Canakinumab Anti-inflammatory Thrombosis Outcomes Study Research Articles

Inflammation and coronary artery disease: from pathophysiology to Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS).

The worldwide prevalence of cardiovascular disease in general and atherosclerotic coronary artery disease in particular is a health and economic concern of unparalleled proportion. Despite a long history of astute observations beginning in 1575 made by Fallopius, followed by those of von Rokatansky, Virchow, Osler, and Ross, and incremental knowledge of the pathobiology of atherosclerosis to include varying stages of inflammation, response to internally and externally mediated vascular injury, and impaired homeostasis, gaps in the field's understanding persist. Here, we summarize the current scope of the problem for coronary artery disease, emerging constructs in its pathobiology and common clinical phenotypes, potentially useful biomarkers, clinical trials designed specifically to test the 'inflammation hypothesis' of disease, and the interface of pathobiology and precision medicine as a foundation for diagnosis, management, and future advances in the diagnosis, prognosis, natural history, prevention, and optimal management.

Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice.

Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. Although a prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, direct evidence of this is lacking. Therefore, we performed intervention studies on smooth muscle cell (SMC) lineage tracing Apoe−/− mice with advanced atherosclerosis using anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage number in the fibrous cap. There was also no change in lesion size and complete inhibition of beneficial outward remodeling. We also found that SMC-specific Il1r1 KO resulted in smaller lesions nearly devoid of SMC and a fibrous cap whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, results show that IL-1β promotes multiple beneficial changes in late-stage murine atherosclerosis including promoting outward remodeling and formation and maintenance of a SMC/collagen-rich fibrous cap.

Usefulness of Canakinumab to Improve Exercise Capacity in Patients With Long-Term Systolic Heart Failure and Elevated C-Reactive Protein

Interleukin-1β (IL-1β) is a cytokine involved in atherothrombosis and is known to depress cardiac function. We hypothesized that blocking IL-1β in patients with symptomatic systolic heart failure (HF) would improve their cardiorespiratory fitness. The purpose of the study was to measure changes in peak oxygen consumption (VO2) in 30 patients with prior myocardial infarction, high-sensitivity C-reactive protein ≥ 2 mg/l and HF with left ventricular ejection fraction (LVEF) < 50% enrolled in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) in an independent single center substudy. We measured peak VO2 before and after 3 and 12 months of treatment with Canakinumab every 3 months (50, 150, or 300mg subcutaneously) or placebo, and measured LVEF before and after 12 months. In December 2013, the CANTOS study announced early termination of enrollment, halting enrollment for this substudy after only 15 patients, of which 3 were assigned to placebo and 12 to Canakinumab (50mg [1; 7%], 150mg [5; 33%], 300mg [6; 40%]). Patients treated with Canakinumab had a significant improvement in peak VO2, from 19.2 to 22.8 ml/kg/min at 3 months (p = 0.023 within-group changes, p = 0.026 for time_x_group interaction versus placebo [primary end point]), and an improvement in LVEF 38% (33-43) to 44% (38-52) at 12 months (p = 0.012 for within-group changes). No significant changes were seen in the placebo group. In conclusion, the findings of this small prespecified secondary analysis of the CANTOS trial support the positive results of the overall study, and confirm IL-1 as a potential therapeutic target in HF. https://clinicaltrials.gov/ct2/show/NCT01900600.

Blood CSF1 and CXCL12 as Causal Mediators of Coronary Artery Disease

BackgroundIdentification of biomarkers that cause coronary artery disease (CAD) has led to important advances in prevention and treatment. Epidemiological analyses have identified many biomarker-CAD relationships; however, these associations may arise from reverse causation and/or confounding and therefore may not represent true causal associations. Mendelian randomization (MR) analyses overcome these limitations. ObjectivesThis study sought to identify causal mediators of CAD through a comprehensive screen of 237 biomarkers using MR. MethodsMR was performed by identifying genetic determinants of 227 biomarkers in ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial participants (N = 4,147) and combining these with genetic effects on CAD from the CARDIoGRAM consortium (60,801 cases and 123,504 controls). Blood concentrations of novel biomarkers identified by MR were then tested for association with incident major adverse cardiovascular events in ORIGIN. ResultsSix biomarkers were found to be causally linked to CAD after adjustment for multiple hypothesis testing. The causal role of 4 of these is well documented, whereas macrophage colony-stimulating factor 1 (CSF1) and stromal cell–derived factor 1 (CXCL12) have not previously been reported, to the best of our knowledge. MR analysis predicted an 18% higher risk of CAD per SD increase in CSF1 (odds ratio: 1.18; 95% confidence interval: 1.08 to 1.30; p = 2.1 × 10−4) and epidemiological analysis identified a 16% higher risk of major adverse cardiovascular events per SD (hazard ratio: 1.16; 95% confidence interval: 1.09 to 1.23; p < 0.001). Elevated CXCL12 levels were also identified as a causal risk factor for CAD with consistent epidemiological results. Furthermore, genetically predicted CSF1 and CXCL12 levels were associated with CAD in the UK Biobank (n = 343,735). ConclusionsThe study identified CSF1 and CXCL12 as causal mediators of CAD in humans. Understanding the mechanism by which these markers mediate CAD will provide novel insights into CAD and could lead to new approaches to prevention. These results support targeting inflammatory processes and macrophages, in particular, to prevent CAD, consistent with the recent CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study). (Outcome Reduction With Initial Glargine Intervention [ORIGIN]; NCT00069784)

Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis

Variants in the PLPP3 gene encoding for lipid phosphate phosphohydrolase 3 have been associated with susceptibility to atherosclerosis independently of classical risk factors. PLPP3 inactivates lysophosphatidic acid (LPA), a pro-inflammatory, pro-thrombotic product of phospholipase activity. Here we performed the first exploratory analysis of PLPP3, LPA, and LPA receptors (LPARs 1–6) in human atherosclerosis. PLPP3 transcript and protein were repressed when comparing plaques versus normal arteries and plaques from symptomatic versus asymptomatic patients, and they were negatively associated with risk of adverse cardiovascular events. PLPP3 localized to macrophages, smooth muscle, and endothelial cells (ECs) in plaques. LPAR 2, 5, and especially 6 showed increased expression in plaques, with LPAR6 localized in ECs and positively correlated to PLPP3. Utilizing in situ mass spectrometry imaging, LPA and its precursors were found in the plaque fibrous cap, co-localizing with PLPP3 and LPAR6. In vitro, PLPP3 silencing in ECs under LPA stimulation resulted in increased expression of adhesion molecules and cytokines. LPAR6 silencing inhibited LPA-induced cell activation, but not when PLPP3 was silenced simultaneously. Our results show that repression of PLPP3 plays a key role in atherosclerosis by promoting EC activation. Altogether, the PLPP3 pathway represents a suitable target for investigations into novel therapeutic approaches to ameliorate atherosclerosis.

NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis.

Inflammation is an important driver of atherosclerosis, the underlying pathology of cardiovascular diseases. Therefore, therapeutic targeting of inflammatory pathways is suggested to improve cardiovascular outcomes in patients with cardiovascular diseases. This concept was recently proven by CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which demonstrated the therapeutic potential of the monoclonal IL (interleukin)-1β-neutralizing antibody canakinumab. IL-1β and other IL-1 family cytokines are important vascular and systemic inflammatory mediators, which contribute to atherogenesis. The NLRP3 (NOD [nucleotide oligomerization domain]-, LRR [leucine-rich repeat]-, and PYD [pyrin domain]-containing protein 3) inflammasome, an innate immune signaling complex, is the key mediator of IL-1 family cytokine production in atherosclerosis. NLRP3 is activated by various endogenous danger signals abundantly present in atherosclerotic lesions, such as oxidized low-density lipoprotein and cholesterol crystals. Consequently, NLRP3 inflammasome activation contributes to the vascular inflammatory response driving atherosclerosis development and progression. Here, we review the mechanisms of NLRP3 inflammasome activation and proinflammatory IL-1 family cytokine production in the context of atherosclerosis and discuss treatment possibilities in light of the positive outcomes of the CANTOS trial.

The IL-33/ST2 pathway, inflammation and atherosclerosis: Trigger and target?

The “inflammatory hypothesis” of atherosclerosis postulates that inflammatory cell signalling drives the formation, growth and ultimately the instability of atherosclerotic plaques, setting up the substrate for the thrombotic response that causes myocardial damage or infarction. The recent Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial has been hailed as the first demonstration, ex iuvantibus, of the inflammatory hypothesis. Indeed, interleukin (IL)-1β inhibition was found to reduce cardiovascular events in patients with previous myocardial infarction and raised high-sensitivity C-reactive protein, despite no effects on the lipid profile. These results prompt a dissection of inflammatory mechanisms of atherosclerosis in order to search for specific biomarkers with prognostic value and/or therapeutic targets.Under this respect, the IL-33/suppression of tumorigenesis 2 (ST2) pathway deserves consideration. Indeed, its elements are particularly expressed in the endothelium of arterial vessels, and the interaction between IL-33 and the ST2 receptor blunts the immune response characteristic of atherosclerosis. By contrast, soluble ST2 (sST2) acts as a decoy receptor for IL-33, thus blocking its protective effects. Despite a solid theoretical framework, no definite demonstration of an involvement of the IL-33/ST2 pathway in atherosclerosis has been provided. Therefore, further studies are warranted to verify if elements of the IL-33/ST2 pathway may be proposed as markers of plaque burden and predictors of future cardiovascular events, and to explore the potential clinical benefit of enhanced IL-33/ST2 signalling in atherosclerosis.

Interplay between hypercholesterolaemia and inflammation in atherosclerosis: Translating experimental targets into clinical practice.

Dyslipidaemia and inflammation are closely interconnected in their contribution to atherosclerosis. In fact, low-density lipoprotein (LDL)-lowering drugs have anti-inflammatory effects. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) has shown that interleukin (IL)-1β blockade reduces the incidence of cardiovascular events in patients with previous myocardial infarction and C-reactive protein levels >2 mg/L. These data confirm the connection between lipids and inflammation, as lipids activate the Nod-like receptor protein 3 inflammasome that leads to IL-1β activation. LDL-lowering drugs are the foundation of cardiovascular prevention. Now, the CANTOS trial demonstrates that combining them with IL-1β blockade further decreases the incidence of cardiovascular events. However, both therapies are not at the same level, given the large evidence showing that LDL-lowering drugs reduce cardiovascular risk as opposed to only one randomized trial of IL-1β blockade. In addition, IL-1β blockade has only been studied in patients with C-reactive protein >2 mg/L, while the benefit of LDL-lowering is not restricted to these patients. Also, lipid-lowering drugs are not harmful even at very low ranges of LDL, while anti-inflammatory therapies may confer a higher risk of developing fatal infections and sepsis. In the future, more clinical trials are needed to explore whether targeting other inflammatory molecules, both related and unrelated to the IL-1β pathway, reduces the cardiovascular risk. In this regard, the ongoing trials with methotrexate and colchicine may clarify whether the cardiovascular benefit of IL-1β blockade extends to other anti-inflammatory mechanisms. A positive result would represent a major change in the future treatment of atherosclerosis.

Insights From Pre-Clinical and Clinical Studies on the Role of Innate Inflammation in Atherosclerosis Regression

Atherosclerosis, the underlying cause of coronary artery (CAD) and other cardiovascular diseases, is initiated by macrophage-mediated immune responses to lipoprotein and cholesterol accumulation in artery walls, which result in the formation of plaques. Unlike at other sites of inflammation, the immune response becomes maladaptive and inflammation fails to resolve. The most common treatment for reducing the risk from atherosclerosis is low density lipoprotein cholesterol (LDL-C) lowering. Studies have shown, however, that while significant lowering of LDL-C reduces the risk of heart attacks to some degree, there is still residual risk for the majority of the population. We and others have observed “residual inflammatory risk” of atherosclerosis after plasma cholesterol lowering in pre-clinical studies, and that this phenomenon is clinically relevant has been dramatically reinforced by the recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial. This review will summarize the role of the innate immune system, specifically macrophages, in atherosclerosis progression and regression, as well as the pre-clinical and clinical models that have provided significant insights into molecular pathways involved in the resolution of plaque inflammation and plaque regression. Partnered with clinical studies that can be envisioned in the post-CANTOS period, including progress in developing targeted plaque therapies, we expect that pre-clinical studies advancing on the path summarized in this review, already revealing key mechanisms, will continue to be essential contributors to achieve the goals of dampening plaque inflammation and inducing its resolution in order to maximize the therapeutic benefits of conventional risk factor modifications, such as LDL-C lowering.

Inhibition of Interleukin-1β by Canakinumab and Cardiovascular Outcomes in Patients With Chronic Kidney Disease

BackgroundInflammation contributes to chronic kidney disease (CKD), in part mediated through activation of interleukin (IL)-1β by the NLRP3 inflammasome within the kidney. This process also likely contributes to the accelerated atherosclerosis associated with nephropathy. ObjectivesThe authors hypothesized that canakinumab, a human monoclonal antibody targeting IL-1β, might reduce cardiovascular event rates and improve renal function among post-myocardial infarction patients with CKD. MethodsStable post-myocardial infarction patients with high-sensitivity C-reactive protein (hsCRP) ≥ 2mg/l were randomly allocated to placebo or to 1 of 3 doses of canakinumab (50, 150, or 300 mg) given subcutaneously once every 3 months. Participants were followed for incident myocardial infarction, stroke, hospitalization for unstable angina requiring urgent revascularization, cardiovascular death, or death from any cause over a median follow-up period of 3.7 years (maximum 5 years). All patients additionally had serial monitoring of estimated glomerular filtration rate (eGFR), creatinine, the urine albumin to creatinine ratio (uACR), and were monitored for adverse renal and urinary events. ResultsOf 10,061 participants, 1,875 (18.6%) had baseline eGFR <60 ml/min/1.73 m2. These moderate CKD patients had higher incidence rates for major adverse vascular events compared with those with eGFR ≥60 ml/min/1.73 m2 (6.92 vs. 4.13 per 100 person-years; p < 0.0001). Random allocation to canakinumab reduced the risk of major adverse cardiovascular events among those with CKD (hazard ratio: 0.82; 95% confidence interval: 0.68 to 1.00; p = 0.05) with the largest cardiovascular benefits accruing among those who achieved on-treatment hsCRP levels below 2 mg/l measured after taking the first dose (hazard ratio: 0.68; 95% confidence interval: 0.53 to 0.86; p = 0.0015). Comparable effects were observed among those with baseline albuminuria or diabetes. Canakinumab had neither clinically meaningful benefits nor substantive harms with respect to serial measures of eGFR, creatinine, the uACR, or reported adverse renal events during trial follow-up. ConclusionsIL-1β inhibition with canakinumab reduces major adverse cardiovascular event rates among high-risk atherosclerosis patients with CKD, particularly among those with a robust anti-inflammatory response to initial treatment. These cardiovascular benefits accrued with no adverse clinical renal events. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846)

Reduction of Vascular Inflammation, LDL-C, or Both for the Protection from Cardiovascular Events?

Background:Low density lipoprotein cholesterol (LDL-C) and low grade arterial inflammation are key pathogenic factors for atherosclerosis and its manifestation, cardiovascular disease (CVD).Objective:In this narrative review we assessed if decreasing LDL-C levels or inflammation or both is more effective in reducing CVD events.Results:In the Scandinavian Simvastatin Survival Study (4S), all statin trials of the 90s’ and the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) the benefit came from the LDL-C reduction. In the GREak and Atorvastatin Coronary heart disease Evaluation (GREACE), the Treating to New Targets (TNT), and the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trials both mechanisms in combination produced significant benefits. In the Atorvastatin for Reduction of MYocardial Damage during Angioplasty (ARMYDA) trials and the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) with a human antibody targeting IL-1β with no lipid lowering effect, the reduction in arterial inflammation played the only beneficial role because there was no change in lipids levels.Conclusion:Both LDL-C and inflammation reduction are beneficial to the reduction of CVD risk. However, canakinumab is a very expensive drug that only induced a 15% reduction in CVD events, thus drastically reducing the possibility for it to be used in clinical practice. Besides, canakinumab is associated with increased infections, some fatal. A potent statin with anti-inflammatory effects is probably the best choice for the majority of those needing hypolipidaemic drug therapy.

The Emerging Role of Inflammation in Cardiovascular Disease.

To review the role of inflammatory suppression in patients with atherosclerotic cardiovascular disease (ASCVD) with a focus on the interleukin-1β blocker canakinumab. An Ovid MEDLINE literature search (1946 to February 2018) was performed using search terms inflammation, ASCVD, atherosclerosis, C-reactive protein, canakinumab. Additional references were identified from a review of literature citations. English-language studies assessing the impact of pharmacological agents, including canakinumab, on inflammation as measured by high-sensitivity C-reactive protein (hsCRP) and the association with reducing ASCVD events were evaluated. Nine studies were included to describe the effect of ASCVD drugs on hsCRP. Aspirin, angiotensin-converting enzyme inhibitors, gemfibrozil, and statins exhibit varying degrees of hsCRP reduction and are associated with a reduction of ASCVD events. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), showed a significant reduction of ASVCD events in patients with elevated baseline hsCRP levels without affecting cholesterol. Patients with elevated inflammatory markers such as hsCRP are at risk for ASVCD events. Several drug classes have shown the ability to decrease hsCRP levels, but the extent to which this reduces ASCVD events in lieu of other drug mechanisms was not clear. Canakinumab specifically targets the inflammatory process in ASCVD and was proven to be effective in preventing ASCVD events in patients with elevated hsCRP levels.

CANTOS: A breakthrough that proves the inflammatory hypothesis of atherosclerosis.

Atherosclerosis is no longer considered solely a disorder of subintimal deposition of modified low-density lipoprotein particles in the arterial wall. Rather, it is known to be a chronic inflammatory disorder. No evidence has shown that reducing vascular inflammation in the absence of concomitant lowering of lipoproteins levels reduces the rates of adverse cardiovascular (CV) events. Canakinumab, a fully human monoclonal antibody that neutralizes interleukin (IL)-1β, significantly reduced the rate of recurrent CV events in patients with prior myocardial infarction in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS). Canakinumab has no effect on CV or all-cause mortality, however it was associated with high incidence of fatal infections. Thus, the net benefit needs to be properly addressed in future studies that evaluate the potential benefit of the anti-inflammatory therapies and whether it can change clinical practice in the near future.

Addressing Acute Coronary Syndromes: New Challenges and Opportunities After the CANTOS Trial (Canakinumab Anti-inflammatory Thrombosis Outcomes Study).

In the mid-1980s, it became clear that plaque quality rather than plaque quantity explained coronary instability, as suggested by data deriving from retrospective angiographic studies, and, in 1985, M.J. Davies proposed that plaque fissure was the link between atherosclerosis and thrombosis. In 1994, we found that patients with acute coronary syndrome (ACS) and high levels of C-reactive protein (CRP), a prototypic marker of inflammation, had a worse outcome than patients with normal levels of CRP, and proposed that plaque inflammation was responsible for plaque fissure.1 Several other studies then confirmed an association between activation of inflammatory cells and ACS but without proving the causality. The recent publication of the CANTOS trial (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) has convincingly proved the inflammatory hypothesis of ACS we proposed 23 years ago.2 Indeed, CANTOS showed that interleukin-1β inhibition by canakinumab administration added to current optimal treatment in patients with a history of myocardial infarction and levels of high-sensitivity CRP >2 mg/L resulted in a 39% reduction of high-sensitivity CRP levels from baseline without any effect on lipids, and in a 15% reduction in the risk of the primary composite efficacy end point of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death, in comparison with placebo-treated patients.2 Yet, the benefit of canakinumab administration on ischemic events was rather modest and …

Anti-Inflammatory Therapy With Canakinumab for the Prevention and Management of Diabetes

BackgroundSubclinical inflammation mediated in part by interleukin (IL)-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion. ObjectivesThe authors tested the hypothesis that the IL-1β inhibitor canakinumab reduces incident diabetes. MethodsThe authors randomized 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/l to placebo or canakinumab at doses of 50 mg, 150 mg, or 300 mg subcutaneously once every 3 months. The authors tested the effects of canakinumab on major cardiovascular events in patients with and without diabetes at baseline, and evaluated as a pre-specified analysis whether canakinumab would reduce the risk of adjudicated cases of new-onset type 2 diabetes among those with protocol-defined pre-diabetes at trial entry. The authors also evaluated the effect of canakinumab on fasting plasma glucose and glycosylated hemoglobin (HbA1c) in patients with and without established diabetes. ResultsOf the participants, 4,057 (40.3%) had baseline diabetes, 4,960 (49.3%) had pre-diabetes, and 1,044 (10.4%) had normal glucose levels. Among those without diabetes, increasing tertiles of hsCRP at baseline associated with an increased risk of developing diabetes during the median follow-up period of 3.7 years (incidence rates 3.2, 4.1, and 4.4 per 100 person-years; p = 0.003). Canakinumab 150 mg as compared with placebo had similar magnitude effects on major cardiovascular event rates among those with diabetes (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.70 to 1.03), pre-diabetes (HR: 0.86; 95% CI: 0.70 to 1.06), and normoglycemia (HR: 0.81; 95% CI: 0.49 to 1.35). Despite large reductions in hsCRP and IL-6, canakinumab did not reduce the incidence of new-onset diabetes, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (log-rank p = 0.84). The HR comparing all canakinumab doses to placebo was 1.02 (95% CI: 0.87 to 1.19; p = 0.82). Canakinumab reduced HbA1c during the first 6 to 9 months of treatment, but no consistent long-term benefits on HbA1c or fasting plasma glucose were observed. ConclusionsAlthough IL-1β inhibition with canakinumab had similar effects on major cardiovascular events among those with and without diabetes, treatment over a median period of 3.7 years did not reduce incident diabetes. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846)

Role of Anti-inflammatory Interventions in Coronary Artery Disease: Understanding the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS).

Coronary artery disease (CAD) is the leading cause of death worldwide. Despite notable advances in understanding the nature of atherosclerotic processes and the use of effective medications such as statins, there remains a significant residual risk. Even after optimal medical treatments and precise revascularisations, the recurrence of MI remains at approximately one-third for 5 years after an acute coronary syndrome (ACS). Over the past two decades, compelling data from animal and human studies has clearly identified atherosclerosis as an inflammatory disease of the arterial wall, but clinical applications related to this accumulated knowledge are still scarce. Recently, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) has provided convincing evidence that an anti-inflammatory intervention with the monoclonal antibody canakinumab reduces cardiovascular events in well-treated CAD patients without affecting LDL cholesterol levels. This article presents a brief description of the role of inflammation in atherogenesis and examines selected anti-inflammatory interventions and their potential use in CAD-affected individuals.

Mortality Differences Associated With Treatment Responses in CANTOS and FOURIER: Insights and Implications.

Similarities and differences in 2 contemporary postrandomization on-treatment analyses from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) and CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) may provide insight into what factors drive reductions in cardiovascular mortality and all-cause mortality among patients with atherosclerosis already treated with high-intensity statins. In the first article, the FOURIER Investigators elegantly demonstrate that lower is better for low-density lipoprotein cholesterol (LDLC) after adjunctive therapy with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab.1 For the FOURIER primary end point (a composite of myocardial infarction, stroke, coronary revascularization, unstable angina, or cardiovascular death), there was a highly significant monotonic relationship between sequentially lower achieved LDLC concentrations and lower cardiovascular risk, extending even to those with on-treatment LDLC 50 mg/dL (for which hazard ratios ranged from 0.94–0.97). These PCSK9 data are important because evolocumab has powerful effects on LDLC but no effect on high-sensitivity C-reactive protein (hs-CRP). In the second article, the CANTOS Investigators similarly demonstrate that lower is better for inflammation reduction, at least with the interleukin-1β inhibitor canakinumab.2 For the CANTOS primary end point (a composite of myocardial infarction, stroke, or cardiovascular death), there was a highly significant 25% reduction among those with on-treatment hs-CRP levels below the approximate on-treatment median of 2 mg/L. In contrast, marginal and nonsignificant reductions …

CANTOS: A Gigantic Proof-of-Concept Trial.

Cumulative evidence links inflammation with atherothrombotic disease. Conversely, the role of modulating the inflammatory process as a therapeutic target has remain an unproven hypothesis until the execution of the CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study). On the one hand, this trial provides robust evidence that interleukin-1β (IL-1β) inhibition by canakinumab reduces the incidence of repetitive atherothrombotic events in patients with postmyocardial infarction already on state-of-the-art treatment but with a residual inflammatory risk. On the other hand, the absolute antiatherothrombotic effect size of this intervention seems small (189 patients had to be intervened during 1 year to prevent 1 myocardial infarction episode) and associated with a mild increase in the incidence of serious adverse events (≈1 in 750 patients intervened during 1 year developed a fatal infection or sepsis). Beyond all these considerations, CANTOS represents a gigantic (10 000 patients) proof-of-concept trial. Atherosclerosis is a systemic disease with a long clinically silent phase. Arterial wall lipid deposition, the hallmark of atherosclerosis, begins early in life. Atherosclerotic plaques grow gradually for several years, the disease becoming clinically overt only when the plaque is large enough to restrict blood flow or becomes unstable and ruptures, causing a thrombus. From its earliest asymptomatic phase through to the late clinical manifest stages, atherosclerosis is predominantly an inflammatory disease, featuring leukocyte activation, cytokine release, and infiltration by eosinophils, neutrophils, and macrophages. Epidemiological studies have revealed that circulating inflammatory biomarkers, especially C-reactive protein (CRP) measured by a high sensitivity (hs) assay, are associated with a higher incidence of atherothrombotic events (myocardial infarction, stroke, etc.).1 All these observations suggested that strategies to reduce inflammation would lead to a reduction in atherothrombotic events. However, it is important to note that the evidence linking inflammation to atherosclerosis is associative, and evidence for a causal role of inflammation in atherothrombotic …

Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial

Canakinumab, a monoclonal antibody targeting interleukin-1β, reduces inflammation and cardiovascular event rates with no effect on lipid concentrations. However, it is uncertain which patient groups benefit the most from treatment and whether reductions in the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) correlate with clinical benefits for individual patients. The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) used computer-generated codes to randomly allocate 10 061 men and women with a history of myocardial infarction to placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. In a prespecified secondary analysis designed to address the relationship of hsCRP reduction to event reduction in CANTOS, we evaluated the effects of canakinumab on rates of major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality according to on-treatment concentrations of hsCRP. We used multivariable modelling to adjust for baseline factors associated with achieved hsCRP and multiple sensitivity analyses to address the magnitude of residual confounding. The median follow-up was 3·7 years. The trial is registered with ClinicalTrials.gov, number NCT01327846. Baseline clinical characteristics did not define patient groups with greater or lesser cardiovascular benefits when treated with canakinumab. However, trial participants allocated to canakinumab who achieved hsCRP concentrations less than 2 mg/L had a 25% reduction in major adverse cardiovascular events (multivariable adjusted hazard ratio [HRadj]=0·75, 95% CI 0·66-0·85, p<0·0001), whereas no significant benefit was observed among those with on-treatment hsCRP concentrations of 2 mg/L or above (HRadj=0·90, 0·79-1·02, p=0·11). For those treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality (HRadj=0·69, 95% CI 0·56-0·85, p=0·0004) and all-cause mortality (HRadj=0·69, 0·58-0·81, p<0·0001) were both reduced by 31%, whereas no significant reduction in these endpoints was observed among those treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or above. Similar differential effects were found in analyses of the trial prespecified secondary cardiovascular endpoint (which additionally included hospitalisation for unstable angina requiring unplanned revascularisation) and in sensitivity analyses alternatively based on median reductions in hsCRP, on 50% or greater reductions in hsCRP, on the median percent reduction in hsCRP, in dose-specific analyses, and in analyses using a causal inference approach to estimate the effect of treatment among individuals who would achieve a targeted hsCRP concentration. The magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that lower is better for inflammation reduction with canakinumab. Novartis Pharmaceuticals.

CANTOS Trial Validates the Inflammatory Pathogenesis of Atherosclerosis: Setting the Stage for a New Chapter in Therapeutic Targeting.

> Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning . > > —Winston Churchill The CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) provides intriguing support for the inflammatory hypothesis of atherosclerosis and cancer in man, demonstrating diverse clinical benefits of inhibiting IL (interleukin)-1β for cardiovascular events and lung cancer. Limited effects on cardiovascular mortality and safety concerns raised by a higher incidence of fatal infection warrant further studies to identify patient subgroups which profit most from anti-inflammatory therapy and a careful pursuit of alternative targets. Abundant evidence from experimental and clinical studies has lend strong support to the hypothesis that inflammation contributes to the pathogenesis of atherosclerotic disease in conjunction with or beyond elevated lipid levels; however, ultimate proof by selective anti-inflammatory treatment in a clinical trial remained elusive for decades. This has now changed with the results of the CANTOS, a double-blind trial involving high-risk patients with prior myocardial infarction (MI) and a residual inflammatory response (defined by hsCRP [high-sensitivity C-reactive protein] levels >2 mg/L despite intensive statin therapy), who were randomized to canakinumab (50, 150, or 300 mg every 3 months) or placebo.1 Canakinumab, a human monoclonal antibody targeting IL-1β as the master cytokine of innate immunity, dose dependently reduced hsCRP and IL-6 levels by ≤43% from baseline. At 150 mg (but not the other doses), canakinumab significantly lowered the risk for the primary (MI, stroke, cardiovascular death) and secondary end points (hazard ratio [HR], 0.85 and 0.83, respectively). Adversely, canakinumab was associated with leukopenia and a higher incidence of fatal infection. Whereas no significant difference in all-cause or cardiovascular mortality was observed, canakinumab strikingly reduced cancer mortality (exploratory results indicating HR 0.23, for lung cancer), supporting a role of inflammation in cancer progression. …