Adjusted Clopidogrel Loading Doses According to VASP Phosphorylation Index Decrease Rate of MACE in Patients With Clopidogrel Resistance - Adjusted Clopidogrel Loading Doses According to VASP Phosphorylation Index Decrease Rate of MACE in Patients With Clopidogrel Resistance

Description:

The goal of this trial was to evaluate the impact of additional loading doses of clopidogrel according to vasodilator-stimulated phosphoprotein (VASP) index in patients with clopidogrel resistance undergoing percutaneous coronary intervention (PCI).

Hypothesis:

Administering additional loading doses of clopidogrel according to the VASP index in patients with clopidogrel resistance will result in a decrease in major adverse cardiac events (MACE).

Study Design

  • Randomized
  • Parallel

Patients Screened: 406
Patients Enrolled: 162
Mean Follow Up: 1 month
Mean Patient Age: 66 years
Female: 22%
Mean Ejection Fraction: 59%

Patient Populations:

Patients undergoing PCI for refractory angina, silent ischemia on stress testing, or NSTEMI

Exclusions:

STEMI, failed PCI, New York Heart Association functional class III or IV, sudden death, contraindications to antiplatelet therapy, platelet count <100 g/L, history of bleeding diathesis, and concurrent severe illness with expected survival of <1 month

Primary Endpoints:

Incidence of MACE at 1 month. MACE was defined as death, angiographic stent thrombosis, repeat acute coronary syndrome, and repeat revascularization.

Secondary Endpoints:

Incidence of major and minor bleeding

Drug/Procedures Used:

Patients with clopidogrel resistance, defined as VASP index >50% after 600 mg clopidogrel, were randomized to VASP-guided additional clopidogrel dosing to achieve a VASP index <50% (n = 78) or PCI without additional clopidogrel dosing (n = 84). In the VASP-guided arm, up to three additional loading doses of 600 mg of clopidogrel (maximum clopidogrel dose 2400 mg) were administered until VASP <50% before PCI.

Concomitant Medications:

Baseline medications for the two groups, VASP-guided additional clopidogrel administration versus standard PCI without additional clopidogrel administration, were: aspirin (56% vs. 51%), beta-blocker (37% vs. 38%), and statin (53% vs. 49%). All patients received aspirin 160 mg and clopidogrel 75 mg daily after PCI.

Principal Findings:

A total of 162 patients were randomized, 78 to the VASP-guided arm, and 84 to the conventional PCI arm. The index diagnosis of non–ST-elevation myocardial infarction (NSTEMI) was present in 46% of patients; 54% of patients were on aspirin therapy. Glycoprotein IIb/IIIa inhibitors were used in 18.5% of the patients.

The time from the first dose of clopidogrel until PCI was 65 hours in the VASP-guided group and 26 hours in the standard PCI group (p < 0.001). In the VASP-guided additional clopidogrel group, 65% of patients required a total of four clopidogrel boluses (600 mg) to achieve a VASP index less than 50%, whereas 14% were unable to achieve this level. The mean VASP was 38% in the VASP-guided additional clopidogrel arm and 68% in the control arm (p < 0.001).

MACE occurred in no VASP-guided additional clopidogrel patients versus eight (10%) control patients (p = 0.007). In the control group, there were two cardiovascular deaths, four stent thromboses, and two recurrent acute coronary syndromes.

Total bleeding episodes occurred in three VASP-guided additional clopidogrel patients and four control patients (p = 1.0). There was one major bleed in each group.

Interpretation:

Among clopidogrel-resistant patients undergoing PCI, the use of VASP-guided additional clopidogrel dosing resulted in fewer MACE compared with standard PCI performed without additional clopidogrel dosing. This strategy resulted in similar major and minor bleeding episodes among both groups of patients.

This is an important study that supports a strategy of testing for clopidogrel resistance and basing the need for additional clopidogrel doses on the VASP index among patients undergoing PCI. Approximately 50% of patients were on aspirin at baseline; therefore, it is unknown if optimal aspirin loading prior to PCI would have altered these results. A potential bias was the relatively longer time until PCI in the VASP-guided additional clopidogrel group, which could have allowed for important medicines like statins to be used for a longer duration. Also, there were no other measures of platelet reactivity to help corroborate their findings. This study will need to be corroborated in a larger group of patients before VASP monitoring can be incorporated into routine clinical practice.

References:

Bonello L, Camoin-Jau L, Arques S, et al. Adjusted Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance. J Am Coll Cardiol [Published online 29 March 2008].

Adjusted Clopidogrel Loading Doses According to VASP Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance: A Multicentre Randomized Prospective Study. Presented by Dr. Laurent Bonello at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Interventions and ACS, Chronic Angina

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Platelet Aggregation Inhibitors, Angina, Stable, Ticlopidine, Vasodilator Agents, Percutaneous Coronary Intervention, Stents, Thrombosis, Phosphoproteins, Platelet Glycoprotein GPIIb-IIIa Complex


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