
While drug-eluting stents were expected to offer advantages over bare-metal stents, overconfidence in patient selection appears to have erased any advantage, Dr. Wilson concluded.
"With drug-eluting stents, the data from randomized trials was so exciting I think we began to treat the more difficult lesions with hopes of long-term success," he said.
An FDA advisory panel concluded late last year that drug-eluting stents are safe and effective when used as indicated in stable patients with single-vessel disease. An estimated 60% of the six-million drug-eluting stents implanted worldwide are used off-label in complex lesions and high-risk patients.
"We have a stent that has a reduced likelihood of failure long term but the patients we've chosen to put them in have given away the early advantage," Dr. Wilson said. "If we were to use our patient selection criteria that we used for bare metal stents our outcomes might be more favorable."
Continued follow-up in this and other studies are needed to show how drug-eluting stents stack up to surgery long term, he added.
"What I think is going to be most interesting is when we extend our survival curves out to five to 7.5 years, and maybe those curves start to separate," Dr. Wilson said. "Right now all we can say is they are close enough to each other that we can't make any predictions."
"This is the type of study that will be very helpful," commented Sidney Smith, M.D., of the University of South Florida in Tampa and a past president of the American Heart Association, who was not involved in the study.