LODOCO TRIAL

1. Colchicine
in Chronic Coronary Disease
Dr Srikrishna MD

2. This article was published on August 31,
2020, at NEJM.org.

3. Background
• CANTOS proved that the specific anti-inflammatory effect of canakinumab
reduced the risk of cardiovascular events in high risk patients with coronary
disease.
• Colchicine has broad anti-inflammatory effects and is widely available.
•
• COLCOT proved that colchicine reduced the risk of cardiovascular events in
patients following a recent myocardial infarction.
• Evidence to support the routine use of colchicine for secondary prevention
in patients with chronic coronary disease is limited.

5. • Objective: To determine whether colchicine 0.5mg once daily
prevents cardiovascular events in patients with chronic coronary
disease.
• Design: Investigator-initiated, double-blind, placebo-controlled,
event-driven trial.
• Enrolment: Began in Australia (GenesisCare) in August 2014.
• Expanded to The Netherlands, Dutch Network for Cardiovascular
Research (WCN) in October 2016. Last enrolment: November 4, 2018.
•

7. Protocol
Patients aged 35 – 82 years with proven coronary disease
Clinically stable >6 months
No advanced renal disease, heart failure or severe valvular heart disease
30-day open label run-in of colchicine 0.5mg daily
Colchicine
Tolerant, clinically stable and willing
Placebo
Planned to begin close-out 12 months after the last participant had been randomized*
* If 331 primary events had accrued – sufficient to detect a 30% effect of therapy with 90% power
Clinical evaluations were
scheduled before the run-in
phase, at the time of
randomization, and at 6-month
intervals until the completion of
the trial

8. Primary end point
The composite of
• Cardiovascular death
• Myocardial infarction
• Ischemic stroke
• Ischemia-driven coronary revascularization

9. Secondary end points (ranked)
•
• 1. Cardiovascular death, Myocardial infarction or Ischemic stroke
• 2. Myocardial infarction or Ischemia-driven coronary revascularization
• 3. Cardiovascular death or Myocardial infarction
• 4. Ischemia-driven coronary revascularization
• 5. Myocardial infarction
• 6. Ischemic stroke
• 7. Death from any cause
• 8. Cardiovascular death

10. 6528
5522
Enrolled
91.3% Tolerated open label therapy
Randomized
Followed for a median of 29 months (12-64 months)
90.3% in each arm continued their trial medication
3.4% in each arm ceased due to perceived effects
Close-out
Began on December 4, 2019; Ended February 17, 2020
99.9%
5521
5521
The reason was GI upset.

11. Baseline characteristics
Colchicine Placebo
N=2762 N=2760
Age, years 65.8 +8.4 65.9 +8.7
Male 2305 (83.5) 2352 (85.9)
Risk Factors and History
Current Smoker 318 (11.5) 330 (12.0)
Hypertension 1421 (51.4) 1387 (50.3)
Diabetes 492 (17.8) 515 (18.7)
Prior Revascularization 2419 (83.4) 2468 (84.0)
Prior ACS 2323 (84.1) 2335 (84.6)
- Last ACS >24m 1570 (67.6) 1609 (68.9)

12. Medication use at baseline
Colchicine Placebo
N= 2762 N= 2760
Single anti-platelet therapy 1849(66.9%) 1852(67.1%)
Dual anti-platelet therapy 638(23.1%) 642(23.3%)
Anticoagulant 342(12.4%) 330(12.0%)
Statin 2594(93.9%) 2594(94.0%)
Any lipid lowering agent 2670(96.7%) 2665(96.6%)
Renin angiotensin inhibitor 1995(72.2%) 1965(71.2%)
Beta-blocker 1692(61.3%) 1735(62.9%)
Calcium-channel blocker 633(22.9%) 611(22.1%)

13. Hazard ratio, 0.69 (95% CI, 0.57-0.83), P<0.001
Placebo
Colchicine
0
5
10
15
20
0 12 24 36 48 60
Months since Randomization
Cumulative
Incidence
(%)
2760 2655 1703 821 590 161
2762 2685 1761 890 629 166
No. at Risk
Primary end point
Cardiovascular death, Myocardial infarction, Ischemic stroke or
Ischemia-driven coronary revascularization
264 placebo vs 187 colchicine

14. Hazard ratio, 0.72 (95% CI, 0.57-0.92), P=0.007
Placebo
Colchicine
0
5
10
15
20
0 12 24 36 48 60
Months since Randomization
Cumulative
Incidence
(%)
2760 2694 1760 863 625 174
2762 2714 1787 913 651 176
No. at Risk
Key secondary end point
Cardiovascular death, Myocardial infarction or Ischemic stroke
157 placebo vs 115 colchicine

15. Ranked secondary end points
Colchicine
(N = 2762)
Placebo
(N = 2760)
Hazard Ratio
(95% CI)
P Value
1. Cardiovascular death, Myocardial infarction,
or Ischemic stroke
115(4.2) 157(5.7) 0.72(0.57-0.92) 0.007
2. Myocardial infarction or Ischemia-driven
coronary revascularization
155(5.6) 224(8.1) 0.67(0.55-0.83) <0.001
3. Cardiovascular death or Myocardial infarction 100(3.6) 138(5.0) 0.71(0.55-0.92) 0.010
4. Ischemia-driven coronary revascularization 135(4.9) 177(6.4) 0.75(0.60-0.94) 0.012
5. Myocardial infarction 83(3.0) 116(4.2) 0.70(0.53-0.93) 0.014
6. Ischemic stroke 16(0.6) 24(0.9) 0.66(0.35-1.25) 0.198
7. Death from any cause 73(2.6) 60(2.2) 1.21(0.86-1.71)
8. Cardiovascular death 20(0.7) 25(0.9) 0.80(0.44-1.44)

16. Prespecified sub-groups

17. Colchicine Placebo
(N = 2762) (N = 2760)
Non-cardiovascular death 53(1.9) 35(1.3)
Diagnosis of new cancer 120(4.3) 122(4.4)
Hospitalization for infection 137(5.0) 144(5.2)
Hospitalization for pneumonia 46(1.7) 55(2.0)
Hospitalization for gastro-intestinal reason 53(1.9) 50(1.8)
Serious adverse events – not significantly
different
Neutropenia 3(0.1) 3(0.1)
Myotoxicity 4(0.1) 3(0.1)
Myalgia 384/1811 (21.2). 334/1807 (18.5)

18. Summary
In patients with chronic coronary disease, low-dose colchicine
Reduced the risk of;
- The primary composite end point
Cardiovascular death, myocardial infarction, ischemic stroke or ischemia-driven coronary revascularization.
- Key secondary composite end points
Cardiovascular death, myocardial infarction or ischemic stroke.
- Individual secondary end points
Myocardial infarction & Ischemia-driven coronary revascularization.
… with broadly consistent effects across a range of clinical subgroups
Was well tolerated and appeared safe
The incidence of premature discontinuation & serious adverse events were both low & equivalent to placebo.

19. • The LoDoCo2 trial has several limitations.
1. The percentage of women in the trial was low
2. Blood-pressure or lipid levels at baseline or during the trial were
not measured , and outcomes according to risk factor control can
not be measured.
3. C-reactive protein levels or other laboratory indicators of
inflammation at baseline were not measured. So the effects of
treatment according to inflammatory state at baseline cannot be
measured.

20. LoDoCo2 provides strong evidence to support repurposing
colchicine for routine secondary prevention in patients with
chronic coronary disease.
Conclusion

21. • Colchicine is a classical anti-mitotic drug which blocks mitotic cells in
metaphase.
• It binds to soluble tubulin to form tubulin-colchicine complexes in a
poorly reversible manner, which then binds to the ends of
microtubules to prevent the elongation of the microtubule polymer.

24. Three-year clinical outcomes of the absorb bioresorbable
vascular scaffold compared to Xience everolimus-eluting stent
in routine PCI in patients with diabetes mellitus—AIDA sub study
Dr Srikrishna MD

26. Concept and rationale
Revascularization
with Transient Support
Benign
Resorption
Restoration
of Physiological
Environment (shear
stress, multidirectional
motion, morphology)
Given the increased peri-strut inflammation in patients with DM absorb BVS
implantation might be associated with favourable clinical outcomes after PCI in
diabetic patients
1
2 3

27. • Diabetic patients represent a major challenge for the interventional
cardiologists
• They have more rapidly progressing coronary artery disease
• More often have long coronary lesions
• Diabetes mellitus is a significant predictor of adverse clinical and
angiographic outcomes after percutaneous coronary intervention
• This higher risk of adverse events may be due to their pronounced chronic
coronary inflammation and abnormal vessel healing

28. Stent / Scaffold Material
Cobalt
Chromium
Poly (L-lactide)
Coating Material
Fluorinated
Copolymer
Poly (DL-lactide)
Absorb: Bioresorbable DES, Built upon XIENCE
Technology
Material / Design XIENCE Absorb
Drug / Elution Everolimus
Stent / Scaffold Design MULTI-LINK Design
Delivery System MULTI-LINK SDS

29. ABSORB BVS arm n=924 Xience EES arm n=921
Patients Randomized n=1845
Design
•Prospective, multi-center, single-blind, randomized controlled trial
•N=1845
• Scaffold (n=924)
• DES(n=921)
•Setting: 5 centres in the Netherlands
•Enrolment: August 28, 2013 to December 27, 2015
•Duration follow-up: 2 years , 3 years and 5 years
•Analysis: Intention-to-treat

30. DESIGN OF THE CURRENT ANALYSIS
The safety and efficacy of Absorb BVS with Xience EES in patients presenting
with a medical history of DM was evaluated.

31. • The primary endpoint of the current analysis is TVF at 3-year after index
procedure.
• Secondary endpoints are
1. All-cause death
2. All myocardial infarction
3. All revascularizations
4. Device thrombosis.
• To evaluate the impact of baseline procedural and lesion differences,
predictors of lesion oriented clinical outcomes (LOCE) were calculated.
• LOCE is a composite of target vessel MI, target lesion revascularization
(TLR) or definite device thrombosis.

32. Statistical analysis
• All analyses were performed with outcomes that occurred between
randomization and 3 years of follow-up by randomized device modality
(Absorb BVS or Xience EES) according to the intention-to treat principle.
• Baseline data are summarized with descriptive statistics using Fisher's exact
test for binary variables and the independent t-test for continuous
variables.
• Three-year event rates were based on Kaplan–Meier estimates in time-to-
first-event analyses and were compared by means of the log rank test.
• Lesion level based predictors of LOCE in diabetic patients were calculated
by univariate and multivariate logistic regression.

34. Procedural and QCA characteristics

35. TVF at 3-years were higher among DM compared to non-DM
patients when pooled across Absorb BVS and Xience EES(18.3
vs. 11.6%; p = .002).
Target vessel failure is defined as a composite of cardiac death, target vessel myocardial infarction or target vessel
revascularization.

37. • Compared with patients without DM, patients with DM had higher
rates of all-cause death (7.8 vs. 4.7%, p = .024), any revascularization
(21.1 vs. 13.1%, p < .001) and TLR at 3 years (9.9 vs. 6.2%, p = .020).
• Definite or probable device thrombosis occurred more frequently in
Absorb BVS compared to Xience EES in DM (4.8 vs. 0.7%, p = .028)
and in non-DM (3.5 vs. 0.9%, p = .001).

38. DISCUSSION
• In the AIDA trial, Absorb BVS was associated with higher rates of target
vessel myocardial infarction (TV-MI) and device thrombosis at 3 years
compared to Xience EES.
• In this sub-study
(1) DM is associated with higher rates of all-cause death, revascularization
and TLR,
(2) TVF and its individual components were not different between absorb
BVS and Xience EES in both DM and non-DM,
(3) Absorb BVS implantation lead to higher rates of device thrombosis in
patients both with and without DM,

39. Definite DeviceThrombosis Definite or ProbableDevice Thrombosis
Target-VesselFailure

40. Two hypotheses have emerged for the relative ineffectiveness of -limus drug
in DM.
1. Direct resistance of vascular smooth muscle cells to mammalian target of
rapamycin (mTOR) inhibition in diabetic patients.
2. The body mass index strongly correlates with risk of DM. Obesity is
associated with elevated levels of the hormone leptin, which has been
found to promote vascular remodeling and neointimal growth in animal
studies.
Increased leptin levels have been associated with in stent restenosis

41. limitations
1. Based on the TVF rate in this study, and a noninferiority boundary of 5%, this
study needed a sample size of 1,003 patients per group to have at least 80%
power.
2. The AIDA population reflects routine PCI. In routine PCI, intracoronary imaging
is not mandatory, and therefore it is not possible to quantify successful lesion
preparation and/or device implantation.
3. Inflammatory and immunologic markers, in order to understand the role of
both inflammation and cell proliferation in restenosis, have not been collected.
4. As a post-hoc analysis, information on HbA1C is lacking which would have
provide better insights.
5. Exact information on the duration of DAPT in every patient would have given
greater insights.

42. The Absorb BVS
• In the ABSORB II trial, BVS was compared with the Xience metallic EES (Abbott
Vascular, USA).
At 1 year
• the rate of first time or worsening angina was lower with BVS than with EES (20%
vs. 30%; P=0.04), whereas non-significant differences were reported for the
Device-Oriented Composite End point (DOCE).
At 3 years
• A higher rate of DOCE due to target vessel MI, including peri-procedural MI, was
observed in the Absorb group.
• The patient oriented composite endpoint, angina status, and exercise testing
were not statistically different between both devices at 3 years

43. • ABSORB Japan was a single-blind, multicenter, randomized trial. The rate of TLF
was numerically higher in the BVS arm than in the EES arm, although this
difference was not statistically significant (p=0.18). VLST was observed only in the
BVS arm at a rate of 1.6% between one and two years .
• The randomized ABSORB-STEMI TROFI II trial studied patients with ST-Segment
Elevation MI (STEMI) treated with Absorb or Xience stent.
• The Optical Coherence Tomography (OCT)-based healing score at 6 months was
lower in Absorb than in EES (1.74 vs. 2.80; p<0.001 for non-inferiority). The DOCE
was similarly low in the two groups

44. ABSORB 3 trial – largest trial
• In the randomized ABSORB III trial at 1-year follow-up, the primary
end point of TLF was non inferior in the BVS group compared with the
EES group.
• No significant difference was also seen for cardiac death (0.6% vs.
0.1%; P=0.29), target-vessel MI (TVMI; 6.0% vs. 4.6%; P=0.18), or
ischemia-driven TLR (3.0% vs. 2.5%; P=0.50). Device Thrombosis (DT)
occurred in 1.5% of patients with BVS and in 0.7% of patients with
EES (P=0.13) [16].

45. • Notably, the enrolment in ABSORB III was restricted to patients with relatively
stable symptoms and noncomplex coronary lesions, not generalizable to real-life
clinical practice.
• Despite this restriction, at 25 months’ follow-up, MACE was more prevalent with
Absorb compared to Xience (TLF 10.9% vs. 7.8%; p=0.03).
• The increased event rate was mainly in the smallest-caliber treated vessels with a
reference vessel diameter (RVD) of <2.25 mm by quantitative coronary
angiography (QCA)

46. GHOST-EU Registry
• In the large multi centre registry of 1189 patients,
• Researchers assessed the performance of the absorb BVS in a real world setting .
• The incidence of TLF was 4.4% at 6 months, and diabetes mellitus was the only
independent predictor of TLF (HR 2.41, p=0.006).
• The cumulative incidence of definite or probable ST was 1.5% at 30 days and 2.1%
at 6 months.
• Ostial lesions (p=0.049) and impaired left ventricular ejection fraction (P=0.019)
were independent predictors of ST.

47. The ISAR-ABSORB registry
• included 419 patients undergoing PCI with BVS, including 39% of
patients with ACS .
• At 12 months, the incidence of TLR among these patients was 13.1%,
whereas definite ST occurred in 2.6% of patients .
• The 2-year data found a disturbing 21.6% MACE rate with ABSORB
BVS. The rate of definite or probable ST at 2 years was 4.2%

48. The various causes of early scaffold thrombosis
1. Malapposition,
2. Underdeployment of scaffold,
3. Incomplete coverage of lesions,
4. Acute disruption
Late scaffold thrombosis
1. Malapposition
2. Late discontinuity of antiplatelet agents
3. Underdeployed stent
4. Uncovered struts
5. Neoatherosclerosis
• A “PSP” (predilatation, correct scaffold sizing, and postdilatation) algorithm for scaffold deployment has
been proposed to improve outcomes after BRS implantation.
• The thicker struts (150–160 μm with ABSORB vs. 50–60 μm with new generation metallic DES) of ABSORB
lead to flow disturbances and delayed neointimal coverage leading to scaffold thrombosis.

49. limitations to the unrestricted use of BVS
First, accurate sizing is necessary when using the device in order to achieve optimal strut apposition
• Choosing too small a scaffold diameter results in the need for overstretch dilation.
• Overstretching the BVS is limited to <1.0 mm above the nominal scaffold diameter.
• As the largest BVS is 3.5 mm and the maximal post-expansion recommended is 0.5 mm over the
nominal diameter, major bifurcations and large vessels (≥4 mm) need best be avoided, including
the left main coronary artery.
• Furthermore, local overexpansion might induce edge dissection.
• On the other hand, the use of an inappropriately large BVS results in oversizing and
underexpansion, which has been linked to scaffold thrombosis .
• The use of the device in small vessels, particularly in vessels <2.25 mm, may augment the
footprint of the device

50. The polymer platform is not as strong and has less radial strength than
metallic stents , which is an issue in highly calcific lesions.
• As bioresorption progresses, radial strength further declines harbouring
the risk for scaffold collapse.
The duration of dual antiplatelet therapy (DAPT) after BVS is an unresolved
• The micro-thrombi visualized in the acute phase on OCT eventually grow
and evolve into chronic organized thrombi visible on OCT imaging and
undistinguishable from neointima.
• This mechanism possibly explains the deleterious effects of insufficient
DAPT prescription, whether in efficacy or in duration.

51. Conclusion on BVS
• Absorb, DESolve, ART Pure, Fantom, and Magmaris—have acquired the
Conformité Européenne (CE) mark, while Absorb has also been approved by the
Food and Drug Administration (FDA) and the Pharmaceuticals and Medical
Devices Agency (PMDA) in Japan.
• Absorb is presently the only BRS that has been tested against a new generation
DES in randomized trials with at least mid-term follow-up.
• A paradoxically increased thrombotic risk of this scaffold emerged and the
manufacturing company eventually stopped its commercial production.

52. • Thank you