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The addition of the anti-ischemic agent trimetazidine to hydration before elective percutaneous coronary intervention (PCI) reduces the risk of contrast-induced nephropathy (CIN) and myocardial damage in diabetic patients with chronic kidney disease (CKD), according to a study published online May 19, 2014, ahead of print in The American Journal of Cardiology.

Mohamed A. Shehata, MD, of Ain Shams University Hospital (Cairo, Egypt), and colleagues randomized 100 consecutive diabetic patients with chronic stable angina and mild-to-moderate CKD to hydration with periprocedural IV saline and oral N-acetylcysteine alone (n = 50) or in combination with trimetazidine (35 mg twice daily for 72 hours starting 48 hours before PCI; n = 50). Patients, who had a mean glomerular filtration rate (GFR) of 48±16 mL/minute/1.73m², were treated at the study author’s institution from October 2011 to February 2013.

Trimetazidine (Vastarel MR; Les Laboratoires Servier; Neuilly-sur-Seine, France) is described as an anti-ischemic (antianginal) metabolic agent that improves myocardial glucose utilization through inhibition of fatty acid metabolism, also known as a fatty acid oxidation inhibitor. The drug may also serve as an antioxidant in decreasing oxygen free radicals.

CIN was defined as an absolute increase of at least 0.5 mg/dL or a relative increase of at least 25% in serum creatinine compared with baseline and measured immediately before PCI and both 72 hours and 10 days postprocedure. Myocardial injury was measured by magnitude increases in troponin I at 6, 12, and 24 hours after PCI via MRI.

There were no significant differences in baseline characteristics nor the amount or type of contrast used between groups.

Trimetazidine Exhibits Renal, Myocardial Protection

At 10 days after PCI, CIN developed in 6 patients in the trimetazidine cohort (12%) and 14 patients in the hydration-only group (28%; P < .05). Compared with baseline (similar between groups), mean serum creatinine levels were higher in those who did not receive trimetazidine vs those who did (2 ± 0.3 mg/dL vs 1.9 ± 0.4 mg/dL, respectively; P < .05).

Though the number of patients with cardiac troponin I measurements above the upper limit of the control range were similar (14 in the trimetazidine group vs 18 in the hydration-only group), mean troponin levels were higher overall in the hydration-only group across all time intervals (table 1).

Table 1.  Troponin Measurements

Patients in the trimetazidine cohort also showed a trend of reaching final TIMI III flow and having fewer procedural complications compared with the hydration-only group.

Clarification of Effect, Safety Needed

The results fit well within existing literature on the impact of trimetazidine administration before PCI, according to Dr. Shehata, adding value in that this study is the first to analyze the effects on both CIN and myocardial injury in this high-risk subgroup.

However, generalizability of the results is limited due to small sample size and the lack of patients with severe renal insufficiency, he notes. The findings “could be attributed to combining N-acetylcysteine with trimetazidine,” Dr. Shehata elaborates, suggesting that better powered studies are needed to determine long-term outcomes, as well as studies in which trimetazidine is “the sole treatment option for prevention of CIN.”

Somjot S. Brar, MD, MPH, of Kaiser Permanente (Los Angeles, CA), told TCTMD in an email, “Unfortunately, a major limitation of this therapy is that the medication is contraindicated when creatinine clearance is less than 30 mL per minute. Dosage adjustment is recommended for patients with creatinine clearance 30-60 mL per minute (CKD stage IV).” Due to this limitation and the apparent lack of dose adjustment based on renal function, according to Dr. Brar, “larger trials are not only needed to evaluate efficacy but also the safety of this therapy.”

Side effects including “Parkinson’s-like symptoms” develop in some patients after treatment with trimetazidine, Dr. Brar continued. Though most likely a greater concern when used to treat refractory angina, he stated, “This may be of less concern when used for the prevention of contrast-induced acute kidney injury where treatment is limited to no more than a few days.”

In addition, Dr. Brar pointed out, that the reported serum creatinine levels do not correlate with the researchers’ calculations for estimated GFR. “This needs to be reconciled because the primary endpoint of the study is based upon an assessment of renal function and renal function is also an important determinant of whether treatment with trimetazidine is possible,” he stressed.

Study Details:

Over two-thirds of the patients were male (68%) and mean age was 59 ± 6 years. Most patients (80% in the trimetazidine and 76% in the control group) received PCI via the femoral approach.

All patients received 5-15 ml boluses of iopramide contrast solution (Ultravist 370/100; Bayer-Schering Pharma; Berlin-Wedding, Germany).

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