Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction

Abstract

Rationale: Preclinical evidence demonstrates that inorganic nitrite, after its in situ conversion to nitric oxide, attenuates consequent myocardial reperfusion injury.

Objective: We investigated whether intracoronary injection of nitrite during primary percutaneous coronary intervention might improve infarct size in ST-elevated myocardial infarction.

Methods and results: Patients undergoing primary percutaneous coronary intervention (n=80) were randomized to receive intracoronary (10 mL) sodium nitrite (1.8 μmol) or NaCl (placebo) before balloon inflation. The primary end point was infarct size assessed by measuring creatine kinase release. Secondary outcomes included infarct size assessed by troponin T release and by cardiac MRI on day 2. Baseline characteristics were similar between the groups. No evidence of differences in creatine kinase release (P=0.92), troponin T (P=0.85), or cardiac MRI-assessed infarct size (P=0.254) were evident. In contrast, there was an improvement [corrected] in myocardial salvage index (P=0.05) and reduction in [corrected] major adverse cardiac event at 1 year (2.6% versus 15.8%; P=0.04) in the nitrite group. In a 66-patient subgroup with thrombolysis in myocardial infarction ≤1 flow, there was reduced serum creatine kinase (P=0.030) and a 19% reduction in cardiac MRI-determined infarct size (P=0.034) with nitrite. No adverse effects of nitrite were detected.

Conclusions: In this phase II study, intracoronary nitrite infusion did not alter infarct size, although a trend to improved myocardial salvage index and a significant reduction in major adverse cardiac event was evident. In a subgroup of patients with thrombolysis in myocardial infarction flow ≤1, nitrite reduced infarct size and major adverse cardiac event and improved myocardial salvage index, indicating that a phase III clinical trial assessing intracoronary nitrite administration as an adjunct to percutaneous coronary intervention in ST-elevated myocardial infarction patients is warranted.

Clinical trial registration url: http://www.clinicaltrials.gov. Unique identifier: NCT01584453.

Keywords: acute myocardial infarction; nitric oxide; percutaneous coronary intervention.

© 2014 American Heart Association, Inc.

Figures

Figure 1. Trial profile

Figure 2. Effect of intracoronary nitrite on cardiac magnetic resonance imaging (CMR)-determined myocardial salvage index

The myocardial salvage index on CMR is presented for (A) 35 TIMI flow=0-3 patients in the control and 33 patients in the nitrite group. (B) Myocardial salvage index is reduced in the nitrite-treated group of 27 TIMI≤1 patients vs 28 in the control. Significance evaluated using unpaired t test and data shown as mean±SEM.

Figure 3. Intracoronary nitrite lowers infarct size by biomarker assessment in the TIMI flow ≤1 subgroup

Serum CK was measured at baseline and between 4-48 hours after coronary reperfusion. Curves for the nitrite and control group are shown in Panel A. Serum troponin T was measured at the same time points as CK and curves shown in Panel B. T bars denote standard errors of the mean (SEM).

Figure 4. Plasma NO2− and NO3− levels pre and post intervention

Plasma NO2− and NO3− levels measured at baseline and 30 minutes after delivery of either intra-coronary nitrite or placebo in all patients. Each line representing the difference between baseline and 30 minute plasma NO2− and NO3− levels shown for each patient in the nitrite group in panel A and placebo in panel B. Error bars represent mean ± SD for each group. ***P<0.0001 using paired t-test. (NO2− = Nitrite, NO3− = Nitrate)

Figure 5. Platelet reactivity post-intervention

Platelet reactivity measured at baseline, 30 minutes, 4 hours, 24 hours and 6 months after coronary reperfusion. Platelet P-Selectin expression assessed in whole blood in response to ADP (10 μmol/L) is shown for nitrite versus placebo for all patients in panel A. Panel B shows whole blood impedancce aggregometry in response to the same ADP stimulus in all patients. Panel C shows P-selectin expression in response to ADP in patients with TIMI flow