Clinical trial NCT03621501: Direct Complete Versus Staged Complete Revascularization in Patients Presenting With Acute Coronary Syndromes and Multivessel Disease
Official title: Percutaneous Complete Revascularization Strategies Using Sirolimus Eluting Biodegradable Polymer Coated Stents in Patients Presenting With Acute Coronary Syndrome and Multivessel Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Acute Coronary Syndrome
Keywords: Percutaneous coronary intervention
Multivessel disease
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: Biotronik SE & Co. KG
First posted: 2018-08-08
Enrollment: 1525
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study is a prospective, multicenter, randomized, two-arm, international, open-label, non-inferiority study. Due to the design characteristics of the study, the study investigators and operators cannot be blinded.
Primary purpose: TREATMENT

Brief summary: To test whether immediate complete revascularization is non-inferior to staged (but within six weeks after index procedure) complete revascularization in Patients presenting with ACS, including Non-ST-elevation ACS (NSTEACS) and ST-elevation myocardial infarction (STEMI), with multivessel disease accepted for PCI

Detailed description: Invasive coronary angiography followed by percutaneous coronary intervention is the treatment of choice in patient presenting with STEMI-ACS1 and NSTE-ACS2. Up to 60 percent of these patients have multivessel disease on angiography3-5. Patients with multivessel disease have a worse prognosis compared with patients having culprit vessel disease only5. It has been debated whether a complete or culprit artery only revascularization strategy is better.

Retrospective data in STEMI patients suggested a lower mortality in patients that were treated with culprit artery only compared with multivessel PCI during index procedure6. Since then, four randomized controlled trials have addressed this question in STEMI population; The Randomized Trial of Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial (n = 465, 23 months follow-up)7, the Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease (CvLPRIT) (n = 296, 12months follow-up)8, the Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI) trial (n = 627, 27months follow-up)9, and the Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction (Compare-Acute) trial (n = 885, 12 months follow-up)10. PCI of the non-infarct related artery was performed at the index procedure (PRAMI and Compare-Acute), staged before discharge (DANAMI-3-PRIMULTI) or at any time during hospitalization (CvLPRIT). Indication for PCI was significant stenosis as assessed by angiography (PRAMI and CvLPRIT) or FFR (DANAMI-3-PRIMULTI and COMPARE-ACUTE). There was a significant reduction in primary outcome in all four trials in favor of complete revascularization. However, there was no significant reduction in total mortality or myocardial infarction. Based on the results for these four trials, the 2017 ESC STEMI-ACS guidelines gave a class II, level of evidence (LOE) A, indication for routine complete revascularization in STEMI patients with multivessel disease, including those presenting with cardiogenic shock1. However, an important shortcoming of the abovementioned studies is the absence of a staged complete revascularization arm. As there is no data that compare immediate and staged complete revascularization, the guidelines don't advise on when to perform non-infarct related artery revascularization.

Data regarding optimal treatment in NSTEMI-ACS are more scarce. In an observational study by Shishesbor and coworkers, they showed that nonculprit multivessel stenting reduced future revascularization rate but this was not associated with lower rate of death or myocardial infarction11. Recently, a substudy from the Bleeding complications in a Multicenter registry of patients discharged with diagnosis of acute coronary syndrome (BleeMACS) registry (N=4520 patients, 1459 NSTEMI) was published12. They showed that in NSTEMI patients, complete revascularization was associated with a significant lower rate of death (4.5% vs. 8.5%; p=0.002), re-AMI (3.7% vs. 6.6%; p=0.016) and MACE (8.1% vs. 13.9%; p=0.001) at one year follow up. The 2015 ESC NSTEMI-ACS guidelines not specifically advise a culprit only or multivessel PCI strategy. Moreover, they advise to base revascularization strategy on patients clinical status and co-morbidities, as well as disease severity, Class II, LEO B. Interestingly, in contrast with the STEMI population, in NSTEMI population there is a small RCT investigating staged versus direct complete revascularization , the Single-Staged Compared With Multi-Staged PCI in Multivessel NSTEMI Patients: The SMILE Trial (N=584 patients)13. There was a significant reduction in primary endpoint 1S-PCI: n = 36 \[13.63%\] vs. MS-PCI: n = 61 \[23.19%\]; hazard ratio \[HR\]: 0.549 \[95% confidence interval (CI): 0.363 to 0.828\]; p = 0.004) at one year follow up. This was mainly driven by a reduction in target vessel revascularization. There was no significant difference in cardiac death or myocardial infarction between the both groups. This finding deserves further investigation, because the TVR rate (15.4% at 1 year) in the multistage group was unprecedentedly high in the era of current-generation drug-eluting stents.

There is no publication specifically addressing the patients with unstable angina regarding the subject of complete or incomplete revascularization or timing of revascularization.

Considering such data, complete revascularization in ACS patients seems advisable, but timing of revascularization is unknown.

Given this background no investigation so far provided a comprehensive evaluation of the complete revascularization strategies for patients with any type of acute coronary syndrome and multivessel disease. Therefore, the investigators aim to investigate in a randomized controlled trial the commonly used complete revascularization strategies for patients presenting with ACS: 1) Immediate complete revascularization 2) Culprit only plus staged complete revascularization within six weeks after index procedure, in terms of the primary endpoint, the composite of death from any cause, nonfatal type 1 myocardial infarction, revascularization, and cerebrovascular events at 1-year post intervention.

Patients will be treated with one commercially available second-generation drug-eluting stent stent to ensure homogeneity of treatment among patients, abolishing the occurrence of bias due to different stent usage. The stents used will be the Biotronik Orsiro DES (Sirolimus-Eluting stent). The Orsiro DES is a second generation DES with a bioabsorbable polymer coating releasing sirolimus and was CE marketed in 2011. The bioabsorbable nature of the polymer could be associated with a reduction of the inflammatory response, reducing neo-intima growth compared to a durable polymer14, 15. The active drug sirolimus is a lipophilic molecule that inhibits mammalian target of rapamycine (mTOR) on smooth muscle cells, also preventing neo-intima hyperplasia16. The Orsiro stent has ultrathin cobalt chromium struts of 60-80micron (depending on stent size) enhancing deliverability and crossability without loss of radial strength or fatigue resistance. The Orsiro stent has been extensively studied in different study populations with more than 32.500 patients studied globally.

Eligibility criteria: Inclusion Criteria:

Inclusion criteria STEMI-ACS ST-segment elevation myocardial infarction (STEMI) Both criteria must be present for eligibility

* Chest pain for more than 20 minutes with an electrocardiographic ST-segment elevation of 1 mm or greater in two or more contiguous leads, or with a new left bundle-branch block
* Admission either within 12 hours of symptom onset or between 12 and 24 hours after onset with evidence of continuing ischemia.

Inclusion criteria for NSTE-ACS Non-ST-segment elevation myocardial infarction (NSTEMI) At least two of the following must be present for eligibility

* History consistent with new, or worsening ischemia, occurring at rest or with minimal activity
* Coronary angiography with indication to PCI
* Troponin T or I or creatine kinase MB above the upper limit of normal
* Electrocardiographic changes compatible with ischemia but not diagnostic for ST-segment elevation myocardial infarction (i.e. ST depression of 1 mm or greater in two contiguous leads, T-wave inversion more than 3 mm, or any dynamic ST shifts) 0 Unstable Angina (UA)

At least two of the following must be present in the absence of cardiomyocyte necrosis (i.e. Troponin T or I and creatine kinase MB must be within normal limits):

* History consistent with new, or worsening ischemia, occurring at rest or with minimal activity
* Coronary angiography with indication to PCI
* Electrocardiographic changes compatible with ischemia but not diagnostic for ST-segment elevation myocardial infarction (i.e. ST depression of 1 mm or greater in two contiguous leads, T-wave inversion more than 3 mm, or any dynamic ST shifts)

General inclusion criteria:

* Age ≥ 18 years ≤ 85 years
* The patient is an acceptable candidate for treatment with a drug eluting stent in accordance with the applicable guidelines on percutaneous coronary interventions, manufacturer's Instructions for Use and the Declaration of Helsinki
* Patient indication, lesion length and vessel diameter of the target lesion(s) are according to the 'Instructions for Use' that comes with every Biotronik Orsiro (Sirolimus-Eluting stent) system.
* The patient is willing and able to cooperate with study procedures and the required follow up visits
* The subject or legal representative has been informed of the nature of the study and agrees to its provisions and has provided an EC approved written informed consent, including data privacy authorization

Exclusion Criteria:

* Age \<18 years and \> 85 years
* Single coronary vessel disease or multivessel disease without clear culprit
* Patients in cardiogenic shock
* Patients who cannot give informed consent or have a life expectancy of less than 1year
* Absolute contraindications or allergy that cannot be pre-medicated, to iodinated contrast or to any of the study medications, including both aspirin and P2Y12 inhibitors.
* Enrollment in another study with another investigational device or drug trial that has not reached the primary endpoint . The patient may only be enrolled once in the BioVAsc study
* PCI in the previous 30 days.
* Presence of a chronic total occlusion
* Previous CABG
* Women of childbearing potential who do not have a negative pregnancy test within 7 days before the procedure and women who are breastfeeding.
* Planned surgery within 6 months after PCI, unless dual antiplatelet therapy is maintained throughout the peri-surgical period

Primary outcomes:
measure: MACCE
timeFrame: 1 year
Secondary outcomes:
measure: MACCE
timeFrame: 30 days
measure: MACCE
timeFrame: 2 years
measure: MACCE
timeFrame: 5 years
measure: All cause mortality
timeFrame: 30 days
measure: All cause mortality
timeFrame: 1 year
measure: All cause mortality
timeFrame: 2 years
measure: All cause mortality
timeFrame: 5 years
measure: Myocardial infarction
timeFrame: 30 days
measure: Myocardial infarction
timeFrame: 1 year
measure: Myocardial infarction
timeFrame: 2 years
measure: Myocardial infarction
timeFrame: 5 years
measure: Coronary revascularization
timeFrame: 30 days
measure: Coronary revascularization
timeFrame: 1 year
measure: Coronary revascularization
timeFrame: 2 years
measure: Coronary revascularization
timeFrame: 5 years
measure: Major bleeding
timeFrame: 30 days
measure: Major bleeding
timeFrame: 1 year
measure: Need for renal replacement therapy
timeFrame: 30 days
measure: Quality of Life Seattle Angina Questionnaire
timeFrame: 30 days
measure: Quality of life Seattle Angina Questionnaire
timeFrame: 1 year
measure: Quality of Life EQ5D
timeFrame: 30 days
measure: Quality of life EQ5D
timeFrame: 1 year
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: Zuid Holland
Study officials:
affiliation: Erasmus Medical Center
name: Roberto Diletti, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Erasmus Medical Center
name: Nicolas Van Mieghem, Prof.
role: STUDY_CHAIR
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