Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Safety & Effectiveness of Drug-Eluting Stents & Anti-platelet Regimen - HOST-ASSURE

Description:

Subgroup analysis of the CURRENT-OASIS 7 trial demonstrated that a maintenance daily dose of 150 mg of clopidogrel for 1 week was associated with superior outcomes at 1 month, as compared with 75 mg daily in patients undergoing drug-eluting stent (DES) percutaneous coronary intervention (PCI). The current trial sought to compare outcomes at 1 month in Korean patients receiving triple therapy with aspirin, clopidogrel 75 mg daily, and cilostazol versus dual therapy with aspirin and clopidogrel 150 mg daily for 1 month.

In a 2 x 2 factorial design, the trial also sought to compare the safety and efficacy of two second-generation DES: platinum chromium-based everolimus-eluting stent (PtCr-EES) and cobalt chromium-based zotarolimus-eluting stent (CoCr-ZES).

Hypothesis:

Triple therapy vs. dual antiplatelet therapy (DAPT): Triple therapy with aspirin, clopidogrel 75 mg daily, and cilostazol would be noninferior for cardiovascular outcomes at 1 month when compared with DAPT with aspirin and clopidogrel 150 mg daily.

PtCr-EES vs. CoCr-ZES: PtCr-EES would be noninferior to CoCr-EES at 1 year for clinical outcomes.

Study Design

  • Randomized
  • Blinded
  • Parallel
  • Factorial

Patient Populations:

  • Age ≥18 years
  • Significant lesion (>50% by visual estimate) in any of the coronary arteries, venous or arterial bypass grafts
  • Evidence of myocardial ischemia or diameter stenosis >70%
  • Target lesion in coronary artery, venous or arterial bypass graft with diameter of ≥2.5 mm and ≤4.25 mm
  • Target lesion amenable for PCI

    Number of enrollees: 3,755
    Duration of follow-up: 1 month
    Mean patient age: 63 years
    Percentage female: 32%
    Ejection fraction: 60%

Exclusions:

  • Known hypersensitivity/contraindication to heparin, aspirin, clopidogrel, cilostazol, everolimus, zotarolimus, or contrast media
  • Systemic (intravenous) everolimus or zotarolimus use ≤12 months
  • Female of childbearing potential
  • History of bleeding diathesis, known coagulopathy (including heparin-induced thrombocytopenia), abnormal complete blood count (hemoglobin <10 g/dl or platelets <100k /μL) or refusal of blood transfusions
  • Left ventricular ejection fraction <25% or cardiogenic shock
  • Gastrointestinal or genitourinary bleeding ≤3 months or major surgery ≤2 months
  • Life expectancy <1 year
  • Actively participating in another drug or device investigational study
  • Symptomatic heart failure

Primary Endpoints:

  • Composite of cardiac death, nonfatal MI, definite or probable ST, stroke, and PLATO major bleeding at 1 month (triple therapy vs. DAPT)
  • Composite of cardiac death, target vessel MI, and TLF at 12 months (PtCr-EES vs. CoCr-ZES)

Secondary Endpoints:

  • Cardiac death, all-cause death
  • Nonfatal MI: periprocedural/spontaneous MI
  • Academic Research Consortium (ARC)-defined ST: definite or probable ST, definite ST, probable ST
  • Stroke
  • PLATO major/minor bleeding
  • Target vessel revascularization
  • Target lesion revascularization
  • VerifyNow P2Y12 assay at 12-24 hours after clopidogrel loading
  • VerifyNow P2Y12 assay at 1 month on maintenance dose of clopidogrel

Drug/Procedures Used:

Eligible patients were randomized in 2 x 2 factorial design to either DES PCI with PtCr-EES or CoCr-ZES, and then to either triple therapy (aspirin 100 mg daily, clopidogrel 75 mg daily, cilostazol 200 mg loading dose followed by 100 mg BID) or DAPT (aspirin 100 mg daily, clopidogrel 150 mg daily).

Concomitant Medications:

All patients received 300 mg aspirin and 300-600 mg of clopidogrel as a loading dose prior to PCI. Beta-blockers (68%), statins (85%), glycoprotein IIb/IIIa inhibitors (2.5%).

Principal Findings:

A total of 3,755 patients were randomized at 40 centers in South Korea: 1,879 to triple therapy and 1,876 to DAPT; 2,503 to PtCr-EES and 1,252 to CoCr-ZES. Baseline characteristics were fairly similar between the two arms. About 31% of patients had diabetes mellitus, 31% were current smokers, and 10% had undergone prior PCI. Indication for PCI was stable angina in 30% and acute coronary syndrome in 65%. About 22% of patients had evidence of three-vessel disease. The mean number of stents per patient was 1.6, with 16% undergoing bifurcation stenting and 3% left main trunk stenting. Nonadherence with both antiplatelet therapies was about 10-12%.

Triple therapy vs. DAPT: The primary composite outcome of cardiac death, myocardial infarction (MI), stroke, stent thrombosis (ST), and PLATO (PLATelet inhibition and patient Outcomes) major bleeding at 1 month was similar between the triple therapy and DAPT arms (1.2% vs. 1.4%, hazard ratio 0.85, 95% confidence interval 0.49-1.48; p < 0.001 for noninferiority, p = 0.57 for superiority). Similar results were noted on landmark analysis at 1 week. Other outcomes including all-cause mortality (0.5% vs. 0.6%, p = 0.65), MI (0.4% vs. 0.7%, p = 0.19), target lesion revascularization (0.2% vs. 0.3%, p = 0.74), ST (0.2% vs. 0.4%, p = 0.37), PLATO major bleeding (0.4% vs. 0.4%, p = 1.0), and PLATO minor bleeding (0.6% vs. 0.3%, p = 0.17) were similar between the two arms.

On-treatment platelet reactivity, as measured by P2Y12 reaction units (PRUs), was significantly lower in the triple therapy arm at both 12-24 hours after clopidogrel loading dose administration (173 vs. 213, p < 0.001) and at 1 month (169 vs. 192, p < 0.001).

PtCr-EES vs. CoCr-ZES: The primary endpoint of target lesion failure (TLF) at 12 months was similar between the PtCr-EES and CoCr-ZES arms (2.9% vs. 2.9%, p for superiority = 0.98, p for noninferiority = 0.028). Individual endpoints including all-cause mortality (2.2 % vs. 1.6%, p = 0.19), target-vessel MI (1% vs. 1%, p = 0.82), TLF (1.2% vs. 1.2%, p = 0.9), and definite or probable stent thrombosis (0.4% vs. 0.7%, p = 0.23). On angiographic assessment of index procedure (5,010 lesions), there were seven occurrences (0.21%) of longitudinal stent deformation (LSD) in the PtCr-EES vs. 0 in the CoCr-ZES arm. None was associated with adverse clinical outcomes at 1 year, although one LSD required an additional stent implantation.

Interpretation:

The results of this trial indicate that triple therapy with low-dose aspirin, clopidogrel 75 mg daily, and cilostazol 100 mg twice daily was noninferior for cardiovascular endpoints at 1 month, as compared with DAPT with low-dose aspirin and clopidogrel 150 mg daily in east Asian (Korean) patients undergoing DES PCI. On-treatment platelet reactivity was better with cilostazol at 1 and 30 days following PCI. Cilostazol for 1 month may thus be a viable alternative to double-dose therapy with clopidogrel in patients undergoing DES PCI. Similarly, DES PCI with PtCr-EES is noninferior to CoCr-ZES for clinical outcomes up to 1 year, including stent thrombosis. There is a low incidence of LSD, but this was observed in the PtCr-EES stents only.

In the ACCEL RESISTANCE trial, cilostazol had previously been shown to be superior to double-dose clopidogrel in patients with high post-treatment PRUs (“clopidogrel resistance”) in improving platelet reactivity. However, in the CILON-T trial, triple therapy was not better than DAPT (clopidogrel 150 mg daily) for cardiovascular outcomes at 6 months, even though platelet reactivity was improved with triple therapy. Cilostazol is commonly used in east Asia as an antiplatelet agent, but outside of peripheral arterial disease, has not found wider acceptance in Western populations due to unpleasant side effects, cost considerations, and lack of large studies demonstrating efficacy in non-Asian populations.

As far as PtCr vs. CoCr DES are concerned, it is reassuring to note low and similar rates of adverse clinical outcomes with both stents in the all-comers population undergoing PCI. LSD has been an ongoing issue with the PtCr-EES (Promus), and it is unclear if the modified Promus Premier DES will adequately address this issue.

References:

Park KW, Kang SH, Kang HJ, et al. Randomized comparison of platinum chromium-based everolimus-eluting stent versus cobalt chromium-based zotarolimus-eluting stent in all-comers receiving percutaneous coronary intervention (HOST-ASSURE): a randomized controlled non-inferiority trial. J Am Coll Cardiol 2014;May 7:[Epub ahead of print].

Park KW, Kang SH, Park JJ, et al. Adjunctive Cilostazol Versus Double-Dose Clopidogrel After Drug-Eluting Stent Implantation: The HOST-ASSURE Randomized Trial (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Safety & Effectiveness of Drug-Eluting Stents & Anti-platelet Regimen). JACC Cardiovasc Interv 2013;6:932-42.

Presented by Dr. Hyo-Soo Kim at ACC.12 & ACC-i2 with TCT, Chicago, IL, March 25, 2012.

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Interventions and ACS, Interventions and Vascular Medicine, Chronic Angina

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Republic of Korea, Stroke, Follow-Up Studies, Platelet Aggregation Inhibitors, Cobalt, Angina, Stable, Drug-Eluting Stents, Immunosuppressive Agents, Peripheral Arterial Disease, Ticlopidine, Sirolimus, Constriction, Pathologic, Fibrinolytic Agents, Tetrazoles, Vasodilator Agents, Percutaneous Coronary Intervention, Thrombosis, Platinum, Chromium, Confidence Intervals, Diabetes Mellitus


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