Primary angioplasty represents the best available strategy for treatment of ST-segment elevation myocardial infarction (STEMI).1 However, its application in patients with chronic kidney disease is particularly problematic and not well characterised. One of the main reasons for this is that such patients have typically been excluded from clinical trials evaluating the outcome of coronary mechanical reperfusion performed in the acute phase of STEMI.2,3 Thus, only limited data deriving from a small number of studies are available to guide our therapeutic approach. As a result, no optimal treatment strategy has been defined for this subgroup of patients, who represent a vulnerable population at a high morbidity and mortality risk.
Renal insufficiency should not preclude the success rate of percutaneous or pharmacological reperfusion therapies, but it may be associated with an increased incidence of major adverse events. It is conceivable that the potential benefit deriving from early reperfusion could be offset by an increase in morbidity, particularly in terms of a higher rate of bleeding complications after thrombolysis, and of contrast-induced nephropathy (CIN) – defined as an absolute serum creatinine increase – after primary angioplasty. Beattie et al.4 investigated patients with advanced renal dysfunction who were not on dialysis therapy. They analysed a prospective coronary care unit registry of 1,724 patients with STEMI admitted over an eight-year period at a single tertiary-care centre. Patients were stratified into groups based on different corrected creatinine clearance (CrCl) values. In-hospital complications and death rate experienced a graded rise, in addition to a reduction of long-term survival, across increasing renal dysfunction strata.
Sadeghi et al.5 evaluated the potential impact of renal insufficiency in patients undergoing primary percutaneous coronary intervention (PCI) and enrolled in the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial. Clinical outcomes were assessed as a function of renal insufficiency by examining CrCl strata. At least moderate renal insufficiency (CrCl <60ml/min) was present in 18% of patients who showed a greater than nine-fold increase in mortality at 30 days and a five-fold increase in mortality at one year. Interestingly, this study was the first to report the prognostic relevance of CIN in STEMI patients undergoing primary angioplasty. Indeed, these patients represent a population at higher risk of CIN than those undergoing elective PCI.
Several conditions may contribute to acute renal injury in this setting:
• hypotension; • shock; • the use of a large volume of contrast media; and • the impossibility of starting renal prophylactic therapy.
In the CADILLAC trial, CIN (serum creatinine increase >0.5mg/dl) developed in 4.6% of patients (being three times more prevalent in patients with renal impairment) and was associated with a strikingly worse prognosis (30-day mortality of 16.2% and one-year mortality of 23.3%). However, the incidence of CIN in this trial was probably underestimated due to the exclusion of patients with cardiogenic shock and severe renal insufficiency (serum creatinine >2.0mg/dl) and the lack of routine daily creatinine measurements. Indeed, serum creatinine levels were assessed at admission, 24 hours after PCI and at discharge. Therefore, transient increase in creatinine, which typically occurs 48–72 hours after contrast exposure, may have been missed in most patients.
The impact of CIN after primary angioplasty has recently been investigated in depth at our institute.6 In 208 STEMI patients undergoing primary angioplasty, the incidence, predictors and clinical consequences of CIN (serum creatinine increase >0.5mg/dl) after primary angioplasty were evaluated. Forty patients (19%) developed CIN. When CrCl was estimated, 48 (23%) of the 208 patients had a moderately impaired renal function (CrCl <60ml/min). Of these, 19 (40%) developed CIN. In contrast, of the 160 patients with a baseline CrCl value >60 ml/min, only 21 (13%) developed this complication after primary PCI (p<0.0001). Patients with CIN experienced a more complicated in-hospital clinical course, and their average length of hospital stay was approximately 1.5 times longer than that of patients without this complication. The overall in-hospital mortality of the entire population was 6.2%. However, morbidity and mortality rates were significantly higher in patients developing CIN than in those without (see Figure 1).
In multivariate analysis, the following variables were significant, independent correlates of CIN: age >75 years (odds ratio (OR) 5.28, 95% confidence interval (CI) 1.98–14.05; p=0.0009); anterior STEMI (OR 2.17, 95% CI 0.88–5.34; p=0.09); time to reperfusion >6 hours (OR 2.51, 95% CI 1.01–6.16; p=0.04); contrast agent volume >300ml (OR 2.80, 95% CI 1.17–6.68; p=0.02); and the use of an intra-aortic balloon pump (OR 15.51, 95% CI 4.65–51.64; p<0.0001). These variables were included as risk indicators for CIN in a risk-scoring system. A value of 1 was assigned when a factor was present, and 0 when it was absent. For each patient, the score was calculated as the sum of the number of independent variables (range 0–5) recorded at hospital admission and at the end of the coronary procedure. The incidence of CIN, as well as the in-hospital mortality rate, revealed a significant gradation as the risk score increased in the study population (see Figure 2<). Thus, this study demonstrated that CIN is a frequent complication after primary angioplasty, even in patients with normal baseline renal function, and is associated with increased in-hospital morbidity and mortality and prolonged hospitalisation. Based on results reported in our study and in the literature, some concern still exists as to whether primary angioplasty is the preferred reperfusion strategy in patients with STEMI and renal insufficiency.
Recently, Dragu et al.7 suggested that thrombolysis may represent the preferred modality of reperfusion therapy in patients with renal failure. Their conclusion was based on a retrospective analysis of patients with renal insufficiency enrolled in the Acute Coronary Syndrome Israeli Survey (ACSIS), in which the effect of different myocardial reperfusion modalities on short- and long-term outcomes was determined. Mortality rate at 30 days was significantly lower in patients treated with thrombolysis than in those undergoing primary angioplasty or no reperfusion (8 versus 40 and 30%, respectively; p=0.03).
Although all patients treated with primary angioplasty are necessarily exposed to the potential nephrotoxicity of contrast media, other factors such as haemodynamic instability (resulting in ischaemic renal injury, which may contribute, at least in part, to acute renal impairment and therefore influence the clinical outcome of patients) cannot be excluded. Indeed, acute worsening of renal function, with similar prognostic implications, has also been shown to occur in patients with STEMI who are not undergoing primary angioplasty.8 Based on this evidence, our awareness of the dire prognosis faced by STEMI patients with renal insufficiency should be further enhanced.
However, it should neither foster the attitude of ‘therapeutic nihilism’ towards patients with renal failure who suffer STEMI, nor suggest that thrombolysis may represent the best reperfusion modality. In fact, pharmacological reperfusion therapies are also associated with increased incidence of major adverse events in patients with renal insufficiency. A pooled analysis of 16,710 patients receiving fibrinolytic therapy and enrolled in four studies (Thrombolysis in Myocardial Infarction (TIMI)-10A, -10B and -14, and the Treatment of Infarcting Myocardium Early (TIME)-2 trial) showed a stepwise decrease in survival from normal to mild to severely impaired renal function that persisted far as long as two years of follow-up.9 The incidence of intracranial haemorrhage was also increased in patients with reduced renal function.
Considering the widespread application of reperfusion strategies, innovative preventative approaches aimed at protecting the kidneys from contrast toxicity and ischaemic burden when STEMI is treated with mortality-reducing therapies such as primary angioplasty need to be developed and tested, particularly in high-risk patients. Among the several possible prophylactic strategies that might be investigated, N-acetylcysteine (NAC) seems to have a promising role. The antioxidant agent NAC has been shown to prevent acute renal dysfunction in patients with chronic kidney disease who are undergoing contrast-utilising procedures.10–12 The ability to scavenge a variety of oxygen-derived free radicals and the improvement of endothelium-dependent vasodilation are properties of NAC that may confer protection against CIN.13,14 This drug has several features that may play a favourable role in STEMI patients undergoing primary angioplasty. First, it can be administered as an intravenous bolus or rapid infusion15,16 immediately before intervention, in contrast to other measures such as saline hydration that need to be started many hours before contrast exposure. Moreover, NAC has demonstrated specific cardiac effects. Its administration in STEMI has been associated with less oxidative stress, a trend towards more rapid coronary reperfusion, infarct size reduction and left ventricular function preservation.17–19
Recently, NAC has been evaluated in our institute for the prevention of CIN in patients undergoing primary angioplasty.20 A total of 352 STEMI patients were randomly assigned to receive placebo (control group, n=119), an intravenous bolus of 600mg of NAC before primary angioplasty followed by an oral administration (600mg tablet twice daily) for the following 48 hours (total dose of NAC = 3,000mg, NAC group, n=116) or an intravenous bolus of 1,200mg of NAC before intervention followed by an oral administration (1,200mg twice daily) for the following 48 hours (total dose of NAC = 6,000mg, high-dose NAC group, n=118).
Reduced renal function (CrCl <60ml/min) was present in 29, 33 and 26% of patients, respectively. The observed rate of CIN (increase in creatinine >25%) was 37% in the control group, 15% in the NAC group and 8% in the high-dose NAC group (p<0.001). When an absolute rise in creatinine (>0.5mg/dl) was considered, the frequency of CIN was 18, 6 and 3%, respectively (p<0.001). The multivariate analysis, adjusting for age, gender, baseline serum creatinine, contrast volume and left ventricular function, resulted in an OR of CIN in the control group compared with the NAC group and the high-dose NAC group of 2.60 (95% CI 1.30–5.18; p=0.007) and 5.78 (95% CI 2.56–13.16; p<0.001), respectively. In-hospital mortality was also significantly reduced by NAC (see Figure 3). The OR of in-hospital death in the control group compared with the NAC and high-dose NAC groups was 1.85 (95% CI 0.54–6.37; p=0.32) and 5.43 (95% CI 1.24–23.81; p=0.03), respectively.
When the combined end-point of death, acute renal failure requiring temporary renal replacement therapy or the need for mechanical ventilation during the acute phase of myocardial infarction was considered, the rate was lower in NAC-treated patients (see Figure 3). Multivariate analysis resulted in an OR of the composite end-point in the control group compared with the NAC and high-dose NAC groups of 2.39 (95% CI 0.89–6.45; p=0.09) and 4.93 (95% CI 1.61–15.15; p=0.006), respectively. A trend towards a reduction of other clinical complications in patients receiving NAC was also observed (see Figure 4).
Thus, the major finding of this study was that prophylactic administration of an intravenous bolus of NAC followed by a 48-hour oral treatment significantly reduced the risk of CIN in STEMI patients undergoing primary angioplasty. Moreover, a higher dose of NAC was more effective than a standard dose, suggesting a dose-dependent effect of this drug.
These results were confirmed by the RENO trial,21 a recent study in which intravenous hydration with sodium bicarbonate and NAC, started immediately before contrast injection, effectively prevented CIN (1.8% incidence) compared with only hydration after the procedure (21.8% incidence, p<0.001) in patients undergoing emergency percutaneous coronary intervention, including primary or rescue angioplasty.
However, the mechanisms through which antioxidant agents, in particular NAC, reduce CIN and improve clinical outcomes in this clinical setting remain unclear, and additional studies are needed to investigate whether the extra-renal effects of NAC play some beneficial role. Indeed, in clinical and experimental acute MI studies, intravenous infusion of NAC has been associated with decreased infarct size and improved left ventricular function recovery – possibly due to the antioxidant and free radical scavenger properties of this drug.17–19 These cardiac effects may be enhanced in patients treated with primary angioplasty, a clinical setting in which oxidative stress and reperfusion injury have been demonstrated to occur22 and are particularly pronounced due to higher coronary patency rates with more rapid and complete flow restoration.23 Moreover, NAC has been shown to inhibit platelet aggregation, and also this effect could be relevant during acute coronary thrombosis and mechanical thrombus fragmentation.24 Unfortunately, in our study, as well as in the RENO trial, it was not assessed how much of the better outcome observed in NAC-treated patients was the expression of a specific renal protective effect of this drug and how much of it was due to its cardio-protective properties resulting in improved left ventricular function recovery and amelioration of systemic and renal haemodynamics.
In conclusion, growing evidence indicates that, among patients with STEMI, those with renal insufficiency represent a subgroup with high morbidity and mortality. In addition, the occurrence of CIN after primary angioplasty impacts heavily on clinical outcome. Thus, personalised prophylactic strategies should be developed in order to protect the kidney against the contrast-induced and ischaemic burden, particularly in high-risk patients. In this setting, use of antioxidant agents such as NAC represents an important and promising step towards the achievement of this ambitious goal.