The advent of drug-eluting stents dramatically reduced the restenosis (reclogging) rate associated with bare-metal stents but prompted new concerns about the rare but potentially lethal complication of stent thrombosis (ST). Cardiologists have relied upon dual antiplatelet therapy to prevent ST but there has been considerable uncertainty and controversy about the ideal duration of therapy.
The Dual Antiplatelet Therapy (DAPT) trial was coordinated by the Harvard Clinical Research Institute as part of a large-scale collaboration with the FDA, stent manufacturers, and pharmaceutical companies…. The main results of the trial were presented on Sunday at the American Heart Association meeting in Chicago and published simultaneously in the New England Journal of Medicine.
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The precise duration of dual antiplatelet therapy (DAPT) following implantation of a drug-eluting stent (DES) has been the subject of considerable controversy. On the one hand, prolonged therapy may help prevent late stent thrombosis, which was particularly evident in first generation DESs. On the other hand, the risk of stent thrombosis may have diminished in newer generation drug-eluting stents, and prolonged DAPT is associated with a greater risk for bleeding complications and additional expense and management issues.
In the Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE) trial 3,119 patients with stable CAD or a history of low-risk acute ACS who received a zotarolimus-eluting stent (Endeavor, Medtronic) were randomized to either short-term (3 months) or long-term (12 months) DAPT. The results of OPTIMIZE were presented at TCT 2013 in San Francisco and published online in JAMA.
At one year there were no significant differences between the groups. The primary endpoint– the composite of death, MI, stroke, or major bleeding– occurred in 6% of patients in the short term group versus 5.8% of patients in the long-term group (risk difference 0.17, CI -1.52 – 1.86, p = 0.002 for noninferiority). Between 3 months and 1 year there was an identical 2.6% rate of events in both groups.
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The use of platelet-function tests to monitor and guide antiplatelet therapy in PCI patients has sparked heated debate. Cardiologists have sought to reconcile biological plausibility with the absence of clinical evidence. Now the ARCTIC (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a Monitoring-guided Strategy for Drug-Eluting Stent Implantation versus Continuation One Year after Stenting) trial brings cold comfort to supporters of the monitoring strategy.
The ARCTIC investigators randomized 2440 PCI patients either to a strategy in which antiplatelet therapy was guided by platelet-function monitoring, or to conventional therapy without monitoring. The VerifyNow P2Y12 and aspirin point-of-care assay was used in the monitoring group. Results of the trial were presented at the American Heart Association scientific sessions in Los Angeles on Sunday and published simultaneously in the New England Journal of Medicine.
The primary endpoint was the composite of death, MI, stent thrombosis, stroke, or urgent revascularization at 1 year:
- 31.1% in the conventional group and 34.6% in the monitoring group (HR 1.13, CI 0.98-1.29, p=0.10)
The ARCTIC investigators also reported a main secondary endpoint consisting of stent thrombosis, revascularized or not, or any urgent revascularization:
- 4.6% and 4.9% (HR 1.06, CI 0.74-1.52, p=0.77)
In the monitoring group, 7.6% of patients were found to be poor responders to aspirin and 34.5% were poor responders to clopidogrel. The authors conclude that platelet-function testing with antiplatelet therapy adjustment does not improve clinical outcomes as compared with standard treatment and that their results “do not support the routine use of platelet-function testing in patients undergoing coronary stenting.”
A second arm of the trial, studying whether clopidogrel therapy should be continued after 1 year, is ongoing. In addition, a follow-up study, ANTARCTIC, is evaluating the value of platelet-function testing in an elderly population “with a paradigm shift towards safety.”
Two new studies published in the Journal of the American College of Cardiology offer hope but not, yet, compelling evidence to support less burdensome requirements for dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation.
In the first study, Spanish investigators followed 1,622 consecutive patients who received a drug-eluting stent (DES) for one year. They found that 10.6% of the DES patients interrupted at least one antiplatelet drug during the first year. Two-thirds (64.5%) of the interruptions were temporary, lasting a median of 7 days. After discontinuation of therapy 4.1% of patients had an acute coronary syndrome (ACS), but this was not significantly different from the 5.5% rate of major cardiac events in patients who remained on DAPT.
The authors concluded that early discontinuation of DAPT “is not exceptional and is usually temporary. Although further knowledge about individual risk is desirable, our results suggest that discontinuation for a few days (median: 7 days) of DAT after the first month of DES implantation may be reasonably safe in terms of major cardiac events.”
In an accompanying editorial, Bernhard Witzenbichler points out several limitations of the study, and concludes that “the data can only suggest that a brief interruption of DAPT does not have a large impact on ischemic risk.”
In the second study, Korean investigators randomized 2,117 patients to receive either the Endeavor zotarolimus-eluting (ZES) stent plus 3 months of DAPT therapy or standard therapy, consisting of another DES with a full year of DAPT. There was no difference between the two groups in the primary endpoint (the composite of CV death, MI, stent thrombosis, TVR, or bleeding), which occurred in 4.7% of patients in each group, and there were no significant differences in any of the components of the endpoint. The authors concluded that the Endeavor ZES plus 3 month DAPT “could be safe and beneficial for the selected patients with coronary artery disease who may need to stop DAPT early after DES implantation.”
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According to current guidelines and clinical practice, PCI patients already taking an oral anticoagulant generally end up on triple therapy comprising the anticoagulant plus clopidogrel and aspirin. However, there is no supporting evidence base for this approach and the triple therapy regimen is known to increase bleeding complications. Now a new study– the first randomized trial to address this situation, according to the investigators– may have a large impact on clinical practice by demonstrating that the omission of aspirin in this context appears to be safe and may reduce adverse events.
Results of the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulantion and Coronary Stenting) trial were presented by Willem Dewilde at the ESC in Munich today. Investigators in the Netherlands and Belgium randomized 573 patients to triple therapy or dual therapy of an anticoagulant plus clopidogrel for at least one month after implantation of a bare-metal stent or one year after a drug-eluting stent. Two-thirds of the patients were receiving oral anticoagulation for atrial fibrillation.
The primary endpoint, the total number of bleeding events, was dramatically reduced in the dual therapy group at one year:
- 44.9% in the triple therapy group versus 19.5% (HR 0.36, CI 0.26-0.50)
There were 3 intracranial bleeds in each group. Most of the difference in bleeding occurred in TIMI minor and minimal bleeding. The difference in TIMI major bleeding (3.3% versus 5.8%) did not achieve statistical significance.
Clinical events, the trials’s secondary endpoint, were numerically lower in the dual therapy group. The difference in mortality achieved statistical significance.
- Mortality: 7 deaths (2.6%) in the dual therapy group versus 18 deaths (6.4%) in the triple therapy group, p=0.027
- MI: 3.3% versus 4.7%, p=0.382
- TVR: 7.3% versus 6.8%, p=0.876
- Stroke: 1.1% versus 2.9%, p=0.128)
- Stent thrombosis: 1.5% versus 3.2%, p=0.165
“The WOEST study demonstrates that omitting aspirin leads to less bleedings but does not increase the risk of stent thrombosis, stroke or myocardial infarction,” said Dewilde in an ESC press release. “Although the number of patients in the trial is limited, this is an important finding with implications for future treatment and guidelines in this group of patients known to be at high risk of bleeding and thrombotic complications.”
David Holmes said the trial addressed “an incredibly important issue” and predicted that it would “change the way we practice medicine, it will change practice right away.” Keith Fox said that the evidence base prior to WOEST was extremely limited and that the trial showed that there was no hazard in doing without aspirin. The ESC discussant, Marco Valgimigli, said the trial showed it was safe to drop aspirin and provided another demonstration that “we have hit the wall” with anticoagulation.
Republished with permission from CardioExchange, a NEJM group publication.
The biggest drawback to drug-eluting stents has been the requirement for prolonged dual antiplatelet (DAPT) therapy following stent implantation to prevent stent thrombosis and other potential complications. The precise length of DAPT has been the subject of considerable discussion and research.
Now the Xience Prime and Xience V everolimus-eluting stents have received the CE Mark in Europe for a DAPT length of only three months, according to an Abbott press release. The manufacturer of the stents, Abbott, said this was the “shortest duration for any major drug eluting stent (DES) in Europe.”
Abbott said that data presented this week at the EuroPCR congress found no cases of stent thrombosis in more than 10,000 patients who received a Xience stent and who discontinued DAPT after three months.
An Abbott spokesperson told CardioBrief that the company is “currently exploring our filing strategies with the FDA for a three-month DAPT indication.”
Click here to read the press release from Abbott…