In patients with acute MI (STEMI or Non-STEMI) who have undergone PCI, the objectives are to determine: 1. If colchicine can reduce the incidence of cardiovascular death, recurrent MI, or stroke. 2. If routine use of spironolactone can reduce the…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
SYNERGY Stent Registry:
• Major Adverse Cardiac Events (see protocol for definitions)
Colchicine and Spironolactone 2x2 Factorial RCT:
• Colchicine vs. placebo: Time to event of the composite of CV death, recurrent
MI, stroke or unplanned ischemia driven revascularization over duration of
follow-up
• Spironolactone vs. placebo: Total composite events of CV death or new or
worsening heart failure over duration of follow-up
Secondary outcome
SYNERGY Stent Registry:
- Incidence of Definite Stent Thrombosis within 1 year.
Background summary
Although first generation durable-polymer drug eluting stents (DES) were
associated with lower rates of stent restenosis compared to bare-metal stents
(BMS), they were associated with increased rates of late and very late stent
thrombosis. This could be due to the durable polymer and
prolonged exposure to the drug leading to chronic vessel inflammation, delayed
hypersensitivity reactions, and chronic fibrin deposition. This prolonged drug
exposure related to permanent polymer may lead to impaired stent strut
endothelialization.
Bioabsorbable polymers were designed to prevent abnormal healing induced by
durable-polymer drug eluting stents (DES), limiting the exposure of the drug
with a bioabsorbable polymer. Randomized trials using bioabsorbable polymers
were associated with superior clinical outcomes compared with bare-metal stents
(BMS) and first-generation DES. Permanent Polymer Everolimus eluting stents
have been shown in meta-analyses of randomized trials to be associated with
lower rates of stent thrombosis compared to BMS and DES.
Colchicine binds to unpolymerized tubulin heterodimers, forming a stable
complex that inhibits the formation of microtubules of neutrophils. Colchicine
inhibits adhesion of neutrophils to vascular endothelium and inhibits release
of IL-1β and IL-18. Colchicine has been shown to lower hs-CRP. By reducing
inflammation, colchicine can reduce infarct size and the incidence of
subsequent new plaque rupture and as a result prevent adverse coronary events.
By reducing aldosterone levels post STEMI by spironolactone
(aldosterone-antagonist), adverse ventricular remodeling may be reduced and
cardiovascular death and new or worsening heart failure events may be
prevented.
Study objective
In patients with acute MI (STEMI or Non-STEMI) who have undergone PCI, the
objectives are to
determine:
1. If colchicine can reduce the incidence of cardiovascular death, recurrent
MI, or stroke.
2. If routine use of spironolactone can reduce the incidence of cardiovascular
death or new or
worsening heart failure.
In patients with STEMI who have undergone PCI, the objectives of these studies
are to determine:
1. The rate of Major Adverse Cardiac Events (MACE) in patients who have
received a SYNERGY everolimus eluting stent
compared to a historical performance goal.
Objective of the biomarker substudy
1. Assess the effect of colchicine on neutrophil activation in response to AMI.
2. Examine clinical and genetic factors that determine heterogeneity of
treatment response and distinguish colchicine responders from nonresponders.
3. Explore the derivation of a risk score that includes markers of neutrophil
activity and is associated with adjudicated MACE over 5 years after AMI,
and assess the impact of colchicine on the relation between this risk score and
MACE.
Study design
Multicenter, international, controlled, randomized, blinded, 2x2 factorial
design with an embedded stent registry.
Intervention
- SYNERGY stent (recommended when available)
- Colchicine 0.5 mg tablet, once daily.
- Spironolactone 25 mg tablet, once daily
Study burden and risks
Burden: low-intermediate: Medical examination (weight, length, bloodpressure,
bloodsampling, ECG) upon randomisation, including medical history, ethnicity.
Once or twice a day one extra tablet and 5-7 extra visits to the hospital
(3,6,12, 24, 36, 48 and60 months).
Stent placement is already part of standard procedure.
Risks: low, colchicine and spironolactone are implemented in daily practice for
other diseases and are extensively investigated (see section E9).
Barton Street East 237
Hamilton ON L8L 2X2
CA
Barton Street East 237
Hamilton ON L8L 2X2
CA
Listed location countries
Age
Inclusion criteria
1. a) Patients with STEMI referred for PCI within 12 hours of symptom onset,
have a culprit lesion amenable to
stenting, and with planned SYNERGY stent implantation for SYNERGY registry
OR
b) Patients with STEMI referred for PCI within 48 hours of symptom onset, not
prospectively enrolled in SYNERGY
STENT registry.
OR
c) Patients with diagnosis of Non STEMI with ischemic symptoms and
either Hs Troponin > or = 200x ULN or Troponin > or = 100x ULN who
have undergone PCI with one of the following:
i. LVEF< or =45%
ii. Diabetes
iii. Multivessel CAD defined as 50% stenosis in 2nd major epicardial
vessel
iv. Prior MI
v. Age >60 years
2. Able to be enrolled/randomized within 72 hours of index PCI (however
patients should be
randomized as soon as possible after PCI)
3. Written informed consent
Exclusion criteria
1. Age <=18 years
2. Pregnancy, breastfeeding, or women of childbearing potential who are not
using an effective method of contraception
3. Any medical, geographic, or social factor making study participation
impractical or precluding required follow-up
4. Systolic blood pressure <90 mm Hg
5. Active diarrhea
6. Known allergy or contraindication to everolimus, the Synergy stent or any of
its components
7. Unable to receive dual antiplatelet therapy
8. Any contraindication or known intolerance to colchicine or spironolactone
9. Requirement of colchicine or mineralocorticoid antagonist for another
indication
10. History of cirrhosis or current severe hepatic disease
11. Current or planned use of any of: cyclosporine, verapamil, HIV protease
inhibitors, azole antifungals, or macrolide antibiotics
12. Creatinine clearance <30 ml/min/1.73m2
13. Serum Potassium >5.0 meq/L
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-000487-15-NL |
| ClinicalTrials.gov | NCT03048825 |
| CCMO | NL71984.100.19 |