Something old, something new: a paradigm for considering immune therapies for cardiovascular disease

The notion of common risk factors driving the development of cardiovascular (CV) disease is deeply ingrained. It is so much so that the idea of CV disease being possibly an immunologically mediated process, amenable to immune therapies, always seems novel. Paradoxically, the idea is quite ancient. Galen understood that the balance between health and disease essentially hinges on the body’s response to potentially harmful exposures. In a sense, we have always known that our immune system, metaphorically understood as our ability to fight off disease, is the key to maintaining health. In effect, most diseases can be viewed as a problem with the body’s immune system going awry. An insufficient or failing immune system renders the host more susceptible to range of both infectious and non-infectious problems. In turn, a dysregulated immune response, which can involve excessive off-target inflammatory activity, is seen in numerous types of chronic disease states, including atherosclerosis and acute coronary events.

Colchicine is one of the oldest known drugs and has been used for decades for the treatment of gout and familial Mediterranean fever. More recently, colchicine has entered the CV space as the frontline agent for the treatment of pericarditis and possibly coronary artery disease (CAD). Colchicine, which inhibits tubulin polymerization and microtubule formation, was tested in the Colchicine Cardiovascular Outcomes Trial (COLCOT) for secondary prevention after acute myocardial infarction (MI).¹ In this prospective study, 4745 patients were randomized to 0.5 mg colchicine or placebo within 30 days of an acute MI and were followed over a median of 22.6 months. Participants had a high prevalence of guideline-recommended treatment: 98% were treated with statins, 99% with dual antiplatelet therapy, and 93% underwent percutaneous coronary intervention (PCI). The primary composite endpoint (death from CV causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization) was lower in the colchicine group compared with the placebo group [5.2% vs. 7.7%; hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.61–0.96]. The composite endpoint was primary driven by a reduction in stroke and recurrent angina with no significant decreases in the individual components of CV death, resuscitated cardiac arrest, or MI. Colchicine did lower the risk of stroke (HR 0.26, 95% CI 0.10–0.70) and urgent hospitalization for angina leading to coronary revascularization (HR 0.50, 95% CI 0.31–0.81).

The results of COLCOT should be interpreted in light of recent trials. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) demonstrated that canakinumab, a monoclonal antibody that inhibits interleukin-1β, may be an effective treatment in chronic CAD.² Treatment with canakinumab in patients with a history of MI and elevated high sensitivity C-reactive protein ( hsCRP ) > 2 mg/dL resulted in a modest reduction in recurrent CV events compared to placebo. However, patients treated with canakinumab also had a small but higher incidence of fatal infections when compared with placebo. Conversely, a less-potent agent, methotrexate, a widely used anti-inflammatory agent in rheumatologic diseases, was tested in the Cardiovascular Inflammation Reduction Trial (CIRT) and did not demonstrate a benefit in recurrent CV events.³ Thus, COLCOT was a much-anticipated trial after these somewhat conflicting results.

COLCOT was a large, simple, and well-designed event-driven trial that has reignited a surge of enthusiasm for targeting inflammation. This trial stands out as an example of repurposing a broadly available generic drug that is orally dosed, well-tolerated, and cost-effective (perhaps less so in the USA), for a new application.⁴ What are the new and unanswered questions after COLCOT? The duration of follow-up for COLCOT was relatively short at 23 months and the risks and benefits of longer-term treatment are not known. After 23 months, there was a modest composite efficacy benefit, primarily driven by an angina endpoint. In the small subset of patients in which data were available, there was no significant reduction in hsCRP compared with placebo, although this could have been masked by the natural rise and fall of hsCRP after acute MI. Nevertheless, colchicine has dose-dependent effects on the inflammasome.⁵ Another question is whether a dose 0.6 mg (which is used in the USA) provide similar results as where observed with 0.5 mg.

Drug interactions are particularly important if colchicine will be applied broadly for CAD. Coadministration of colchicine with moderate to strong CYP3A4 inhibitors or a P-gp inhibitor causes a two- to four-fold increment in colchicine concentration and many commonly prescribed CV medications fall into this class (e.g. ticagrelor, atorvastatin, carvedilol, and many calcium channel blockers).⁶ Colchicine is also renally cleared and more data are needed to know if colchicine is safe in patients with CAD and chronic kidney disease.

What is the mechanism of CV risk reduction and is colchicine beneficial in risk reduction in the absence of acute coronary syndrome? The low Dose Colchicine (LoDoCo) pilot trial showed that colchicine 0.5 mg once daily appeared safe and effective for secondary prevention of CV disease in chronic CAD patients.⁷ The results of LoDoCol2 is eagerly anticipated this year which randomized 5522 patients with stable CAD to colchicine 0.5 mg or placebo with follow-up of 5 years.⁸ Where does this leave us with the role of targeting inflammation in primary prevention of high-risk patients? COLCOT-2 is now ongoing and is recruiting patients with T2DM who will be randomized to colchicine vs. placebo.

Colchicine is also being evaluated in post-PCI and ST-elevation myocardial infarction (STEMI) populations. In the colchicine-PCI trial, a one-time dose of 1.8 g colchicine was given 1–2 h peri-procedure. The results were released at AHA 2019 and demonstrated a lack of benefit in peri-procedural MI or 30-day CV events. However, the investigators did observe a reduction in inflammatory markers around the 24-h time point post-PCI, which raises the question of optimal timing and efficacy.⁹ The CLEAR-Synergy trial targets patient who present with STEMI and undergo primary PCI and aims to enroll 4000 patients. A summary of the current trials of colchicine in CV risk reduction is shown in Table 1.

Table 1.

Randomized controls trials with colchicine in cardiovascular risk reduction

Study name	Population	Dosing regimen	Sample size	Results	Limitations
LoDoCo	Stable coronary disease	0.5 mg qd vs. placebo	554	67% in primary outcome (ACS, OSH cardiac arrest, non-embolic stroke) with colchicine compared to control (HR 0.33, 95% CI 0.18–0.59; P < 0.001). Median follow-up 2 years	Small sample size, no placebo
COLCOT	Recent MI	0.5 mg qd vs. placebo	4745	33% reduction in composite endpoint of (CV death, MI, stroke, and hospitalization for angina) in colchicine compared to placebo (HR 0.77, 95% CI 0.61–0.96; P = 0.02) Median follow-up 23 months	Short follow-up, few patients had inflammatory markers analysed, complete adverse events not ascertained
Colchicine-PCI	Periprocedural PCI	1.8 g over 1h vs. placebo 1–2 hr before procedure	400	Unpublished, AHA 2019: no difference in peri-procedural MI or 30-day CV events	Single dose and appropriate timing unclear
LoDoCo2	Stable coronary disease	0.5 mg qd vs. placebo	5522	Anticipated late 2020
CLEAR-Synergy	STEMI with primary PCI	2 × 2 factorial: colchicine 0.5 mg qd or b.i.d. with spironloactone 25 mg qd	∼4000	Recruiting
COLCOT2	T2DM, high-risk primary prevention	0.5 mg qd vs. placebo	10 000	Recruiting

AHA, American Heart Association Scientific Sessions 2019, Philadelphia, Pennsylvnia; ACS, acute coronary syndrome; OSH, outside hospital; MI, myocardial infarction, STEMI, ST elevation MI; T2DM, Type II Diabetes, CLEAR-Synergy NCT03048825.

A key unresolved question is whether immune therapies should be employed in everyone or will precision medicine be able to identify the subset of patients who derive the most benefit? Drug side effects, drug–drug interactions, cost and long-term effects of immune suppression are important considerations that will also vary between individuals. With the advent of advanced pharmacogenomics and deep phenotyping, the hope is such that the future of immune therapies in CV health will be informed by the use of various blood biomarkers and can be addressed in context of the individual.

Galen had the astute insight to recognize the beneficial effects of inflammation far before the immune system was discovered. The immune system is our frontline defense to initiate physiological inflammation as the initial phase of the tissue reparative process, and as a consequence, plays an equally robust role in pathological inflammation. It is the pathological inflammation in atherosclerosis and myocardial injury we hope to target, without altering the delicate balance of the reparative and physiologic inflammation. We now have an ‘old yet new’ potential agent in our CV armamentarium to tackle one of the most common causes of cardiovascular morbidity and mortality in developed countries.

Conflict of interest: none declared.

Funding

Dr. Weber is supported by a T32 postdoctoral training grant from the National Heart, Lung, and Blood Institute (T32 HL094301).

Authors

Biography: Brittany N. Weber, MD, PhD is an advanced cardiovascular fellow at the Brigham and Women’s Hospital, Harvard Medical School, in Boston, MA, USA. Her initial research focused was on immune development and dysregulation. She then completed her MD and a PhD in Immunology at the University of Pennsylvania. Her thesis work focused on the transcriptional regulation of early T-cell development in Dr Avinash Bhandoola’s laboratory. She completed her internal medicine training at the Brigham and Women’s Hospital and served as a chief medical resident. Her clinical and scientific interests are at the intersection of her two passions—immunology and cardiology—with a focus on cardio-rheumatology. She is currently a T32-funded research fellow under the mentorship of Dr Marcelo Di Carli, Professor of Radiology and Medicine at Harvard Medical School, the Chief of the Division of Nuclear Medicine and Molecular Imaging and Executive Director of Cardiovascular Imaging at the Brigham and Women’s Hospital. Here, she is focused on the role of systemic inflammation on vascular health and cardiac structure and function. She is currently studying common systemic inflammatory diseases (psoriasis, rheumatoid arthritis, and systemic lupus erythematosus) to understand the role of inflammation on microvasculature dysfunction using advanced cardiovascular imaging techniques, specifically cardiac positron emission tomography (PET).

Biography: Dr Ron Blankstein is the Associate Director of the Cardiovascular Imaging Program, Director of Cardiac Computed Tomography, Co-Director of the Cardiovascular Imaging Training Program, and a Preventive Cardiologist at Brigham and Women’s Hospital. He is also an Associate Professor of Medicine and Radiology at Harvard Medical School. Dr Blankstein’s clinical expertise and research interests focus on the evaluation and management of coronary artery disease, prevention of cardiovascular disease, and cardiac sarcoidosis. As a multimodality imager, he has clinical and research expertise in cardiac CT, cardiac MRI, and nuclear cardiology. Dr Blankstein has authored over 350 publications. His research has focused on how to use the results of cardiovascular imaging tests in improving patient outcomes. Dr Blankstein is president of the Society of Cardiovascular Computed Tomography and serves on the Board of Directors of the American Society of Preventive Cardiology. He is a member of the ACC’s Prevention of Cardiovascular Disease Leadership Council and is also a member of the ACC Nutrition and Lifestyle Work Group. He has previously served on the Board of Directors of the American Society of Nuclear Cardiology and the Council for the Certification of Cardiovascular Imaging. Dr Blankstein is an Associate Editor of JACC: Cardiovascular Imaging and Radiology: Cardiothoracic Imaging; he serves on the Editorial Board of the Journal of Nuclear Cardiology and Circulation: Cardiovascular Imaging.