Clinical trial NCT03753269: Early Intracoronary Administration of Fasudil in the Primary PCI of ST-segment-Elevation Myocardial Infarction
Official title: Efficacy of Early Intracoronary Administration of Fasudil Hydrochloride on Myocardial Perfusion in the Primary PCI of ST-elevation Myocardial Infarction: an Prospective, Randomized and Multicenter Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: ST Segment Elevation Myocardial Infarction
Keywords: myocardial infarction
reperfusion therapy
microvascular dysfunction
Fasudil Hydrochloride
myocardial perfusion
Lead sponsor: RenJi Hospital
Sponsor class: OTHER
First posted: 2018-11-26
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study aims to evaluate whether an early intracoronary administration of Fasudil Hydrochloride during primary PCI of STEMI can improve epicardial and myocardial perfusion as well as clinical outcomes.

Detailed description: Timely reperfusion therapy is the most effective treatment for acute STEMI patients. Primary PCI has been documented as the best method for restoration of epicardial blood flow. Nevertheless, recovery of epicardial blood flow does not necessarily equate to a sufficient reperfusion at myocardial level. Although epicardial TIMI 3 flow could be achieved in the majority of STEMI patients by contemporary PPCI, it has been well acknowledged that microvascular obstruction (MVO) is far more prevalent than the epicardial no-reflow phenomenon and has huge detrimental impact on clinical outcomes.

Routine thrombus aspiration by special catheter during primary PCI has shown negative or even harmful results in clinical trials. Distal coronary protective devices are also ineffective to improve myocardial perfusion. On the contrary, peri-procedual administration of several medications has shown possibilities to reduce MVO. These medications are mostly anti-platelet agents such as GP IIb/IIIa receptor and microvascular dilators like adenosine, sodium nitroprusside and verapamil. Theoretically, intracoronary delivery of medications can be more effective and potentially decrease side effects. Empirical application of aforementioned agents seems to improve the epicardial flow in patients not achieving TIMI 3 flow after PCI. However, it is debatable whether early administration of intracoronary medication (meaning before PCI) may further reduce MVO assuming it could be better to reduce reperfusion injury. However, this has not been well investigated yet.

Rho-associated protein kinase (Rho kinase) is expressed in many cells, including smooth muscle cells and vascular endothelial. Activation of Rho kinase leads to increased smooth muscle intracellular calcium and robust vasoconstriction. Fasudil hydrochloride is a rho-kinase inhibitor that severs clinically as a potent small vessel dilator, especially in the field of cerebral circulation. Meanwhile, It has been empirically used in individual STEMI cases and showed effectiveness in improving coronary flow for PCI therapy. This study aims to evaluate whether an early intracoronary administration of Fasudil Hydrochloride can improve myocardial perfusion and clinical outcomes for STEMI patients undergoing primary PCI. To ensure the complete delivery of agents within coronary, a special-designed targeted perfusion micro-catheter will be used for drug delivery. Patients in the control arm will be administrated by intracoronary saline.

For the results, coronary angiography-based index of epical and myocardial perfusion will be analyzed. MVO will be determined by cardiac magnetic resonance imaging and quantified as the percentage of left ventricular myocardial mass (% LV). The rate of composite major adverse cardiac events (MACEs) at 30 days and 6 months since symptom onset will be the clinical outcomes.

Eligibility criteria: Inclusion Criteria:

* Age: over 18 or 18 years old, less than 75 years old;

  * Patents with myocardial infarction who have symptom onset within 6h before randomization;
  * ECG: ≥2 mm ST-segment elevation in 2 contiguous precordial leads or ≥1 mm ST-segment elevation in 2 contiguous extremity leads ;
  * Signed informed consent form prior to trial participation

Exclusion Criteria:

1. ECG with new left bundle branch block;
2. Contraindications for CMR
3. Repeated STEMI
4. History of cardiovascular diseases

   * PCI within previous 1 month or Previous coronary-artery bypass surgery (CABG)
   * Previously known multi-vessel coronary artery disease not suitable for revascularization
   * Hospitalization for cardiac reason within past 48 hours
   * Known acute pericarditis and/or subacute bacterial endocarditis
   * Arterial aneurysm, arterial/venous malformation and aorta dissection;
5. History of other severe diseases

   * Any other diseases with life expectancy ≤12 months
   * • Any history of severe renal or hepatic dysfunction (hepatic failure, cirrhosis, portal hypertension and active hepatitis); Neutropenia, thrombocytopenia; Known acute pancreatitis
6. Severe cardiac complications

   * Any sign of cardiac rupture
   * Cardiogenic shock (SBP \<90 mmHg after fluid infusion or SBP\<100 mmHg after vasoactive drugs)
7. Not suitable for clinical trial

   * Inclusion in another clinical trial;
   * Previous enrolment in this study or treatment with an investigational drug or device under another study protocol in the past 7 days;
   * Pregnancy or lactating;
   * Body weight \<40kg or \>125kg;
   * Known allergy to any drug that may appear in the study
   * Inability to follow the protocol and comply with follow-up requirements or any other reason that the investigator feels would place the patient at increased risk.

Primary outcomes:
measure: Complete epicardial and myocardial reperfusion after PCI
timeFrame: PCI procedure
measure: CMR-derived microvascular obstruction (MVO)
timeFrame: Within one week after the STEMI onset
Secondary outcomes:
measure: CMR-derived infarction size
timeFrame: Within one week of STEMI onset, repeated on the sixth month
measure: TIMI Flow Grade (TFG)
timeFrame: PCI procedure
measure: TIMI Myocardial Perfusion Grade (TMPG)
timeFrame: PCI procedure
measure: TMPFC
timeFrame: PCI procedure
measure: Complete ST-segment Resolution
timeFrame: 90 minutes after PCI procedure
measure: MACEs
timeFrame: 30 days and 6 months after STEMI onset
Other outcomes:
Locations:
Study officials:
References:
citation: Ding S, Pu J, Qiao ZQ, Shan P, Song W, Du Y, Shen JY, Jin SX, Sun Y, Shen L, Lim YL, He B. TIMI myocardial perfusion frame count: a new method to assess myocardial perfusion and its predictive value for short-term prognosis. Catheter Cardiovasc Interv. 2010 Apr 1;75(5):722-32. doi: 10.1002/ccd.22298.
citation: Gibson CM, Cannon CP, Murphy SA, Ryan KA, Mesley R, Marble SJ, McCabe CH, Van De Werf F, Braunwald E. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation. 2000 Jan 18;101(2):125-30. doi: 10.1161/01.cir.101.2.125.
citation: Kidambi A, Mather AN, Motwani M, Swoboda P, Uddin A, Greenwood JP, Plein S. The effect of microvascular obstruction and intramyocardial hemorrhage on contractile recovery in reperfused myocardial infarction: insights from cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2013 Jun 27;15(1):58. doi: 10.1186/1532-429X-15-58.
citation: Taniguchi Y, Funayama H, Matsuda J, Fujita K, Nakagawa T, Nakamura T, Umemoto T, Mitsuhashi T, Ako J, Momomura S. Super-selective intracoronary injection of Rho-kinase inhibitor relieves refractory coronary vasospasms: a case report. Int J Cardiol. 2014 Sep;176(1):270-1. doi: 10.1016/j.ijcard.2014.06.096. Epub 2014 Jul 8. No abstract available.
citation: TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med. 1985 Apr 4;312(14):932-6. doi: 10.1056/NEJM198504043121437. No abstract available.
citation: Masumoto A, Hirooka Y, Shimokawa H, Hironaga K, Setoguchi S, Takeshita A. Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension. 2001 Dec 1;38(6):1307-10. doi: 10.1161/hy1201.096541.
citation: Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997 Oct 30;389(6654):990-4. doi: 10.1038/40187.