An intracoronary injection of nitrite during primary PCI does not reduce infarct size in STEMI patients, according to a small, randomized proof-of-concept trial published in the January 30, 2015, issue of Circulation Research. However, in a subgroup of patients with thrombolysis in myocardial infarction (TIMI) flow ≤ 1, administration of nitrite did reduce infarct size. 

During ischemic episodes, inorganic nitrite is converted to nitric oxide, which has anti-inflammatory and antiplatelet actions, write Amrita Ahluwalia, BSc, PhD, of Barts and the London School of Medicine and Dentistry (London, England), and colleagues. Preclinical research suggests that nitric oxide also is cardioprotective by preventing “the opening of the mitochondrial permeability transition pore, which is a critical… final step in reperfusion [injury].”

For the phase II trial, the researchers randomized 80 suspected STEMI patients (mean age 57 years; 84% male) 1:1 to a high-dose bolus intracoronary injection of sodium nitrite (1.8 μmol in 10 mL of .9% sodium chloride) or a placebo before balloon inflation and within 6 hours of symptom onset between April and December 2012. After injection, operator preference determined access route, type of stent, and method of stenting.

Baseline characteristics were similar between the groups, except for ischemia time, which was longer in nitrite patients (median 207.05 vs 171.63 minutes).

Infarct size was assessed via blood sampling the first 2 days postprocedure and CMR imaging at 2 days, 6 months, and 1 year.

Infarct Size Unaffected Overall

The median area under the curve (AUC) for creatine kinase (CK; primary endpoint), as a proxy for infarct size, was similar between the nitrite-treated group and controls (P = .92). There also was no difference in AUC for troponin T release (P = .85).

Of the 68 patients who consented to CMR, there were no differences between the nitrite and control groups in LVEF and LV mass and volumes. Trends were observed toward improved myocardial salvage index (P = .051), smaller infarct size, and less microvascular obstruction in nitrite patients compared with controls. Both CK and troponin T were positively associated with infarct size (P < .01 for each).

In analysis of a subgroup of 66 patients with successful drug delivery and preprocedure TIMI flow ≤ 1, nitrite injection reduced both CK- and CMR-determined infarct size (both P = .03). The latter was associated with an increase in myocardial salvage index (0.56 vs 0.43; P = .002) and a reduction in microvascular obstruction (37% vs 72.4%; P = .02).

In contrast, nitrite injection was not associated with reduced infarct size by any measurement in those with TIMI flow > 1 (n = 9).

No Adverse Effects

Incidence and magnitude of early systolic blood pressure drops were similar between those who did and did not receive nitrites and did not alter clinical management.

Within 48 hours postprocedure, there were 3 major adverse events in the nitrite group (2 cases of acute heart failure and 1 of contrast-induced nephropathy) compared with 7 in the control group. 

At 6 months, MACE (death, MI, recurrent revascularization, stroke, and heart failure) occurred less frequently in nitrite-treated patients than in controls (0 vs 4 events; P = .04).

Two patients from each group were lost to follow-up at 1 year; among the remaining patients, 1-year MACE rates were lower in those who received nitrite (1 repeat revascularization) compared with those who did not (3 repeat revascularizations, 1 MI, and 2 hospitalizations for heart failure; P = .04). There were no medication prescription differences between the groups at 1 year.   

Though similar at baseline, postprocedure platelet reactivity levels—which post hoc analyses positively associated with CMR-derived infarct size at 6 months—were repressed in the nitrite arm compared with the control arm both overall and within the TIMI flow ≤ 1 subgroup.

How Important Are the Subgroup Results?

Though nitrite injection was not associated with reduced infarct size overall, there was an 18% increase in myocardial salvage index, which approached statistical significance, and reductions in MACE at 6 months and 1 year, the study authors say.

Moreover, that nitrite patients had longer mean ischemia times, which are associated with reduced myocardial salvage and larger infarct size, may have skewed the results in the overall cohort, the investigators observe. They note that area at risk—another “important determinant of infarct size”—may also be a confounding variable.

That the TIMI flow ≤ 1 subgroup analysis showed positive results despite similarity in baseline characteristics and ischemia time between nitrite patients and controls “suggests that, for nitrite to be most effective in reducing infarct size in STEMI patients, it needs to be administered whilst the culprit artery is still occluded,” Dr. Ahluwalia and colleagues say.

However, in an email with TCTMD, Michael Marber, BSc, PhD, of King’s College London (London, England), cautioned that “too much has been made of the TIMI < 1 subgroup” in this study.

Although he agreed with the authors that a phase III trial is warranted, he warned that there are “many examples of phase [II] studies offering false hope in the field of cardioprotection.”

Source:
Jones DA, Pellaton C, Velmurugan S, et al. Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction. Circ Res. 2015;116:437-447.

Disclosures:

• Dr. Ahluwalia is a director of Heartbeet Ltd.
• Dr. Marber reports no relevant conflicts of interest.

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