#CardsJC: The LODOCO2 Trial

  • Post category:Journal Club

CardioNerds Journal Club is a monthly forum for Cardionerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the LoDoCo2 Trial.

Table of contents for the LoDoCo2 Trial summary:

November 5, 2020

Colchicine in Patients with Chronic Coronary Disease

The LoDoCo2 Trial

Stefan M. Nidorf, M.D., Aernoud T.L. Fiolet, M.D., Arend Mosterd, M.D., John W. Eikelboom, M.D., Astrid Schut, M.Sc., Tjerk S.J. Opstal, M.D., Salem H.K. The, M.D., Xiao-Fang Xu, M.D., Mark A. Ireland, M.D., Timo Lenderink, M.D., Donald Latchem, M.D., Pieter Hoogslag, M.D., Anastazia Jerzewski, M.D., Peter Nierop, M.D., Alan Whelan, M.D., Randall Hendriks, M.D., Henk Swart, M.D., Jeroen Schaap, M.D., Aaf F.M. Kuijper, M.D., Maarten W.J. van Hessen, M.D., Pradyot Saklani, M.D., Isabel Tan, M.D., Angus G. Thompson, M.D., Allison Morton, M.D., Chris Judkins, M.D., Willem A. Bax, M.D., Maurits Dirksen, M.D., Marco Alings, M.D., Graeme J. Hankey, M.D., Charley A. Budgeon, Ph.D., Jan G.P. Tijssen, Ph.D., Jan H. Cornel, M.D., and Peter L. Thompson, M.D. for the LoDoCo2 Trial Investigators

Link to article

  • Despite advances in modern therapy, ischemic heart disease continues to be the leading cause of death globally and in the United States. (1, 2)
  • Though excess lipids are a key component, lesion formation in atherosclerosis is predominantly a disease built on endothelial dysfunction and inflammation. The inflammatory basis of atherogenesis  begins with a trigger for endothelial dysfunction (e.g. elevated LDL, hypertension, diabetes, free radicals from cigarette smoking), which increases the adhesiveness and permeability of the endothelium. This leads to an inflammatory response that can continue indefinitely, eventually narrowing the arterial lumen with an advanced, complicated lesion consisting of smooth-muscle cells, fibrous and necrotic tissue, and inflammatory debris. (3)
  • The benefits of modifying this inflammatory pathway to limit the progression of atherosclerosis were first reported in a retrospective analysis showing patients with gout treated with colchicine had a lower prevalence of myocardial infarction than those  not treated with colchicine. (4)
  • This theory was then directly tested in the LoDoCo trial, where patients with stable ischemic heart disease were randomly assigned to receive colchicine or no colchicine. Patients who received colchicine were significantly less likely to have an acute cardiovascular event (NNT 9.3), however, the results were confounded by the small size (532 patients), the lack of a placebo control, and open label design. (5)
  • The use of anti-inflammatory therapy to treat atherosclerosis was further supported in the CANTOS trial, where patients with elevated C-reactive protein levels after myocardial infarction had fewer subsequent cardiovascular events when treated with canakinumab, a monoclonal antibody that targets interleukin-1β. (6)
  • Finally, the COLCOT trial randomized patients within 30 days after a myocardial infarction to colchicine vs placebo and found that low dose colchicine reduced the risk of future ischemic cardiovascular events (NNT 62.5). (7)
  • Given the concerns with the LoDoCo trial, a randomized, double-blind, placebo-controlled trial was conducted to investigate the roll of daily low dose colchicine for the treatment of stable ischemic heart disease (LoDoCo 2).

Table 1. Previous randomized controlled trials investigating colchicine and other anti-inflammatory therapies in the treatment of atherosclerotic ischemic heart disease

Relevant Guidelines for the LoDoCo2 Trial

  • The 2021 European Society of Cardiology/European Association of Preventive Cardiology guidelines on cardiovascular disease prevention recommend that low-dose colchicine (0.5 mg per day) may be considered in secondary prevention of CVD, particularly in patients with recurrent ASCVD events on optimal medical therapy or if other risk factors are not sufficiently controlled (Class IIb recommendation, LOA A). (8)

Study Rational

Multiple previous randomized and non-randomized studies support the use of daily low dose colchicine for patients post myocardial infarction or with stable ischemic heart disease to reduce the risk of future cardiovascular events. Given concerns with the design of the LoDoCo trial, a larger more robust trial was conducted to investigate the use of colchicine in stable ischemic heart disease.

Objective

To determine if daily low dose colchicine could reduce the risk of future cardiovascular events in patients with stable ischemic heart disease. 

LoDoCo2 Trial:
Randomized, double-blind placebo-controlled, phase III trial. Conducted in two countries (13 centers in western Australia and 30 in the Netherlands), with enrollment from August 2014 to December 2018. Follow up: median 28.6 months (interquartile range, 20.5 to 44.4).

Intervention
Patients with stable coronary artery disease who met inclusion criteria were enrolled in a 1 month run in phase to determine if they were tolerant to colchicine therapy. Those who were intolerant (611 patients) were excluded. Participants were then randomized to receive 0.5mg colchicine once daily (N=2762) or matching placebo (N=2760) in addition to their standard treatment for coronary artery disease. 

Enrollment criteria 

Outcomes

Statistical Analysis
Intention-to-treat analysis. Cause-specific hazard ratios and 95% confidence intervals were determined with the use of Cox proportional-hazards models. Ranked secondary end points were tested in a hierarchical fashion once the primary composite end point was statistically significant. Two-sided P waves for superiority were calculated by using log-rank tests. Prespecified subgroup analyses were also performed with the use of Cox proportional hazards method. Cumulative incidence estimated with Kaplan-Meier method

Notable Baseline Characteristics

Primary and Secondary Outcomes

Adverse events

LoDoCo2 Trial Conclusions

Among patients with stable ischemic heart disease, low dose colchicine taken once daily reduced the incidence of the composite endpoint of cardiovascular death, myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization driven primarily by a reduction in myocardial infarction or ischemia-driven coronary revascularization. There was also a non-significant trend towards increased non-cardiovascular mortality in the colchicine group.

Limitations & Considerations

  • Baseline or changes in inflammatory markers were not measured in this study, making it difficult to determine if there is a target subgroup of patients with stable ischemic heart disease who would benefit more or less from treatment with colchicine.
  • Lipid levels were not assessed at baseline or during the trial, making it difficult to tell if changes in LDL could have confounded the results.
  • There was a trend towards increased non-cardiovascular mortality in the colchicine group (HR 1.51; 95% CI, 0.99 to 2.31) without a change in cardiovascular or all cause mortality. It is unclear if there is a subset of patients who might incur a higher level of risk from low dose colchicine therapy.
  • 15.4% of patients in the run-in phase did not undergo randomization due to intolerance of colchicine. This likely means that the trial underestimates the risk of adverse events when taking colchicine.
  • Only 61.8% of patients in the trial were treated with high-dose statins despite ~84% of patients having a history of prior coronary revascularization (though 94% were on a statin at any dose). This could have magnified the benefits of colchicine.
  • The percentage of women in the trial was lower than expected (15.4%).

1. The top 10 causes of death. Available at: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death.

2. FastStats. 2021. Available at: https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm.

3. Ross R. Atherosclerosis — An Inflammatory Disease. N. Engl. J. Med. 1999;340:115–126.

4. Crittenden DB, Lehmann RA, Schneck L, et al. Colchicine Use Is Associated with Decreased Prevalence of Myocardial Infarction in Patients with Gout. J. Rheumatol. 2012;39:1458–1464.

5. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease. J. Am. Coll. Cardiol. 2013;61:404–410.

6. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N. Engl. J. Med. 2017;377:1119–1131.

7. Tardif J-C, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N. Engl. J. Med. 2019;381:2497–2505.

8. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: Developed by the Task Force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies With the special contribution of the European Association of Preventive Cardiology (EAPC). Eur. Heart J. 2021;42:3227–3337.

The published archive features curated twitter highlights from the journal club event.

The History of Colchicine with Dr. Martha Gulati “Get Vaccinated Please” (@DrMarthaGulati)

The history of colchicine is really interesting.
Colchicine is one of the oldest remedies still in use today. It is derived from the Colchicum autumnale plant, also known as autumn crocus. Its history as an herbal remedy for joint pain goes back at least to the 1500 BCE Egyptian manuscript, the Ebers Papyrus. The active ingredient- colchicine was isolated in the 1800 s by French chemists: JP Pelletier & Joseph Caventou. The name ‘colchicine’ derives from the ancient legendary kingdom of Colchis, where Jason recovered the Golden Fleece, where C. autumnale plants are today.

Colchicine is a historic treatment for gout that has been used for more than a millennium. Despite its use for thousands of years, colchicine’s exact mechanism of action is still not completely known. Given its extensive effects on inflammation, it is not surprising that the use of colchicine has been explored in a number of inflammatory conditions. It is the treatment of choice for Familial Mediterranean Fever and its associated complication, amyloidosis.

Your clinic patient has chronic, stable CAD. You’ve maximized their anti-platelets, statin, and beta-blocker but you’d like to reduce their cardiovascular risk further. What can you do?

Alison L. Bailey, MD (@a_l_bailey): Promote diet high in veggies/fruits, low in processed food, especially processed meat. Exercise! Maintain optimal weight.

Aliza Hussain, MD (@AlizaHussainMD): Lifestyle! Lifestyle! Lifestyle. AHA Lifespan’s Simple 7.

Devesh Rai, MD (@DeveshRaiMD): We can never go wrong with diet and lifestyle modification.

Devesh Rai, MD (@DeveshRaiMD): Cardiac rehab is often underutilized, such an important topic. Women are less referred to cardiac rehab as well.

Q1: The role inflammation plays in CAD is well described, but what medications can we consider to halt this process?

**Reviews on atherosclerosis pathophysiology**

Nature

NEJM

Dr. Martha Gulati “Get Vaccinated Please” (@DrMarthaGulati): The inflammatory basis of atherogenesis is well-established. So why wouldn’t such medications that target inflammation work? We have been asking this for a looonnngggg time!

Dr. Martha Gulati “Get Vaccinated Please” (@DrMarthaGulati): The 2009 FDA approval of colchicine as a new drug had research consequences. Recent investigations in large cohorts of gout patients who had been taking colchicine for years have demonstrated novel applications within oncology, immunology, cardiology and dermatology

Alison L. Bailey, MD (@a_l_bailey): Love #flozins but in a non-diabetic patient not sure there’s any data for secondary prevention of CAD.

James Januzzi Jr MD (@JJheart_doc): Agree with Dr. Bailey; if anything–not endorsing–GLP1RAs (with their impact on atherothrombotic dz)–might be the choice.

Justice Oranefo (@OranefoJustice): It appears the patients in the LoDoCo2 trial were on a good baseline medical regimen. I wonder if there is a benefit to checking hs-crp in such patients to identify who will benefit most from colchicine therapy?

Allan L. Klein (@AllanLKleinMD1): That was a major limitation for the trial in not measuring CRP as we do with recurrent pericarditis.

Q2: CABG patients were only included if > 10 years old, if cath-proven graft failure, or PCI since surgery. Is this appropriate inclusion criteria to answer the clinical question regarding reduction in inflammation?

Alison L. Bailey, MD (@a_l_bailey): The hypothesis being tested is reduction in arterial inflammation which is a different process than what occurs in CABG.  Reasonable exclusion in my mind.

Aliza Hussain, MD (@AlizaHussainMD): This trial is a significant addition to the inflammation hypothesis, proving that directly targeting inflammation may decrease residual cardiovascular risk.

Erin D. Michos, M.D. (@ErinMichos): Atherosclerosis is a leading cause of morbidity & mortality. Inflammation has major role in pathogenesis of atherosclerotic plaque & its stability. Patients with ACS remain at increased risk of recurrent CV events (~20% at 3 years) with higher risk than index event.

Nehal N. Mehta (@NehalMehtaMD): Agreed adds to growing body of data on treating those with most residual inflammatory risk. I certainly will eagerly await more data coming in to provide a definitive answer since this microtubule inhibitor shows promise in various CAD of differing ages.

Nehal N. Mehta (@NehalMehtaMD): Microtubule formation play an important role in early vascular disease development and ruptured plaque destabilization! Inhibition of these processes by colchicine aids in its important potential impact in acute MI!

Q3: Interestingly, before randomization, LoDoCo2 did a 1 month “run-in”phase when 6528 patients received the medication. Do you think this is a good idea for every trial? Can it impact/bias our findings?

Aliza Hussain, MD (@AlizaHussainMD): This is an important point. While this made sure patients in the colchicine arm adhered to the treatment, it does question the generalizability to all patients. Patients experience significant GI side effects with it. 15% in run in phases did not tolerate it.

Allan L. Klein (@AllanLKleinMD1): Note 15% in run in did not get randomized thus preselecting population. Less people with GI upset were randomized.

Colin Blumenthal, MD MS (@CBlumenthal2): Definitely reduces the number of adverse events in the trial, which are likely a significant underestimate. Many were excluded before the trial even began because of side effects.

Alison L. Bailey, MD (@a_l_bailey): Pros and cons of this design.
Cons: In the real world, if no run-in you should expect more intolerance to therapy.
Pros: You have some idea of magnitude of intolerance in similar patients.
I like this info when counseling a patient on starting new drug!

Gary Singer (@GarySingerMD) Unfortunately that excludes a majority of my patients with kidney disease – a chronic inflammatory condition with accelerated atherosclerosis.

Richard Ferraro (@RichardAFerraro): Really important point. Need studies that include patients with different predisposing conditions! Worth noting that some other major CV prevention trials like ISCHEMIA had sub-cohorts with CKD/ESRD.

Q4: Non-CV mortality was not statistically significant but had a high hazard ratio. Should we take it seriously?

Erin D. Michos, M.D. (@ErinMichos): While not conclusive given limited studies and paucity of events, this is still rather worrisome. I don’t think we can ignore this potential signal for harm. 

Aliza Hussain, MD (@AlizaHussainMD): Non significant increase in non-CVD death in LoDoCo2. CANTOS had higher incidence of fatal infection rates not seen in this trial. These are interesting findings but overall low number of events to make any definitive association.

Nehal N. Mehta (@NehalMehtaMD): There is no consistent pattern of the reported deaths; a number of causes likely just power. I see there no specific issue (eg liver cancer or renal failure).

Demographic & clinical characteristics were well balanced between the groups. Do you notice any other significant differences? Are there other characteristics not mentioned?

Devesh Rai, MD (@DeveshRaiMD): Women (16%) were highly underrepresented in this study, otherwise, the baseline characteristics and patients look to be on good therapy.

Dr. Martha Gulati “Get Vaccinated Please” (@DrMarthaGulati): Women have more angina…so why weren’t they included? Women live with chronic angina too.

Allan L. Klein (@AllanLKleinMD1): Minor point about dosing. Usually, 0.6 mg in US, while trials used 0.5 mg.

Aliza Hussain, MD (@AlizaHussainMD): Balanced yes, but certainly not diverse, low number of women.

Colin Blumenthal, MD MS (@CBlumenthal2): Overall maybe not as high risk of a group as I would think. Not a lot of diabetic patients on insulin. Very good statin use. Very few patients who smoke. Maybe tempered the effect a bit?

Only 61.8% of pts in the trial were treated with high-dose statins despite ~84% of patients having a history of prior coronary revasc. (94% were on a statin at any dose). Could this have increased the benefits of colchicine?

Alison L. Bailey, MD (@a_l_bailey): Statin use great but high-intensity statins only ~60%. We have a LOT of work to do in secondary prevention!  This could have made colchicine look better in lowering events as pts not really maximized.

Dr. Martha Gulati “Get Vaccinated Please” (@DrMarthaGulati): Sadly, this reflects real life even with known CAD. That also contributes to the residual risk when patients are unable to take or not given high dose statins.

Alison L. Bailey, MD (@a_l_bailey): And we know that many patients WILL tolerate a statin…if given the chance! https://www.nejm.org/doi/full/10.1056/NEJMc2031173

Aliza Hussain, MD (@AlizaHussainMD): We have to consider that this was done in Australia and Netherlands, statin use is not as high in the US.

Are the results believable?

Nehal N. Mehta (@NehalMehtaMD): Yes, but I eagerly await more data which will provide a more definitive answer. In MI, inflammation plays a role. In progressive CAD, inflammation plays a role. The proper patient to identify for these therapies is critical for successful implementation of these findings.

Allan L. Klein (@AllanLKleinMD1): Results believable when you combine LoDoCo, COLCOT, and now LoDoCo2. Biggest issue like in pericarditis is side effects: GI, hair loss and low WBC.

Dr. Martha Gulati “Get Vaccinated Please” (@DrMarthaGulati): Yes, the combination of all these trials is so impressive. I truly feel the main reason we aren’t using colchicine is that it is cheap and generic. But side effects are real when occur for sure.

Dr. Martha Gulati “Get Vaccinated Please” (@DrMarthaGulati): In Canada: Colchicine is 26 cents a pill. In USA : it is 4-6$ for a generic pill

What are the implications of the study? Will you consider prescribing colchicine to your patients?

Alison L. Bailey, MD (@a_l_bailey): Will consider in patients optimized on statins, antiplatelets, and elevated risk agreeable to taking another med…  AFTER a patient-centered discussion on risks, $$ and other ways to lower risk (hint: plants, exercise….)

Aliza Hussain, MD (@AlizaHussainMD): With so many therapeutics available or in development for ASCVD prevention it is important to identify patients that would derive highest benefit from colchicine, likely those with higher inflammation. Baseline and follow up HS-CRP levels would have helped. More colchicine trials are coming that will hopefully provide a clearer answer to the risk/benefit of colchicine

Nehal N. Mehta (@NehalMehtaMD): Yes, but I eagerly await more data which will provide a more definitive answer. In MI, inflammation plays a role. In progressive CAD, inflammation plays a role. The proper patient to identify for these therapies is critical for successful implementation of findings.

Dr. Martha Gulati “Get Vaccinated Please” (@DrMarthaGulati): Just for perspective, myotoxicity was previously a concern with use of colchicine + statin. So, we used to be warned not to use together. More data like these trials showed low incidence (<1%) w/ concomitant use of colchicine and statin therapy.

Justice Oranefo (@OranefoJustice): There is mounting evidence on benefit of colchicine. It would be beneficial to see a study which measures hs-crp to identify which patients would benefit most from therapy.

Devesh Rai, MD (@DeveshRaiMD) Will it benefit to find a special subset of chronic CAD patients with elevated HS-CRP levels? If yes, what would be advisable cut-off?

Erin D. Michos, M.D. (@ErinMichos): @al_abdouh & I performed colchicine meta-analysis prior to LoDoCo2 & found little evidence of benefit. PMID 32732517. Updated meta-analysis by Xia et al including LoDoCo2 found reduction in MACE, MI, revascularization & stroke but not CV death. 

The Future of Colchicine: Ongoing RCTs

SUMMARY:  

Dr. Colin Blumenthal, @CBlumenthal2, Cardiology Fellow at the University of Pennsylvania, Philadelphia, PA. 

VISUAL ABSTRACT:  

Dr. Juliette Power, @JuliettePower44, Cardiology Fellow at the University of Minnesota, Minneapolis, MN. 

JOURNAL CLUB PROMO GRAPHIC:  

Dr. Ahmed Ghoneem, @a_h_ghoneem, Internal Medicine Resident at Beth Israel Lahey Medical Center, Burlington, MA. 

HOUSE EINTHOVEN CHIEF FELLOW: 

Dr. Colin Blumenthal, @CBlumenthal2, Cardiology Fellow at the University of Pennsylvania, Philadelphia, PA. 

DIRECTOR of JOURNAL CLUB: 

Dr. Rick Ferraro, @RichardAFerraro, Cardiology Fellow at the Johns Hopkins Hospital, Baltimore, MD.

#CardsJC: The LODOCO2 Trial