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Mahboob Alam, Rafael Gonzalez, Ariel Delarosa, Jaromir Bobek, Hisham Dokainish and Nasser Lakkis
American Heart Journal Volume 7 No.1

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Background:
Patients with impaired renal function are a growing subset at higher risk for cardiovascular complications due to vasculopathic state, inducing accelerated atherosclerosis and arteriosclerosis. These patients are at increased risk for complications after coronary interventions, especially major bleeding events. As a result, this at-risk population of patients has not been well studied in most of the major clinical trials evaluating coronary interventions. Of particular interest is the optimal dosing of glycoprotein IIb-IIIa inhibitors in the setting of acute myocardial infarction. In this study,we attempted to find the in vitro concentration of tirofiban required to inhibit platelet aggregation to < 10% in patients with moderate to severe renal insufficiency.

Methods:
A total of 21 patients were divided into two groups based on estimated creatinine clearance (group 1 < 46ml/min; group 2 >46ml/min). Platelet-rich plasma from each subject was then incubated in vitro with increasing concentrations of tirofiban (25, 37.5, and 50ng/ml), and light transmission aggregometry assay was used to assess the degree of platelet aggregation in response to adenosine diphosphate (ADP).

Results:
Patients in group 1 had a baseline platelet aggregation of 45%, which decreased to 10% at a 25.0ng/ml concentration of tirofiban; the effect was enhanced to a platelet aggregation of < 5% at higher doses. In contrast, subjects in group 2 with creatinine clearance > 46ml/min had an average platelet aggregation inhibition of 12% with 50ng/ml of tirofiban.We found a significant decrease in platelet aggregation in group 2 at 25, 37.5, and 50ng/ml of tirofiban (p< 0.05) in comparison with group 1.

Conclusions:
Our data indicate that patients with moderate to severe renal dysfunction suppress their platelet aggregation to < 10% with 25ng/ml of tirofiban, one-third of the standard effective dose for patients with normal renal function.We suggest further clinical trials to define an objective means to calculate proper renal dosing of glycoprotein IIb-IIIa inhibitors in these patients to prevent potentially fatal complication of major hemorrhagic events.

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Platelet aggregation plays a central role in primary hemostasis.^1-3 Chronic renal failure is associated with the occurrence of excessive bleeding.^4,5 The bleeding tendency of uremia is considered to represent an acquired defect in primary hemostasis.⁶ Uremic platelets show a reduced adhesion to vascular sub-endothelium^7,8 and an impaired aggregation response to various stimuli,^9,10 which is reversible with improvement in renal function or hemodialysis.¹¹ Renal insufficiency was found to be a significant risk factor for bleeding in the PRISM-PLUS trial.¹² The addition of heparin to tirofiban increased bleeding risk irrespective of renal function.¹⁴ Glycoprotein IIb-IIIa inhibitors are potent inhibitors that can prevent platelet aggregation in a dose- and concentration-dependent fashion. They are indicated for treatment of acute coronary syndrome (ACS) and patients undergoing percutaneous coronary intervention (PCI).^13-16 Renal impairment is common in patients with coronary artery disease and often requires dose adjustment for drugs that are eliminated by the kidneys. Many investigators have suggested that a lower dose of tirofiban be used in patients with chronic renal insufficiency (CRI) to decrease adverse outcomes, the most common being bleeding. The purpose of this in vitro study is to determine the optimal serum concentration of tirofiban to inhibit platelet aggregation to < 10% in patients with moderate to severe renal insufficiency.

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