Feasibility, Safety, And Long-Term Outcomes Of Zero-Contrast Percutaneous Coronary Intervention in Patients With Chronic Kidney Disease Ⅱ

Results

A total of 698 patients underwent PCI at our center between October 2015 and December 2018 (Figure 1). From these consecutive patients, emergent PCI, history of maintenance hemodialysis, or planned rotational atherectomy cases were excluded. A total of 517 patients underwent elective PCI (748 procedures). There were 5 patients with stage 5 CKD and 8 with stage 4 CKD, all of whom underwent zero-contrast PCI. Among the 66 patients with stage 3 CKD, 42 underwent zero-contrast PCI. Thus, a total of 55 patients consented to the zero-contrast PCI strategy, and 78 elective PCI procedures were performed without contrast for these patients. Twenty-four patients with stage 3 CKD chose mini-contrast PCI and those patients were included to the conventional PCI group. The remaining 462 patients underwent conventional PCI.

The clinical characteristics of 55 patients who underwent zero-contrast PCI and 462 patients who underwent conventional PCI are shown in Table 1. The age was similar between the 2 groups. The patients from the zero-contrast PCI group were more frequently male and had diabetes mellitus and a history of cardiovascular disease such as heart failure and stroke. Lower hemoglobin and higher B-type natriuretic peptides were observed in the zero-contrast PCI group. All patients in the zero-contrast PCI group had stage 3–5 CKD with a median creatinine level of 1.38mg/dL (1.15–1.76), and an eGFR of 38.3±14.8mL/min/1.73m2. There were some differences in medication at discharge.

After propensity score matching between the 55 patients treated with zero-contrast PCI and 462 patients treated with conventional PCI, 50 patients were matched for each group. The chi-squared test statistic was 8.13 (P=0.77), which indicates a good fit. The c-statistic for the model was 0.763, indicating good discrimination. A comparison of clinical and angiographical characteristics between the 2 groups is shown in Tables 2 and 3. The clinical characteristics were well balanced, except the parameters regarding CKD. The patients from the zero-contrast PCI group more frequently had calcified lesions and tended to have more complex lesions. The radiation duration was longer in the zero-contrast PCI group than in the conventional PCI group (P=0.046); however, the radiation dose was lower in the zero-contrast PCI group (P<0.0001). The minimum lumen area before PCI and minimum stent area after PCI were comparable between the 2 groups. which indicates a good fit. The c-statistic for the model was 0.763, indicating good discrimination. A comparison of clinical and angiographical characteristics between the 2 groups is shown in Tables 2 and 3. The clinical characteristics were well balanced, except the parameters regarding CKD. The patients from the zero-contrast PCI group more frequently had calcified lesions and tended to have more complex lesions. The radiation duration was longer in the zero-contrast PCI group than in the conventional PCI group (P=0.046); however, the radiation dose was lower in the zero-contrast PCI group (P<0.0001). The minimum lumen area before PCI and minimum stent area after PCI were comparable between the 2 groups.

Data are presented as n (%), mean±SD, and/or median (Q1–Q3). ACE-i, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker; BNP, B-type natriuretic peptide; CABG, coronary artery bypass grafting; CVD, cerebrovascular disease; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention.

There were 15 patients in the conventional PCI group and 13 patients in the zero-contrast PCI group who underwent PCI with a trans-femoral approach. The main reason for the trans-femoral approach was the large guiding catheter use of more than 7 Fr for bifurcation lesions, especially in the left main trunk, or a chronic total occlusion (CTO) lesion (13 patients in the conventional PCI group and 11 patients in the zero-contrast PCI group). Another reason was the difficulty of radial artery access because of a curved artery or occlusion. Access was impossible from the radial artery in 2 patients in each group.

The in-hospital and long-term outcomes are summarized in Table 4. The median follow-up period was 1,083 (437– 1,460) days in the zero-contrast PCI and 909 (390–1,340) days in the conventional PCI groups. There was no failurePCI and no procedural complications such as persistent coronary dissection or hematoma, peri-procedural MI, or wire perforation in the zero-contrast PCI group. In the follow-up period, 8 and 7 patients experienced MACE in  

In 55 patients who underwent zero-contrast PCI, renal events such as AKI and the requirement for emergent hemodialysis did not occur during hospitalization. In terms of long-term outcomes, 7 patients died (1 cardiac, 6 non-cardiovascular) and 4 patients were introduced to renal replacement therapy. Dialysis was performed in 3 patients with stage 5 CKD (60.0%) and in 1 patient with stage 4 CKD (12.5%) during the long-term follow-up period.

Variations in renal function assessed by serum creatine level are shown in Figure 3. In the conventional PCI group, serum creatinine levels tended to increase at 1 month and 1 year compared with baseline values. In the zero-contrast PCI group, serum creatinine levels did not change until 1 month and were significantly increased at 1 year. Serum creatinine levels decreased in 32 out of 50 patients (64%) at 1 day, 20 out of 49 patients (40.8%) at 1 month, and 16 out of 46 patients (34.8%) at 1 year. Serum creatinine levels decreased by 0.13 (0.093–0.27) in 16 patients who had an improvement in renal function at 1 year (Supplementary Table)

Discussion 

In the present study, we evaluated the effect of zero-contrast PCI on acute and long-term clinical outcomes in patients with stage 3–5 CKD and ischemic heart disease. Variation in renal function was also assessed using serum creatinine levels. The major findings of the present study are as follows: (1) all zero-contrast PCI procedures were successful without any complications; (2) renal events such as AKI and requirement of emergent hemodialysis did not occur during hospitalization; (3) the incidence of MACE was comparable between the zero-contrast and conventional PCI groups; (4) in long-term follow-up, the incidence of renal replacement therapy was low after zero-contrast PCI; and (5) the serum creatinine level of patients with CKD significantly increased at 1 year; however, one-third of patients showed improvement of renal function after zero-contrast PCI and the effect was persistent at 1 year.

Very recently, a systematic review regarding the safety and efficacy of minimum- or zero-contrast PCI in patients with CKD with CCS was published.19 Their search did not find evidence regarding zero-contrast PCI, except for 2 studies, which had only short-term follow-up without a control group.17,18 To the best of our knowledge, this is the first report to assess the long-term feasibility, safety, and efficacy of zero-contrast PCI in patients with CKD. The present study also assessed the possibility of renal function improvement by zero-contrast PCI in some patients with CKD.

Previous Studies 

There is considerable evidence that contrast-associated AKI is related to a worse prognosis after PCI. Contrast-associated AKI is more common and serious in patients with CKD.24 Prevention of contrast-associated AKI may be the key to improving prognosis after PCI, especially in patients with CKD. There is some evidence that PCI with minimal contrast prevents contrast-associated AKI.6–8 Thus, reducing contrast volume is believed to be the best strategy to prevent contrast-associated AKI and improve outcomes in patients with CKD. As Burlacu et al emphasized in their systematic review,19 recent guidelines on CCS recommend minimizing the use of iodinated contrast agents during PCI in patients with severe CKD and pre-serving urine production to prevent further deterioration (class I, level of evidence B).25

Zero-contrast PCI is the ultimate strategy in terms of preventing AKI in patients with CKD, although it is technically challenging. Limited evidence is available regarding the feasibility, safety, or efficacy of zero-contrast PCI. Ali et al investigated the impact of zero-contrast PCI on renal function and the need for renal replacement therapy in a total of 31 patients with CKD with a follow-up time of 79 days.17 Zero-contrast PCI was successful in all cases and resulted in no MACEs and preserved renal function without the need for renal replacement therapy. Although the study had a low number of patients, short-term outcomes, and a single arm without a control group, these findings make zero-contrast PCI a more attractive and promising strategy.

Feasibility, Safety, and Use of Zero-Contrast PCI

Patients with CKD form a high-risk group in terms of PCI procedures and long-term cardiovascular events.3 The population of the present study had conditions that included multi-vessel disease, left main trunk, calcified lesions, and complex lesions such as bifurcation or CTO. Even in high-risk patients, zero-contrast PCI was successful in all cases with optimal revascularization without contrast use. There were no procedural complications, such as persistent coronary dissection or hematoma, peri-procedural MI, or wire perforation. Furthermore, there were no renal events, such as AKI or emergent hemodialysis. Thus, the results of the present study support the feasibility and safety of elective zero-contrast PCI for patients with CKD. In the long-term follow-up, with an average of 32 months, 6 patients experienced non-cardiovascular death and 1 patient experienced cardiovascular death. There was 1 target lesion revascularization and no non-fatal MI. The incidence of MACE in the zero-contrast PCI group was comparable to that of the conventional PCI group, which consisted mostly of patients without CKD. Thus, the present study also supports the long-term safety and use of zero-contrast PCI.

There were 4 events of renal replacement therapy in the long-term follow-up after zero-contrast PCI. Among the 4 patients, 3 patients had stage 5 CKD and 1 patient had stage 4 CKD before the zero-contrast PCI procedure. The rate of dialysis initiation has been reported to be 0.6% for stage 3 CKD, 11.4% for stage 4 CKD, and 61.1% for stage 5 CKD for 2 years (during an observation period of 22.6±11.9 months).26 In the present study population, the incidence of dialysis initiation was lower than that over the natural course of CKD. More than one-third of patients showed improved renal function even 1 year after zerocontrast PCI. Thus, zero-contrast PCI is not only safe but also has some potential benefits to improve renal function in patients.

The results of the present study support the safety of zero-contrast PCI; however, there may be some unsuitable lesions that can be treated using this procedure. A heavy calcified and curved lesion, which is an extremely high-risk lesion that has a rotational atherectomy planned as treatment, may not be suitable for zero-contrast PCI. Procedural complications such as perforation or dissection are more serious effects compared with contrast-associated AKI. The strategy should be changed to mini-contrast PCI in some cases. The CTO lesion, which requires a tip insertion or micro-channel angiography, may not be suitable for zero-contrast PCI because lesions treated with angiography need a small amount of contrast to increase the success rate of the CTO-PCI. Thus, case selection for zerocontrast PCI or mini-contrast PCI is important.

Even if the amount of contrast used was low, it might affect the incidence of contrast-associated AKI. Although the time interval between diagnostic coronary angiography and PCI was at least 10 days in the present study, it may be better to wait more than 1 month to prevent contrast-associated AKI, as Bugani et al recommended in their review.27

Benefit of Zero-Contrast 

PCI for Renal Function It is unknown whether zero-contrast PCI improves renal function in patients with CKD and ischemic heart disease. Recently, we reported a case of ischemic cardiomyopathy who was scheduled to start hemodialysis for end-stage diabetic nephropathy but exhibited improved renal function after PCI with an extremely low contrast dose.23 The patient did not require dialysis >2 years after revascularization. Intrinsic renal failure due to injured renal parenchyma in conjunction with diabetes, hypertension, or chronic glomerulonephritis is irreversible. However, the cause of renal insufficiency should be multifactorial in some patients. If the cause of renal insufficiency is mainly ischemic cardiomyopathy, renal function may be partly reversible in accordance with left ventricular function after revascularization without contrast media. The median serum creatinine level significantly increased 1 year after zero-contrast PCI due to primary CKD; however, the serum creatinine level decreased even at 1 year in more than one-third of the patients in the present study. The results of the present study suggest the possibility that zero-contrast PCI may improve renal function in a specific population

The ISCHEMIA-CKD trial demonstrated that an initial invasive strategy did not improve the clinical outcomes in patients with ischemic heart disease and CKD compared to an initial conservative strategy;5 however, in the trial, the prevention of contrast-associated AKI and optimal stent implantation by IVUS-guided zero-contrast PCI were not assessed. Zero-contrast PCI may improve the clinical outcomes in patients with ischemic heart disease and CKD compared to an initial conservative strategy.

Study Limitations 

This study had several limitations. First, this is a small, non-randomized, single-center study. Second, although we tried to adjust for confounding factors via propensity score matching, we cannot exclude the possibility of residual contributing factors as a result of the presence of an unmeasured confounder or measurement errors in the included factors. Third, although the follow-up period was long, with an average of 32 months, the number of cardiovascular events was low and may be underpowered to compare the 2 groups. Fourth, although the contrast volume was reduced for coronary angiography, it may have affected clinical outcomes. Fifth, to investigate the possible benefit of zero-contrast PCI on contrast-associated AKI, it is better to assess the more sensitive biomarker for AKI, such as urinary L-FABP (Liver-type Fatty AcidBinding Protein) in addition to serum creatinine level in the prospective study. Sixth, the presence of proteinuria is one of the important values for the diagnosis of CKD; however, the data about proteinuria was not available in the registry. Finally, zero-contrast PCI is challenging and requires special expertise and experience; thus, the results of the present study may not be generalizable to other populations. Further studies are needed to confirm the safety and use of zero-contrast PCI.

Conclusions

In this study, all zero-contrast PCI procedures were successful without any procedural complications in patients with CKD. The incidence of MACE was comparable between patients with CKD treated with zero-contrast PCI and patients without CKD treated with conventional PCI. Renal events did not occur during the hospital course, and the incidence of renal replacement therapy was low after zero-contrast PCI, suggesting the benefit of zero-contrast PCI for renal function and clinical outcomes.

References 

1. Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003; 41: 47–55. 

2. McCullough PA, Soman SS, Shah SS, Smith ST, Marks KR, Yee J, et al. Risks associated with renal dysfunction in patients in the coronary care unit. J Am Coll Cardiol 2000; 36: 679–684. 

3. Best PJM, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002; 39: 1113–1119. 

4. Hashimoto Y, Ozaki Y, Kan S, Nakao K, Kimura K, Ako J, et al. Impact of chronic kidney disease on in-hospital and 3-year clinical outcomes in patients with acute myocardial infarction treated by contemporary percutaneous coronary intervention and optimal medical therapy: Insights from the J-MINUET Study. Circ J 2021; 85: 1710–1718. 

5. Bangalore S, Maron DJ, O'Brien SM, Fleg JL, Kretov EI, Briguori C, et al. Management of coronary disease in patients with advanced kidney disease. N Engl J Med 2020; 382: 1608–1618.

6. Ledru F, Théroux P, Lespérance J, Laurier J, Ducimetière P, Guermonprez JL, et al. Geometric features of coronary artery lesions favoring acute occlusion and myocardial infarction: A quantitative angiographic study. J Am Coll Cardiol 1999; 33: 1353–1361. 

7. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: Development and initial evaluation. J Am Coll Cardiol 2004; 44: 1393– 1399. 

8. James MT, Samuel SM, Manning MA, Tonelli M, Ghali WA, Faris P, et al. Contrast-induced acute kidney injury and risk of adverse clinical outcomes after coronary angiography: A systematic review and meta-analysis. Circ Cardiovasc Interv 2013; 6: 37–43.

9. Marenzi G, Assanelli E, Campodonico J, Lauri G, Marana I, De Metrio M, et al. Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality. Ann Intern Med 2009; 150: 170–177. 

10. Kang SJ, Mintz GS, Park DW, Lee SW, Kim YH, Whan Lee C, et al. Mechanisms of in-stent restenosis after drug-eluting stent implantation: Intravascular ultrasound analysis. Circ Cardiovasc Interv 2011; 4: 9–14.

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