Interleukin-1 blockade in cardiovascular diseases: a clinical update

Interleukin-1 blockade in cardiovascular diseases: a clinical update Abstract Interleukin-1 (IL-1) is the prototypical pro-inflammatory cytokine. IL-1 was implicated as a cardiodepressant factor in septic shock, and subsequent pre-clinical and clinical research has defined important roles for IL-1 in atherosclerosis, acute myocardial infarction (AMI), and heart failure (HF). IL-1 promotes the formation of the atherosclerotic plaque and facilitates its progression and complication. In a large phase III clinical trial of stable patients with prior AMI, blocking IL-1 activity using a monoclonal antibody prevented recurrent atherothrombotic cardiovascular events. IL-1 also contributes to adverse remodelling and left ventricular dysfunction after AMI, and in phase II studies, IL-1 blockade quenched the inflammatory response associated with ST-segment elevation AMI and prevented HF. In patients with established HF, IL-1 is thought to impair beta-adrenergic receptor signalling and intracellular calcium handling. Phase II studies in patients with HF show improved exercise capacity with IL-1 blockade. Thus, IL-1 blockade is poised to enter the clinical arena as an additional strategy to reduce the residual cardiovascular risk and/or address inflammatory cardiovascular conditions refractory to standard treatments. There are several IL-1 blockers available for clinical use, which differ in mechanism of action, and potentially also efficacy and safety. While IL-1 blockade is not immunosuppressive and not associated with opportunistic infections or an increased risk of cancer, fatal infections may occur more frequently while on treatment with IL-1 blockers likely due to a blunting of the inflammatory signs of infection leading to delayed presentation and diagnosis. We discuss the practical use of IL-1 blockade, including considerations for patient selection and safety monitoring. Interleukin-1, Inflammation, Coronary artery disease, Heart failure Introduction Despite the improvements in preventive, diagnostic, and therapeutic strategies, patients with cardiovascular disease (CVD) retain elevated inflammation-mediated residual risk for recurrent events.1 Cytokines are soluble signalling proteins that regulate the inflammatory response to host invasion and tissue injury by directing the intercellular response—interleukins. Interleukin-1 (IL-1) is the classic pro-inflammatory cytokine, occupying an apical role in the innate immune response.2 Heightened IL-1 activity contributes to the pathogenesis of several pro-inflammatory conditions, and, more recently, has been linked to CVD. In this review, we highlight the key advances in experimental and clinical IL-1 research and discuss the practical application of IL-1 blockade in clinical care. Since abundant evidence is available to define the role of IL-1 in atherosclerotic CVD and heart failure (HF), we focus this review on these areas and refer the reader to other reviews on the expanding investigation of IL-1 in other cardiovascular conditions, including pericarditis, cardiac arrhythmias, and valvular disease.3–5 Pharmacologic Interleukin-1 blockers IL-1 exists in two isoforms: IL-1α, a membrane-bound, autocrine, and paracrine messenger, and IL-1β, a soluble, autocrine, paracrine, and endocrine messenger.2 Both isoforms bind the IL-1 receptor (type I) and recruit the accessory and adaptor proteins to amplify the inflammatory response through the disinhibition of the effects of I-κB of the nuclear factor κB.2 A naturally occurring soluble receptor antagonist [IL-1 receptor antagonist (Ra)], is produced alongside IL-1β, and also binds the IL-1 receptor but does not activate intracellular signalling pathways. Interleukin-1α acts primarily as an alarmin and initiates the inflammatory cascade, including the production of IL-1β, which in turn further amplifies the inflammatory response. In the acute phase, the surge in IL-1α contributes to infarct size, whereas in the sub-acute phases IL-1β becomes the main cytokine responsible for cardiomyocyte apoptosis, adverse cardiac remodelling and HF. The interest in IL-1β as a therapeutic target over past decades has led to the development of several IL-1 blockers, including a recombinant human IL-1Ra, two human monoclonal antibodies, and one soluble decoy receptor (Table 1). None of IL-1 blockers have an indication for CVD at the present time, although an indication-seeking trial for canakinumab (Ilaris®) has been completed and published.6 Table 1 Pharmacologic Interleukin-1 blockers in cardiovascular clinical trials Agent  Mechanism  Blockade of   Dose tested  Frequency  Clinical condition(s)  Notes  IL-1α  IL-1β  IL-1Ra  Anakinra  Recombinant human receptor antagonist  Y  Y  N  100 mg  Once–twice daily  STEMI, NSTEMI, HFrEF, HFpEF  Flexible dose adjustment and rapid offset and onset but frequent injections  Canakinumab  Human monoclonal antibody  N  Y  N  50, 150, and 300 mg  Every 3  months  Prior myocardial infarction  Infrequent injections but slow offset  Gevokizumab  Humanized monoclonal antibody  N  Y  N  30 mg  Monthly  Not studied in clinical trials  U-shaped dose–response curve, gevokizumab-bound IL-1 retains agonist activity in preclinical studies  Rilonacept  Soluble IL-1R1-AcP as decoy protein  Y  Y  Y  320 mg  Every other week  Not studied in clinical trials  U-shaped dose–response curve in preclinical studies  Agent  Mechanism  Blockade of   Dose tested  Frequency  Clinical condition(s)  Notes  IL-1α  IL-1β  IL-1Ra  Anakinra  Recombinant human receptor antagonist  Y  Y  N  100 mg  Once–twice daily  STEMI, NSTEMI, HFrEF, HFpEF  Flexible dose adjustment and rapid offset and onset but frequent injections  Canakinumab  Human monoclonal antibody  N  Y  N  50, 150, and 300 mg  Every 3  months  Prior myocardial infarction  Infrequent injections but slow offset  Gevokizumab  Humanized monoclonal antibody  N  Y  N  30 mg  Monthly  Not studied in clinical trials  U-shaped dose–response curve, gevokizumab-bound IL-1 retains agonist activity in preclinical studies  Rilonacept  Soluble IL-1R1-AcP as decoy protein  Y  Y  Y  320 mg  Every other week  Not studied in clinical trials  U-shaped dose–response curve in preclinical studies  HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction. Table 1 Pharmacologic Interleukin-1 blockers in cardiovascular clinical trials Agent  Mechanism  Blockade of   Dose tested  Frequency  Clinical condition(s)  Notes  IL-1α  IL-1β  IL-1Ra  Anakinra  Recombinant human receptor antagonist  Y  Y  N  100 mg  Once–twice daily  STEMI, NSTEMI, HFrEF, HFpEF  Flexible dose adjustment and rapid offset and onset but frequent injections  Canakinumab  Human monoclonal antibody  N  Y  N  50, 150, and 300 mg  Every 3  months  Prior myocardial infarction  Infrequent injections but slow offset  Gevokizumab  Humanized monoclonal antibody  N  Y  N  30 mg  Monthly  Not studied in clinical trials  U-shaped dose–response curve, gevokizumab-bound IL-1 retains agonist activity in preclinical studies  Rilonacept  Soluble IL-1R1-AcP as decoy protein  Y  Y  Y  320 mg  Every other week  Not studied in clinical trials  U-shaped dose–response curve in preclinical studies  Agent  Mechanism  Blockade of   Dose tested  Frequency  Clinical condition(s)  Notes  IL-1α  IL-1β  IL-1Ra  Anakinra  Recombinant human receptor antagonist  Y  Y  N  100 mg  Once–twice daily  STEMI, NSTEMI, HFrEF, HFpEF  Flexible dose adjustment and rapid offset and onset but frequent injections  Canakinumab  Human monoclonal antibody  N  Y  N  50, 150, and 300 mg  Every 3  months  Prior myocardial infarction  Infrequent injections but slow offset  Gevokizumab  Humanized monoclonal antibody  N  Y  N  30 mg  Monthly  Not studied in clinical trials  U-shaped dose–response curve, gevokizumab-bound IL-1 retains agonist activity in preclinical studies  Rilonacept  Soluble IL-1R1-AcP as decoy protein  Y  Y  Y  320 mg  Every other week  Not studied in clinical trials  U-shaped dose–response curve in preclinical studies  HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction. Anakinra (Kineret®) is a recombinant human IL-1Ra and therefore blocks IL-1α and IL-1β. Anakinra has a half-life of 4–6 h and is administered subcutaneously once daily for the treatment of rheumatoid arthritis, juvenile arthritis, and gouty arthritis. Anakinra is also approved for cryopyrin-associated period syndromes (CAPS), rare genetic syndromes characterized by enhanced NLRP3 inflammasome activity resulting in elevated IL-1β levels. In CAPS, the recommended anakinra dose is 1 mg/kg, but it is often uptitrated to response. Anakinra’s short half-life may be advantageous as doses can be up- or down-titrated on a daily basis and, if an adverse effect occurs, the drug is cleared from circulation within 24 h. However, subcutaneous injection of anakinra causes local injection site reactions such as pain and erythema in ∼20% of patients that lead to discontinuation in ∼5%. Canakinumab (Ilaris®) is a humanized monoclonal antibody against IL-1β and does not block IL-1α. Canakinumab is approved for the treatment of CAPS and juvenile arthritis. Canakinumab requires infrequent once monthly dosing and is suitable for chronic use. The long duration of action, however, may not be advantageous when managing side effects. Rilonacept (Arcalyst®) is a chimeric recombinant form of IL-1 receptor and receptor accessory protein, functioning as a soluble decoy that binds IL-1α, IL-1β, and IL-1ra. Rilonacept is approved for the treatment of CAPS and is administered as a subcutaneous injection every 2 weeks. In pre-clinical studies of experimental acute myocardial infarction (AMI), rilonacept has shown an undesirable U-shaped dose–response curve.7 Gevokizumab is a humanized monoclonal antibody against IL-1β that has residual agonistic activity and a U-shaped dose–response curve. The clinical development of gevokizumab has been halted. Recent advances in understanding the upstream regulators of IL-1 production have led to the development of several inhibitors of the NLRP3 inflammasome, an intracellular macromolecular complex that allows the formation of pro-caspase-1 dimers and autocleavage leading to active caspase, and the conversion of pro-IL-1β to mature IL-1β.8 Several novel inflammasome inhibitors that block the ATPase activity of NLRP3 [BAY 11-7082, INF4E, and OLT1177 (dapansutrile)] or prevent NLRP3 oligomerization (OLT1177, 16673-34-0, and MCC950) are under development. Colchicine also appears to prevent NLRP3 triggering by blocking opening of the membrane P2X7 receptor and polymerization of the ASC domain of the inflammasome. The interested reader is referred to a recent in-depth review of the NLRP3 inflammasome in myocardial infarction.8 Atherosclerosis Experimental pre-clinical evidence shows that IL-1 both initiates and propagates the formation, growth, and rupture of vascular atherosclerotic plaques (Figure 1).9–12 IL-1 impairs vasodilation, increases oxidative stress, and increases procoagulant mediators, predisposing to atherothrombosis.13–15 Interleukin-6, which regulates pro-inflammatory and procoagulant signals, is produced in response to IL-1.16 Atherosclerotic plaques are capable of producing IL-1 and further enhancing disease progression.17 Histology studies demonstrate the presence of IL-1β in human atherosclerotic plaques.18 Interleukin-1 and IL-1ra predict atherosclerotic outcomes.19 Several epidemiologic studies have established a strong relationship between increasing risk for atherosclerotic disease and increasing levels of C-reactive protein (CRP), whose levels appear to closely reflect the amount of active IL-1 signalling and are reduced by the use of IL-1 blockers in a variety of inflammatory diseases.20,21 Figure 1 View largeDownload slide Interleukin-1 in coronary atherosclerosis. A variety of experimental and clinical evidence points to interleukin-1 as a key modulator of the development and progression of coronary atherosclerosis. Cell and animal models provided evidence of the key pathways involved in inflammatory atherosclerosis. The ‘inflammatory hypothesis of atherosclerosis’ was subsequently tested in the CANTOS trial in which it was proven that an anti-inflammatory therapy targeting interleukin-1 prevented recurrent cardiovascular events in high-risk patients. Ongoing pre-clinical research and early phase clinical trials are focused on expanding the field by elucidating the role of interleukin-1α in the initiation of post-infarction myocardial inflammation as well as the role of interleukin-1β in adverse cardiac remodeling after myocardial infarction and heart failure. Inhibition of the NLRP3 inflammasome appears to be a promising strategy. Additional studies are however needed to better characterize the differences between the various interleukin-1 blocking strategies. Figure 1 View largeDownload slide Interleukin-1 in coronary atherosclerosis. A variety of experimental and clinical evidence points to interleukin-1 as a key modulator of the development and progression of coronary atherosclerosis. Cell and animal models provided evidence of the key pathways involved in inflammatory atherosclerosis. The ‘inflammatory hypothesis of atherosclerosis’ was subsequently tested in the CANTOS trial in which it was proven that an anti-inflammatory therapy targeting interleukin-1 prevented recurrent cardiovascular events in high-risk patients. Ongoing pre-clinical research and early phase clinical trials are focused on expanding the field by elucidating the role of interleukin-1α in the initiation of post-infarction myocardial inflammation as well as the role of interleukin-1β in adverse cardiac remodeling after myocardial infarction and heart failure. Inhibition of the NLRP3 inflammasome appears to be a promising strategy. Additional studies are however needed to better characterize the differences between the various interleukin-1 blocking strategies. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)6 randomized 10 061 patients with prior AMI and evidence of systemic inflammation, defined as a CRP level of at least 2 mg/L, to either placebo or canakinumab 50, 150, or 300 mg every 3 months. The primary endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death was reduced by 15% in the canakinumab 150-mg treated patients compared to placebo [hazard ratio (HR) 0.85, 95% confidence interval (95% CI) 0.74–0.98; P = 0.021] over 48 months of follow-up. In the 300-mg canakinumab group, the primary endpoint was similarly reduced (HR 0.86, 95% CI 0.75–0.99; P = 0.031), but this difference was not considered statistically significant after multiple testing adjustments. There was no significant difference in the primary endpoint between the 50-mg canakinumab group and placebo. Canakinumab 150-mg also reduced the in need for coronary revascularization (HR 0.83; 95% CI 0.73–0.95; P = 0.005). These definitive results show that IL-1β blockade with canakinumab in patients with stable atherosclerotic CVD prevents recurrent cardiovascular events.22 The benefit seems also to be closely related to the inflammatory response, as patients showing the greatest reduction in CRP had improved survival with canakinumab.23 Acute myocardial infarction Unopposed IL-1 activity also impairs myocardial healing and favours cardiac rupture in experimental acute myocardial infarction (AMI) (Figure 1).24 IL-1 activates haematopoietic stem cell proliferation and mobilization in AMI.25 Adverse cardiac remodelling after AMI is limited by blockade of IL-1 signalling. The very early rise in IL-1 activity appears to be driven by IL-1α isoform rather than IL-1β.26,27 IL-1β blockade improves post-infarction healing.28 Patients with ST-segment elevation myocardial infarction (STEMI) show an intense inflammatory response, reflected in a classic rise and fall of inflammatory markers. The intensity of inflammatory response predicts worse outcomes including cardiac rupture and incidence of HF.29 Fourteen days of anakinra treatment in 40 patients with STEMI reduced area under the curve for CRP, and showed a signal for reduced progression to HF vs. placebo in the VCU-ART pilot studies.30–32 An ongoing clinical trial is investigating whether a higher doses of anakinra provides greater suppression of the inflammatory response after STEMI (NCT01950299). In the MRC-ILA-Heart study of 182 patients with non-ST-segment elevation myocardial infarction (NSTEMI), IL-1 blockade with anakinra also reduced CRP levels at 7 days after non-ST-segment elevation acute coronary syndrome but failed to improve clinical outcomes.33 After an initial significant suppression of CRP levels, there was an increase after treatment discontinuation in the anakinra arm.34 A similar pattern was seen also in the REDHART and DHART2 trials in which anakinra was given for 2 or 12 weeks for HF.35,36 This increase of CRP after stopping anakinra has been referred to as rebound, but the expression appears only partially correct, since the values don’t appear to rebound to the same values as prior to treatment or higher, but rather settle for a lesser degree of reduction and therefore likely reflects loss of inhibition with stopping anakinra while the stimuli for inflammation are still present. A recent sub-analysis of the MRC-ILA heart data has shown that those patients considered to have had a ‘rebound’ were actually the ones who had a lesser response to anakinra in the first place, thus suggesting that these patients are cases of incomplete inhibition.34 Heart failure Heart failure is a condition of chronic systemic inflammation. Chronic hypoxia and low-grade cell death signals stimulate IL-1 production in the failing heart.37 The ability of IL-1 to directly modulate cardiomyocyte contractility has been long recognized, and IL-1 has been considered to be one of the ‘soluble cardiodepressant factors’ in sepsis.38 IL-1 impairs β-adrenergic receptor signalling downstream of the receptor by multiple mechanisms related to cytoplasmic calcium handling (Figure 2).38 IL-1 also increases cardiomyocyte anaerobic glycolysis.39 Importantly, the negative inotropic effects of IL-1 are reversible.40 IL-1 interferes also with active relaxation and diastolic function.41 IL-1 blockade appears to restore calcium homeostasis through removal of a negative regulator (i.e., IL-1), in contrast to available inotropes, which increase intracellular calcium levels, predispose to arrhythmias, and increase oxygen consumption.42 Figure 2 View largeDownload slide Interleukin-1 and cardiac contractility. A complex interplay between subcellular components mediates cardiac dysfunction due to interleukin-1. Through an effect on gene transcription and/or a direct signalling cascade through the interleukin-1 receptor's toll-interleukin-1 receptor domain, interleukin-1 interferes primarily with downstream β-adrenergic signalling pathways, including G-protein-adenylyl cyclase interactions, L-type calcium channel function, and sarcoplasmic reticulum calcium handling. Figure 2 View largeDownload slide Interleukin-1 and cardiac contractility. A complex interplay between subcellular components mediates cardiac dysfunction due to interleukin-1. Through an effect on gene transcription and/or a direct signalling cascade through the interleukin-1 receptor's toll-interleukin-1 receptor domain, interleukin-1 interferes primarily with downstream β-adrenergic signalling pathways, including G-protein-adenylyl cyclase interactions, L-type calcium channel function, and sarcoplasmic reticulum calcium handling. Several clinical studies have demonstrated heightened IL-1 activity in chronic HF. Circulating IL-1β and IL-1Ra levels increase as the severity of HF symptoms worsens.43 Increased circulating levels of IL-6, a surrogate for IL-1 activity, predict HF events, and death.44 C-reactive protein level predicts the onset of new HF and correlates with exercise capacity in patients with systolic HF.45,46 In a pilot study in 80 patients with rheumatoid arthritis and with (n = 20) or without coronary artery disease (n = 60), anakinra improved left ventricular contractility and relaxation as measured by tissue Doppler echocardiography.47 In an initial open label study of seven patients with chronic systolic HF and elevated CRP (> 2 mg/L), anakinra given for 14 days significantly reduced CRP levels by 84% and improved peak oxygen consumption.48 When administered to 30 patients with acute decompensated HF in a double-blind randomized controlled trial (RCT), anakinra 100 mg twice daily for 3 days, and then daily for 11 days significantly reduced the acute inflammatory response, compared with placebo.49 In a separate trial of 60 patients with acute decompensated HF, anakinra started within 2 weeks of discharge and continued for 12 weeks improved peak oxygen consumption, quality-of-life, and NTproBNP levels.36 In a cross-over trial of 12 patients with HF with preserved left ventricular ejection fraction (LVEF) and diastolic dysfunction, anakinra led to a small yet significant improvement in peak oxygen consumption.50 A follow-up RCT in 30 patients with showed a significant improvement in quality-of-life, treadmill exercise time, and a reduction in NTproBNP levels, but no change in peak oxygen consumption.35 The absence of significant changes in peak oxygen consumption may be attributed to the effect of concomitant skeletal muscle dysfunction on cardiorespiratory fitness in patients with HFpEF and severe obesity. The outcomes of IL-1 blockers in HF are substantially different from previous clinical attempts with other anti-inflammatory treatments. The tumour necrosis factor-α (TNF-α) monoclonal blocking antibody infliximab failed to improve outcomes in patients in systolic HF.51 Of note, infliximab increased, rather than decreased, CRP levels. A dose–response relationship was observed between higher doses and longer treatment duration and worse outcomes, including an increased risk of death.51 There is little overlap between IL-1 and TNF-α signalling pathways as each are regulated by different gene families and different receptors and adaptor proteins.38 Whereas IL-1 binds a single receptor, TNF-α binds two separate receptors that induce opposing effects, with one receptor promoting survival and the other cell death. Safety profile of Interleukin-1 blockers While IL-1 blockers are generally well tolerated, and without direct organ toxicity, their use can complicate the presentation and clinical course of an infection, and they have been associated with an excess of infection-related deaths.6 IL-1 blockers reduce the leucocyte and neutrophil counts, but rarely to the level of severe neutropenia (<500/mm3), and the leucocyte cell count does not appear to correlate with the risk of infection. The use of IL-1 blockers is not associated with an increased risk of opportunistic infection. The mechanism(s) by which IL-1 blockers increase fatal infection risk is most likely related to blunting of the local and systemic inflammatory response to infection (i.e. redness, swelling, fever), which masks the presence of infection and may delay diagnosis and treatment. Importantly, the excess risk of fatal infection with IL-1 blockade is rather small in absolute terms. In more than 30 000 patient-years of treatment in CANTOS, there was an excess of only 1.3 fatal infections per 1000 patient-years (number needed to harm 769).6 Of note the overall number of serious infections and of serious adverse events of any cause was not increased with canakinumab. This small excess in infection-related fatalities over a median of 3.7 years of treatment and >30 000 patient-years indicates that IL-1 blockade does not interfere with healing from infection in the great majority of cases.6 This safety profile is consistent with the data of very high-dose anakinra infusion in sepsis which showed no excess mortality or harm vs. placebo52,53 and a signal for benefit in those patients with more aggressive sepsis.54 In registry studies, the concomitant use of IL-1 blockade as an add-on to immunosuppressants such as prednisone and/or methotrexate in patients with rheumatoid arthritis is associated with increased risk of serious infections.55 The risk of infection is substantially higher for TNF-α blockers compared to IL-1 blockers, including a several-fold increased risk of opportunistic and fungal infections, including tuberculosis, pneumocystis, and aspergillosis.55,56 TNF-α blockers are also associated with an increased risk of cancer, primarily haematologic,57 whereas IL-1 blockers are not. IL-1β blockade with canakinumab showed a dose–dependent reduction in the incidence of lung cancer and in cancer-related mortality.58 Use of interleukin-1 blockade in clinical practice IL-1 blockade targets a novel causal pathway of CVD that provides incremental benefit beyond optimal medical therapy. The potential reductions in CVD are great, yet as with any clinical decision, the risks and benefits must be weighed on an individual basis to identify optimal candidates for IL-1 blockade. Clinical trials of IL-1 blockers in CVD are summarized in Table 2 and Figure 3. Table 2 Clinical trials of interleukin-1 blockers in cardiovascular disease Study  Year(s)  Patients  Study design and strategy  Main finding(s)  References  VCU-ART VCU-ART2  2010 2013  ST-segment elevation MI (n = 10) (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg or placebo daily for 14 days  Reductions in CRP Trend toward reduced heart failure Ongoing clinical trial exploring two anakinra dosing regimens  30–32  AIR-HF  2012  Stable NYHA II–III HF with LVEF < 50% and CRP > 2 mg/L (n = 10)  Single-arm anakinra 100 mg daily for 14 days  Reduction in CRP Improved aerobic exercise capacity and ventilatory efficiency  48  DHART  2014  Stable NYHA II–III HF with LVEF > 50% and CRP > 2 mg/L (n = 12)  Double-blinded placebo-controlled cross-over anakinra 100 mg daily or placebo for 14 days  Reduction in CRP Improvement in peak aerobic exercise capacity and quality-of-life at 2 weeks  50  MRC-ILA Heart Study  2015  Non-ST-segment elevation MI (n = 182)  Double-blind, placebo-controlled RCT anakinra 100 mg once daily for 14 days  Reduction in CRP No differences in major adverse cardiac events at 30 days and 3 months Excess events at 12 months in the anakinra-treated group  33  ADHF  2016  Acute decompensated systolic HF with CRP > 5 mg/L (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg twice daily for 72 h then 100 mg once daily for 11 days or placebo  Reduction in CRP at 72 h and 14 days Trend toward more favourable effects on congestion and left ventricular ejection fraction with anakinra  49  AIRTRIP  2016  Idiopathic pericarditis with CRP > 10 mg/L, colchicine-refractory, steroid-dependent and at least three prior recurrences (n = 21)  Anakinra 2 mg/kg daily up to 100 mg for 2 months (open-label) then anakinra or placebo withdrawal trial for 6 months (double-blind, placebo-controlled RCT)  Anakinra reduced recurrent pericarditis and increased flare-free survival  61  REDHART  2017  Recently decompensated HF with LVEF < 50% and CRP > 2 mg/L (within 2 weeks of hospital discharge) (n = 60)  Double-blind, placebo-controlled RCT of anakinra 100 mg daily for 2 weeks or for 12 weeks or placebo for 12 weeks (1:1:1 ratio)  Reduction in CRP levels Improvement in aerobic exercise capacity and quality-of-life with 12-week anakinra Trend toward reduced heart failure readmissions at 6 months with 12-week anakinra  36  CANTOS  2017  Prior AMI with CRP > 2 mg/L (at least 30 days after AMI) (n = 10060)  Double-blind, placebo-controlled RCT of canakinumab 50, 150, or 300 mg or placebo (1:1:1:1.5 ratio)  Reduction in the incidence of the composite endpoint of cardiac death, non-fatal AMI or non-fatal stroke with canakinumab 150 mg vs. placebo  6  Study  Year(s)  Patients  Study design and strategy  Main finding(s)  References  VCU-ART VCU-ART2  2010 2013  ST-segment elevation MI (n = 10) (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg or placebo daily for 14 days  Reductions in CRP Trend toward reduced heart failure Ongoing clinical trial exploring two anakinra dosing regimens  30–32  AIR-HF  2012  Stable NYHA II–III HF with LVEF < 50% and CRP > 2 mg/L (n = 10)  Single-arm anakinra 100 mg daily for 14 days  Reduction in CRP Improved aerobic exercise capacity and ventilatory efficiency  48  DHART  2014  Stable NYHA II–III HF with LVEF > 50% and CRP > 2 mg/L (n = 12)  Double-blinded placebo-controlled cross-over anakinra 100 mg daily or placebo for 14 days  Reduction in CRP Improvement in peak aerobic exercise capacity and quality-of-life at 2 weeks  50  MRC-ILA Heart Study  2015  Non-ST-segment elevation MI (n = 182)  Double-blind, placebo-controlled RCT anakinra 100 mg once daily for 14 days  Reduction in CRP No differences in major adverse cardiac events at 30 days and 3 months Excess events at 12 months in the anakinra-treated group  33  ADHF  2016  Acute decompensated systolic HF with CRP > 5 mg/L (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg twice daily for 72 h then 100 mg once daily for 11 days or placebo  Reduction in CRP at 72 h and 14 days Trend toward more favourable effects on congestion and left ventricular ejection fraction with anakinra  49  AIRTRIP  2016  Idiopathic pericarditis with CRP > 10 mg/L, colchicine-refractory, steroid-dependent and at least three prior recurrences (n = 21)  Anakinra 2 mg/kg daily up to 100 mg for 2 months (open-label) then anakinra or placebo withdrawal trial for 6 months (double-blind, placebo-controlled RCT)  Anakinra reduced recurrent pericarditis and increased flare-free survival  61  REDHART  2017  Recently decompensated HF with LVEF < 50% and CRP > 2 mg/L (within 2 weeks of hospital discharge) (n = 60)  Double-blind, placebo-controlled RCT of anakinra 100 mg daily for 2 weeks or for 12 weeks or placebo for 12 weeks (1:1:1 ratio)  Reduction in CRP levels Improvement in aerobic exercise capacity and quality-of-life with 12-week anakinra Trend toward reduced heart failure readmissions at 6 months with 12-week anakinra  36  CANTOS  2017  Prior AMI with CRP > 2 mg/L (at least 30 days after AMI) (n = 10060)  Double-blind, placebo-controlled RCT of canakinumab 50, 150, or 300 mg or placebo (1:1:1:1.5 ratio)  Reduction in the incidence of the composite endpoint of cardiac death, non-fatal AMI or non-fatal stroke with canakinumab 150 mg vs. placebo  6  AMI, acute myocardial infarction; CRP, C-reactive protein; HF, heart failure; IL, interleukin; NYHA, New York Heart Association. Table 2 Clinical trials of interleukin-1 blockers in cardiovascular disease Study  Year(s)  Patients  Study design and strategy  Main finding(s)  References  VCU-ART VCU-ART2  2010 2013  ST-segment elevation MI (n = 10) (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg or placebo daily for 14 days  Reductions in CRP Trend toward reduced heart failure Ongoing clinical trial exploring two anakinra dosing regimens  30–32  AIR-HF  2012  Stable NYHA II–III HF with LVEF < 50% and CRP > 2 mg/L (n = 10)  Single-arm anakinra 100 mg daily for 14 days  Reduction in CRP Improved aerobic exercise capacity and ventilatory efficiency  48  DHART  2014  Stable NYHA II–III HF with LVEF > 50% and CRP > 2 mg/L (n = 12)  Double-blinded placebo-controlled cross-over anakinra 100 mg daily or placebo for 14 days  Reduction in CRP Improvement in peak aerobic exercise capacity and quality-of-life at 2 weeks  50  MRC-ILA Heart Study  2015  Non-ST-segment elevation MI (n = 182)  Double-blind, placebo-controlled RCT anakinra 100 mg once daily for 14 days  Reduction in CRP No differences in major adverse cardiac events at 30 days and 3 months Excess events at 12 months in the anakinra-treated group  33  ADHF  2016  Acute decompensated systolic HF with CRP > 5 mg/L (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg twice daily for 72 h then 100 mg once daily for 11 days or placebo  Reduction in CRP at 72 h and 14 days Trend toward more favourable effects on congestion and left ventricular ejection fraction with anakinra  49  AIRTRIP  2016  Idiopathic pericarditis with CRP > 10 mg/L, colchicine-refractory, steroid-dependent and at least three prior recurrences (n = 21)  Anakinra 2 mg/kg daily up to 100 mg for 2 months (open-label) then anakinra or placebo withdrawal trial for 6 months (double-blind, placebo-controlled RCT)  Anakinra reduced recurrent pericarditis and increased flare-free survival  61  REDHART  2017  Recently decompensated HF with LVEF < 50% and CRP > 2 mg/L (within 2 weeks of hospital discharge) (n = 60)  Double-blind, placebo-controlled RCT of anakinra 100 mg daily for 2 weeks or for 12 weeks or placebo for 12 weeks (1:1:1 ratio)  Reduction in CRP levels Improvement in aerobic exercise capacity and quality-of-life with 12-week anakinra Trend toward reduced heart failure readmissions at 6 months with 12-week anakinra  36  CANTOS  2017  Prior AMI with CRP > 2 mg/L (at least 30 days after AMI) (n = 10060)  Double-blind, placebo-controlled RCT of canakinumab 50, 150, or 300 mg or placebo (1:1:1:1.5 ratio)  Reduction in the incidence of the composite endpoint of cardiac death, non-fatal AMI or non-fatal stroke with canakinumab 150 mg vs. placebo  6  Study  Year(s)  Patients  Study design and strategy  Main finding(s)  References  VCU-ART VCU-ART2  2010 2013  ST-segment elevation MI (n = 10) (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg or placebo daily for 14 days  Reductions in CRP Trend toward reduced heart failure Ongoing clinical trial exploring two anakinra dosing regimens  30–32  AIR-HF  2012  Stable NYHA II–III HF with LVEF < 50% and CRP > 2 mg/L (n = 10)  Single-arm anakinra 100 mg daily for 14 days  Reduction in CRP Improved aerobic exercise capacity and ventilatory efficiency  48  DHART  2014  Stable NYHA II–III HF with LVEF > 50% and CRP > 2 mg/L (n = 12)  Double-blinded placebo-controlled cross-over anakinra 100 mg daily or placebo for 14 days  Reduction in CRP Improvement in peak aerobic exercise capacity and quality-of-life at 2 weeks  50  MRC-ILA Heart Study  2015  Non-ST-segment elevation MI (n = 182)  Double-blind, placebo-controlled RCT anakinra 100 mg once daily for 14 days  Reduction in CRP No differences in major adverse cardiac events at 30 days and 3 months Excess events at 12 months in the anakinra-treated group  33  ADHF  2016  Acute decompensated systolic HF with CRP > 5 mg/L (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg twice daily for 72 h then 100 mg once daily for 11 days or placebo  Reduction in CRP at 72 h and 14 days Trend toward more favourable effects on congestion and left ventricular ejection fraction with anakinra  49  AIRTRIP  2016  Idiopathic pericarditis with CRP > 10 mg/L, colchicine-refractory, steroid-dependent and at least three prior recurrences (n = 21)  Anakinra 2 mg/kg daily up to 100 mg for 2 months (open-label) then anakinra or placebo withdrawal trial for 6 months (double-blind, placebo-controlled RCT)  Anakinra reduced recurrent pericarditis and increased flare-free survival  61  REDHART  2017  Recently decompensated HF with LVEF < 50% and CRP > 2 mg/L (within 2 weeks of hospital discharge) (n = 60)  Double-blind, placebo-controlled RCT of anakinra 100 mg daily for 2 weeks or for 12 weeks or placebo for 12 weeks (1:1:1 ratio)  Reduction in CRP levels Improvement in aerobic exercise capacity and quality-of-life with 12-week anakinra Trend toward reduced heart failure readmissions at 6 months with 12-week anakinra  36  CANTOS  2017  Prior AMI with CRP > 2 mg/L (at least 30 days after AMI) (n = 10060)  Double-blind, placebo-controlled RCT of canakinumab 50, 150, or 300 mg or placebo (1:1:1:1.5 ratio)  Reduction in the incidence of the composite endpoint of cardiac death, non-fatal AMI or non-fatal stroke with canakinumab 150 mg vs. placebo  6  AMI, acute myocardial infarction; CRP, C-reactive protein; HF, heart failure; IL, interleukin; NYHA, New York Heart Association. Figure 3 View largeDownload slide Cardiovascular clinical trials of interleukin-1 blockade. (A–D) show results from CANTOS (n = 10061), combined VCU-ART/VCU-ART2 (n = 40), MRC-ILA Heart (n = 182), and REDHART (n = 60). While the effects of interleukin-1 blockade in patients with prior myocardial infarction has been studied in the landmark CANTOS, the pilot studies of interleukin-1 blockade in patients with acute myocardial infarction (VCU-ART series, MRC-ILA) and with heart failure (REDHART) have included only a small number of patients, and thus these findings require validation in further and larger studies. CI, confidence interval; HR, hazard ratio; MI, myocardial infarction. Figure 3 View largeDownload slide Cardiovascular clinical trials of interleukin-1 blockade. (A–D) show results from CANTOS (n = 10061), combined VCU-ART/VCU-ART2 (n = 40), MRC-ILA Heart (n = 182), and REDHART (n = 60). While the effects of interleukin-1 blockade in patients with prior myocardial infarction has been studied in the landmark CANTOS, the pilot studies of interleukin-1 blockade in patients with acute myocardial infarction (VCU-ART series, MRC-ILA) and with heart failure (REDHART) have included only a small number of patients, and thus these findings require validation in further and larger studies. CI, confidence interval; HR, hazard ratio; MI, myocardial infarction. Patients with residual inflammatory risk as indicated by CRP levels >2 mg/L are at increased risk for adverse CVD events in primary and secondary prevention.59,60 Clinical trials of IL-1 blockers have primarily targeted patients with elevated CRP. Following the CANTOS trial, canakinumab is being considered for secondary CVD prevention of patients with prior AMI and CRP > 2 mg/L. An analysis of the CANTOS trial showed that those patients who were ‘responders’ to treatment, achieving CRP < 2 mg/L at 3 months, had significantly less adverse cardiac events including reduced mortality compared to placebo or non-responders.23 This indication implies that patients with a prior AMI should be screened for elevated CRP levels. Prior to treatment with an IL-1 blocker, acute or chronic infection should be ruled out in each patient. In addition, clinicians should assess risk factors for infection and, based upon patient characteristics, may consider testing for undiagnosed infection, such as latent tuberculosis, or for risk factors for infection, such as immunodeficiency or intravenous drug use. The prescribing information for Canakinumab (Ilaris) in the USA approved by the Food & Drug Administration contains a general warning common to all immunomodulatory drugs advising to screen for latent tuberculosis using one of the strategies recommended by the Center for Disease Control. Such strict recommendation is lacking in the prescribing information for Canakinumab approved by the European Medicine Agency. If the patient has an active acute or chronic infection, the potential benefits of treatment need to be weighed against the risks of masking the signs of progression of the infection. Anakinra has been used successfully in patients with chronic or recurrent pericarditis, in particular those refractory to non-steroidal anti-inflammatory drugs and colchicine and in many cases corticosteroid-dependent. In such cases, anakinra 100 mg daily has been used to control symptoms and wean corticosteroids.5,61 Clinicians should monitor patients for signs and symptoms of infection at each clinic visit and be cognizant of IL-1 blockade’s anti-inflammatory effects that may prevent the patient from presenting with local and systemic symptoms and signs of infection, fever, or leucocytosis. As such, patients should be educated on the need to rely on other symptoms or signs of infection and seek help if an infection is suspected. Patients should also be instructed to relay the information of chronic IL-1 blocker use to a new provider if being evaluated for a possible infection. Routine measuring of leucocyte count is not warranted since severe leucopenia requiring discontinuation has not been observed, and leucopenia does not appear to represent the mechanism(s) by which IL-1 blockers increase fatal infection risk. In patients who develop an acute infection while being treated with a short-acting IL-1 blocker (anakinra), we recommend suspension of the IL-1 blocker until complete resolution of the infection, due to the fact that continuation of the treatment may interfere with the clinical assessment. Patients on an intermediate- or long-acting IL-1 blocker (rilonacept or canakinumab) who are scheduled to receive the next dose while an infection is active should have the next dose delayed until the infection is resolved. Standard management for infection should be provided to patients with acute infections. In patients who develop chronic infection, repeated infections or become chronically immunocompromised due to illness or medications, permanent discontinuation of IL-1 blockers should be considered. Conclusions A considerable body of evidence implicates IL-1 in the pathophysiology of CVD. IL-1 blockade reduces recurrent atherosclerotic cardiovascular events in patients with prior AMI and elevated CRP levels. In patients with STEMI and acute decompensated HF, IL-1 blockade blunts the acute inflammatory response, and in patients with chronic HF IL-1 blockade improves peak aerobic exercise capacity. There are currently four clinically available IL-1 blockers, each with a different efficacy and safety profile. As a class, IL-1 blockers prevent typical symptoms and signs of inflammation associated with infections and may delay the diagnosis and/or interfere with the prognostic assessment of patients with infection. As a result, infections in patients on IL-1 blockade can have a serious and/or fatal presentation. As IL-1 blockade becomes incorporated into standard of care for a variety of CVDs, cardiovascular clinicians must become experts in the management of biologic IL-1 blockers. 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JAMA  2016; 316: 1906– 1912. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

Interleukin-1 blockade in cardiovascular diseases: a clinical update

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Abstract

Abstract Interleukin-1 (IL-1) is the prototypical pro-inflammatory cytokine. IL-1 was implicated as a cardiodepressant factor in septic shock, and subsequent pre-clinical and clinical research has defined important roles for IL-1 in atherosclerosis, acute myocardial infarction (AMI), and heart failure (HF). IL-1 promotes the formation of the atherosclerotic plaque and facilitates its progression and complication. In a large phase III clinical trial of stable patients with prior AMI, blocking IL-1 activity using a monoclonal antibody prevented recurrent atherothrombotic cardiovascular events. IL-1 also contributes to adverse remodelling and left ventricular dysfunction after AMI, and in phase II studies, IL-1 blockade quenched the inflammatory response associated with ST-segment elevation AMI and prevented HF. In patients with established HF, IL-1 is thought to impair beta-adrenergic receptor signalling and intracellular calcium handling. Phase II studies in patients with HF show improved exercise capacity with IL-1 blockade. Thus, IL-1 blockade is poised to enter the clinical arena as an additional strategy to reduce the residual cardiovascular risk and/or address inflammatory cardiovascular conditions refractory to standard treatments. There are several IL-1 blockers available for clinical use, which differ in mechanism of action, and potentially also efficacy and safety. While IL-1 blockade is not immunosuppressive and not associated with opportunistic infections or an increased risk of cancer, fatal infections may occur more frequently while on treatment with IL-1 blockers likely due to a blunting of the inflammatory signs of infection leading to delayed presentation and diagnosis. We discuss the practical use of IL-1 blockade, including considerations for patient selection and safety monitoring. Interleukin-1, Inflammation, Coronary artery disease, Heart failure Introduction Despite the improvements in preventive, diagnostic, and therapeutic strategies, patients with cardiovascular disease (CVD) retain elevated inflammation-mediated residual risk for recurrent events.1 Cytokines are soluble signalling proteins that regulate the inflammatory response to host invasion and tissue injury by directing the intercellular response—interleukins. Interleukin-1 (IL-1) is the classic pro-inflammatory cytokine, occupying an apical role in the innate immune response.2 Heightened IL-1 activity contributes to the pathogenesis of several pro-inflammatory conditions, and, more recently, has been linked to CVD. In this review, we highlight the key advances in experimental and clinical IL-1 research and discuss the practical application of IL-1 blockade in clinical care. Since abundant evidence is available to define the role of IL-1 in atherosclerotic CVD and heart failure (HF), we focus this review on these areas and refer the reader to other reviews on the expanding investigation of IL-1 in other cardiovascular conditions, including pericarditis, cardiac arrhythmias, and valvular disease.3–5 Pharmacologic Interleukin-1 blockers IL-1 exists in two isoforms: IL-1α, a membrane-bound, autocrine, and paracrine messenger, and IL-1β, a soluble, autocrine, paracrine, and endocrine messenger.2 Both isoforms bind the IL-1 receptor (type I) and recruit the accessory and adaptor proteins to amplify the inflammatory response through the disinhibition of the effects of I-κB of the nuclear factor κB.2 A naturally occurring soluble receptor antagonist [IL-1 receptor antagonist (Ra)], is produced alongside IL-1β, and also binds the IL-1 receptor but does not activate intracellular signalling pathways. Interleukin-1α acts primarily as an alarmin and initiates the inflammatory cascade, including the production of IL-1β, which in turn further amplifies the inflammatory response. In the acute phase, the surge in IL-1α contributes to infarct size, whereas in the sub-acute phases IL-1β becomes the main cytokine responsible for cardiomyocyte apoptosis, adverse cardiac remodelling and HF. The interest in IL-1β as a therapeutic target over past decades has led to the development of several IL-1 blockers, including a recombinant human IL-1Ra, two human monoclonal antibodies, and one soluble decoy receptor (Table 1). None of IL-1 blockers have an indication for CVD at the present time, although an indication-seeking trial for canakinumab (Ilaris®) has been completed and published.6 Table 1 Pharmacologic Interleukin-1 blockers in cardiovascular clinical trials Agent  Mechanism  Blockade of   Dose tested  Frequency  Clinical condition(s)  Notes  IL-1α  IL-1β  IL-1Ra  Anakinra  Recombinant human receptor antagonist  Y  Y  N  100 mg  Once–twice daily  STEMI, NSTEMI, HFrEF, HFpEF  Flexible dose adjustment and rapid offset and onset but frequent injections  Canakinumab  Human monoclonal antibody  N  Y  N  50, 150, and 300 mg  Every 3  months  Prior myocardial infarction  Infrequent injections but slow offset  Gevokizumab  Humanized monoclonal antibody  N  Y  N  30 mg  Monthly  Not studied in clinical trials  U-shaped dose–response curve, gevokizumab-bound IL-1 retains agonist activity in preclinical studies  Rilonacept  Soluble IL-1R1-AcP as decoy protein  Y  Y  Y  320 mg  Every other week  Not studied in clinical trials  U-shaped dose–response curve in preclinical studies  Agent  Mechanism  Blockade of   Dose tested  Frequency  Clinical condition(s)  Notes  IL-1α  IL-1β  IL-1Ra  Anakinra  Recombinant human receptor antagonist  Y  Y  N  100 mg  Once–twice daily  STEMI, NSTEMI, HFrEF, HFpEF  Flexible dose adjustment and rapid offset and onset but frequent injections  Canakinumab  Human monoclonal antibody  N  Y  N  50, 150, and 300 mg  Every 3  months  Prior myocardial infarction  Infrequent injections but slow offset  Gevokizumab  Humanized monoclonal antibody  N  Y  N  30 mg  Monthly  Not studied in clinical trials  U-shaped dose–response curve, gevokizumab-bound IL-1 retains agonist activity in preclinical studies  Rilonacept  Soluble IL-1R1-AcP as decoy protein  Y  Y  Y  320 mg  Every other week  Not studied in clinical trials  U-shaped dose–response curve in preclinical studies  HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction. Table 1 Pharmacologic Interleukin-1 blockers in cardiovascular clinical trials Agent  Mechanism  Blockade of   Dose tested  Frequency  Clinical condition(s)  Notes  IL-1α  IL-1β  IL-1Ra  Anakinra  Recombinant human receptor antagonist  Y  Y  N  100 mg  Once–twice daily  STEMI, NSTEMI, HFrEF, HFpEF  Flexible dose adjustment and rapid offset and onset but frequent injections  Canakinumab  Human monoclonal antibody  N  Y  N  50, 150, and 300 mg  Every 3  months  Prior myocardial infarction  Infrequent injections but slow offset  Gevokizumab  Humanized monoclonal antibody  N  Y  N  30 mg  Monthly  Not studied in clinical trials  U-shaped dose–response curve, gevokizumab-bound IL-1 retains agonist activity in preclinical studies  Rilonacept  Soluble IL-1R1-AcP as decoy protein  Y  Y  Y  320 mg  Every other week  Not studied in clinical trials  U-shaped dose–response curve in preclinical studies  Agent  Mechanism  Blockade of   Dose tested  Frequency  Clinical condition(s)  Notes  IL-1α  IL-1β  IL-1Ra  Anakinra  Recombinant human receptor antagonist  Y  Y  N  100 mg  Once–twice daily  STEMI, NSTEMI, HFrEF, HFpEF  Flexible dose adjustment and rapid offset and onset but frequent injections  Canakinumab  Human monoclonal antibody  N  Y  N  50, 150, and 300 mg  Every 3  months  Prior myocardial infarction  Infrequent injections but slow offset  Gevokizumab  Humanized monoclonal antibody  N  Y  N  30 mg  Monthly  Not studied in clinical trials  U-shaped dose–response curve, gevokizumab-bound IL-1 retains agonist activity in preclinical studies  Rilonacept  Soluble IL-1R1-AcP as decoy protein  Y  Y  Y  320 mg  Every other week  Not studied in clinical trials  U-shaped dose–response curve in preclinical studies  HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction. Anakinra (Kineret®) is a recombinant human IL-1Ra and therefore blocks IL-1α and IL-1β. Anakinra has a half-life of 4–6 h and is administered subcutaneously once daily for the treatment of rheumatoid arthritis, juvenile arthritis, and gouty arthritis. Anakinra is also approved for cryopyrin-associated period syndromes (CAPS), rare genetic syndromes characterized by enhanced NLRP3 inflammasome activity resulting in elevated IL-1β levels. In CAPS, the recommended anakinra dose is 1 mg/kg, but it is often uptitrated to response. Anakinra’s short half-life may be advantageous as doses can be up- or down-titrated on a daily basis and, if an adverse effect occurs, the drug is cleared from circulation within 24 h. However, subcutaneous injection of anakinra causes local injection site reactions such as pain and erythema in ∼20% of patients that lead to discontinuation in ∼5%. Canakinumab (Ilaris®) is a humanized monoclonal antibody against IL-1β and does not block IL-1α. Canakinumab is approved for the treatment of CAPS and juvenile arthritis. Canakinumab requires infrequent once monthly dosing and is suitable for chronic use. The long duration of action, however, may not be advantageous when managing side effects. Rilonacept (Arcalyst®) is a chimeric recombinant form of IL-1 receptor and receptor accessory protein, functioning as a soluble decoy that binds IL-1α, IL-1β, and IL-1ra. Rilonacept is approved for the treatment of CAPS and is administered as a subcutaneous injection every 2 weeks. In pre-clinical studies of experimental acute myocardial infarction (AMI), rilonacept has shown an undesirable U-shaped dose–response curve.7 Gevokizumab is a humanized monoclonal antibody against IL-1β that has residual agonistic activity and a U-shaped dose–response curve. The clinical development of gevokizumab has been halted. Recent advances in understanding the upstream regulators of IL-1 production have led to the development of several inhibitors of the NLRP3 inflammasome, an intracellular macromolecular complex that allows the formation of pro-caspase-1 dimers and autocleavage leading to active caspase, and the conversion of pro-IL-1β to mature IL-1β.8 Several novel inflammasome inhibitors that block the ATPase activity of NLRP3 [BAY 11-7082, INF4E, and OLT1177 (dapansutrile)] or prevent NLRP3 oligomerization (OLT1177, 16673-34-0, and MCC950) are under development. Colchicine also appears to prevent NLRP3 triggering by blocking opening of the membrane P2X7 receptor and polymerization of the ASC domain of the inflammasome. The interested reader is referred to a recent in-depth review of the NLRP3 inflammasome in myocardial infarction.8 Atherosclerosis Experimental pre-clinical evidence shows that IL-1 both initiates and propagates the formation, growth, and rupture of vascular atherosclerotic plaques (Figure 1).9–12 IL-1 impairs vasodilation, increases oxidative stress, and increases procoagulant mediators, predisposing to atherothrombosis.13–15 Interleukin-6, which regulates pro-inflammatory and procoagulant signals, is produced in response to IL-1.16 Atherosclerotic plaques are capable of producing IL-1 and further enhancing disease progression.17 Histology studies demonstrate the presence of IL-1β in human atherosclerotic plaques.18 Interleukin-1 and IL-1ra predict atherosclerotic outcomes.19 Several epidemiologic studies have established a strong relationship between increasing risk for atherosclerotic disease and increasing levels of C-reactive protein (CRP), whose levels appear to closely reflect the amount of active IL-1 signalling and are reduced by the use of IL-1 blockers in a variety of inflammatory diseases.20,21 Figure 1 View largeDownload slide Interleukin-1 in coronary atherosclerosis. A variety of experimental and clinical evidence points to interleukin-1 as a key modulator of the development and progression of coronary atherosclerosis. Cell and animal models provided evidence of the key pathways involved in inflammatory atherosclerosis. The ‘inflammatory hypothesis of atherosclerosis’ was subsequently tested in the CANTOS trial in which it was proven that an anti-inflammatory therapy targeting interleukin-1 prevented recurrent cardiovascular events in high-risk patients. Ongoing pre-clinical research and early phase clinical trials are focused on expanding the field by elucidating the role of interleukin-1α in the initiation of post-infarction myocardial inflammation as well as the role of interleukin-1β in adverse cardiac remodeling after myocardial infarction and heart failure. Inhibition of the NLRP3 inflammasome appears to be a promising strategy. Additional studies are however needed to better characterize the differences between the various interleukin-1 blocking strategies. Figure 1 View largeDownload slide Interleukin-1 in coronary atherosclerosis. A variety of experimental and clinical evidence points to interleukin-1 as a key modulator of the development and progression of coronary atherosclerosis. Cell and animal models provided evidence of the key pathways involved in inflammatory atherosclerosis. The ‘inflammatory hypothesis of atherosclerosis’ was subsequently tested in the CANTOS trial in which it was proven that an anti-inflammatory therapy targeting interleukin-1 prevented recurrent cardiovascular events in high-risk patients. Ongoing pre-clinical research and early phase clinical trials are focused on expanding the field by elucidating the role of interleukin-1α in the initiation of post-infarction myocardial inflammation as well as the role of interleukin-1β in adverse cardiac remodeling after myocardial infarction and heart failure. Inhibition of the NLRP3 inflammasome appears to be a promising strategy. Additional studies are however needed to better characterize the differences between the various interleukin-1 blocking strategies. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)6 randomized 10 061 patients with prior AMI and evidence of systemic inflammation, defined as a CRP level of at least 2 mg/L, to either placebo or canakinumab 50, 150, or 300 mg every 3 months. The primary endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death was reduced by 15% in the canakinumab 150-mg treated patients compared to placebo [hazard ratio (HR) 0.85, 95% confidence interval (95% CI) 0.74–0.98; P = 0.021] over 48 months of follow-up. In the 300-mg canakinumab group, the primary endpoint was similarly reduced (HR 0.86, 95% CI 0.75–0.99; P = 0.031), but this difference was not considered statistically significant after multiple testing adjustments. There was no significant difference in the primary endpoint between the 50-mg canakinumab group and placebo. Canakinumab 150-mg also reduced the in need for coronary revascularization (HR 0.83; 95% CI 0.73–0.95; P = 0.005). These definitive results show that IL-1β blockade with canakinumab in patients with stable atherosclerotic CVD prevents recurrent cardiovascular events.22 The benefit seems also to be closely related to the inflammatory response, as patients showing the greatest reduction in CRP had improved survival with canakinumab.23 Acute myocardial infarction Unopposed IL-1 activity also impairs myocardial healing and favours cardiac rupture in experimental acute myocardial infarction (AMI) (Figure 1).24 IL-1 activates haematopoietic stem cell proliferation and mobilization in AMI.25 Adverse cardiac remodelling after AMI is limited by blockade of IL-1 signalling. The very early rise in IL-1 activity appears to be driven by IL-1α isoform rather than IL-1β.26,27 IL-1β blockade improves post-infarction healing.28 Patients with ST-segment elevation myocardial infarction (STEMI) show an intense inflammatory response, reflected in a classic rise and fall of inflammatory markers. The intensity of inflammatory response predicts worse outcomes including cardiac rupture and incidence of HF.29 Fourteen days of anakinra treatment in 40 patients with STEMI reduced area under the curve for CRP, and showed a signal for reduced progression to HF vs. placebo in the VCU-ART pilot studies.30–32 An ongoing clinical trial is investigating whether a higher doses of anakinra provides greater suppression of the inflammatory response after STEMI (NCT01950299). In the MRC-ILA-Heart study of 182 patients with non-ST-segment elevation myocardial infarction (NSTEMI), IL-1 blockade with anakinra also reduced CRP levels at 7 days after non-ST-segment elevation acute coronary syndrome but failed to improve clinical outcomes.33 After an initial significant suppression of CRP levels, there was an increase after treatment discontinuation in the anakinra arm.34 A similar pattern was seen also in the REDHART and DHART2 trials in which anakinra was given for 2 or 12 weeks for HF.35,36 This increase of CRP after stopping anakinra has been referred to as rebound, but the expression appears only partially correct, since the values don’t appear to rebound to the same values as prior to treatment or higher, but rather settle for a lesser degree of reduction and therefore likely reflects loss of inhibition with stopping anakinra while the stimuli for inflammation are still present. A recent sub-analysis of the MRC-ILA heart data has shown that those patients considered to have had a ‘rebound’ were actually the ones who had a lesser response to anakinra in the first place, thus suggesting that these patients are cases of incomplete inhibition.34 Heart failure Heart failure is a condition of chronic systemic inflammation. Chronic hypoxia and low-grade cell death signals stimulate IL-1 production in the failing heart.37 The ability of IL-1 to directly modulate cardiomyocyte contractility has been long recognized, and IL-1 has been considered to be one of the ‘soluble cardiodepressant factors’ in sepsis.38 IL-1 impairs β-adrenergic receptor signalling downstream of the receptor by multiple mechanisms related to cytoplasmic calcium handling (Figure 2).38 IL-1 also increases cardiomyocyte anaerobic glycolysis.39 Importantly, the negative inotropic effects of IL-1 are reversible.40 IL-1 interferes also with active relaxation and diastolic function.41 IL-1 blockade appears to restore calcium homeostasis through removal of a negative regulator (i.e., IL-1), in contrast to available inotropes, which increase intracellular calcium levels, predispose to arrhythmias, and increase oxygen consumption.42 Figure 2 View largeDownload slide Interleukin-1 and cardiac contractility. A complex interplay between subcellular components mediates cardiac dysfunction due to interleukin-1. Through an effect on gene transcription and/or a direct signalling cascade through the interleukin-1 receptor's toll-interleukin-1 receptor domain, interleukin-1 interferes primarily with downstream β-adrenergic signalling pathways, including G-protein-adenylyl cyclase interactions, L-type calcium channel function, and sarcoplasmic reticulum calcium handling. Figure 2 View largeDownload slide Interleukin-1 and cardiac contractility. A complex interplay between subcellular components mediates cardiac dysfunction due to interleukin-1. Through an effect on gene transcription and/or a direct signalling cascade through the interleukin-1 receptor's toll-interleukin-1 receptor domain, interleukin-1 interferes primarily with downstream β-adrenergic signalling pathways, including G-protein-adenylyl cyclase interactions, L-type calcium channel function, and sarcoplasmic reticulum calcium handling. Several clinical studies have demonstrated heightened IL-1 activity in chronic HF. Circulating IL-1β and IL-1Ra levels increase as the severity of HF symptoms worsens.43 Increased circulating levels of IL-6, a surrogate for IL-1 activity, predict HF events, and death.44 C-reactive protein level predicts the onset of new HF and correlates with exercise capacity in patients with systolic HF.45,46 In a pilot study in 80 patients with rheumatoid arthritis and with (n = 20) or without coronary artery disease (n = 60), anakinra improved left ventricular contractility and relaxation as measured by tissue Doppler echocardiography.47 In an initial open label study of seven patients with chronic systolic HF and elevated CRP (> 2 mg/L), anakinra given for 14 days significantly reduced CRP levels by 84% and improved peak oxygen consumption.48 When administered to 30 patients with acute decompensated HF in a double-blind randomized controlled trial (RCT), anakinra 100 mg twice daily for 3 days, and then daily for 11 days significantly reduced the acute inflammatory response, compared with placebo.49 In a separate trial of 60 patients with acute decompensated HF, anakinra started within 2 weeks of discharge and continued for 12 weeks improved peak oxygen consumption, quality-of-life, and NTproBNP levels.36 In a cross-over trial of 12 patients with HF with preserved left ventricular ejection fraction (LVEF) and diastolic dysfunction, anakinra led to a small yet significant improvement in peak oxygen consumption.50 A follow-up RCT in 30 patients with showed a significant improvement in quality-of-life, treadmill exercise time, and a reduction in NTproBNP levels, but no change in peak oxygen consumption.35 The absence of significant changes in peak oxygen consumption may be attributed to the effect of concomitant skeletal muscle dysfunction on cardiorespiratory fitness in patients with HFpEF and severe obesity. The outcomes of IL-1 blockers in HF are substantially different from previous clinical attempts with other anti-inflammatory treatments. The tumour necrosis factor-α (TNF-α) monoclonal blocking antibody infliximab failed to improve outcomes in patients in systolic HF.51 Of note, infliximab increased, rather than decreased, CRP levels. A dose–response relationship was observed between higher doses and longer treatment duration and worse outcomes, including an increased risk of death.51 There is little overlap between IL-1 and TNF-α signalling pathways as each are regulated by different gene families and different receptors and adaptor proteins.38 Whereas IL-1 binds a single receptor, TNF-α binds two separate receptors that induce opposing effects, with one receptor promoting survival and the other cell death. Safety profile of Interleukin-1 blockers While IL-1 blockers are generally well tolerated, and without direct organ toxicity, their use can complicate the presentation and clinical course of an infection, and they have been associated with an excess of infection-related deaths.6 IL-1 blockers reduce the leucocyte and neutrophil counts, but rarely to the level of severe neutropenia (<500/mm3), and the leucocyte cell count does not appear to correlate with the risk of infection. The use of IL-1 blockers is not associated with an increased risk of opportunistic infection. The mechanism(s) by which IL-1 blockers increase fatal infection risk is most likely related to blunting of the local and systemic inflammatory response to infection (i.e. redness, swelling, fever), which masks the presence of infection and may delay diagnosis and treatment. Importantly, the excess risk of fatal infection with IL-1 blockade is rather small in absolute terms. In more than 30 000 patient-years of treatment in CANTOS, there was an excess of only 1.3 fatal infections per 1000 patient-years (number needed to harm 769).6 Of note the overall number of serious infections and of serious adverse events of any cause was not increased with canakinumab. This small excess in infection-related fatalities over a median of 3.7 years of treatment and >30 000 patient-years indicates that IL-1 blockade does not interfere with healing from infection in the great majority of cases.6 This safety profile is consistent with the data of very high-dose anakinra infusion in sepsis which showed no excess mortality or harm vs. placebo52,53 and a signal for benefit in those patients with more aggressive sepsis.54 In registry studies, the concomitant use of IL-1 blockade as an add-on to immunosuppressants such as prednisone and/or methotrexate in patients with rheumatoid arthritis is associated with increased risk of serious infections.55 The risk of infection is substantially higher for TNF-α blockers compared to IL-1 blockers, including a several-fold increased risk of opportunistic and fungal infections, including tuberculosis, pneumocystis, and aspergillosis.55,56 TNF-α blockers are also associated with an increased risk of cancer, primarily haematologic,57 whereas IL-1 blockers are not. IL-1β blockade with canakinumab showed a dose–dependent reduction in the incidence of lung cancer and in cancer-related mortality.58 Use of interleukin-1 blockade in clinical practice IL-1 blockade targets a novel causal pathway of CVD that provides incremental benefit beyond optimal medical therapy. The potential reductions in CVD are great, yet as with any clinical decision, the risks and benefits must be weighed on an individual basis to identify optimal candidates for IL-1 blockade. Clinical trials of IL-1 blockers in CVD are summarized in Table 2 and Figure 3. Table 2 Clinical trials of interleukin-1 blockers in cardiovascular disease Study  Year(s)  Patients  Study design and strategy  Main finding(s)  References  VCU-ART VCU-ART2  2010 2013  ST-segment elevation MI (n = 10) (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg or placebo daily for 14 days  Reductions in CRP Trend toward reduced heart failure Ongoing clinical trial exploring two anakinra dosing regimens  30–32  AIR-HF  2012  Stable NYHA II–III HF with LVEF < 50% and CRP > 2 mg/L (n = 10)  Single-arm anakinra 100 mg daily for 14 days  Reduction in CRP Improved aerobic exercise capacity and ventilatory efficiency  48  DHART  2014  Stable NYHA II–III HF with LVEF > 50% and CRP > 2 mg/L (n = 12)  Double-blinded placebo-controlled cross-over anakinra 100 mg daily or placebo for 14 days  Reduction in CRP Improvement in peak aerobic exercise capacity and quality-of-life at 2 weeks  50  MRC-ILA Heart Study  2015  Non-ST-segment elevation MI (n = 182)  Double-blind, placebo-controlled RCT anakinra 100 mg once daily for 14 days  Reduction in CRP No differences in major adverse cardiac events at 30 days and 3 months Excess events at 12 months in the anakinra-treated group  33  ADHF  2016  Acute decompensated systolic HF with CRP > 5 mg/L (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg twice daily for 72 h then 100 mg once daily for 11 days or placebo  Reduction in CRP at 72 h and 14 days Trend toward more favourable effects on congestion and left ventricular ejection fraction with anakinra  49  AIRTRIP  2016  Idiopathic pericarditis with CRP > 10 mg/L, colchicine-refractory, steroid-dependent and at least three prior recurrences (n = 21)  Anakinra 2 mg/kg daily up to 100 mg for 2 months (open-label) then anakinra or placebo withdrawal trial for 6 months (double-blind, placebo-controlled RCT)  Anakinra reduced recurrent pericarditis and increased flare-free survival  61  REDHART  2017  Recently decompensated HF with LVEF < 50% and CRP > 2 mg/L (within 2 weeks of hospital discharge) (n = 60)  Double-blind, placebo-controlled RCT of anakinra 100 mg daily for 2 weeks or for 12 weeks or placebo for 12 weeks (1:1:1 ratio)  Reduction in CRP levels Improvement in aerobic exercise capacity and quality-of-life with 12-week anakinra Trend toward reduced heart failure readmissions at 6 months with 12-week anakinra  36  CANTOS  2017  Prior AMI with CRP > 2 mg/L (at least 30 days after AMI) (n = 10060)  Double-blind, placebo-controlled RCT of canakinumab 50, 150, or 300 mg or placebo (1:1:1:1.5 ratio)  Reduction in the incidence of the composite endpoint of cardiac death, non-fatal AMI or non-fatal stroke with canakinumab 150 mg vs. placebo  6  Study  Year(s)  Patients  Study design and strategy  Main finding(s)  References  VCU-ART VCU-ART2  2010 2013  ST-segment elevation MI (n = 10) (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg or placebo daily for 14 days  Reductions in CRP Trend toward reduced heart failure Ongoing clinical trial exploring two anakinra dosing regimens  30–32  AIR-HF  2012  Stable NYHA II–III HF with LVEF < 50% and CRP > 2 mg/L (n = 10)  Single-arm anakinra 100 mg daily for 14 days  Reduction in CRP Improved aerobic exercise capacity and ventilatory efficiency  48  DHART  2014  Stable NYHA II–III HF with LVEF > 50% and CRP > 2 mg/L (n = 12)  Double-blinded placebo-controlled cross-over anakinra 100 mg daily or placebo for 14 days  Reduction in CRP Improvement in peak aerobic exercise capacity and quality-of-life at 2 weeks  50  MRC-ILA Heart Study  2015  Non-ST-segment elevation MI (n = 182)  Double-blind, placebo-controlled RCT anakinra 100 mg once daily for 14 days  Reduction in CRP No differences in major adverse cardiac events at 30 days and 3 months Excess events at 12 months in the anakinra-treated group  33  ADHF  2016  Acute decompensated systolic HF with CRP > 5 mg/L (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg twice daily for 72 h then 100 mg once daily for 11 days or placebo  Reduction in CRP at 72 h and 14 days Trend toward more favourable effects on congestion and left ventricular ejection fraction with anakinra  49  AIRTRIP  2016  Idiopathic pericarditis with CRP > 10 mg/L, colchicine-refractory, steroid-dependent and at least three prior recurrences (n = 21)  Anakinra 2 mg/kg daily up to 100 mg for 2 months (open-label) then anakinra or placebo withdrawal trial for 6 months (double-blind, placebo-controlled RCT)  Anakinra reduced recurrent pericarditis and increased flare-free survival  61  REDHART  2017  Recently decompensated HF with LVEF < 50% and CRP > 2 mg/L (within 2 weeks of hospital discharge) (n = 60)  Double-blind, placebo-controlled RCT of anakinra 100 mg daily for 2 weeks or for 12 weeks or placebo for 12 weeks (1:1:1 ratio)  Reduction in CRP levels Improvement in aerobic exercise capacity and quality-of-life with 12-week anakinra Trend toward reduced heart failure readmissions at 6 months with 12-week anakinra  36  CANTOS  2017  Prior AMI with CRP > 2 mg/L (at least 30 days after AMI) (n = 10060)  Double-blind, placebo-controlled RCT of canakinumab 50, 150, or 300 mg or placebo (1:1:1:1.5 ratio)  Reduction in the incidence of the composite endpoint of cardiac death, non-fatal AMI or non-fatal stroke with canakinumab 150 mg vs. placebo  6  AMI, acute myocardial infarction; CRP, C-reactive protein; HF, heart failure; IL, interleukin; NYHA, New York Heart Association. Table 2 Clinical trials of interleukin-1 blockers in cardiovascular disease Study  Year(s)  Patients  Study design and strategy  Main finding(s)  References  VCU-ART VCU-ART2  2010 2013  ST-segment elevation MI (n = 10) (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg or placebo daily for 14 days  Reductions in CRP Trend toward reduced heart failure Ongoing clinical trial exploring two anakinra dosing regimens  30–32  AIR-HF  2012  Stable NYHA II–III HF with LVEF < 50% and CRP > 2 mg/L (n = 10)  Single-arm anakinra 100 mg daily for 14 days  Reduction in CRP Improved aerobic exercise capacity and ventilatory efficiency  48  DHART  2014  Stable NYHA II–III HF with LVEF > 50% and CRP > 2 mg/L (n = 12)  Double-blinded placebo-controlled cross-over anakinra 100 mg daily or placebo for 14 days  Reduction in CRP Improvement in peak aerobic exercise capacity and quality-of-life at 2 weeks  50  MRC-ILA Heart Study  2015  Non-ST-segment elevation MI (n = 182)  Double-blind, placebo-controlled RCT anakinra 100 mg once daily for 14 days  Reduction in CRP No differences in major adverse cardiac events at 30 days and 3 months Excess events at 12 months in the anakinra-treated group  33  ADHF  2016  Acute decompensated systolic HF with CRP > 5 mg/L (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg twice daily for 72 h then 100 mg once daily for 11 days or placebo  Reduction in CRP at 72 h and 14 days Trend toward more favourable effects on congestion and left ventricular ejection fraction with anakinra  49  AIRTRIP  2016  Idiopathic pericarditis with CRP > 10 mg/L, colchicine-refractory, steroid-dependent and at least three prior recurrences (n = 21)  Anakinra 2 mg/kg daily up to 100 mg for 2 months (open-label) then anakinra or placebo withdrawal trial for 6 months (double-blind, placebo-controlled RCT)  Anakinra reduced recurrent pericarditis and increased flare-free survival  61  REDHART  2017  Recently decompensated HF with LVEF < 50% and CRP > 2 mg/L (within 2 weeks of hospital discharge) (n = 60)  Double-blind, placebo-controlled RCT of anakinra 100 mg daily for 2 weeks or for 12 weeks or placebo for 12 weeks (1:1:1 ratio)  Reduction in CRP levels Improvement in aerobic exercise capacity and quality-of-life with 12-week anakinra Trend toward reduced heart failure readmissions at 6 months with 12-week anakinra  36  CANTOS  2017  Prior AMI with CRP > 2 mg/L (at least 30 days after AMI) (n = 10060)  Double-blind, placebo-controlled RCT of canakinumab 50, 150, or 300 mg or placebo (1:1:1:1.5 ratio)  Reduction in the incidence of the composite endpoint of cardiac death, non-fatal AMI or non-fatal stroke with canakinumab 150 mg vs. placebo  6  Study  Year(s)  Patients  Study design and strategy  Main finding(s)  References  VCU-ART VCU-ART2  2010 2013  ST-segment elevation MI (n = 10) (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg or placebo daily for 14 days  Reductions in CRP Trend toward reduced heart failure Ongoing clinical trial exploring two anakinra dosing regimens  30–32  AIR-HF  2012  Stable NYHA II–III HF with LVEF < 50% and CRP > 2 mg/L (n = 10)  Single-arm anakinra 100 mg daily for 14 days  Reduction in CRP Improved aerobic exercise capacity and ventilatory efficiency  48  DHART  2014  Stable NYHA II–III HF with LVEF > 50% and CRP > 2 mg/L (n = 12)  Double-blinded placebo-controlled cross-over anakinra 100 mg daily or placebo for 14 days  Reduction in CRP Improvement in peak aerobic exercise capacity and quality-of-life at 2 weeks  50  MRC-ILA Heart Study  2015  Non-ST-segment elevation MI (n = 182)  Double-blind, placebo-controlled RCT anakinra 100 mg once daily for 14 days  Reduction in CRP No differences in major adverse cardiac events at 30 days and 3 months Excess events at 12 months in the anakinra-treated group  33  ADHF  2016  Acute decompensated systolic HF with CRP > 5 mg/L (n = 30)  Double-blind, placebo-controlled RCT anakinra 100 mg twice daily for 72 h then 100 mg once daily for 11 days or placebo  Reduction in CRP at 72 h and 14 days Trend toward more favourable effects on congestion and left ventricular ejection fraction with anakinra  49  AIRTRIP  2016  Idiopathic pericarditis with CRP > 10 mg/L, colchicine-refractory, steroid-dependent and at least three prior recurrences (n = 21)  Anakinra 2 mg/kg daily up to 100 mg for 2 months (open-label) then anakinra or placebo withdrawal trial for 6 months (double-blind, placebo-controlled RCT)  Anakinra reduced recurrent pericarditis and increased flare-free survival  61  REDHART  2017  Recently decompensated HF with LVEF < 50% and CRP > 2 mg/L (within 2 weeks of hospital discharge) (n = 60)  Double-blind, placebo-controlled RCT of anakinra 100 mg daily for 2 weeks or for 12 weeks or placebo for 12 weeks (1:1:1 ratio)  Reduction in CRP levels Improvement in aerobic exercise capacity and quality-of-life with 12-week anakinra Trend toward reduced heart failure readmissions at 6 months with 12-week anakinra  36  CANTOS  2017  Prior AMI with CRP > 2 mg/L (at least 30 days after AMI) (n = 10060)  Double-blind, placebo-controlled RCT of canakinumab 50, 150, or 300 mg or placebo (1:1:1:1.5 ratio)  Reduction in the incidence of the composite endpoint of cardiac death, non-fatal AMI or non-fatal stroke with canakinumab 150 mg vs. placebo  6  AMI, acute myocardial infarction; CRP, C-reactive protein; HF, heart failure; IL, interleukin; NYHA, New York Heart Association. Figure 3 View largeDownload slide Cardiovascular clinical trials of interleukin-1 blockade. (A–D) show results from CANTOS (n = 10061), combined VCU-ART/VCU-ART2 (n = 40), MRC-ILA Heart (n = 182), and REDHART (n = 60). While the effects of interleukin-1 blockade in patients with prior myocardial infarction has been studied in the landmark CANTOS, the pilot studies of interleukin-1 blockade in patients with acute myocardial infarction (VCU-ART series, MRC-ILA) and with heart failure (REDHART) have included only a small number of patients, and thus these findings require validation in further and larger studies. CI, confidence interval; HR, hazard ratio; MI, myocardial infarction. Figure 3 View largeDownload slide Cardiovascular clinical trials of interleukin-1 blockade. (A–D) show results from CANTOS (n = 10061), combined VCU-ART/VCU-ART2 (n = 40), MRC-ILA Heart (n = 182), and REDHART (n = 60). While the effects of interleukin-1 blockade in patients with prior myocardial infarction has been studied in the landmark CANTOS, the pilot studies of interleukin-1 blockade in patients with acute myocardial infarction (VCU-ART series, MRC-ILA) and with heart failure (REDHART) have included only a small number of patients, and thus these findings require validation in further and larger studies. CI, confidence interval; HR, hazard ratio; MI, myocardial infarction. Patients with residual inflammatory risk as indicated by CRP levels >2 mg/L are at increased risk for adverse CVD events in primary and secondary prevention.59,60 Clinical trials of IL-1 blockers have primarily targeted patients with elevated CRP. Following the CANTOS trial, canakinumab is being considered for secondary CVD prevention of patients with prior AMI and CRP > 2 mg/L. An analysis of the CANTOS trial showed that those patients who were ‘responders’ to treatment, achieving CRP < 2 mg/L at 3 months, had significantly less adverse cardiac events including reduced mortality compared to placebo or non-responders.23 This indication implies that patients with a prior AMI should be screened for elevated CRP levels. Prior to treatment with an IL-1 blocker, acute or chronic infection should be ruled out in each patient. In addition, clinicians should assess risk factors for infection and, based upon patient characteristics, may consider testing for undiagnosed infection, such as latent tuberculosis, or for risk factors for infection, such as immunodeficiency or intravenous drug use. The prescribing information for Canakinumab (Ilaris) in the USA approved by the Food & Drug Administration contains a general warning common to all immunomodulatory drugs advising to screen for latent tuberculosis using one of the strategies recommended by the Center for Disease Control. Such strict recommendation is lacking in the prescribing information for Canakinumab approved by the European Medicine Agency. If the patient has an active acute or chronic infection, the potential benefits of treatment need to be weighed against the risks of masking the signs of progression of the infection. Anakinra has been used successfully in patients with chronic or recurrent pericarditis, in particular those refractory to non-steroidal anti-inflammatory drugs and colchicine and in many cases corticosteroid-dependent. In such cases, anakinra 100 mg daily has been used to control symptoms and wean corticosteroids.5,61 Clinicians should monitor patients for signs and symptoms of infection at each clinic visit and be cognizant of IL-1 blockade’s anti-inflammatory effects that may prevent the patient from presenting with local and systemic symptoms and signs of infection, fever, or leucocytosis. As such, patients should be educated on the need to rely on other symptoms or signs of infection and seek help if an infection is suspected. Patients should also be instructed to relay the information of chronic IL-1 blocker use to a new provider if being evaluated for a possible infection. Routine measuring of leucocyte count is not warranted since severe leucopenia requiring discontinuation has not been observed, and leucopenia does not appear to represent the mechanism(s) by which IL-1 blockers increase fatal infection risk. In patients who develop an acute infection while being treated with a short-acting IL-1 blocker (anakinra), we recommend suspension of the IL-1 blocker until complete resolution of the infection, due to the fact that continuation of the treatment may interfere with the clinical assessment. Patients on an intermediate- or long-acting IL-1 blocker (rilonacept or canakinumab) who are scheduled to receive the next dose while an infection is active should have the next dose delayed until the infection is resolved. Standard management for infection should be provided to patients with acute infections. In patients who develop chronic infection, repeated infections or become chronically immunocompromised due to illness or medications, permanent discontinuation of IL-1 blockers should be considered. Conclusions A considerable body of evidence implicates IL-1 in the pathophysiology of CVD. IL-1 blockade reduces recurrent atherosclerotic cardiovascular events in patients with prior AMI and elevated CRP levels. In patients with STEMI and acute decompensated HF, IL-1 blockade blunts the acute inflammatory response, and in patients with chronic HF IL-1 blockade improves peak aerobic exercise capacity. There are currently four clinically available IL-1 blockers, each with a different efficacy and safety profile. As a class, IL-1 blockers prevent typical symptoms and signs of inflammation associated with infections and may delay the diagnosis and/or interfere with the prognostic assessment of patients with infection. As a result, infections in patients on IL-1 blockade can have a serious and/or fatal presentation. As IL-1 blockade becomes incorporated into standard of care for a variety of CVDs, cardiovascular clinicians must become experts in the management of biologic IL-1 blockers. 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JAMA  2016; 316: 1906– 1912. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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European Heart JournalOxford University Press

Published: Mar 23, 2018

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