American Heart Journal
Volume 146, Issue 2 , Pages 213-214, August 2003

Percutaneous coronary interventions in patients with renal insufficiency: a high-risk, under-studied cohort

  • Steven R. Steinhubl, MD

      Affiliations

    • University of North Carolina, Chapel Hill, NC, USA
    • Corresponding Author InformationReprint requests: Steven R. Steinhubl, MD, Associate Professor of Medicine, University of North Carolina, CB#7075, Chapel Hill, NC 27599-7075, USA.

Article Outline

 

Renal insufficiency, at any level, is associated with poor short- and long-term outcomes after a revascularization procedure. Several observational series have found that patients with a baseline creatinine level >1.5 mg/dL who undergo a percutaneous coronary intervention (PCI) experience a significantly lower procedural success rate, an at least 5-fold increase in major in-hospital adverse events, and nearly 4-times the mortality rate on long-term follow-up than patients with a baseline creatinine level ≤1.5 mg/dL.1, 2 Patients with more severe levels of renal insufficiency (creatinine clearance <30 mL/min, or dialysis dependence) have mortality rates approaching 20% in the year after a PCI,3 with similarly high mortality rates after coronary artery bypass graft surgery.4. Among patients with acute coronary syndrome, renal insufficiency doubles mortality rates and is third only to cardiogenic shock and decompensated heart failure as a predictor of mortality.5 What makes these extraordinarily high morbidity and mortality rates so disturbing is that they are applicable to a surprisingly large population: >11 million Americans, which includes almost 10% of the male adult population, have serum creatinine levels >1.5 mg/dL.6 Although at least a portion of the high risk associated with renal insufficiency is attributable to the frequent presence of multiple comorbidities such as diabetes mellitus, hypertension, multivessel disease, and a more complex coronary anatomy, renal disease itself has consistently been found to be an independent predictor of morbidity and mortality.1, 2, 3, 7

Logically, patients with renal insufficiency would appear to be the ideal population in whom recent therapeutic advances in peri-PCI antithrombotic therapy, in particular the glycoprotein (GP) IIb/IIIa antagonists, should be most aggressively applied to minimize their excessive risk. However, despite their proven benefit in the reduction of periprocedural thrombotic events and long-term mortality,8, 9 it is challenging to apply the results of the GP IIb/IIIa antagonist trials to the treatment of patients with renal insufficiency. This is because many of the placebo-controlled trials of the GP IIb/IIIa antagonists excluded patients with renal insufficiency (creatinine level ≥2.5 mg/dL for tirofiban and >4.0 mg/dL for eptifibatide). There are primarily 2 reasons for this. First, as both tirofiban and eptifibatide are cleared through the kidneys, moderate to severe renal insufficiency would be expected to lead to increased plasma levels and, therefore, greater levels of inhibition of platelet aggregation. Because abciximab is cleared through the reticuloendothelial system and not renally, renal insufficiency does not influence its therapeutic efficacy. Although it is of concern that higher levels of platelet GP IIb/IIIa receptor blockade may be associated with an increased risk of bleeding, this has never been shown in patients with normal renal function,10 although the question has not been extensively studied. However, higher levels of inhibition might be expected to actually increase the efficacy of these agents by maximizing the level of platelet inhibition.11 In a retrospective analysis of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, just such a relationship was seen, with a greater magnitude of treatment effect of eptifibatide in patients with lower calculated creatinine clearances.12

The second, and most clinically relevant issue that led study designers to exclude patients with renal dysfunction from the GP IIb/IIIa trials was the numerous, well-recognized qualitative platelet abnormalities and coagulation disorders associated with kidney failure.13 Concerns about the risks of aggressively inhibiting platelet aggregation among patients already known to be at high risk for bleeding prevented the enrollment in placebo-controlled, randomized trials of the patients needed to provide adequate guidance about the risks and benefits of GP IIb/IIIa antagonist therapy in patients with renal insufficiency—in particular those with severe renal insufficiency. It is this lack of randomized data in a patient population with the greatest potential for therapeutic benefit, but also risk, that makes the observational data from large centers, suchas the data from the Mayo Clinic published in this issue, so critical for determining the best treatment in this very high risk cohort.14 Not unexpectedly, Best and coworkers found that increasing levels of renal insufficiency were associated with a significant increase in bleeding risk. In contradiction to recent randomized trials in which abciximab treatment was not associated with an increased risk of major bleeding compared with placebo,15, 16 for patients in the Mayo Clinic registry, the non-randomized use of abciximab was associated with twice the risk of major bleeding compared with that for patients not receiving it, but this likely reflects the greater comorbidities among the patients treated with abciximab. The risk of bleeding with abciximab did not significantly increase with increasing levels of renal insufficiency.

These data, with similar findings from the Cleveland Clinic,17 confirm the safety of abciximab in the setting of a PCI in patients with any level of renal dysfunction. This, along with the historically poor outcomes after PCI in this cohort suggests a need for more aggressive use of abciximab. Although it is likely that the safety findings of these registries with abciximab can be extrapolated to other GP IIb/IIIa antagonists, the variability in plasma levels and unpredictability in levels of platelet inhibition and, therefore, efficacy should still preclude the use of tirofiban and eptifibatide in patients with moderate to severe renal insufficiency. In the future, pharmacodynamic studies, followed by clinical trials focusing on patients with renal insufficiency, are desperately needed to identify optimal antithrombotic regimens (involving not only GP IIb/IIIa antagonists, but also low-molecular-weight heparins, bivalirudin and clopidogrel) for the high-risk, under-studied patient with renal insufficiency.

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References 

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PII: S0002-8703(03)00232-1

doi:10.1016/S0002-8703(03)00232-1

American Heart Journal
Volume 146, Issue 2 , Pages 213-214, August 2003

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