Randomized Evaluation of Shenfu Injection to Reduce Myocardial Injury

Shenfu injection is a traditional Chinese medicine formulation containing ginseng (Panax; family: Araliaceae) and aconite (Radix aconiti lateralis preparata, Aconitum carmichaeli Debx; family: Ranunculaceae) with Ginsenosides and aconite alkaloids as the main active ingredients. Its quality is strictly controlled in compliance with the standard of the China Ministry of Public Health (official approval code: certification number Z20043117; No. 110804, Ya'an, China). Animal studies have shown that Shenfu injection has protective effects against reperfusion injury through multiple pharmacologic effects, including scavenging free radicals, inhibiting inflammatory mediators, suppressing cell apoptosis, and inhibiting calcium overload. However, few data are available regarding its efficacy in humans. We aimed to determine whether perioperative use of Shenfu injection, as compared to placebo, might reduce infarct size in patients with STEMI undergoing primary PCI.

• Shenfu Injection (Drug): 80ml Shenfu Injection + 70ml 5% glucose injection, ivdrip, within 30 minutes before PCI and 1 to 5 days (once a day) after PCI (6 times in total). Drug titration time should be no less than 30 minutes.
• 5% Glucose Injection (Drug): 150 ml 5% glucose injection, ivdrip, within 30 minutes before PCI and 1 to 5 days (once a day) after PCI (6 times in total). Drug titration time should be no less than 30 minutes.

Primary outcomes

• Infarct size (% of left ventricular mass) [5±2 days after PCI]: Infarct size was assessed by performing CMR imaging at 5±2 days after PCI

Secondary outcomes

• Microvascular obstruction (% of left ventricular mass) [5±2 days after PCI]
• Intramyocardial hemorrhage (% of left ventricular mass) [5±2 days after PCI]
• Area under the curve (AUC) of creatine kinase isoenzyme (CK-MB) [Immediately after admission (0 hour), and 6, 12, 18, 24, 48, and 72 hours after PCI]
• AUC of cardiac troponin I [Immediately after admission (0 hour), and 6, 12, 18, 24, 48, and 72 hours after PCI]
• Peak value of CK-MB and cTnI [72 hours after PCI]
• ST segment resolution (%) according to ECG [24 hours after PCI]
• TIMI flow grade [Immediately after PCI]
• Corrected TIMI frame count (CTFC) [Immediately after PCI]
• TIMI myocardial perfusion grade (TMPG) [Immediately after PCI]
• Myocardial salvage index [5±2 days after PCI]
• Area at risk (myocardial edema, % of left ventricular mass) [5±2 days after PCI]
• Left ventricular end-diastolic volume (LVEDV) [5±2 days after PCI]
• Left ventricular end-systolic volume (LVESV) [5±2 days after PCI]
• Left ventricular ejection fraction (LVEF) [5±2 days after PCI]
• Major adverse cardiovascular and cerebrovascular events (MACCE, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, emergency revascularization) [30 days after PCI]
• Individual events (including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, emergency revascularization, re-hospitalization for heart failure) [30 days after PCI]

Other outcomes

• Slow flow and no flow [Index procedure]
• Malignant arrhythmia (ventricular fibrillation, ventricular tachycardia, etc.) [Index procedure]
• Value of high-sensitivity C-reactive protein (Hs-CRP) [Immediately after admission (0 hour), and 24, 72 hours and 5 days after PCI]
• Value of brain natriuretic peptide (BNP) [Immediately after admission (0 hour), and 24, 72 hours and 5 days after PCI]
• The Myocardial Infarction Dimensional Assessment Scale (MIDAS) [6 hours and 30 days after PCI]: 0 to 140 scores, higher scores mean worse outcome

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

1. Age ≥18 and <75 years.
2. First-time acute anterior STEMI scheduled for primary PCI.
3. ST segment elevation in at least two contiguous precordial leads according to electrocardiogram (>30 min).
4. Symptoms onset ≤12 hours.
5. The presence of proximal or middle left anterior descending branch (LAD) occlusion with pre-PCI TIMI flow 0 or 1 according to baseline coronary angiogram.
6. Written informed consent.

Exclusion Criteria:

1. Cardiogenic shock, serious heart failure (Killip class III or above), malignant ventricular arrhythmia, or mechanical complications.
2. Post cardiopulmonary resuscitation (CPR) (including cardioversion).
3. Patients who have received thrombolytic therapy or upstream GPIIb/IIIa inhibitors (GPI).
4. Uncontrolled hypertension (systolic BP ≥180 mm Hg or a diastolic BP ≥110 mmHg).
5. Prior myocardial infarction, PCI or coronary artery bypass graft.
6. Known severe hepatic insufficiency (AST/ALT >3-fold the upper limit of normal value) or known renal insufficiency.
7. Malignant tumor, lymphoma, HIV-positive, or cirrhosis with life expectancy <1 year.
8. Patients with active bleeding, intracranial hemorrhage, major surgery or trauma within 1 months, or ischemic stroke or transient ischemic attack (TIA) within 6 months.
9. History of anemia (hemoglobin<90g/L) or thrombocytopenia (thrombocyte<100×109/L).
10. Patients who require simultaneous intervention of left main disease during primary PCI or those with multi-vessel disease who plan to intervene in non-culprit vessels within 7 days (simultaneous or staged).
11. Scheduled for CABG within one month after randomization.
12. Pregnancy, lactation, or potentially fertile women.
13. Patients who have known to be allergic to Shenfu Injection or its components or patients with serious adverse effect.
14. Patients with contraindication to CMR (metal foreign body in the body, claustrophobia, etc.).
15. Participation in other clinical trial in recent 3 months.
16. Patients who cannot complete this trial or comply with the protocol.

• Results publication: Wang X, Guo R, Guo Y, Guo Q, Yan Y, Gong W, Zheng W, Wang H, Xu L, Ai H, Que B, Yan X, Ma X, Nie S. Rationale and design of the RESTORE trial: A multicenter, randomized, double-blinded, parallel-group, placebo-controlled trial to evaluate the effect of Shenfu injection on myocardial injury in STEMI patients after primary PCI. Am Heart J. 2023 Jun;260:9-17. doi: 10.1016/j.ahj.2023.02.005. Epub 2023 Feb 22. PMID 36822255