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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: permissions@oupjournals.org

Preventing in-hospital cardiac and renal complications in high-risk PCI patients

Jeffrey A. Brinker1, Charles J. Davidson2 and Warren Laskey3,*

1Johns Hopkins Medical Institutions, Baltimore, MD, USA
2Northwestern University Medical School, Chicago, IL, USA
3UNM Health Sciences Center, School of Medicine, Department of Internal Medicine, ACC 5223, 1 University of New Mexico, Albuquerque, NM 87131-5001, USA

* Corresponding author. Tel: +1 505 272 6020. E-mail address: wlaskey{at}salud.unm.edu


   Abstract
Top
 Abstract
Introduction
 Complications of PCI
 Predicting in-hospital...
 Conclusion
 Acknowledgements
 References
 
Percutaneous coronary intervention, a highly effective therapy for angina, is associated with in-hospital complications including death, myocardial infarction (MI), emergency coronary artery bypass grafting, stroke, contrast-induced nephropathy (CIN), and vascular access-site problems. Patients with risk factors including advanced age, unstable angina or acute MI, impaired ejection fraction, multivessel disease, peripheral vascular disease, and renal insufficiency (RI) are at increased risk of major adverse cardiac events (MACE). Furthermore, patients with RI, diabetes, congestive heart failure, hypertension, or pre-procedure shock are at increased risk of CIN, which may result in renal failure as well as increased morbidity and mortality from cardiovascular disease. Algorithms have been developed to predict the likelihood of peri-procedural MACE or CIN for individual patients, and at-risk patients should be managed carefully. Measures to avoid MACE include use of antithrombotic therapies such as aspirin, thienopyridines, glycoprotein Gp IIb/IIIa inhibitors, and anticoagulants. In addition, evidence shows that the use of the iso-osmolar, non-ionic, dimeric contrast medium iodixanol may reduce the in-hospital incidences of both MACE (particularly MI) and CIN when compared with the low-osmolar contrast media that it has been tested against. Other approaches to avoid CIN include discontinuation of nephrotoxic drugs, such as non-steroidal anti-inflammatory medications, use of a minimum volume of contrast, provision of intravenous hydration for 24 h beginning before the procedure, and possibly administration of N-acetylcysteine.

Key Words: Contrast-induced nephropathy • CIN • Renal insufficiency • Contrast media • Osmolality • Major adverse cardiac events • MACE • Risk assessment


   Introduction
Top
 Abstract
 Introduction
Complications of PCI
 Predicting in-hospital...
 Conclusion
 Acknowledgements
 References
 
Although drug treatment is the mainstay of therapy for patients with angina,1 treating angina by revascularizing the coronary arteries with percutaneous endovascular techniques is now at least five times more common than it was 20 years ago.2 In 2001, approximately one million patients underwent percutaneous coronary intervention (PCI) in the United States alone.2

Similar to most invasive procedures, PCI is accompanied by a risk of procedural and peri-procedural complications. Potential complications include death, myocardial infarction (MI), emergency coronary artery bypass grafting (CABG), stroke, contrast-induced nephropathy (CIN), and vascular access-site complications.3 The possibility of these complications must be considered while assessing the risks and benefits of PCI for a given patient. Although stenting in the presence of a Gp IIb/IIIa inhibitor reduces mortality by ~20% over 6–12 months compared with medical therapy in patients with unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI),4 PCI has not been shown to significantly decrease mortality in patients with stable angina.5

Fortunately, technical improvements have decreased the incidence of in-hospital complications associated with PCI. The development of stents has reduced the incidence of emergent CABG and death in patients receiving stents when compared with those receiving other forms of PCI.6–8 Between 1986 and 1997, which is the interval in which stents were widely adopted, the in-hospital incidence of MI decreased by half and the need for emergent CABG decreased more than three-fold.9

Although stenting has reduced the incidence of in-hospital complications, there remains a small but significant incidence of adverse events associated with PCI, which is determined by patient-related characteristics.3,10,11 A subgroup of ‘high-risk’ patients, including those with acute coronary syndrome (ACS), diabetes mellitus (DM), renal insufficiency (RI), or advanced age—a population that is increasingly common in ordinary practice, may require special care during PCI.

This review will characterize the short-term hazards of PCI and discuss methods for identifying patients at high risk for these events. The role of pharmacological and procedural strategies in reducing the risk of major complications will be considered, including the optimal use of antithrombotic therapies and the importance of contrast media (CM).


   Complications of PCI
Top
 Abstract
 Introduction
 Complications of PCI
Predicting in-hospital...
 Conclusion
 Acknowledgements
 References
 
Because of the importance of complications of PCI, they have been discussed by a task force organized by the American College of Cardiology and the American Heart Association (ACC/AHA).3 The ACC/AHA guidelines on PCI divide post-procedural complications into six individual components: death, MI, emergency CABG, stroke, CIN, and vascular access-site complications (bleeding, occlusion, dissection, pseudoaneurysm, and arteriovenous fistula). Interestingly, definitions of post-PCI MI can be controversial. MIs without ST-segment elevations are defined by myocardial enzyme elevations, and the reported incidence of MI is generally higher if creatinine kinase is measured routinely in all patients rather than in symptomatic patients only.3

Numerous trials have studied the incidence rates of each of the potential adverse events listed previously. However, few trials have measured the incidence of all of these complications. Therefore, the studies described subsequently are organized according to the complications studied.

Death, MI, and CABG
The incidence of in-hospital complications due to PCI in actual practice has been declining over the past few decades.9 When the outcomes of first interventions in 1559 consecutive patients in the 1997–98 Dynamic Registry were compared with the outcomes of 2431 patients in the 1985–86 National Heart, Lung, and Blood Institute (NHLBI) Registry, the rate of in-hospital death, MI, and emergency CABG was lower in the former group (4.9 vs. 7.9%; P=0.001). Interestingly, patients treated more recently had more unstable and complex coronary disease, but their rate of complications was lower. This was attributed to the observation that 70.5% of patients in the Dynamic Registry were treated with stents, whereas all patients in the older registry were treated with balloon angioplasty alone.9

A larger systematic analysis of the Registry for the Society of Cardiac Angiography and Interventions (SCAI) including more than 19 500 procedures between 1996 and 1998 was also performed.12 The results showed a consistent 0.5% frequency of in-hospital death and a 0.5% incidence of urgent CABG. However, during this time, a marked shift in device selection took place. Reliance on balloon angioplasty decreased from 51 to 26%, whereas stent utilization increased from 44 to 71%. Subgroup analysis confirmed that the short-term incidence of death and emergent CABG was significantly lower in patients given stents.13

The rate of complications associated with optimum care was recently defined in a study that compared the efficacy of a drug-eluting stent with that of a standard stent.14 The in-hospital incidences of death, MI, and emergent CABG in typical patients with single target lesions were 0.2, 2.3, and 0%, respectively, for the drug-eluting stent and 0, 1.5, and 0%, respectively, for the standard stent (not significant). Despite the marked decrease in lesion restenosis, drug-eluting stents have not decreased the incidence of major procedural complications. Non-Q-wave MI was the most frequent complication in both groups.14 Overall, the incidence of adverse events was low and similar between the two groups, supporting the safety of PCI in a low-risk patient population.

Despite the overall reductions in complications due to technical improvements, complications are more common in high-risk patients.13 The impact of risk factors on the in-hospital incidence of death, MI, and CABG after PCI was studied using data from large registry databases. The National Cardiovascular Data Registry established by the American College of Cardiology (ACC-NCDR) examined in-hospital outcome for more than 100 000 procedures in 139 centres between 1998 and 2000. The incidence of poor short-term outcome, that is, post-PCI MI, CABG, and death, was dramatically increased for patients undergoing PCI because of acute MI when compared with those with stable or unstable angina (Table 1), emphasizing the importance of this patient-related risk factor.15


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  		Table 1 In-hospital complications after PCI in patients with specific diagnoses
 
The importance of cardiac dysfunction manifested as a low ejection fraction (EF) was also studied in a large patient registry trial. A separate analysis of NHLBI Dynamic Registry data collected between 1997 and 1998 examined the outcomes and left ventricular EF measurements of 1158 patients and found that the rates of in-hospital death and post-PCI MI were significantly related to EF (Table 2).16 In patients with normal EF (≥50%), the risk of in-hospital death was low (0.1%), and in patients with EF ≤40%, the rate of in-hospital death was significantly higher (3%; P≤0.001).16


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  		Table 2 Observed incidence of in-hospital complications after PCI
 
Risk factors, other than acute MI and impaired EF, for in-hospital complications have been established by multivariate analysis as part of prediction algorithms and will be discussed subsequently.

Contrast-induced nephropathy
The CIN is a complication of PCI that can have serious consequences. It is defined as an impairment of renal function manifesting 1–3 days subsequent to contrast administration in the absence of an alternative aetiology.17 It is detected by measuring serum creatinine (SCr) and is usually defined as an increase in SCr concentration of ≥0.5 or 1.0 mg/dL or a relative increase of ≥25 or 50% over baseline.18 Cholesterol embolization due to arterial catheterization is an alternative cause of renal failure, but usually manifests with additional cutaneous, neurological, or digestive signs, and may be associated with eosinophilia or significant proteinuria or haematuria.19

Development of CIN has important effects on patient outcome and may contribute to other post-PCI complications including death, MI, and stroke. In the Mayo Clinic PCI Registry study, the incidence of in-hospital death, most of which resulted from MI, was increased >10-fold in the 254 patients who developed CIN when compared with patients who did not (Figure 1).20 Patients with CIN also experienced higher rates of access-site bleeding, haematoma formation, pseudoaneurysms, stroke, coma, adult respiratory distress syndrome, pulmonary embolus, and gastrointestinal haemorrhage.20



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  		Figure 1 The incidence of in-hospital death associated with CIN.20

 
Other studies also emphasize the poor short-term outcomes associated with CIN. An analysis of nearly 20 500 patients who underwent PCI showed that the 2% of patients who developed CIN had a 15-fold higher rate of major adverse cardiac events (MACE) during hospitalization than those patients without CIN. They had a six-fold increase in risk for MI, an 11-fold increased risk of re-occlusion, and a 22-fold higher risk of death when compared with patients without CIN.10

Long-term outcome is also affected. The Mayo Clinic PCI Registry study showed that only 88% of patients who experienced CIN survived for 1 year and only 55% survived for 5 years when compared with 96 and 85% of patients without CIN who survived for 1 or 5 years, respectively (P<0.0001).20 In another study, 80% of patients who developed CIN requiring dialysis after coronary intervention did not survive for 2 years.21 This number was high for both patients who needed only temporary dialysis and for those who needed it permanently.

A retrospective study of the Mayo Clinic PCI Registry including about 7600 patients treated between 1996 and 2000 examined the incidence and in-hospital consequences of CIN defined as an increase in SCr ≥0.5 mg/dL from pre-procedure values.20 The incidence of CIN was found to be greater in patients with baseline RI (>22% at SCr baseline of 2–2.9 mg/dL), especially if there was co-existent DM (4.5% at SCr baseline of 1.2–1.9 mg/dL) (Table 3). In the absence of these risk factors, the incidence of CIN was ~2%.


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  		Table 3 Observed incidence of CIN after PCI
 
Other complications
The remaining complications listed by the ACC/AHA guidelines are either less serious than the complications listed previously or found to occur less frequently. For example, vascular access-site bleeding occurs in 1–2% of patients undergoing PCI.22 This complication is more easily managed than those discussed previously, and it generally has fewer consequences for the patient. In contrast, stroke is a severe complication of PCI, but according to the Mayo Clinic PCI Registry, it occurs in only 0.03% of patients without CIN. This incidence is increased 40-fold (to 1.2%) in patients with CIN (P=0.05).20


   Predicting in-hospital complications
Top
 Abstract
 Introduction
 Complications of PCI
 Predicting in-hospital...
Conclusion
 Acknowledgements
 References
 
General algorithms
The importance of risk factors such as MI, reduced EF, RI, or RI with diabetes in predicting complications such as death, MI, emergent CABG, and CIN has led to the development of risk assessment algorithms that can be used routinely to identify patients who need additional care before, during, and after PCI. Several risk-assessment algorithms will be described subsequently.

Predictors of in-hospital mortality
Historically, multiple models were developed to predict the incidence of in-hospital death.23–28 These models generally associated similar clinical characteristics, particularly advanced age, cardiogenic shock, multivessel disease, and RI, with increased risk (Table 4). Recently, several models (Cleveland Clinic, New York State, Northern New England) developed in the pre-stent era were tested for their applicability to current practice patterns.29 These models, originally validated at multiple sites performing 13 000–62 700 procedures, were revalidated in approximately 11 700 patients undergoing coronary stenting. All of the models were able to discriminate between high-, moderate-, and low-risk groups. However, the actual percentages of anticipated events tended to be overestimated because stenting has improved short-term outcome. Recalibration of the models improved the accuracy of predictions.29


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  		Table 4 Variables used in algorithms predicting in-hospital death
 
Predictors of major complications
Because long-term patient outcomes can be compromised by complications such as MI or emergent CABG, algorithms including non-fatal adverse events were also developed for identifying at-risk patients. In the early 1990s, a predictive index of major complications (death, MI, or emergent CABG) was derived from more than 10 600 patient records from the Registry of the Society for Cardiac Angiography and Interventions and was validated using 5200 non-stented first PCI procedures between 1992 and 1993.30 The variables independently associated with risk included multivessel disease, unstable angina, recent MI, type-C lesion or left main angioplasty, shock, and age. A predictive index assigned 1 point for each of these variables, and aortic valve disease was used to classify patients into 4 risk groups: low (0 points), moderate (1–2 points), high (3 points), and very high risk (>3 points). In the validation set, these patient groups experienced complication rates of 1.3, 2.5, 5.4, and 16.7%, respectively.30

In a later study, 29 variables were identified for PCI combined outcomes (in-hospital death, STEMI, and in-hospital CABG) using databases from multicentre registries including more than 158 000 cases.11 Among the most powerful predictors for the risk of death were measures of haemodynamic instability, such as cardiogenic shock and use of an intra-aortic balloon pump, which increased the risk of death to 38- and 15-fold, respectively. Other predictors of complications were similar to predictors of in-hospital death, including acute MI, age, type-C lesions, congestive heart failure (CHF), diabetes, female gender, multivessel disease, peripheral vascular disease, reduced EF, RI or failure, presence of thrombus, and the need for urgent or emergent procedures.11 Additional variables related to adverse in-hospital outcomes were aortic valvular disease, left main coronary artery disease, mitral regurgitation >2+, disabling angina (Canadian Cardiovascular Society Class IV), and a history of stroke.11

Recently, a simplified multivariable model for predicting in-hospital complications after PCI was developed at the Mayo Clinic.31 This model involves assigning a risk score to each patient using integer scores for variables including the presence of cardiogenic shock, left main coronary artery disease, RI, urgent intervention, serious heart failure [New York Heart Association (NYHA) class III or IV], thrombus, multivessel disease, and advanced age (Table 5). These numbers are added together to obtain a risk score, which predicts the combined event rate for death, STEMI, emergent CABG, and stroke (Figure 2).31


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  		Table 5 Individual components of the Mayo Clinic risk score
 


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  		Figure 2 The relationship between the risk score calculated in the Mayo Clinic Model and the incidence of death, STEMI, emergent CABG, and stroke. Adapted with permission from the American College of Cardiology Foundation.31

 
This model has been externally validated by testing its predictions against the outcomes of nearly 3300 patients undergoing PCI (stenting) from the NHLBI Dynamic Registry.31 External validation revealed that the model had robust predictive power: the predicted 2.86% events matched well with the observed 2.94% procedural complications. The model was highly predictive for all patient subgroups except for patients who had undergone CABG previously.31

Predictors of contrast-induced RI
Risk factors predicting the likelihood of CIN differ from those predicting death, MI, or emergent CABG. A retrospective analysis of approximately 6000 patients from a single centre identified pulmonary oedema, arterial repair, a neurological event, diabetes, peripheral or cerebral vascular diseases, and the volume of CM as independent predictors of CIN.32 Similarly, the Mayo Clinic PCI Registry study identified age, CHF, diabetes, pre-procedure shock, recent MI, peripheral vascular disease, RI or failure, and amount of CM as independent correlates of CIN after PCI.20

Several algorithms have been developed to predict a patient's risk of CIN.10,33 In one, RI with a creatinine clearance of <60 mL/min was the strongest independent risk factor. In addition, use of an intra-aortic balloon pump during PCI, need for urgent or emergency PCI, diabetes, CHF, hypertension, peripheral vascular disease, and use of contrast volume >260 mL were collectively associated with an increased risk for CIN. The scores associated with these risk factors are given in Table 6. In patients with a score of ≤1, CIN was absent, whereas in patients with scores ≥9, ≥26% developed CIN (P<0.0001) as shown in Figure 3.10


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  		Table 6 Components of a risk score for predicting CIN
 


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  		Figure 3 The relationship between the risk score and the incidence of CIN.10

 
An alternative model for predicting CIN weighted some of the same risk factors differently (IABP use, CHF, RI, diabetes, and contrast volumes), omitted hypertension, peripheral vascular disease, and the urgency of the intervention as variables, and instead included hypotension, age >75 years, and anaemia (Figure 4).33 Both of these models have been validated in patients undergoing PCI. Regardless of the risk score used, patients at increased risk of CIN may require additional therapies to reduce the incidence of in-hospital complications.



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  		Figure 4 An alternative risk score for calculating the incidence of CIN. Reprinted with permission from the American College of Cardiology Foundation.33

 
Strategies to reduce in-hospital complications
Fortunately, therapeutic modalities are available, which reduce the incidence of in-hospital complications in PCI patients, assuming that appropriate devices and optimal interventional techniques are used. A single treatment has not been proved to prevent all complications (although the introduction of stenting reduced many of them), so several classes of therapies will be described.

Therapies to prevent thrombosis
Prevention of thrombosis is central to reducing the incidence of death, MI, emergency CABG, and stroke. Choice of CM may also affect the incidence of thrombotic complications.

Antithrombotic therapies
Advances in pharmacological therapies to prevent thrombosis continue to improve the safety and effectiveness of PCI. The primary medications used to prevent thrombosis include antiplatelet agents [aspirin, thienopyridines, and glycoprotein (Gp) IIb/IIIa receptor blockers] and anticoagulants [unfractionated heparin (UFH), low molecular-weight heparin (LMWH), and bivalirudin] (Table 7). One of the side effects of heparin may be an activation of platelets, which is not present with the direct thrombin inhibitors (e.g. bivalirudin).34 The ACC/AHA Guidelines recommend use of aspirin (80–325 mg) and UFH in all patients undergoing PCI and use of Gp IIb/IIIa inhibitors in high-risk patients.3


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  		Table 7 Antithrombotic agents approved for use in PCI patients
 
Gp IIb/IIIa inhibition
A series of six large-scale placebo-controlled trials was conducted to establish the benefits of using a bolus of Gp IIb/IIIa inhibitor followed by sustained infusion (>12 h) in patients undergoing PCI.35 As a group, these trials examined the 30-day outcomes of high-risk and standard PCI procedures and found a major reduction in death or non-fatal MI with use of Gp IIb/IIIa inhibitors (Figure 5). The EPIC, IMPACT-II, RESTORE, and CAPTURE trials were performed exclusively in patients undergoing balloon angioplasty or directional atherectomy. The EPILOG trial included >300 patients treated with stents, and subgroup analysis noted a significant benefit of Gp IIb/IIIa inhibition in these patients.35 As a result, EPISTENT was designed as a dedicated trial to examine the role of Gp IIb/IIIa inhibitors with stenting. In this trial of almost 2400 patients conducted at 63 hospitals in the United States and Canada, patients were treated with heparin and aspirin during PCI.36 The primary endpoint was a combination of death, MI, and need for urgent revascularization at 30 days. Differences between the groups emerged early and revealed a significant 52% decrease in events with Gp IIb/IIIa treatment when compared with placebo. The majority of the difference resulted from a reduced incidence of death and MI (Figure 6),36 most of which derived from a reduction in peri-procedural MI related to a reduction in non-Q-wave infarctions.



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  		Figure 5 The incidence of death or MI at 30 days for six trials of Gp IIb/IIIa inhibitors in conventional PCI. Reproduced with permission from Topol and Serruys.35

 


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  		Figure 6 The incidence of death and MI during the first 30 days of treatment with Gp IIb/IIIa inhibitors or placebo after stenting in the EPISTENT trial. Adapted with permission from Elsevier.62

 
Patients with RI also benefited from use of Gp IIb/IIIa inhibitors in a single-centre study of about 900 patients with ACS.37 In this study, the 312 patients with RI had a significantly increased risk of in-hospital death when compared with those without RI (8.1 vs. 2.6%; P<0.001), but Gp IIb/IIIa inhibitors reduced their adjusted risk of death by 66% (P=0.04).37 Although the risk of bleeding was doubled, there was a marked reduction in mortality in patients with RI treated with Gp IIb/IIIa inhibitors.37

Thienopyridine therapy
Although pre-PCI treatment with a thienopyridine is not yet recommended in the ACC/AHA guidelines for PCI, several studies suggest that it may reduce the likelihood of adverse events. In a subgroup analysis of the EPISTENT trial, pre-procedural treatment with ticlopidine reduced the 30-day incidence of death, MI, and urgent revascularization by one-third.38 Furthermore, the recent PCI-CURE study demonstrated that pre-procedural clopidogrel reduced short-term complications of PCI.39 The benefit of antiplatelet therapy with clopidogrel in addition to standard aspirin therapy was tested in a prospective randomized trial of more than 2600 patients with acute non-ST-elevation ACS undergoing PCI.39 Patients were given a loading dose of clopidogrel (300 mg) or placebo before the procedure and then given an open-label thienopyridine (clopidogrel or ticlopidine) for 2–4 weeks, followed by resumption of clopidogrel or placebo. The primary outcome of cardiovascular death, MI, or urgent revascularization by 30 days after PCI was reduced significantly in the clopidogrel group, with 4.5% of patients experiencing an adverse event when compared with 6.4% in the aspirin-only group (P=0.03) (Figure 7).39 A non-significant benefit was observed as early as 48 h post-PCI, suggesting that pre-treatment with a thienopyridine may reduce in-hospital events in a larger study. The CREDO study also showed that long-term therapy for 1 year with clopidogrel significantly (P=0.02) reduced the risk of adverse ischaemic events following PCI.40



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  		Figure 7 Thirty-day outcome of the PCI-CURE trial. Significantly fewer patients pre-treated with clopidogrel experienced the composite outcome of cardiovascular death, MI, or urgent revascularization by 30 days after PCI compared with the placebo group. Reproduced with permission from Elsevier.39

 
Thienopyridine therapy was used during the testing of the two FDA-approved drug-eluting stents (Table 8).14,41 Delayed healing may occur with drug-eluting stents, which is the rationale for using thienopyridines in the peri- and post-procedure period. On the basis of the benefits of thienopyridine found in the previous trials, it is likely that optimum procedural results will be obtained when the indicated antithrombotic protocols are followed.


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  		Table 8 Antithrombotic therapies in the key clinical trials of drug-eluting stents
 
Direct thrombin inhibition
The direct thrombin inhibitor bivalirudin has been tested as an alternative to the combination of heparin and Gp IIb/IIIa therapies during PCI23 and was found to reduce in-hospital bleeding rates, particularly bleeding associated with vascular access. In the REPLACE-2 trial, about 6000 patients undergoing PCI were randomly assigned to receive intravenous bivalirudin or heparin with Gp IIb/IIIa inhibition.22 The 30-day incidence of death, MI, urgent repeat revascularization, or in-hospital major bleeding (primary endpoint) and the 30-day incidence of death, MI, or urgent revascularization (secondary endpoint) were similar between the treatment groups. However, bivalirudin significantly reduced major bleeding events by 41% (2.4 vs. 4.1%; P<0.001). This effect was more pronounced for haemorrhage associated with vascular access puncture, with an incidence of only 0.8% with bivalirudin compared with 2.5% with heparin and Gp IIb/IIIa inhibitors.22

Renal impairment was observed to increase the risk of ischaemic and bleeding complications in a meta-analysis of three randomized trials comparing bivalirudin and heparin use during PCI.42 The composite incidence of ischaemic and bleeding events in patients treated with bivalirudin was 2.2% for patients without RI, 5.8% with mild RI, 7.7% with moderate RI, and 14.4% with severe RI (P<0.001). However, bivalirudin significantly reduced complications when compared with heparin in each stratum.42

The effect of CM on thrombosis
Although CM is essential during PCI, it can have adverse effects on cells and tissues. The most commonly used CM are low-osmolar CM (LOCM). These LOCM have osmolarities two to three-fold higher than blood, and although less toxic than high-osmolar CM, still may be somewhat toxic to tissues because of their chemical composition.43 Iso-osmolar CM (IOCMTM) with osmolality matching that of blood is also available (Table 9).


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  		Table 9 Modifications in CM over time include increased molecular size, non-ionic composition, and lower osmolality43,63–65
 
In vitro, all CM have anticoagulant properties. On the basis of in vitro studies with different chemical classes of LOCM, ioxaglate has the greatest anticoagulant potential and iodixanol (an IOCM) has the lowest.44 Furthermore, incubation of CM with whole blood resulted in virtually no platelet activation over 30 min with ioxaglate, rapid platelet activation over 1 min with iohexol, and moderate platelet activation over 30 min with iodixanol.44 In a similar study of whole blood anticoagulated with hirudin and stimulated with various agonists, more platelet aggregation was observed with iopamidol than with iodixanol, which induced more aggregation than ioxaglate.45 Thus, it appears that CM have distinct effects on the coagulation cascade and platelet activity.

Clinical differences in the incidence of MACE with different CM do not support the hypothesis that ioxaglate (an ionic LOCM) reduces thrombotic events when compared with iodixanol (a non-ionic IOCM with physiological concentrations of Na+ and Ca2+). The VIP trial, a multicentre, randomized, double-blind study of 1411 patients undergoing PCI (stenting or balloon angioplasty) compared the incidence of MACE in patients given iodixanol with those given ioxaglate.46 Patients with stable or unstable angina or silent ischaemia were included, and patients with a recent MI or EF ≤35% were excluded. All patients received heparin and antiplatelet agents during the procedure and ticlopidine afterwards. With MACE defined as a composite of death, stroke, MI, and emergent need for revascularization after 2 days, the incidence was similar in both groups, being 4.7% in patients given iodixanol and 3.9% in patients given ioxaglate (P=0.45).46

The COURT trial was another study that explored the effect of CM on MACE and found an important difference. This randomized trial included 856 patients undergoing balloon angioplasty or stenting.47 In contrast to the VIP trial, high-risk patients, defined as those with angina at rest, MI within the past 72 days, or post-MI ischaemia, were enrolled. Patients with severe RI or contraindications to anticoagulation were excluded. Patients were randomized to iodixanol or ioxaglate during PCI, and all patients received aspirin before and during the procedure, ticlopidine after the procedure, and abciximab at the physician's discretion.47 The incidence of in-hospital MACE was 5.4% in patients receiving iodixanol vs. 9.5% in patients given ioxaglate (P=0.027), a 45% reduction (Figure 8). Reduction in abrupt closure and non-fatal MI accounted for the majority of benefit,47 suggesting that the incidence of clinically significant thrombosis was lower with iodixanol than with ioxaglate in these high-risk patients. Of further interest, the greatest benefit of iodixanol occurred in patients not treated with the Gp IIb/IIIa receptor inhibitor, with a significant reduction in MACE of ~80% (P=0.001) compared with patients given ioxaglate.



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  		Figure 8 The incidence of in-hospital MACE in the COURT trial.47

 
A similar result was observed in the VICC trial.48 This randomized study of 1276 patients undergoing PCI compared the outcomes of iodixanol with those of iopamidol. The majority of patients underwent PCI for acute MI, unstable MI, or post-MI ischaemia. Stents were used in 87% of the procedures, and 78% of patients received Gp IIb/IIIa inhibitors.48 The incidence of in-hospital MACE was significantly reduced with iodixanol: 4.8 vs. 9% with iopamidol (P=0.003). This difference in outcome was primarily due to lower rates of non-Q-wave MI following PCI.48

Taken together, these data may justify the use of an IOCM in patients at increased risk of post-PCI MACE.

Therapies to prevent CIN
Using therapies that prevent CIN is important to prevent both direct and indirect effects of poor renal function on the cardiovascular system. Procedures for preventing CIN in at-risk patients are directed at preventing CM-related renal injury. Initial steps include avoiding use of NSAIDs and other nephrotoxic drugs, beginning a few days before the procedure. Metformin is not nephrotoxic but is contraindicated in patients with renal failure because it may result in serious lactic acidosis. In patients without renal failure, it can be used up to the day of contrast administration but should be withheld thereafter for 48 h or until SCr returns to normal.49

Another important risk-reduction strategy is minimizing the volume of CM.17,50 In patients with pre-existing RI, there was a 2% incidence of CIN in those who received <125 mL of radiocontrast when compared with a 19% incidence in those who received ≥125 mL CM.51 Furthermore, use of lower CM volumes has been associated with better outcomes in a study of over 1800 consecutive PCI patients; none of the patients in this study who received <100 mL CM required dialysis.21

A formula has been developed for calculating the maximum recommended CM dose (MRCD):

MRCD=5 mLxbody weight (kg)/SCr (mg/dL)

This equation was validated against a registry of more than 16 500 PCI procedures with LOCM.52 The incidence of CIN requiring dialysis was 2.4% in patients exceeding the MRCD and 0.2% in patients within this limit (P=0.001). In-hospital mortality was also significantly higher in patients who exceeded the MRCD when compared with patients who did not.52

Adequate hydration is also important for maintaining renal function.53 A clinically tested protocol recommends infusion of 1 mL/kg body weight of normal saline, beginning at 8 AM on the day of the procedure and continuing until 8 AM the next morning.54 Intravenous saline infusion has been shown to significantly reduce the rate of CIN in coronary heart disease patients with mild to moderate RI.54–57 The optimal intravenous infusion for hydration appears to be isotonic (0.9% NaCl) saline, because the incidence of CIN was significantly reduced with this solution when compared with a half-isotonic solution (0.45% NaCl+5% glucose) (0.7% compared with 2.0%, respectively, P=0.04).54

Hydration with a 154 mEq./L sodium bicarbonate solution rather than with sodium chloride solution may also be useful. A partially blinded, randomized trial of 119 patients with RI undergoing intra-arterial or intravenous CM infusion has recently shown that the incidence of CIN was only one of 60 patients hydrated with sodium bicarbonate when compared with eight of 59 in patients hydrated with normal saline.58 This was an interim analysis of the data; however, the results are from a single institution and the sample sizes are small. Confirmation of these results in a larger multicentre trial would be appropriate.58

Adjunctive therapies including adenosine receptor antagonists, endothelin antagonists, and acetylcysteine have also been suggested as strategies for reducing CIN, but evidence of benefit has not been convincing for most of these agents. The most promising and widely used of these is N-acetylcysteine (NAC).

Two large meta-analyses examined the role of NAC in preventing CIN.59,60 The first analysis found a significant 56% reduction in CIN (P=0.02). However, a consecutive systematic review of even more studies with more than twice the number of patients demonstrated marked heterogeneity in response, yielding a net risk reduction of 35% (P = 0.049).60 It is apparent from these inconsistencies that more studies are needed to determine which patients may benefit most from NAC.

The type of CM used may influence the risk of CIN. The benefits of using a CM with physiological osmolality in renally impaired patients have been studied in two trials. In the first study, 124 renally impaired patients underwent angiography using iodixanol (an IOCM) or iohexol (a LOCM). An SCr increase >10% was found to occur half as often in the iodixanol groups when compared with the iohexol group (Figure 9).61



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  		Figure 9 A comparison of the incidence of CIN in renally impaired patients undergoing angiography with an IOCM or a LOCM.61

 
Another study, NEPHRIC (a double-blind, randomized, multicentre study of IOCM and low-osmolar non-ionic CM), was conducted in 129 patients at increased risk of CIN because of both RI and diabetes.18 Baseline SCr concentrations were between 1.5 and 3.5 mg/dL. Patients were randomized to angiography with iodixanol or iohexol. A significantly lower incidence of CIN (11-fold lower) was found in the group receiving iodixanol when compared with the group receiving iohexol (P=0.002) (Figure 10).



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  		Figure 10 Peak SCr concentrations in patients with RI and diabetes undergoing angiography in the NEPHRIC trial. Reproduced with permission Copyright © 2003 Massachusetts Medical Society.18 All rights reserved.

 

   Conclusion
Top
 Abstract
 Introduction
 Complications of PCI
 Predicting in-hospital...
 Conclusion
Acknowledgements
 References
 
Improvements in PCI over time have certainly reduced the short-term morbidity and mortality associated with these procedures. Even so, to further enhance patient outcome, risk factors have to be recognized and factored in for optimal patient management. Patients at greatest risk of in-hospital complications, including death, MI, emergency CABG, and stroke, can be identified using validated scoring systems. Important patient risk characteristics include presence of cardiogenic shock, left main coronary artery disease, RI, urgent intervention, serious heart failure, thrombus, multivessel disease, and advanced age. Strategies to reduce these events in high-risk patients consist of appropriate antithrombotic therapies. These include aspirin and a thienopyridine given before, during, and after the procedure. If a drug-eluting stent is used, clopidogrel treatment should be continued for at least 3 months. Furthermore, heparin and a Gp IIb/IIIa inhibitor or a direct thrombin inhibitor may be given during the procedure. Gp IIb/IIIa inhibition should then be continued for ≥12 h, depending on the agent.

Patients specifically at risk of CIN can also be identified with validated scoring systems. Important characteristics of these patients include baseline RI, use of an IABP during PCI, need for urgent or emergency PCI, diabetes, CHF, hypotension, hypertension, peripheral vascular disease, age >75 years, and high volumes of CM. Patients who develop CIN are at increased risk to develop short- and long-term adverse events. To reduce the risk for potential renal complications associated with use of CM in high-risk patients, NSAID use should be avoided, CM volumes should be limited, and adequate hydration should be provided. Furthermore, IOCM has been shown in trials to reduce the incidence of both CIN and MACE when compared with LOCMs that it has been tested against.

In summary, it is possible to considerably decrease the rate of in-hospital complications associated with PCI if high-risk patients are properly identified and treated.


   Acknowledgements
Top
 Abstract
 Introduction
 Complications of PCI
 Predicting in-hospital...
 Conclusion
 Acknowledgements
References
 
We thank Mary Beth DeYoung, PhD, for her assistance with the literature research, preparation of an initial rough draft of the manuscript, and incorporation of multiple rounds of revisions. We also thank Barbara Conway for fact-checking and copy-editing the manuscript.


   References
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 Abstract
 Introduction
 Complications of PCI
 Predicting in-hospital...
 Conclusion
 Acknowledgements
 References
 

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