Abstract
Background
Contrast induced nephropathy (CIN) may be defined as Acute Renal Failure (ARF) that occurs within 24–72 h of exposure to intra-venous or intra-arterial iodinated contrast media that cannot be attributed to other causes. CIN occurs in up to 5% of hospitalized patients with normal renal function prior to injection of contrast media. It occurs more frequently in patients with renal impairment particularly if associated with diabetic nephropathy.
Among all procedures utilizing contrast agents for either diagnostic or therapeutic purposes, coronary angiography and percutaneous coronary interventions are associated with the highest rates of CIN. Trimetazidine has been described as a cellular anti-ischemic agent. Previous studies demonstrated that Trimetazidine prevents the deleterious effects of ischemia–reperfusion at both the cellular and mitochondrial levels and exerts an anti-oxidant effect. It inhibits excess release of oxygen free radicals, limits cellular acidosis, protects Adenosine Triphosphate (ATP) stores, reduces membrane lipid peroxidation and inhibits neutrophil infiltration.
Aim
To evaluate the role of Trimetazidine (TMZ) in prevention of contrast induced nephropathy (CIN) in patients with renal impairment undergoing coronary angiography.
Methods and results
This study was conducted on one hundred patients having a basal creatinine clearance below 90 ml/min and presenting for coronary angiography procedures. The patients were divided into two equal groups each including fifty patients where both groups received parenteral hydration in the form of isotonic saline at a rate of 1 mg/kg body weight per hour starting 12 h before angiography and up to 12 h thereafter. In Group 1, patients received additional medication in the form of trimetazidine 35 mg twice daily for 72 h and starting 48 h before the procedure which was not received in group 2 (control). There was a significant difference regarding the rate of CIN among TMZ versus control groups (10% vs. 26%). The amount of contrast was significantly higher in the CIN group (165.00 ± 108.41 vs 89.85 ± 38.60, P = 0.000).
Conclusion
Administration of trimetazidine in a dose of 35 mg twice daily orally in conjunction with standard early saline hydration is an effective method to prevent or reduce the incidence of contrast-induced renal dysfunction following the administration of contrast media during coronary angiography procedures in patients with mild–moderate basal renal insufficiency.
1
Introduction
Contrast induced nephropathy (CIN) may be defined as acute renal failure (ARF) that occurs within 24–72 h of exposure to I.V. or intra-arterial iodinated contrast media that cannot be attributed to other causes. In most cases it is a non-oliguric ARF with an asymptomatic transient decline in renal function .
The renal function impairment is mirrored by an absolute increase by 0.5 mg/dl (or greater) or relative increase by 25% (or greater) of serum creatinine from baseline or better by a decrease in urine output to 30–60 ml/min. The rise in serum creatinine peaks on the third to fifth day post-contrast exposure returning to baseline within 10–14 days . CIN occurs in up to 5% of hospitalized patients with normal renal function prior to injection of contrast media . It occurs more frequently in patients with renal impairment particularly if associated with diabetic nephropathy .
Among all procedures utilizing contrast agents for either diagnostic or therapeutic purposes, coronary angiography and percutaneous coronary interventions are associated with the highest rates of CIN . This is mainly related to intra-arterial injection and high doses of contrast used. Also, the type of patients encountered are usually in advanced age with one or more comorbid conditions such as advanced vascular disease, severe long standing hypertension, diabetes and some renal function impairment .
It has been demonstrated that the use of low-osmolar contrast media (LOCM) rather than high-osmolar contrast media (HOCM) is beneficial in reducing the incidence of CIN in patients with pre-existing renal failure. Adverse reactions to contrast media with occurrence of CIN range from 5% to 12% for HOCM and for 1%–3% for LOCM . The European Society of Urogenital Radiology has stated that the real risk of CIN is represented by the presence of pre-existing renal impairment particularly when secondary to diabetic nephropathy, but also to salt depletion and dehydration, congestive heart failure, an age greater than 79 years and concurrent use of nephrotoxic drugs . It is necessary to use precautions to prevent contrast media induced nephrotoxicity . The first precaution is to monitor renal function by measuring serum creatinine before and daily for 5 days after contrast injection . The second precaution is to discontinue the nephrotoxic drugs (aminoglycosides, vancomycin, amphotericin B, metformin & non-steroidal anti-inflammatory) before the procedure . The third precaution is adequate hydration of the patient . IV infusion of 0.9% saline at a rate of about 1 ml/kg body weight per hour beginning 6–12 h before the procedure and continuing for 12–24 h after the procedure . The fourth precaution is choosing LOCM to be the contrast of choice . The fifth precaution is the use of anti-oxidants such as N-acetyl cysteine , ascorbic acid and statins .
Trimetazidine, which has been described as a cellular anti-ischemic agent was shown to prevent the deleterious effects of ischemia–reperfusion at both the cellular and mitochondrial levels and exerts an anti-oxidant effect . It inhibits excess release of oxygen free radicals, limits cellular acidosis, protects ATP stores, reduces membrane lipid peroxidation and inhibits neutrophil infiltration . The administration of trimetazidine (35 mg twice daily) is an effective way for preventing transient renal dysfunction due to radio-contrast agents.
3
Patients and methods
This prospective study was conducted at Ain Shams University Hospitals in the period between August 2015 and June 2016. Patients enrolled in the study were admitted for coronary angiography procedures with a basal estimated creatinine clearance less than 90 ml/min regarded as mild renal impairment.
3.1
Patients
Patients were subdivided into two groups:
- ▪
Group I: Included 50 patients who received standard parenteral hydration in the form of isotonic saline at a rate of 1 ml/kg bodyweight per hour starting 12 h before angiography and up to 12 h after in addition to trimetazidine 35 mg twice daily orally for 72 h starting 48 h before the procedure.
- ▪
Group II: Included 50 patients who received standard hydration only as mentioned above and was considered as the control group.
- ▪
All patients gave a written consent before being enrolled in the procedure.
Exclusion criteria:
- ▪
Patients refusing to give a consent.
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Severe congestive heart failure.
- ▪
Creatinine clearance <30 ml/min.
- ▪
Patients with acute coronary syndromes requiring urgent intervention.
- ▪
Patients having a contraindication of trimetazidine use (e.g. Parkinsonism, severe tremors and severe renal impairment with a creatinine clearance below 30 ml/min)
3.2
Methods
All patients were subjected to:
- I.
Thorough history taking
- II.
Full clinical examination
- III.
Twelve lead surface ECG
- IV.
Laboratory investigations
Basal serum creatinine and estimated creatinine clearance were assessed within a week before the procedure, and 24 h and 72 h after the administration of contrast media.
Creatinine clearance was estimated through Cockroft–Gault equation. Estimated creatinine clearance equals {((140 − age in years) × weight in kg)/(72 × serum creatinine in mg/dl)}. The result is multiplied by 0.8 in females .
- V.
Echocardiography
Echocardiographic assessment was done to each patient prior to admission for the coronary angiography procedure to assess ejection fraction, LV dimensions, presence of segmental wall motion abnormality or severe valvular abnormality.
- VI.
Procedure related protocol
All patients received standard parenteral hydration in the form of isotonic saline at a rate of 1 ml/kg body weight per hour starting 12 h before the angiography procedure and up to 12 h after the procedure in addition to the regular treatment before undergoing coronary angiography procedure ± percutaneous coronary intervention.
Patients with impaired left ventricular ejection fraction received saline at a rate of 0.5 ml/kg body weight per hour.
Cases in the trimetazidine group received 35 mg twice daily of trimetazidine orally for 72 h starting 48 h before the procedure and continuing for another 24 h after the procedure.
All patients were assessed for the development of CIN, as an absolute increase in serum creatinine of 0.5 mg/dl, or a relative increase of 25% in serum creatinine or creatinine clearance at 24 or 72 h after the procedure compared to the baseline level.
The amount and the type of contrast were assessed and recorded.
3.3
Statistical analysis
Data were expressed as mean value ± SD for continuous variables, and as percentages for categorical variables. In this study, statistical significance was set at p < 0.05 . Comparisons between continuous variables were performed using the paired t-test, unpaired t-test or Mann–Whitney U-test. For comparisons of categorical variables, frequency tables and Chi-square analyses were used. All analyses of the present study were done using the IBM ® SPSS ® Statistics version 21 software.
4
Results
There was a significant difference between both groups as regards past history of dyslipidemia (61.1% vs 29.3%, P = 0.010) ( Tables 1 and 2 ). There was no significant difference between the CIN and no CIN groups as regards basal creatinine level (1.61 ± 0.24 vs 1.56 ± 0.22, P = 0.367) and creatinine clearance (47.34 ± 10.11 vs 52.15 ± 13.26, P = 0.151) ( Table 3 ). There was a significant difference between both groups as regards creatinine (2.13 ± 0.42 vs 1.66 ± 0.29, P = 0.000) and clearance (36.47 ± 9.63 vs 49.38 ± 13.87, P = 0.000) 24 h after the procedure. There was, as well, a significant difference as regards the creatinine (2.67 ± 1.13 vs 1.62 ± 0.28, P = 0.000) and clearance (31.24 ± 11.43 vs 50.56 ± 13.41, P = 0.000) 72 h after the procedure showing that the values were remarkably higher in the CIN group. There was no significant difference among both groups regarding the route of entry, target vessel for revascularization and dye type. However, the dye amount was significantly higher in the CIN group (165.00 ± 108.41 vs 89.85 ± 38.60, P = 0.000) ( Table 4 ).
| Trimetazidine No. = 50 | Control group No. = 50 | Independent t-test | ||
|---|---|---|---|---|
| T | p-value | |||
| Age (years) | 64.83 ± 7.36 | 62.88 ± 8.30 | 0.922 | 0.359 |
| Gender: | ||||
| Males | 27 (54.0%) | 30 (60.0%) | 0.367 | 0.545* |
| Females | 23 (46%) | 20 (40%) | ||
| Smoking | 33 (66.0%) | 26 (52.0%) | 2.026 | 0.155* |
| Prior MI | 10 (20.0%) | 11 (22.0%) | 0.060 | 0.806 |
| Prior angina | 14 (28.0%) | 18 (36.0%) | 0.735 | 0.391 |
| Prior PCI | 8 (16.0%) | 11 (22.0%) | 0.585 | 0.444 |
| DM | 26 (52.0%) | 31 (62.0%) | 1.020 | 0.313 |
| Hypertension | 30 (60.0%) | 34 (68.0%) | 0.694 | 0.405 |
| Dyslipidemia | 17 (34.0%) | 18 (36.0%) | 0.044 | 0.834 |
| PVD | 3 (6.0%) | 0 (0.0%) | 3.093 | 0.079 |
| CVS | 2 (4.0%) | 2 (4.0%) | 0.000 | 1.000 |
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