Millions of patients undergo coronary angiography and placement of a drug eluting stent (DES) for treatment of ischaemic heart disease every year. DES have a lower rate of neointimal hyperplasia and restenosis than BMS, but are more thrombogenic than BMS, which may result in stent stent thrombosis, MI and death

Following DES insertion, peak bodies* (*American Heart Association (AHA), American College of Cardiology Foundation (ACCF), Society for Cardiovascular Angiography and Interventions (SCAI), European Society of Cardiology (ESC), and European Association for Cardio-Thoracic Surgery (EACTS) ) recommend at least 6-12 months of dual antiplatelet therapy (DAPT - aspirin and a P2Y12 receptor inhibitor (clopidogrel or prasugrel))^ to prevent in-stent thrombosis, followed by aspirin monotherapy, but the duration of DAPT is controversial

However, events! may occur after this period, and risks and benefits of DAPT beyond 1 year are unclear

Many RCTs over past few years looking at optimal duration of DAPT after insertion of a DES

Discussed topic with cardiology registrars. Minimum duration at MBH seems to be 12 months. Studies look at either short term (12 months) therapy

MeSH Terms and Boolean Searching of Medline: Drug Eluting Stents and Platelet Aggregation Inhibitors and Time Factors 405 articles
Inclusion/Exclusion Criteria: Last 5 years and RCTs  362 articles excluded
Title/Abstract Screen: 41 articles excluded
2 remained: DAPT, ARCTIC-Interruption

Coprimary efficacy end-points
Incidence of definite or probably in stent thrombosis
Major cardiovascular and cerebrovascular events (death, MI, CVA)

Primary safety end-point
Incidence of moderate to severe bleeding (as per GUSTO criteria:
Severe or life-threatening
Intracerebral hemorrhage
Resulting in substantial hemodynamic compromise requiring treatment

Moderate
Requiring blood transfusion but not resulting in hemodynamic compromise

Mild
Bleeding that does not meet above criteria


Efficacy hypotheses
Null hypothesis: randomised treatment is equivalent to control (standard) treatment
Alternative hypothesis: randomised treatment is superior to control (standard) treatment

Safety hypotheses
Null hypothesis: randomised treatment is equivalent to control (standard) treatment
Alternative hypothesis: randomised treatment is non-inferior to control (standard) treatment

Prospective, multi-centre, randomised, double-blind trial (n=9961)

Several brands of DES* included:
Sirolimus-eluting stents (Cypher, Cordis)
Zotarolimus eluting stents (Endeavour, Medtronic)
Everolimus-eluting stents (Xience, Abbott Vascular and Promus, Boston Scientific)
Paclitaxel-eluting stents (TAXUS, Boston Scientific)

Patients enrolled within 72 hours after placement of stent

Recommended regimen for 12-months post DES insertion:
Aspirin 75-162mg PO daily
Clopidogrel 75mg PO daily OR prasugrel 10mg PO daily (5mg PO daily if

At 12 months, patients reassessed and excluded if:
Had events (MI, CVA, stent thrombosis, revascularisation, severe or moderate bleeding)

Non-adherent to thienopyridine therapy (120% treatment dose)

Withdrew consent

Eligible, but did not undergo randomisation

Lost to follow up etc.

Patients who were still eligible were randomised to:

Aspirin 75-162mg PO daily (indefinitely) AND clopidorel 75mg PO daily OR prasugrel 10mg PO daily (additional 18 months [30 months total]) 5mg PO daily if
Aspirin 75-162mg PO daily (indefinitely) AND placebo
At the end of the trial period, patients were followed for an additional 3 month observation period during which they took aspirin alone (30- to 33- months after enrolment)

n = 9961% (5020 continued thienopyridine, 4941 received placebo)
Baseline characteristics of groups were similar

Efficacy end-points – 30 months DAPT associated with:
Lower incidence of:
In-stent thrombosis (0.4% vs. 1.4%, HR 0.29, p
Myocardial infarction (2.1% vs. 4.1%, HR 0.47, p
Major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%, HR 0.71, p
Similar incidence of:
Death from cardiac causes (0.9% and 1.0% respectively; P=0.98)
Death from vascular causes (0.1% in each group, P = 0.98)
Stroke (0.8% and 0.9% respectively; P = 0.32)
Higher incidence of:
Death from any cause (2.0% vs. 1.5%, HR 1.36, p=0.05)^
Cancer-related deaths (31 vs. 14, P=0.02) (see discussion)
Safety end-points – 30 months DAPT associated with:
Higher incidence of:
Moderate or severe bleeding (2.5% vs. 1.6%, HR 1.61, p=0.001)


% 25682 started study (DES + BMS), 22866 (DES), 9961 for randomisation (process described above).
Note that myocardial infarction that was not related to stent thrombosis (1.8% vs. 2.9%; hazard ratio, 0.59; P^ During the secondary-analysis period (month 12 to month 33), all-cause mortality was 2.3% versus 1.8% (HR 1.36; P = 0.04), with the rate of death from noncardiovascular causes (1.1% vs. 0.6%; hazard ratio, 1.80; P=0.01) accounting for the difference in rates between the two analysis periods.

Strengths
Large, prospective, multi-centre, randomised, double-blind trial
Population similar to that in Australia so results generalisable to our patients

Limitations
Study funded by companies that produce the stents and drugs (but freely disclosed)
Randomisation at 12 months – after patients known to be adherent to therapy and did not have a major adverse event
The study included four different metal-platform, durable polymer, drug-eluting stents and two platelet P2Y12 inhibitors, whether the treatment benefits observed will be generalisable to other stent types or non-thienopyridine P2Y12 inhibitors is unknown

Among patients with a history of cancer at the time of enrollment in the study, 22 more pa- tients were randomly assigned to the thienopyri- dine group than to the placebo group (Table S8 in the Supplementary Appendix), and a blinded review of cancer-related deaths identified a be- tween-group imbalance in the number of pa- tients who underwent randomization in whom cancer had been diagnosed before enrollment (8 vs. 1) (Table S9 in the Supplementary Appendix). When these patients were excluded in a post hoc sensitivity analysis, the differences in mortality were no longer significant

Conclusions

“Among patients treated with drug-eluting stents, continuation of thienopyridine-plus-aspirin therapy, as compared with aspirin therapy alone, beyond 1 year reduced the risks of ischemic events. The reduction in the risk of ischemic events was consistent across stent type and specific thienopyridine drug used and was evident regardless of the risk of stent thrombosis. The clinical benefit of extended thienopyridine treatment was tempered by an increase in bleeding events.”

EXTENDED TERM
ARCTIC Interruption: Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption versus Continuation One Year after Stenting

DES-LATE: Optimal Duration of Clopidogrel Therapy with DES to Reduce Late Coronary Arterial Thrombotic Event