Optimal platelet inhibition in patients undergoing PCI: Data from the Multicenter Registry of High-Risk Percutaneous Coronary Intervention and Adequate Platelet Inhibition (MR PCI) study

Article Outline

• Abstract
• Methods
  • Study protocol and patient selection
  • Study end points
  • Randomization
  • PCI and concomitant drugs
  • Blood sampling and platelet function assessment
  • Statistical analysis
• Results
• Discussion
  • Study limitations
  • Conclusion
• References
• Copyright

Background

Optimal inhibition of platelet aggregation (IPA) may afford greater protection against ischemic events during percutaneous coronary intervention (PCI). The objective of this study was to test several antiplatelet regimens in elective high-risk PCI patients by comparing different combinations of glycoprotein IIb/IIIa inhibitors and clopidogrel.

Methods

The study was a randomized open-label study at 3 heart centers in India. One hundred twenty patients were enrolled between July 2006 and September 2006. Patients were randomized to 1 of the 4 groups: group A—tirofiban, group B—eptifibatide, group C—tirofiban + clopidogrel 600-mg loading dose, and group D—eptifibatide + clopidogrel 600-mg loading dose. All patients received a clopidogrel maintenance dose after PCI. The primary outcome measure was the IPA assessed at 10 minutes, at 6 to 8 hours, and at 24 hours.

Results

The IPA was higher with high-dose tirofiban compared with eptifibatide at 10 minutes (95.88 ± 5.85% vs 91.22 ± 7.52%, P = .003) and at 6 to 8 hours (93.11 ± 7.6% vs 85.45 ± 11.03, P < .001). Significantly more patients achieved >95% IPA with the high-dose tirofiban regimen.

Conclusions

This head-to-head study comparing high-dose tirofiban with double-bolus eptifibatide demonstrated higher degree of platelet inhibition with high-dose tirofiban at 10 minutes and at 6 to 8 hours in patients undergoing elective high-risk PCI. The addition of clopidogrel did not acutely extend the IPA from intravenous glycoprotein IIb/IIIa inhibitors, but did so at 24 hours.

Over the last decade, a vast amount of information has confirmed the central role of platelets in acute coronary syndromes (ACS) and complications after high-risk percutaneous coronary intervention (PCI).¹ This has prompted the development of aggressive antiplatelet regimens particularly for ACS patients undergoing PCI. Many recent trials have used different dosing, timing of administration, and combinations of antiplatelet agents with the intention of achieving greater antithrombotic protection. Dual antiplatelet therapy with aspirin and clopidogrel has become a cornerstone in clinical practice guidelines for patients undergoing PCI with stenting.², ³ Another class of antiplatelet drugs that have shown consistent benefit in ACS-PCI is the glycoprotein (GP) IIb/IIIa antagonists. Currently, GP IIb/IIIa antagonists are considered the most specific and potent inhibitors of platelet aggregation in acute thrombosis.⁴ The GP IIb/IIIa antagonists, eptifibatide and tirofiban, have been approved for the treatment of patients with ACS who are undergoing PCI.⁵

The results from recent studies suggest that a more vigorous approach to the inhibition of platelet aggregation (IPA) may afford greater protection against ischemic events. It remains to be seen if high clopidogrel loading (600 mg) further reduces ischemic events in patients who are already receiving aspirin and clopidogrel. If it does, this information will be particularly useful in optimizing the antiplatelet strategy among patients who receive pretreatment with clopidogrel for several days before intervention. The MR PCI study was performed to define optimal antiplatelet therapy in high-risk patients undergoing PCI. The primary objective was to compare high-dose tirofiban with double-bolus eptifibatide regarding the extent of platelet inhibition. A secondary aim was to evaluate the efficacy of 600-mg loading clopidogrel dose during PCI in reducing the inhospital and 30-day adverse outcome in ACS patients.

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Methods 

Study protocol and patient selection 

The MR PCI was a prospective, randomized, multicenter head-to-head comparison of high-dose tirofiban and high-dose eptifibatide with a factorial randomization to concomitant high-dose clopidogrel loading or not. The protocol was approved by the local hospital ethics committees before its initiation. All patients were recruited after giving written informed consent. One hundred twenty patients meeting the eligibility criteria were enrolled between July 2006 and September 2006 for the registry in 3 centers in India. Inclusion criteria were as follows: (1) patient on chronic antiplatelet therapy (aspirin daily, clopidogrel >5 days therapy or total dose of >300 mg >24 hours ago) and (2) severe coronary artery disease amenable to PCI and at least one of the following clinical criteria: (a) prior stroke, (b) prior peripheral vascular disease, (c) diabetes mellitus, (d) documented microalbuminuria, (e) prior myocardial infarction (MI), or (f) presence of unstable angina with electrocardiographic changes (transient [<20 min] ST-segment elevations of =1 mm or ST-segment depressions ≥1 mm) or elevated cardiac enzymes consistent with MI (creatine kinase [CK]–MB or troponin T or I). Exclusion criteria were as follows: (1) ST-segment elevation MI, (2) history of bleeding diathesis, (3) stroke within 3 months, (4) chronic total occlusion/angiographically visible thrombus, (5) alcohol abuse, (6) prothrombin time >1.5 times control, (7) platelet count <100000/mm³, (8) creatinine >4.0 mg/dL, and (9) hematocrit <30%.

Study end points 

The primary end point of the study was the degree of platelet inhibition at 6 to 8 hours and after 24 hours. Secondary end points were as follows: (1) degree of platelet inhibition at 10 minutes; (2) inhospital outcomes of major adverse cardiac events (MACE), which included death, MI, and need for urgent target vessel revascularization; (3) Thrombolysis in Myocardial Infarction major and minor bleeding inhospital; and (4) 30-day MACE. Myocardial infarction was defined as rise of CK-MB ≥3 times the baseline value.

Randomization 

A computer-based randomization scheme was used to assign subjects to 1 of the 4 antiplatelet regimens (group A—tirofiban, group B—eptifibatide, group C—tirofiban + clopidogrel 600 mg, and group D—eptifibatide + clopidogrel 600 mg; serial numbers 1 to 120) so that each regimen was assigned to 30 numbers. Sealed envelopes containing the serial numbers were distributed randomly among 3 centers, and the envelope was opened at the time of PCI.

PCI and concomitant drugs 

All patients were on chronic antiplatelet therapy (aspirin, clopidogrel >5 days or total dose ≥300 mg >24 hours ago). The 600-mg clopidogrel loading dose was given to patients in groups C and D before starting the intervention (median time of 10 minutes in both groups). Tirofiban was given to patients in groups A and C as 25-μg/kg bolus followed by an infusion 0.15 μg/(kg min) for 6 to 8 hours after the procedure. Eptifibatide was given to patients in groups B and D as double bolus of 180 μg/kg followed by 2 μg/(kg min) for 6 to 8 hours. Unfractionated heparin was administered according to the recent American College of Cardiology/American Heart Association guidelines for PCI as a bolus of 50 U/kg to all patients in the catheterization laboratory immediately before procedure to achieve a target activated clotting time of >200 seconds.² Bare-metal or drug-eluting stents were implanted during PCI. After the procedure, all patients were prescribed clopidogrel 75 mg daily for at least 30 days and aspirin lifelong. Patients receiving drug-eluting stents were asked to continue clopidogrel for a year after PCI.

Blood sampling and platelet function assessment 

Baseline blood samples were obtained just before clopidogrel loading and GP IIb/IIIa inhibitor bolus. Subsequent samples were taken at 10 minutes, 6 to 8 hours, and 24 hours after the bolus dose of GP IIb/IIIa inhibitor. Samples were immediately collected in blood tubes containing Phe-Pro-Arg chloromethyl ketone (PPACK).⁶ The PPACK tubes were used to avoid the divalent cation-chelating effect of anticoagulants such as citrate or EDTA that might overestimate the degree of platelet inhibition by tirofiban and eptifibatide.⁷ A part of the sample drawn at baseline, 6 to 8 hours, and 24 hours after the GP IIb/IIIa inhibitor bolus was collected in separate tubes for measurement of CK-MB levels.

Blood samples drawn in PPACK tubes were analyzed by Ultegra Rapid platelet function assay (VerifyNow; Accumetrics, San Diego, CA). In brief, the VerifyNow IIb/IIIa assay is designed to assess platelet function based upon the ability of activated platelets to bind fibrinogen. Fibrinogen-coated microparticles aggregate in whole blood in proportion to the number of unblocked platelet GP IIb/IIIa receptors. The rate of microbead aggregation is more rapid and reproducible if platelets are activated; therefore, the reagent iso–thrombin receptor agonist peptide (TRAP) is incorporated into the assay to induce platelet activation without fibrin formation. Light transmittance increases as activated platelets bind and aggregate fibrinogen-coated beads. The instrument measures this change in optical signal and reports results in platelet aggregation units. Inhibition of platelet aggregation was calculated as follows: [(aggregation at baseline − aggregation at time t) / aggregation at baseline] × 100.

Statistical analysis 

Statistical analysis was performed with SAS 9.1 (SAS Institute, Cary, NC). A sample size of 120 was based on 80% power to detect a 15% difference in IPA at 10 minutes between the regimens. The 15% difference in IPA was empirically based on a report by Lakkis et al that demonstrated ∼10% difference in IPA with the tirofiban and abciximab doses used in the TARGET trial.⁸ Because the TARGET trial demonstrated differences in clinical outcomes between tirofiban and abciximab, we came up with a conservative assessment that a 15% difference in IPA may potentially translate into differences in clinical outcome taking into account some variability in IPA assessment. Continuous variables were expressed as mean ± SD. We used the nonparametric tests of Kruskal-Wallis and the Westenberg-Mood median test to compare differences across groups for continuous variables because IPA levels are not normally distributed. Categorical variables were expressed as frequencies. The Kendall τ-b, which is a measure of association often used with but not limited to 2 × 2 tables, was used to compare clinical outcomes across groups given low event rates. A P value < .05 was considered statistically significant.

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Results 

Demographics and clinical characteristics of the sample population within each group are shown in Table I. There were no observed baseline differences among the groups except that significantly more patients in group C (tirofiban + 600 mg clopidogrel) had a history of prior MI. The median time between the 600-mg bolus of clopidogrel and the onset of PCI was ∼10 minutes in both groups C and D.

Table I. Demographics and clinical characteristics of the study cohort

	Group A	Group B	Group C	Group D	P
	Tirofiban (n = 30)	Eptifibatide (n = 30)	Tirofiban + 600 mg clopidogrel (n = 30)	Eptifibatide + 600 mg clopidogrel (n = 30)
Demographics
Age, y (mean ± SD)	60.8 ± 10.8	57.3 ± 10.1	60.5 ± 15.6	54 ± 8.8	.10
Sex (male)	83.3%	90%	86.6%	80%	.73
Comorbidities
Prior stroke	3.3%	3.3%	0%	10%	.27
Diabetes mellitus	46.6%	40%	30%	23.33%	.24
Documented microalbuminuria	3.33%	0%	0%	0%	.39
Prior MI	30%	53.3%	70%	46.66%	.02
Unstable angina	70%	53.3%	50%	50%	.34
Prior angina	46.6%	43.3%	56.6%	60%	.53
Prior PCI	3.3%	3.3%	6.6%	3.33%	.89
Prior bypass surgery	3.3%	3.3%	3.3%	6.66%	.89
Renal failure	0%	3.3%	0%	0%	.39
Family history of coronary disease	26. 6%	26.6%	26.6%	30%	.98
Hypertension	43.3%	50%	36.6%	36.66%	.68
Hyperlipidemia	36.6%	46.6%	63.3%	33.33%
Current smokers	33.3%	33.3%	30%	10%	.09
History smoking	23.3%	30%	26.6%	46.66%	.38

At 10 minutes post bolus (Table II), IPA with tirofiban (95.7 ± 5.2%) was higher than that of double-bolus eptifibatide (89.4 ± 8.6%) (P = .003 ). The IPA with tirofiban + clopidogrel (96.1 ± 6.5%) was also higher than that in the eptifibatide + clopidogrel group (92.9 ± 5.8%) (P = .003). The degree of platelet inhibition was also higher with tirofiban (91.9 ± 8.5) compared with that of eptifibatide (84.8 ± 12.1) (P < .001), and the IPA in the tirofiban + clopidogrel group (94.2 ± 6.4) was higher compared with that in the eptifibatide + clopidogrel group (86.1 ± 10.1) (P < .001) at 6 to 8 hours. At 24 hours, the difference in IPA was not significantly different between tirofiban-alone and eptifibatide-alone groups (P = .11) and within the clopidogrel combination group (P = .11) (Table II). Table II also provides the proportion of patients who reached >95% IPA at each of the time points with each of the regimens.

Table II. Inhibition of platelet aggregation at 10 minutes, 6 to 8 hours, and 24 hours

Four patients had inhospital MIs (Table III), 2 in group C and 1 each in groups A and B. There were no significant differences in inhospital events (P = .55) among the different groups. There was one case of major bleed in group A and one case of minor bleed in group B. There were no additional adverse events reported at 30-day follow-up in any of the groups, with no differences across groups.

Table III. Inhospital outcomes of MACE and bleeding inhospital

MACE defined as death or nonfatal MI or urgent target vessel revascularization.

Combining data from groups A and C (representing IPA of tirofiban) and comparing that with combined data from groups B and D (representing IPA effect of eptifibatide), high-dose tirofiban showed higher IPA at 10 minutes and 6 to 8 hours post PCI (Table IV). At 24 hours post PCI, the difference in IPA was not significantly different between the 2 GP IIb/IIIa inhibitors.

Table IV. Overall comparison of high-dose tirofiban with double-bolus eptifibatide

Group A—tirofiban, group B—eptifibatide, group C—clopidogrel 600 mg loading + tirofiban, and group D—clopidogrel 600 mg loading + eptifibatide.

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Discussion 

The MR PCI trial results indicate that high-dose tirofiban effectively inhibits platelet aggregation at 10 minutes and 6 to 8 hours and compares favorably with double-bolus eptifibatide. The degree of platelet inhibition observed in tirofiban and eptifibatide groups at 10 minutes is similar to that observed in prior studies.⁹ Our findings add to these existing data favoring the use of high-dose tirofiban during elective high-risk PCI in ACS patients. The clinical importance of achieving a high degree (≥95%) of platelet inhibition at 10 minutes after the start of GP IIb/IIIa antagonist therapy has been previously demonstrated,¹⁰ and the data suggest that high-dose tirofiban is able to achieve such degree of inhibition in a significant proportion of patients. However, the 95% level was evaluated in a mainly abciximab study; and the utility of this level with other GP IIb/IIIa inhibitors has not been validated.

In 2002, the COMPARE trial provided a direct pharmacodynamic comparison of conventional doses of abciximab, eptifibatide, and tirofiban based upon previous trial experience.¹¹ It demonstrated that a 10-μg/kg tirofiban bolus inhibited platelet activity to a lower degree than that with abciximab and eptifibatide. The study did not evaluate the pharmacodynamics of currently used doses of eptifibatide (ESPRIT trial¹²) or tirofiban (ADVANCE trial¹³), although it would be expected that these more potent doses would provide greater degree of platelet inhibition. More recently, Danzi et al compared these 2-molecule agents in their newly prescribed doses (eptifibatide 180 μg/kg double bolus followed by 2 μg/[kg min] for 24 hours according to the ESPRIT dosing regimen and tirofiban 25 μg/kg bolus followed by an infusion 0.15 μg/[kg min] for 18 hours as recommended in ADVANCE trial).⁹ This study concluded that high-dose tirofiban was a more effective drug in rapidly (10 minutes) achieving optimal platelet inhibition after PCI.

The PCI-CURE, a substudy of the CURE study, provided a strong evidence for addition of clopidogrel in the management of ACS patients who undergo PCI with stenting.¹⁴ The CLEAR PLATELETS study showed that in clopidogrel-naive patients, using a parenteral GPIIb/IIIa inhibitor along with a high clopidogrel loading dose (600 mg) provides more substantial platelet inhibition and is associated with a low incidence of postprocedural MI and excellent myocardial protection.¹⁵

The addition of the 600-mg clopidogrel loading to the tirofiban and eptifibatide groups showed a trend toward higher antiplatelet effect at 6 to 8 hours as compared with tirofiban- and eptifibatide-only groups, respectively. This was an interesting finding considering only GP IIb/IIIa assay (using TRAP to activate platelets) was used to measure the antiplatelet effect of all the groups. However, there are data from Behan et al¹⁶ and others that clopidogrel does inhibit TRAP-induced aggregation in higher dosages, which may explain these findings. A 600-mg loading dose of clopidogrel also showed a trend toward higher IPA at 24 hours, but with high variability in all the groups.

In our study, there were no significant differences in the inhospital events and 30-day outcomes among the groups; but the study was not powered to assess differences in clinical outcomes. There was concern for increased major and minor bleeds with the use of aggressive antiplatelet therapies, particularly in groups C and D; but there were no major bleeds noted in groups C and D. Based on this, high-dose tirofiban or double-bolus eptifibatide with clopidogrel 600-mg loading dose seems safe.

Study limitations 

The sample size was not powered to assess differences in clinical outcome. Because there were no adverse events reported beyond hospitalization during the 30-day follow-up, we could not establish any significant association between the treatment regimens and clinical efficacy outcomes. Secondly, shorter infusions (6-8 hours) of GP IIb/IIIa antagonists were used after PCI because this is the standard practice in India for economic reasons. Finally, our study did not include a measure of platelet function that specifically assesses the antiplatelet effect of clopidogrel.

Conclusion 

This study demonstrates that high-dose tirofiban in patients undergoing high-risk elective PCI is associated with greater IPA at 10 minutes and at 6 to 8 hours as compared with double-bolus eptifibatide. The use of 600-mg loading clopidogrel dose along with GP IIb/IIIa inhibitors seems to be safe and may allow a shorter duration of intravenous IIb/IIIa inhibitor therapy. Larger clinical trials are required to assess the benefit of high-dose bolus and shorter infusion duration tirofiban with a high concomitant dose of clopidogrel.

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