Introduction

The use of antithrombotic therapies has led to a significant reduction in morbidity and mortality, and several such agents, including aspirin, clopidogrel and heparin, have become the mainstays of treatment for patients with acute coronary syndrome (ACS)1. Treatment with percutaneous coronary intervention (PCI) plus GP IIb/IIIa platelet receptor antagonist has been proven to provide further benefits for high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients2, 3, 4 and is recommended in recent guidelines5, 6. Although the elderly are known to be at high risk7, they are underrepresented in many clinical trials. Compared with younger patients, the elderly would gain absolute benefits from an early invasive strategy and antithrombotic regimens, but at the cost of increased bleeding8, 9, 10, which has been associated with increased rates of mortality13. Major bleeding was defined as intracranial bleeding or a decrease in the hemoglobin concentration of 5 g/dL or more or a decrease in hematocrit of 15% or more. Bleeding was considered minor if the hemoglobin concentration decreased by <5 g/dL or the hematocrit decreased by <15%.

Statistical analysis

Assuming a 25% lower total bleeding rate in the low-dose group compared with the standard-dose group, we estimated that 90 patients would provide ≥80% statistical power (1–β≥0.80; α=0.05) to detect such difference. SPSS 12.0 software was used for statistical analysis.

All continuous variables were presented as mean± standard deviation (SD) or median and interquartile range according to their distribution; the Student's t-test was used for variables with a normal distribution and the Wilcoxon rank test was used for variables with a non-normal distribution. Categorical variables were presented as percentages and analyzed by the chi-square test or Fisher's exact test. Kaplan-Meier methods were utilized to estimate endpoints at 7 d, 1 month and 6 months. P values of less than 0.05 were considered statistically significant.

Results

Patient characteristics

The clinical characteristics of the 94 patients enrolled in the study are summarized in Table 1. No statistically significant differences in the baseline distribution of clinical and demographic characteristics between the two groups were found.

Table 1 Baseline characteristics of the patients.
Full size table

The angiographic characteristics of the patients are shown in Table 2. No significant differences were found in the distribution of the culprit lesion or pre- and post-PCI TIMI-grade flow (TGF) between the two groups. All the patients in the two groups underwent implantation of bare-metal or drug-eluting stents. There was no significant difference in the type of stents between the two groups.

Table 2 Angiographic characteristics and procedures results of the patients.
Full size table

Platelet aggregation testing

Platelet aggregation decreased shortly after tirofiban infusion, with a significantly higher platelet aggregation inhibition in the standard-dose group than in the low-dose group (P<0.05, Figure 1).

Figure 1
figure 1

Mean platelet aggregation inhibition (%)±SD at different time points. IPA, inhibition of platelet aggregation.

Full size image

Efficacy endpoint

The ischemic events are summarized in Table 3, and the rates of MACEs are shown in Figure 2. The incidence of MACEs was not significantly different between the standard-dose group and the low-dose group at 7 days (2.1% vs 4.4%, P=0.61), at 1 month (6.3% vs 8.7%, P=0.71) and at 6 months (14.6% vs 17.4%, P=0.71).

Table 3 Major adverse cardiac events at 7 days, 1 month and 6 month.
Full size table
Figure 2
figure 2

Cumulative Kaplan-Meier estimates of the rates of the efficacy endpoint during the follow-up period. MI, myocardial infarction; TVR, target-vessel revascularization.

Full size image

Safety endpoint

The incidence of major and minor bleeding, bleeding sites, and frequency of transfusion thrombocytopenia are listed in Table 4. The total bleeding rate (29.2% vs 10.8%, P=0.03) and the major bleeding rate (10.4% vs 0%, P=0.03) were significantly higher in the standard group than in the low-dose group. There was no statistically significant difference in minor bleeding events between the two groups.

Table 4 Bleeding events at 7 days.
Full size table

Discussion

In this single-center study, we compared the efficacy and safety of two different doses of tirofiban on elderly patients with high-risk NSTE-ACS undergoing PCI. A bolus dose of 0.4 μg kg−1·min−1 over a period of 30 min was applied in both groups, but the subsequent maintenance infusion dose varied. To our knowledge, this is the first study to compare different maintenance doses of tirofiban in very elderly people. Our major findings show that, when compared to the standard dose of tirofiban, the low dose provided similar protection from MACEs in very elderly patients with NSTE-ACS who underwent PCI. In addition, the low dose was associated with fewer total bleeding events overall and fewer major bleeding events over 6 months of follow-up.

According to recent guidelines, the use of GPI is strongly recommended in high-risk NSTE-ACS patients when PCI is planned, and eptifibatide or tirofiban is recommended for upstream use (before diagnosis angiography) in these patients. However, in patients not treated upstream, so-called downstream treatments, eptifibatide or abciximab, are recommended instead of tirofiban1, 5, 6. As detailed in these guidelines, tirofiban (bolus dose of 0.4 μg·kg−1·min−1 for 30 minutes, followed by 0.1 μg·kg−1·min−1 of infusion) should be administered before the invasive procedure. The use of tirofiban in patients with ACS further reduces the incidence of death and MI2, 3, 4. However, compared with heparin alone, tirofiban plus heparin increased major and minor bleeding significantly2. In the ACUITY trial15, which compared upstream with downstream approaches, upstream GPI (eptifibatide or tirofiban) initiation before angiography decreased the rate of the composite ischemia endpoint (although not by a statistically significant amount) but resulted in significantly higher rates of major bleeding, minor bleeding, and blood transfusions.

Age is an important determinant of outcomes for patients with ACS. Platelets isolated from older people were more inhibited by antiplatelet therapy16 than those of younger patients. Elderly patients benefit from the invasive strategy of PCI at the cost of an increased number of bleeding events9, 10. In a study designed to evaluate the safety profile of GPI in octogenarians undergoing PCI, the incidence of bleeding and the need for transfusion were higher in the very elderly patients treated with GPI. In NSTE-ACS patients, there is a strong, consistent and dose-related association between bleeding and death11; the mortality was 7.3% in patients with major bleeding compared with 1.1% in patients without major bleeding (RR, 6.71; 95% CI, 4.64−9.71; P<0.001)15. In the clinical reality, guideline-recommended therapies are used less frequently in the elderly17, 18, 19, which is probably based on a generalized consideration of protecting elderly patients from overuse of GPI during invasive interventions. This unjustified treatment paradox prompts an adjustment of the drug dose to maximize the net clinical outcome for the elderly.

Because the coronary anatomy and suitability for PCI are unknown in most patients presenting with ACS, and GPIs decrease adverse events prior to angiography, current guidelines recommend their initiation in patients with ACS either upstream to all patients or selectively in the cardiac catheterization laboratory after angiography has identified those appropriate for PCI, with no clear preference (class I, level of evidence: B). Among the three available GPIs — abciximab, eptifibatide, and tirofiban — only tirofiban is available in China. In our current study, a low dose of tirofiban has been confirmed to yield a net benefit comparable to that of the standard dose, ie, a similar rate of prevention of ischemic events and fewer bleeding events. To obtain more benefit but less risk from the invasive strategy, this adjustment to the standard dose of tirofiban would be more appropriate and practical for elderly patients with high-risk NSTE-ACS in China.

There are several limitations in this study. First, the open-label design may have raised the possibility of bias. We attempted to minimize this potential with the requirement that all ischemic and hemorrhagic events be adjudicated by observers blinded to the treatment assignation. Second, this is a small study, so the results obtained should be further tested in larger randomized blind trials in the future.

Conclusions

In very elderly Chinese patients with high-risk NSTE-ACS, a low dose of tirofiban provides protection from ischemic events similar to that of the standard dose over a 6 month follow-up period, but it significantly reduces the number of major bleeding events.

Author contribution

Yun-lin LIN and Liang-long CHEN designed the research; Yu-kun LUO and **ng-chun ZHENG performed the research; Wei-wei LI analyzed data; Yun-lin LIN and Liang-long CHEN wrote the paper.