ZEro contrast percutaneous Revascularization Outcome

A randomized pilot trial 

(ZERO trial)

Principal Investigator:

Nandhakumar Vasu 

Co-Investigators:

Mullasari S Ajit

LatchumanadhasKalidoss

EzhilanJanakiraman

Ramkumar soli Rajaram

VijayakumarSubban

KalaichelvanUthayakumaran

BalajiPakshirajan

Suma M Victor

Srinivasan Narayanan

Aashish Chopra

AFFILIATION 

All the investigators are affiliated with Madras Medical Mission Hospital.

1. INTRODUCTON

1.1 Background Information

Prevention of contrast induced acute kidney injury (CI-AKI) after percutaneous coronary intervention (PCI) especially in chronic kidney disease population is feasible by reducing the iodinated contrast volume as minimal as possible.1 Complete elimination of iodinated contrast guidance during PCI is feasible by intravascular ultrasound (IVUS) and coronary flow reserve (CFR) guidance.2 Recent reports revealed the feasibility of zero contrast PCI with IVUS guidance alone without additional need for CFR.3

The awareness of CI-AKI among interventional cardiologists already made changes in their PCI strategy in order to reduce the contrast volume with or without intravascular imaging and/or coronary physiology guidance.4 Previous study suggested that iodinated contrast volume should not exceed more than two times of creatinine clearance(CrCl) in patients with an estimated glomerular filtration rate(eGFR) less than 30ml/min/1.73m2 to prevent CI-AKI.5 Whether complete elimination iodinated contrast by zero contrast IVUS guided PCI technique will improve the cardio-vascular or renal outcome when compared to standard of care PCI in at risk of CI-AKI population is unknown. 

Not only eGFR less than 60ml/min/1.73m2, but also other predictors, namely congestive heart failure, IABP within 24 hour peri procedurally, hypotension (systolic blood pressure less than 80mmHg for at least one hour requiring inotropic support), anemia (hematocrit <39%), advanced age beyond 75 years and diabetes are considered almost equally important in the development of CI-AKI.6 Hence a wider group of population with the above-mentioned predictors other than the advanced kidney disease population will benefit by adopting IVUS guided zero contrast PCI technique. Mehran et al. proposed a scoring system in-which if the score is 11 to 16 or more than 16, the chances of developing CI-AKI is 26.1% and 57.3% respectively. 

This study aims to compare the clinical outcome of patients with a mehran’s score more than 10 who undergo Percutaneous coronary intervention (PCI) by zero contrast PCI technique Vs standard method with the intention of reducing contrast volume to CrCl ratio of less than 1.

1.2 Rationale 

Zero-contrast PCI technique will be beneficial in wider range of population who are at risk of CI-AKI, apart from the advanced kidney disease population. This randomized controlled study (RCT) will compare the one-year combined cardio-renal outcome in the population who are at risk of CI-AKI, will undergo PCI by zero-contrast technique vs standard of care with the intention of reducing contrast volume to CrCl ratio of less than 1.

2. METHODS

2.1 OBJECTIVES

2.1.1Primary Objective

To assess the one-year composite cardiovascular and renal outcomes between zero-contrast PCI group vs. standard of PCI group.

1. All cause death

2. Cardiovascular death

3. Renal death

4. Myocardial infarction

5. Stroke

6. Target vessel failure

7. Target vessel revascularization

8. Need for new onset of renal replacement therapy

2.1.2 Secondary Objective

The secondary objective of this study is to compare the incidence of AKI, change in eGFR at 1 month and Change in eGFR at 1 year between zero-contrast PCI group vs. standard of care PCI group.

1. Development of acute kidney injury upto 72 hours post procedure.

2. Change in eGFR at 1 month

3. Change in eGFR at 1 year

2.2  STUDY DESIGN

This is a single centre, investigator initiated, prospective, single blinded, randomized controlled study 

Randomization method:

Computer generated random numbers

Block randomization. Blocks of Four

No prespecified stratification factors

Tool: Sealed Envelope Ltd.2021. Create a blocked randomization list. [Online] Available from: https:// www.sealedenvelope.com/simple-randomiser/v1/lists [Accessed 5 Nov 2021].

2.3 STUDY POPULATION& PLACE

All consecutive patients, at high risk for contrast induced AKI with mehran’s score more than 10 and undergo PCI at Madras medical mission hospital will be randomized.

2.4 SAMPLE SIZE

Pilot study- 50 patients in each arm (Zero-contrast PCI group and Standard of care PCI group). Total of 100 patients.

2.5 DURATION OF THE STUDY

Enrollment period – Until 50 subjects will be enrolled in each arm (Zero arm and Standard of PCI arm): approximately 24 months.

Follow-up period – Until the completion of one-year follow-up by the last enrolled patient.

Total duration of the study – approximately 36 months.

2.6 INCLUSION CRITERIA 

All consecutive patients, at high risk of  developing CI-AKI (Mehran’s score>10) and undergo PCI will be randomized .  

2.7 EXCLUSION CRITERIA

1. ST elevation myocardial infarction patients who will undergo primary PCI

2. Chronic total occlusion

3. Not willing to give consent for the study

2.8 PCI PROTOCOL

2.8.1 Zero-contrast PCI protocol

Informed consent will be obtained from each patientparticipating in this study. After randomization, intravenous 0.9% normal saline(NS) will be started at least 6 hours before PCI and it will be continued for 24 hours after PCI. The rate of infusion was 150ml, 100ml, 75ml or 50ml per hour for left ventricular ejection fraction(LVEF) more than 50%, 41-50%, 31-40% or less than 30% respectively.Usage ofN-acetyl cystine will beleft tophysician’s discretion. Before PCI on the day of the procedure, LVEF and absence of pericardial effusion will be documented using the transthoracic echocardiogram(TTE). The treating IC will choose the access between radial vs. femoral at their convenience. Femoral access will be obtained using a 21G micro-puncture needle under fluoroscopy or ultrasound guidance.One hundred units per kilogram of heparin will be given at the beginning of procedure.Additional heparin doses will be given based on activated clotting time (ACT) to maintain more than 300 sec during the PCI. 

The diagnostic angiogram images will be uploaded, and an ideal working view will be transferred to a reference monitor. Guide catheter engagement will be confirmed by synchronizing movement with cardiac motion and tracking of a 0.014” coronary wire into the operating coronary artery in the same reference view. Deep guide catheter engagement will be ruled out by careful assessment of pressure tracings for damping or ventricularization. For cases where damping or ventricularizationwould be noted, LCA or RCA will be wired by keeping the guide catheter in the aortic sinus.A manual IVUS scout over the coronary wire will be done to identify the aorto-ostium then the guide catheter will be railed over the IVUS catheter.Operators engaged the guide catheter at their convenient fluoroscopic views. The target vessel and its proximal or distal branches near the proximal or distal landing zones will be wired to create a metallic silhouette. Guide catheter shall be flushed every 3-5 min with 10ml of NS to avoid thrombus formation. The distal reference diameter will be measured by quantitative coronary analysis from the diagnostic angiogram images. Predilatation of the lesion will be done with the metallic silhouette guidance using a non-compliant balloon with 75% of distal reference diameter. After predilatation, the first IVUS run with automatic pullback at a speed of 0.5mm/sec will be performed to measure the average diameter at the proximal and distal landing zones and the length between them.A 40MHz OpticrossTM(Boston scientific India Pvt Ltd, New Delhi, India) IVUS catheter will be used in this study.  IVUS imaging depth was kept in such a way to cover the first 5mm of the side branches. Manual IVUS catheter search will be done to identify the distal and proximal landing zones and those positions will be recorded fluoroscopically with the already established metallic silhouette. Stent diameter will be decided, based on the smaller of the two reference diameters, and length of the stent was decided based on the IVUS measurement. The stent will be positionedusing the nearest wired branch, either at the proximal or distal landing zone. While the other landing zone of stent corresponded to the length that IVUS had measured. In the case of non-availability of nearest branches, a 0.014” coronary marker wire will be used for reference.

The ostial stent positioning, wherever required, will be done using real-time IVUS guidance from ostium of the adjacent branch.  An 8F guide catheter system will be required to accommodate stent, IVUS, and three 0.014” wires. Aorto-ostial precise stent positioning was carried out by keeping the free-floating wire in the aortic sinus. IVUS guidance through aortic sinus wire will be left to operator’s discretion.  Stent deployment will be done at nominal pressure, and post dilatation will be left to operator’s discretion. A second automatic IVUS pullback at 0.5mm/sec will be done to analyze the following 4 plus 4 checklists; (A)Inside the stent: (1)>90% minimum stent area compared to the proximal or distal reference areas whichever is smaller, (2)no malapposition or < 300 microns of malapposition, (3)preserved side branches ostium and its first 5mm, (4)absence of major  tissue prolapse (>10% of the stent area), (B)Outside the stent: (1)edge dissection, (2)intra-mural hematoma, (3)geographic miss (absence of > 50% plaque burden or vulnerable plaque at the landing zones), (4)absence of slow-moving bright red blood cell(RBC) speckles distal to the stent. After the second IVUS pullback,malapposition or under expansion will be corrected by further post dilatationsaccording to the vessel size if needed. If edge dissection or intramural hematoma would be identified in IVUS,additional stents will be deployed to correct those issues.  A third automatic IVUS pullback at a speed of 0.5mm/sec will be performed if necessary, to confirm the same check lists.  Coronary flow will be checked with the IVUS by using a 10ml NS flush protocol(Supplement) during every IVUS pull backs. A dedicated IVUS pull back of the side branches inside the stented segment will be performed if the diameter of the side branch is 2.5mm or more.   Post PCI, TTE will be done to look for new-onset regional wall motion defects and pericardial effusion (to rule out coronary perforation). Bail-out contrast will be used in the following prespecified scenarios: (a)unexplained deterioration of haemodynamics, (b)unexplained ST segment or T wave changes, or (c)unexplained angina or dyspnoea. For radial access, a trans-radial band application followed by sheath removal will beperformed at the end of PCI.Manual compression vs. device closure using PercloseProglideTM (Abbott vascular, CA, USA) or Angio-sealTM-VIP 6F/8F vascular closure device (Terumo International systems, Somerset, NJ, USA) for transfemoral access will be left to operator’s discretion.If contrast would be used during PCI the procedure is considered as technical failure and the subject will be added in the standard of care PCI group during per protocol analysis.

2.8.2 Standard of care PCI protocol

Informed consent will be obtained from each patientparticipating in this study. After randomization, intravenous 0.9% normal saline(NS) will be started at least 6 hours before PCI and it will be continued for 24 hours after PCI. The rate of infusion was 150ml, 100ml, 75ml or 50ml per hour for left ventricular ejection fraction(LVEF) more than 50%, 41-50%, 31-40% or less than 30% respectively. Usage ofN-acetyl cystine will be left to physician’s discretion. The treating IC will choose the access between radial vs. femoral at their convenience. Femoral access will be obtained using a 21G micro-puncture needle under fluoroscopy or ultrasound guidance.One hundred units per kilogram of heparin will be given at the beginning of procedure.Additional heparin doses will be given based on activated clotting time (ACT) to maintain more than 300 sec during the PCI. The procedure will be done with the intention of reducing the contrast volume to eGFR ratio to less than one. IVUS or optical coherence tomography (OCT) guidance will be at the operator’s discretion. The flush medium for OCT can be diluted contrast, normal saline or ringer lactate. Pre dilatation, stent sizing and post dilatation will be left to the choice of operators. For radial access, a trans-radial band application followed by sheath removal will be performed at the end of PCI. Manual compression vs. device closure using PercloseProglideTM (Abbott vascular, CA, USA) or Angio-sealTM-VIP 6F/8F vascular closure device (Terumo International systems, Somerset, NJ, USA) for transfemoral access will be left to operator’s discretion. If the total volume of contrast would exceed more than eGFR, the subject will be removed from the standard of care PCI group during per protocol analysis.

2.9 DATA COLLECTION

2.9.1 Before Discharge

The following parameters will be collected:

1. A list of presenting complaints 

2. Demographic details: The demographic details of the patient such as age (in years), height (in centimeters), weight (in kilograms), and gender (male or female), BSA(m2),  

BMI(Kg/m2) will be collected.

3. Family history, Medical history and Medication history of the patients will be collected

4. Details of vital signs (Heart rate, Blood pressure, respiratory rate and temperature), 

5. Mehran’s score will be calculated

6. Left ventricular ejection fraction (simpson/eyeball assessment)  - Normal/Mild/Moderate/Severe 

7. Hemoglobin (g/dl), HCT(%),HbA1C(%), Lipid profile, Sodium, Potassium

8. Urea(mg/dL), creatinine(mg/dL) eGFR(ml/min/1.73m2  noted during admission, pre PCI, 24 hrs post PCI, 1 month and 1 year

9. PCI vessel, lesion characteristics, syntax I and II score, QCA, IVUS measurements, hardwares used, procedure time, fluoroscopy time and radiation parameters

10. Discharge medications

11. Adverse events

12. Duration of hospital stay

2.9.2One-month from the day of enrollment

The data pertaining to the renal function namely blood urea, serum creatinine, serum sodium and serum potassium.

2.9.3 Until one year from the day of enrollment

The following events will be checked if present and the data relevant to the event will be collected.

1. All cause death

2. Cardiovascular death

3. Renal death

4. Myocardial infarction

5. Stroke

6. Target vessel failure

7. Target vessel revascularization

8. Need for new onset of renal replacement therapy

3.ENDPOINTS

3.1 Primary Endpoint

• All cause death

• Cardiovascular death

• Renal death

• Myocardial infarction

• Stroke

• Target vessel failure

• Target vessel revascularization

• Need for new onset of renal replacement therapy

3.2 Secondary Endpoint

1. Development of AKI

Defined as increase in serum creatinine by 0.3 mg/dl within 48 hours or Increase in serum creatinine to 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days or urine volume less than 0.5 ml/kg/hour for 6 hours.7

2. Change in eGFR at 1 month

3. Change in eGFR at 1 year

4. STATISTICAL CONSIDERATIONS

4.1 Study Hypothesis

This study aims to compare the combined cardio-renal outcome of patients at high risk of developing CI-AKI who undergo PCI by zero-contrast technique Vs standard of care with the intention of reducing contrast volume to e-GFR ratio less than 1. 

4.2 Sample size calculation

Pilot study- 50 patients in each arm (Zero-contrast PCI group and Standard of care PCI group). Total of 100 patients.

4.3Analysis Populations

Both intention to treat (ITT) population and per protocol population will be analyzed separately. 

4.4 Demographic and Baseline characteristics

Continuous variables will be summarized as mean with standard deviation or median with interquartile range according to their normality curves. Shapiro wilk test will be used to assess the normality curves. Categorical data will be summarized as frequency and percentages. Continuous data will be compared by student T test or mann-whitney U test according to the normality. Categorical data will be compared by Chi square test or Fisher exact test. Demographic and baseline characteristics will be compared separately for intention to treat and per protocol groups.    

4.5 Primary Outcome analysis

The following composite cardio-renal outcome at one-year post PCI will be compared between the zero-contrast PCI and standard of care PCI groups using Kaplan-meier curve. Log rank test will be used to analyze the statistical significance. 

1. All cause death

2. Cardiovascular death

3. Renal death

4. Myocardial infarction

5. Stroke

6. Target vessel failure

7. Target vessel revascularization

8. Need for new onset of renal replacement therapy

Kaplan-meier survival analysis will be done separately for ITT and per protocol populations. The individual events also will be compared using log rank test.   

4.6 Secondary Outcomes analysis

The secondary outcomes also compared separately for ITT and per protocol populations.

The incidence of acute kidney injury within 72 hours of PCI will be compared by Chi square test or Fisher exact test. One-month and one-year change in eGFR between the groups will be compared by paired T test.  

5. FUNDING - NIL

6. REFERENCES

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2. Ali ZA, KarimiGalougahi K, Nazif T, Maehara A, Hardy MA, Cohen DJ, Ratner LE, Collins MB, Moses JW, Kirtane AJ, Stone GW, Karmpaliotis D, Leon MB. Imaging- and physiology-guided percutaneous coronary intervention without contrast administration in advanced renal failure: a feasibility, safety, and outcome study. Eur Heart J. 2016 Oct 21;37(40):3090-3095. doi: 10.1093/eurheartj/ehw078. Epub 2016 Mar 7. PMID: 26957421; PMCID: PMC6279210.

3. Nandhakumar V, Pakshirajan B, Chopra et al. Safety and feasibility of intravascular ultrasound guided zero-contrast percutaneous coronary intervention – A prospective study. International journal of cardiology.https://doi.org/10.1016/j.ijcard.2022.01.034

4.Almendarez M, Gurm HS, Mariani J Jr, Montorfano M, Brilakis ES, Mehran R, Azzalini L. Procedural Strategies to Reduce the Incidence of Contrast-Induced Acute Kidney Injury During Percutaneous Coronary Intervention. JACC CardiovascInterv. 2019 Oct 14;12(19):1877-1888. doi: 10.1016/j.jcin.2019.04.055. Epub 2019 Sep 11. PMID: 31521648.

5. Gurm HS, Dixon SR, Smith DE, Share D, Lalonde T, Greenbaum A, Moscucci M; BMC2 (Blue Cross Blue Shield of Michigan Cardiovascular Consortium) Registry. Renal function-based contrast dosing to define safe limits of radiographic contrast media in patients undergoing percutaneous coronary interventions. J Am CollCardiol. 2011 Aug 23;58(9):907-14. doi: 10.1016/j.jacc. 2011.05.023. PMID: 21851878.

6. Mehran R, Nikolsky E. Contrast-induced nephropathy: definition, epidemiology, and patients at risk. Kidney Int Suppl. 2006 Apr;(100):S11-5. doi: 10.1038/sj.ki.5000368. PMID: 16612394.

7. Section 2: AKI Definition. Kidney IntSuppl (2011). 2012;2(1):19-36. doi:10.1038/kisup.2011.32