Inflammation as a Therapeutic Target in Atherosclerosis
Abstract
:1. Introduction
2. Inflammation in the Pathophysiology of Atherosclerosis
3. Burden of Cardiovascular Disease in Chronic Inflammatory Diseases
4. Beyond Statins: Where to Now for Anti-Atherosclerotic Therapies?
5. Anti-Cytokine Therapy in Atherosclerosis: The Basis for Human Trials
6. A New Era: Human Trials Targeting Cytokine Inhibition
6.1. Canakinumab: The CANTOS Trial
6.2. Methotrexate: The Cardiovascular Inflammation Reduction Trial (CIRT) Trial
6.3. Alternative Targets in the IL-1β/IL-6 Signaling Pathway
6.4. Colchicine: The LoDoCo Trial
7. Clonal Haematopoiesis: A Novel Risk Factor for Atherosclerosis
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Trial Name | Study Design | Patient Number | Intervention | Primary Outcomes | Results | Benefit Observed |
---|---|---|---|---|---|---|
Broad-spectrum anti-inflammatory approach | ||||||
Methotrexate | ||||||
Cardiovascular Inflammation Reduction Trial (CIRT) [77] | Phase 3 multicentre, randomised, double-blind, placebo-controlled | 4786 | Oral low methotrexate (target dose of 15–20 mg weekly) vs. placebo | Non-fatal myocardial infarction, non-fatal stroke and cardiovascular death | HR 1.01; 95% CI 0.82–1.25; p = 0.91 | |
Colchicine | ||||||
Low-dose colchicine for secondary prevention of cardiovascular disease (LoDoCo) [78] | Phase 3 multicentre, randomised, double-blind, placebo-controlled | 532 | Colchicine 0.5 mg/day vs. placebo | MI, fatal or non-fatal out-of-hospital cardiac arrest, or non-cardioembolic ischaemic stroke | HR 0.33; 95% CI 0.18–0.59; p < 0.001 | |
Narrow-spectrum anti-inflammatory approach | ||||||
IL-1β | ||||||
Anti-inflammatory Therapy with Cankinumab for Atherosclerosis (CANTOS) [76] | Phase 3 multicentre, randomised, double-blind, placebo-controlled | 10,061 | Subcutaneous injection of canakinumab (50 mg, 150 mg or 300 mg) every 3 months vs. placebo | Non-fatal MI, non-fatal stroke and cardiovascular death | HR 0.85; 95% CI 0.74–0.98; p = 0.021 in the 150 mg-treated group | |
Lipoprotein-associated phospholipase A2 (Lp-PLA2) | ||||||
SOLID-TIMI 52 [79] | Phase 3 multicentre, randomised, double-blind, placebo-controlled | 13,026 | Daily oral darapladib 160 mg vs. placebo | Coronary heart disease death, non-fatal MI and urgent revascularisation for myocardial ischaemia | HR 1.00; 95% CI 0.91–1.09; p = 0.93 | |
P38 mitogen-activated protein kinase (MAPK) | ||||||
LATITUDE-TIMI 60 [80] | Phase 3 multicentre, randomised, double-blind, placebo-controlled | 3503 | Oral losmapimod 7.5 mg twice daily vs. placebo | Non-fatal MI, severe recurrent ischaemia requiring urgent coronary artery revascularisation and cardiovascular death | HR 1.16; 95% CI 0.91–1.47; p = 0.24 |
Trial Name | Primary Site(s) | Study Design | Patient Number | Intervention | Primary Outcomes | Follow-up | Completion Date |
---|---|---|---|---|---|---|---|
Stable coronary artery disease | |||||||
LoDoCo II: Low-dose Colchicine for Secondary Prevention of Cardiovascular Disease (ACTRN12614000093684) | Australia, Netherlands | Phase 3 multicentre, double blind, randomised placebo-controlled | 5500 | Colchicine 0.5 mg/day vs. placebo | ACS, cardiovascular death or stroke | 3 years | 20 Jan |
Acute Coronary Syndrome (ACS) | |||||||
COLCOT: Colchicine Cardiovascular Outcomes Trial (NCT02551094) | Canada | Phase 3 randomised placebo-controlled | 4745 | Colchicine 0.5 mg/day vs. placebo | MI, cardiovascular death, resuscitated cardiac arrest, stroke, or angina pectoris requiring revascularisation | 3–4 years | 19 Sep |
COACS: Colchicine for Acute Coronary Syndromes (NCT01906749) | Italy | Phase 4 multicentre, double blind, randomised placebo- controlled | 500 | Colchicine 0.5 mg/day vs. placebo | ACS, ischaemic stroke, and overall mortality | 2 years | N/A |
CLEAR-SYNERGY (OASIS-9): Colchicine and Spironolactone in Patients with STEMI/SYNERGY Stent Registry (NCT03048825) | Canada | Phase 3 multicentre, blinded, randomised placebo-controlled. 4 study arms, 2 × 2 factorial design | 4000 | Colchicine 1 mg/day and/or spironolactone 25 mg/day and/or placebo and/or SYNERGY stent | Cardiovascular death, recurrent MI, or stroke in the colchicine-treated group | 2 years | 21 Dec |
Cerebrovascular disease | |||||||
CONVINCE: Colchicine for Prevention of Vascular Inflammation in Non-cardio Embolic Stroke (NCT02898610) | Belgium, Ireland, Greece and Spain | Phase 3 multicentre, open-label, placebo controlled | 2623 | Colchicine 0.5 mg/day vs. placebo | Non-fatal major cardiac event and vascular death | 5 years | 21 Oct |
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Nguyen, M.T.; Fernando, S.; Schwarz, N.; Tan, J.T.; Bursill, C.A.; Psaltis, P.J. Inflammation as a Therapeutic Target in Atherosclerosis. J. Clin. Med. 2019, 8, 1109. https://doi.org/10.3390/jcm8081109
Nguyen MT, Fernando S, Schwarz N, Tan JT, Bursill CA, Psaltis PJ. Inflammation as a Therapeutic Target in Atherosclerosis. Journal of Clinical Medicine. 2019; 8(8):1109. https://doi.org/10.3390/jcm8081109
Chicago/Turabian StyleNguyen, Mau T, Sanuja Fernando, Nisha Schwarz, Joanne TM Tan, Christina A Bursill, and Peter J Psaltis. 2019. "Inflammation as a Therapeutic Target in Atherosclerosis" Journal of Clinical Medicine 8, no. 8: 1109. https://doi.org/10.3390/jcm8081109
APA StyleNguyen, M. T., Fernando, S., Schwarz, N., Tan, J. T., Bursill, C. A., & Psaltis, P. J. (2019). Inflammation as a Therapeutic Target in Atherosclerosis. Journal of Clinical Medicine, 8(8), 1109. https://doi.org/10.3390/jcm8081109