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(Circulation. 2002;105:2361.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Benefits and Safety of Tirofiban Among Acute Coronary Syndrome Patients With Mild to Moderate Renal Insufficiency

Results From the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Trial

James L. Januzzi, Jr, MD; Steven M. Snapinn, PhD; Peter M. DiBattiste, MD; Ik-Kyung Jang, MD, PhD; Pierre Theroux, MD

From the Cardiology Division, Massachusetts General Hospital, Boston, Mass (J.L.J., I.-K.J.); Merck Research Laboratories, West Point, Pa (S.M.S., P.M.D.); and the Cardiology Division, Montreal Heart Institute, Montreal, Quebec, Canada (P.T.).

Correspondence to Pierre Theroux, MD, Montreal Heart Institute, Research Center, 5000 East Belanger St, Montreal, Quebec, Canada H1T 1C8. E-mail theroux{at}icm.umontreal.ca

	Abstract

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Background— The role of glycoprotein IIb/IIIa receptor antagonists for the treatment of patients with acute coronary syndrome and renal insufficiency remains undefined.

Methods and Results— Patients from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial were stratified by creatinine clearance (CrCl) and assessed with respect to treatment assignment to tirofiban/heparin versus heparin alone for the risk of adverse outcomes and bleeding. Patients with severe renal insufficiency (defined as a serum creatinine 2.5 mg/dL) were excluded from PRISM-PLUS as a whole. Patients with the lowest CrCl (<30 mL/min) were more likely to present with high-risk clinical features. Decreasing renal function was strongly associated with adverse outcome, increasing the risk for ischemic complications at all time points examined (all P<0.002). Irrespective of CrCl, therapy with tirofiban reduced the odds of the composite end point of death, myocardial infarction, or refractory ischemia at 48 hours (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.46 to 1.0; P=0.05), 7 days (OR, 0.68; 95% CI, 0.52 to 0.88; P= 0.003), 30 days (OR, 0.78; 95% CI, 0.63 to 0.98; P=0.03), and 6 months (OR, 0.81; 95% CI, 0.68 to 0.98; P=0.03). The risk of myocardial infarction/death was also significantly decreased to a similar magnitude at all time points examined. There was no evidence of treatment-by-CrCl interaction. The presence of declining renal function independently increased the risk for bleeding (OR, 1.57; P<0.001 for trend across categories), as did therapy with tirofiban, but no unexpected incremental risk of bleeding due to tirofiban was observed among lowest CrCl categories.

Conclusions— Among patients with mild-to-moderate renal insufficiency in PRISM-PLUS, tirofiban was well tolerated and effective in reducing ischemic acute coronary syndrome complications.

Key Words: kidney • myocardial infarction • platelets

	Introduction

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Among patients with the non–ST-segment elevation acute coronary syndrome (ACS) of unstable angina pectoris or non–ST-segment elevation myocardial infarction (MI), the prognosis of those with renal insufficiency is particularly poor.^1–7 This effect on prognosis is most likely due to the fact that compared with those without renal insufficiency, patients with significant reductions in creatinine clearance (CrCl) tend to be more advanced in age and to have a higher likelihood for concomitant medical illness, often including diffuse, severe coronary artery disease (CAD). In addition, this adverse interaction between ACS and renal insufficiency may also be due to a lesser use of antithrombotic therapies with demonstrated benefit, such as glycoprotein (GP) IIb/IIIa receptor antagonists.^6,8,9

The true interaction between renal insufficiency and therapy with intravenous platelet receptor antagonists remains undefined. Accordingly, we examined the interaction between renal failure, prognosis, and bleeding risk among patients treated with the small molecule GP IIb/IIIa receptor antagonist tirofiban in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial.¹⁰

	Methods

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Patient Population
The details of the PRISM-PLUS study design are published elsewhere.¹⁰ Briefly, 1915 patients with an ACS were enrolled within 12 hours of presentation to 1 of the following 3 regimens in a double-blind fashion for at least 48 hours: tirofiban (0.4 µg · kg^–1 · min^–1 for 30 minutes followed by 0.1 µg · kg^–1 · min^{– 1}) plus heparin, heparin plus tirofiban placebo, or tirofiban (0.6 µg · kg^–1 · min^–1 for 30 minutes followed by 0.15 µg · kg^–1 · min^{– 1}) plus heparin placebo. Heparin or heparin placebo was administered as an intravenous bolus of 5000 U, followed by an infusion of 1000 U/h; the infusion rate was adjusted to achieve an activated partial thromboplastin time twice control. All patients received 325 mg of aspirin daily. The tirofiban plus placebo arm of the trial was terminated after the enrollment of 345 patients due to excess mortality at an interim analysis. This group was excluded from the final analysis of PRISM-PLUS and is not considered in this study, thus leaving 1570 patients eligible for analysis.

When available, prerandomization values of creatinine were used to calculate CrCl, and the first postrandomization value was used when prerandomization values were not available; 1451 patients had prerandomization creatinine data available, and 86 had postrandomization data only, thus leaving a total of 1537 analyzable patients. Results in the subset of 1451 patients with a pretreatment creatinine value were examined to ensure consistency with the reported results. The 33 patients with missing creatinine values were distributed evenly between the treatment assignments and demonstrated a heterogeneous range of demographics.

Patients with severe renal insufficiency (defined as a serum creatinine 2.5 mg/dL) were excluded from PRISM-PLUS and are therefore not considered in this analysis.

Benefits of Tirofiban by CrCl
For the purposes of this study, patients from PRISM-PLUS were assessed by renal function, expressed as CrCl, which was determined using the Cockroft-Gault equation.¹¹ This formula defines CrCl=[(140-age)x(weight in kilograms)]/[(serum creatinine in mg/dL)x(72)]. For women, the product of this equation is multiplied by a correction factor of 0.85. The benefits of therapy with tirofiban/heparin on the composite end points of death/MI/refractory ischemia, as well as death/MI, were assessed as a function of CrCl at 48 hours, 7 days, 30 days, and 6 months.

Effects of Tirofiban on Bleeding Rates
Bleeding was assessed according to the classification of the Thrombolysis in Myocardial Infarction (TIMI) investigators¹² and by using the criteria of the PRISM-PLUS trial,¹⁰ which ranged from oozing to life threatening.

Statistical Analysis
Although the CrCl distribution was broken into categories for display purposes, all analyses were based on the original continuous distribution. Associations between baseline CrCl and dichotomous patient characteristics were assessed using a logistic regression model, ordinal variables were assessed with a proportional odds model, and continuous variables were analyzed by Pearson correlation coefficient. The bleeding events were measured on ordinal scales and analyzed using proportional odds models. Clinical events were analyzed using Cox proportional odds models, and the reported risk ratios are based on these models. All probability values are 2-sided; values <0.05 were considered significant.

	Results

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Clinical Characteristics of Study Population
Clinical characteristics of the study subjects are detailed in Table 1, which demonstrates that decreasing CrCl was associated with significant increases in high-risk findings, including advanced age, prior CAD, prior angina or MI, and congestive heart failure (all P< 0.05). Furthermore, decreasing CrCl resulted in an associated increase in the prevalence of ischemic changes on ECG, particularly consisting of a higher prevalence of ST segment depression (all P<0.001). Angiography demonstrated that declining renal function was associated with an increased severity of CAD (Table 1), including a higher prevalence of 3-vessel CAD (P<0.001) and left main CAD (P=0.001).

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Patients in the PRISM-PLUS Trial Based on CrCl

When the clinical characteristics of the study subjects were compared on the basis of CrCl and treatment assignment, the patients were generally well balanced, with no important differences noted (data not shown).

Benefits of Tirofiban/Heparin Therapy Versus Heparin Alone
Decreasing renal function was a risk factor for adverse outcomes, with a step-wise increase in ischemic cardiac event rates (Tables 2 and 3; P<0.002 for all analyses). Irrespective of renal function, this increased risk was significantly reduced by the combination of tirofiban/heparin versus heparin alone (Tables 2 and 3), and the absolute and relative risk reductions as a consequence of therapy with tirofiban/heparin were generally similar. Of note, a high incidence of refractory ischemia was present among patients in the lower categories of CrCl at 30 days and 6 months (Table 2). However, significant reductions in the incidence of death/MI from the addition of tirofiban to heparin were still generally evident among these patient groups at these time points.

View this table: [in this window] [in a new window]   Table 2. Incidence of the Composite End Point at the Various Time Points of PRISM-PLUS

View this table: [in this window] [in a new window]   Table 3. Incidence of Death/MI at the Various Time Points of PRISM-PLUS

Bleeding
As previously demonstrated in the PRISM-PLUS study, bleeding was somewhat more common among patients treated with combination therapy compared with heparin monotherapy.¹⁰ Irrespective of CrCl, however, bleeding was generally mild to moderate in patients receiving tirofiban and heparin, with no intracranial hemorrhages, and no deaths attributable to bleeding.

The severity of bleeding among patients in the present study is detailed in Table 4, both in terms of the TIMI bleeding scale and the more detailed scale used in the PRISM-PLUS trial. For TIMI-defined major bleeding, neither the effects of renal insufficiency nor the addition of tirofiban to heparin resulted in statistically significant increases in major bleeding rates (P=0.35 and 0.20, respectively). For TIMI-defined major and minor bleeding, however, worsening renal function was associated with significantly increased bleeding rates (P=0.004), as was the addition of tirofiban to heparin (P=0.04). With the more detailed PRISM-PLUS bleeding scale (Table 4), the rates of all bleeding increased with decreases in CrCl (P< 0.001 for trend), and the addition of tirofiban to heparin resulted in statistically significant increases in bleeding rates (P<0.001) that were consistent across levels of CrCl.

View this table: [in this window] [in a new window]   Table 4. Bleeding Among Patients in PRISM-PLUS

Using the PRISM-PLUS bleeding scale, the proportional odds for any form of bleeding among the patients in PRISM-PLUS as a function of CrCl were determined, and they are detailed in the Figure, which demonstrates that irrespective of treatment assignment, renal insufficiency was a significant risk for bleeding (lowest versus highest CrCl category: odds ratio, 1.57; P<0.001). In addition, irrespective of renal function, the addition of tirofiban to heparin resulted in an incremental risk for bleeding (P<0.001), but these risks were not further amplified among patients with renal insufficiency, as illustrated by the nonsignificant difference in slopes predicted by the proportional odds model.

View larger version (11K): [in this window] [in a new window]   Proportional odds for any severity of bleeding among patients in PRISM-PLUS treated with tirofiban and heparin (combination) versus heparin, expressed as a function of CrCl (in mL/min). Declining renal function was significantly associated with hemorrhage, irrespective of treatment assignment (P<0.001), as was the addition of tirofiban to heparin (P<0.001). However, although each of these was associated with significant increases in the risk for mild to moderate bleeding, the addition of tirofiban in the presence of renal insufficiency was not accompanied by an incremental increase in risk for hemorrhage (incremental risk of bleeding from adding tirofiban to heparin from lowest to highest category of CrCl: odds ratio [O.R.], 1.80 vs 1.61; P= NS).

	Discussion

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Compared with patients with intact renal function, patients with reduced CrCl have repeatedly been demonstrated to have significantly worse outcomes after ACS.^1–7 This may be due to the fact that patients with renal insufficiency tend to have a higher prevalence of risk factors for a complicated course after ACS and tend to have more extensive CAD. In addition, patients with impaired renal function tend to have suboptimal long-term outcomes from revascularization therapy.^13–15

Other explanations for the poorer outcomes of patients with renal insufficiency may be operative, however. It has been recently suggested that patients with renal failure are less likely to be treated with therapies with proven benefits, such as GP IIb/IIIa receptor antagonists, possibly because of clinician fears of a potential increment in bleeding risk among ACS patients with impaired renal function who are treated with these agents.⁶ In fact, this concern may have a basis, because renal insufficiency is associated with numerous qualitative platelet abnormalities, including reduced adhesion,¹⁶ and significant abnormalities of aggregation. The abnormalities of aggregation are thought to be due to reversible, functional derangements of the platelet GP IIb/IIIa receptor. Although the receptor is normally distributed in the platelets of patients with renal insufficiency, it demonstrates numerous functional changes that may be reversed with improvements in renal function or hemodialysis.¹⁷ Among these are an impaired ability of the GP IIb/IIIa receptor to change to an "activated" conformation, ¹⁸ as well as a reduced ability to bind ligand.¹⁷ The latter defect may be due in part to receptor inhibition by uremic toxins,¹⁷ as well as to receptor occupancy by circulating fragments of von Willebrand factor and fibrinogen, which tend to be elevated among these patients.¹⁹ In addition, compounding the potential bleeding risk in these patients is the fact that the small-molecule GP IIb/IIIa receptor blockers are largely renally excreted, which might lead to their accumulation.

Despite these concerns, little is known about the interaction between mild to moderate impairments in renal function and therapy with platelet GP IIb/IIIa receptor blockers with respect to safety and efficacy. Accordingly, we performed the present analysis among patients in the PRISM-PLUS trial.

We demonstrated, consistent with prior studies, that ACS patients with mild to moderate decreases in CrCl more often demonstrate high-risk clinical features, including more ST segment depression, a particularly high-risk finding among patients with the non–ST-segment elevation ACS.²⁰ Furthermore, the angiographic data from our substudy confirms the high-risk nature of these patients, because the vast majority of patients in the lowest category of CrCl presented with either 3-vessel or left main CAD, whereas single vessel disease was more expected among the patients with preserved renal function. With respect to outcomes, although patients with severe impairments in renal function were excluded from PRISM-PLUS as a whole, a potently negative effect of decreasing renal function on cardiovascular outcomes was still observed, with increasing adverse ischemic events demonstrated among those patients with lower CrCl, which was closely related to decline in renal function. Furthermore, across the range of renal function seen among the patients in this analysis, tirofiban therapy was effective in reducing clinical events, without an increment in the expected risk for bleeding over patients with preserved renal function, despite the expected qualitative platelet abnormalities and impaired drug excretion among patients with abnormal CrCl.

The effects of declining renal function on outcomes deserve particular mention. As we have demonstrated, with even mild decreases in CrCl, a concomitant increase in adverse outcomes was observed, particularly in the incidence of refractory ischemia and/or MI. The addition of tirofiban to heparin reduced the risk for the composite end point in a consistent fashion, irrespective of CrCl, with an acceptable risk for bleeding. Although the incidence of death/MI was reduced at 30 days and 6 months in the lowest category of CrCl, the benefits of tirofiban on the incidence of the composite end point were less clear, largely due to a high incidence of refractory ischemia among this patient subgroup at a time distant to initial treatment with tirofiban. These data suggest that although tirofiban is efficacious in significantly reducing early ischemic ACS complications among patients with impaired renal function, significant improvements in the longer term care of these patients are clearly needed.

Our data have limitations that deserve mention. First, although a wide spectrum of CrCl was examined, it is important to acknowledge that patients with severe renal insufficiency (serum creatinine 2.5 mg/dL) were excluded from PRISM-PLUS as a whole. Thus, generalizations from this study may not apply to such patients with severe renal insufficiency, particularly because the dose reductions recommended for such patients were not used in PRISM-PLUS. Nonetheless, because tubular secretion of creatinine continues even with severe impairment of glomerular filtration rate, serum creatinine is a poor surrogate marker for glomerular filtration rate^11,21,22 and frequently underestimates the true severity of renal impairment; therefore, a significant overlap between patients with severely impaired renal function may exist with those patients among our study in the lowest category of CrCl. Thus, although potentially suggestive of benefit among patients with even more severe renal impairment, any potential benefits of tirofiban therapy for ACS patients with severe renal insufficiency remain speculative. Another potential limitation of our study is that we estimated CrCl using the Cockroft-Gault formula rather than using a more direct measurement of renal function. Obviously, although certainly preferable, it would not have been feasible for a study as large as PRISM-PLUS to make such measurements, and the Cockroft-Gault formula has been well validated for the estimation of CrCl.¹¹ One important limitation of the Cockroft-Gault formula to consider is that it prominently incorporates the effect of age on renal function and thus would be expected to result in a higher proportion of elderly patients in the lowest category of CrCl. Although advanced age is certainly a high-risk marker among patients with ACS, it is unlikely to explain fully the high rates of both clinical events and the rise in bleeding noted among the patients in the lowest CrCl categories. Furthermore, among elderly patients, the serum creatinine (also prominently figured in the formula) is even more likely to underestimate glomerular filtration rate impairment for the reasons outlined above,^21,22 so the true severity of renal insufficiency among elderly patients in PRISM-PLUS is likely to be more significant rather than the converse. A final factor worth mention are the 33 patients not analyzed due to incomplete serum creatinine data. This factor may influence our data, because we had relatively few patients in the lowest range of CrCl and, as such, any conclusions about the efficacy or safety of tirofiban in this patient group might be influenced by even small numbers of missing patients. However, the demographic and randomization characteristics of these patients make it unlikely that their absence would be expected to influence results.

In summary, we demonstrated that among non–ST-segment elevation ACS patients in the PRISM-PLUS trial, the effects of declining renal function included a concomitant increase in the risk for ischemic cardiovascular complications at all end points examined but that the risk for ischemic complications was significantly reduced at all end points among the patients treated with tirofiban, with little evidence that the benefit varied with renal function. Although mild to moderate bleeding was more common among all patients treated with tirofiban, treatment with tirofiban in the presence of renal insufficiency did not amplify the risk for bleeding further than expected. Our data have significant implications because the number of ACS patients with impaired renal function is increasing, and improvements in treatment strategies for this population are clearly needed. Our data suggest that non– ST-segment elevation ACS patients with mild to moderate impairment in renal function may be treated safely and effectively with a combination of tirofiban and heparin to reduce their risk for adverse ischemic cardiovascular events.

Received December 31, 2001; revision received March 11, 2002; accepted March 11, 2002.

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