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Paul M Ridker - One of the best experts on this subject based on the ideXlab platform.
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adverse effects related to methotrexate polyglutamate levels adjudicated results from the Cardiovascular Inflammation reduction trial
Rheumatology, 2021Co-Authors: Jacob Selhub, Paul M Ridker, Paul F Jacques, Nina P Paynter, Jean G Macfadyen, Robert J Glynn, Daniel H SolomonAbstract:Objectives Methotrexate is widely used at low dosages (LD-MTX) for non-oncologic indications and is associated with a variety of adverse effects (AEs). We sought to determine whether concentrations of the active metabolite, MTX polyglutamates (MTX-PGs) 1-5, correlate with AEs. Method We examined data from the LD-MTX arm of the randomized double-blind Cardiovascular Inflammation Reduction Trial (CIRT). All AEs were blindly adjudicated and monitoring laboratories were tested centrally. The MTX-PGs 1-5 were assessed in one reference laboratory using liquid chromatography-tandem mass spectrometry. Based on prior literature, MTX-PGs 3-5 were chosen as the exposure of interest and quartiles of MTX-PGs 3-5 were assessed for their relationship with all AEs and each pre-specified category of AE using adjusted Cox proportional hazards regression. Results Of the 2391 subjects randomized to LD-MTX, MTX-PG levels were available for 1319 subjects (median dosage 16.1 mg/week) from the 8 month visit. We followed these subjects for a median of 2.2 years [interquartile range (IQR) 1.5-2.9]. Higher MTX-PG3-5 levels were related to an increased risk of anaemia [compared with quartile 1 (Q1); hazard ratio (HR) for Q4 1.27 (95% CI 0.98, 1.65), P for trend = 0.05] and a decreased risk of thrombocytopenia [HR for Q4 0.52 (95% CI 0.32, 0.84), P for trend = 0.05]. MTX-PG3-5 levels >134 nmol/l were associated with an increased risk of liver abnormalities [HR 1.36 (95% CI 1.08, 1.72)]. Conclusions Higher MTX- PG3-5 levels were modestly associated with LD-MTX AEs, including anaemia and liver function abnormalities, but a reduced risk of thrombocytopenia and haemorrhage. Clinical trial registration NCT01594333.
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comparison of interleukin 6 c reactive protein and low density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice secondary analyses from the Cardiovascular Inflammation reduction trial
European Heart Journal, 2020Co-Authors: Paul M Ridker, Jean G Macfadyen, Robert J Glynn, Gary Bradwin, Ahmed Hasan, Nader RifaiAbstract:AIMS In epidemiologic cohorts initiated >30 years ago, inflammatory biomarkers, such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were shown to independently predict future Cardiovascular events with a magnitude of effect comparable to that of low-density lipoprotein cholesterol (LDLC). Whether aggressive contemporary therapy for atherosclerosis has altered these relationships is unknown yet has major implications for future drug development. METHODS AND RESULTS Interleukin-6, hsCRP, and LDLC were measured at baseline in up to 4168 North American patients enrolled in the contemporary Cardiovascular Inflammation Reduction Trial with prior myocardial infarction or multivessel coronary disease who additionally had diabetes or metabolic syndrome and were followed for a period of up to 5 years for incident major recurrent Cardiovascular events and all-cause mortality. Three-quarters of the cohort were previously revascularized and the great majority was taking statins, angiotensin blocking agents, beta-blockers, and antithrombotic agents. Participants were randomly allocated to low-dose methotrexate 15 mg weekly or to placebo. Randomized use of methotrexate had no effect on event rates nor plasma levels of IL-6, hsCRP, or LDL over time. Yet, baseline levels of IL-6, hsCRP, and LDLC were all predictors of major recurrent Cardiovascular events; adjusted hazard ratios [HR; 95% confidence interval (CI)] for the lowest to highest baseline quartiles of IL-6 were 1.0 (referent), 1.66 (1.18-2.35), 1.92 (1.36-2.70), and 2.11 (1.49-2.99; P < 0.0001), while adjusted HRs for increasing quartiles of hsCRP were 1.0 (referent), 1.28 (0.92-1.79), 1.73 (1.25-2.38), and 1.79 (1.28-2.50; P < 0.0001) and adjusted HRs for increasing quartiles of LDLC were 1.0 (referent), 1.12 (0.78-1.62), 1.25 (0.87-1.79), and 2.38 (1.72-3.30; P < 0.0001). Effect estimates were not statistically different in these analyses for comparisons between IL-6, hsCRP, or LDLC, although IL-6 was the strongest predictor of all-cause mortality. The highest absolute risks were observed among those with elevated levels of both cholesterol and Inflammation [HR 6.4 (95% CI 2.9-14.1) for those in the top quartiles of baseline IL-6 and LDLC, HR 4.9 (95% CI 2.6-9.4) for those in the top quartiles of baseline hsCRP and LDLC, both P < 0.0001]. CONCLUSION Despite aggressive contemporary secondary prevention efforts, the relationships between Inflammation, cholesterol, and Cardiovascular risk are largely unchanged from those described two decades ago. These data are consistent with the hypothesis that future treatments for atherosclerosis may require a combination of Inflammation inhibition and additional cholesterol reduction. CLINICAL TRIAL ClinicalTrials.gov NCT01594333.
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pulmonary adverse events in patients receiving low dose methotrexate in the randomized double blind placebo controlled Cardiovascular Inflammation reduction trial
Arthritis & Rheumatism, 2020Co-Authors: Jeffrey A Sparks, Paul M Ridker, Nina P Paynter, Robert J Glynn, Paul F Dellaripa, Daniel H SolomonAbstract:OBJECTIVE We previously reported that low-dose methotrexate (MTX) was associated with an increased risk of pulmonary adverse events (AEs) in a large randomized, placebo-controlled trial. Herein, we report details on the predictors and severity of pulmonary AEs. METHODS We conducted a prespecified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial. Adults with known Cardiovascular disease and diabetes/metabolic syndrome were randomly allocated to receive low-dose MTX (target dose 15-20 mg/week) or placebo after a 6-8-week open-label run-in phase in which all patients received low-dose MTX. Individuals with systemic inflammatory diseases were excluded. Pulmonary AEs were adjudicated in a blinded manner. We described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs in patients receiving low-dose MTX. RESULTS A total of 2,391 subjects were randomized to receive low-dose MTX and 2,395 to receive placebo. There were 13 severe pulmonary AEs (0.5%) and 7 cases of possible pneumonitis (0.3%) in the low-dose MTX group, compared to 8 (0.3%) and 1 (<0.1%), respectively, in the placebo group. Among those randomized to receive low-dose MTX, risk factors for any pulmonary AE included female sex (hazard ratio [HR] 1.69 versus male sex [95% confidence interval (95% CI) 1.16-2.45]), white race (HR 2.35 versus other race [95% CI 1.03-5.36]), and insulin use (HR 1.60 versus non-use [95% CI 1.11-2.30]). The only risk factor for severe pulmonary AEs was older age at baseline (HR 1.09 per year increase [95% CI 1.02-1.16]). CONCLUSION In this large placebo-controlled trial, pulmonary AEs, including possible pneumonitis, were uncommon but were more likely to occur in those randomized to receive low-dose MTX. White race, older age, male sex, and insulin use were associated with an increased risk of pulmonary AEs in those receiving low-dose MTX.
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targeting Cardiovascular Inflammation next steps in clinical translation
European Heart Journal, 2020Co-Authors: Patrick R Lawler, Deepak L Bhatt, Lucas C Godoy, Thomas F Luscher, Robert O Bonow, Subodh Verma, Paul M RidkerAbstract:Systemic vascular Inflammation plays multiple maladaptive roles which contribute to the progression and destabilization of atherosclerotic Cardiovascular disease (ASCVD). These roles include: (i) driving atheroprogression in the clinically stable phase of disease; (ii) inciting atheroma destabilization and precipitating acute coronary syndromes (ACS); and (iii) responding to cardiomyocyte necrosis in myocardial infarction (MI). Despite an evolving understanding of these biologic processes, successful clinical translation into effective therapies has proven challenging. Realizing the promise of targeting Inflammation in the prevention and treatment of ASCVD will likely require more individualized approaches, as the degree of Inflammation differs among Cardiovascular patients. A large body of evidence has accumulated supporting the use of high-sensitivity C-reactive protein (hsCRP) as a clinical measure of Inflammation. Appreciating the mechanistic diversity of ACS triggers and the kinetics of hsCRP in MI may resolve purported inconsistencies from prior observational studies. Future clinical trial designs incorporating hsCRP may hold promise to enable individualized approaches. The aim of this Clinical Review is to summarize the current understanding of how Inflammation contributes to ASCVD progression, destabilization, and adverse clinical outcomes. We offer forward-looking perspective on what next steps may enable successful clinical translation into effective therapeutic approaches-enabling targeting the right patients with the right therapy at the right time-on the road to more individualized ASCVD care.
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Inflammation coronary flow reserve and microvascular dysfunction moving beyond cardiac syndrome x
Jacc-cardiovascular Imaging, 2013Co-Authors: Viviany R Taqueti, Paul M RidkerAbstract:Conventional approaches to risk assessment in patients with coronary artery disease (CAD), including assessment of systolic left ventricular function, inducible myocardial perfusion defects, and angiographic appearance of epicardial stenoses, have been unable to account fully for risk of future Cardiovascular events (1). Part of this unexplained risk may be attributable to low-grade systemic Inflammation that contributes to lesion progression, vascular dysfunction, insufficiency, and plaque rupture (2). In clinical practice, biomarkers of Inflammation such as high-sensitivity C-reactive protein (hsCRP), identify higher risk individuals, even in the apparent absence of other conventional risk factors (3). In a recent meta-analysis of 54 prospective cohort studies, the magnitude of independent risk associated with a 1 SD change in hsCRP was equal to or greater than that of a comparable 1 SD change in blood pressure or cholesterol (4). Nonetheless, the complex biology linking Inflammation to atherothrombotic risk has not been fully elucidated. Coronary flow reserve (CFR) is emerging as an additional noninvasive quantitative imaging marker of vascular age and clinical risk (5–7). Significant progress has been made in the development of dynamic positron emission tomography (PET) perfusion imaging to accurately quantify CFR as the ratio of absolute global myocardial blood flow (MBF) measured at peak stress (i.e., during vasodilator-induced hyperemia) over that at rest (which is corrected for rate-pressure product as an index of baseline cardiac work). From a pathophysiologic perspective, CFR provides a measure of the integrated effects of epicardial CAD, diffuse atherosclerosis, vessel remodeling, and microvascular dysfunction on myocardial tissue perfusion (1) (Fig. 1). Figure 1 Coronary Function Versus Anatomy With Diffuse Coronary Artery Disease and Remodeling CFR quantified using vasodilator PET can predict cardiac death and myocardial infarction, even in the absence of overt obstructive disease, independently of perfusion score (5–7). These associations are especially evident among high, but heterogeneous, risk cohorts, including patients with diabetes (8) and chronic renal impairment (9). In diabetics, diffuse coronary vascular dysfunction precedes overt atherosclerosis (10), and absence of myocardial ischemia on noninvasive testing does not necessarily identify a lower risk cohort (11). Diabetic patients without known CAD with impaired CFR show a risk of cardiac death comparable to, and possibly higher than, that for nondiabetic patients with known CAD (8). There is growing evidence that microvascular dysfunction is associated with increased systemic Inflammation, and may precede or coexist with high-risk coronary atherosclerosis. In a previous work, Recio-Mayoral et al. (12) showed that, compared with a healthy control group, patients with systemic lupus erythematosus or rheumatoid arthritis, who had no significant CAD on invasive angiography, demonstrated impaired CFR in a manner that was directly related to disease duration. Recently, in patients presenting with acute coronary syndrome who were found to have nonobstructive CAD by angiography, those demonstrating coronary microvascular dysfunction (as assessed by coronary flow velocity reserve using invasive Doppler flow velocity monitoring) also showed higher frequency of thin-cap fibroatheroma, greater plaque burden, and higher levels of hsCRP, despite similar amounts of epicardial disease by luminal area and fractional flow reserve measurements (13). In this issue of iJACC, Recio-Mayoral et al. (14) extend this work, showing that in a cohort of patients with cardiac syndrome X (CSX), elevation in hsCRP correlates with reduced CFR (Spearman r = −0.49, p = 0.02). In brief, 21 nonsmokers who met a strict clinical definition for CSX, including exertional angina, ST-segment depression on exercise stress testing, and normal coronary angiography but without rest or Prinzmetal’s variant angina, diabetes mellitus, hypertension, obesity, or hyperlipidemia, underwent PET imaging following intravenous injection of adenosine and water labeled with oxygen-15. These 21 cases of CSX, none taking statins, were then compared with 21 well-matched asymptomatic controls. The cases differed, however, in 1 important risk factor. Eight of the 21 patients with CSX, but none of the control group, had elevated levels of hsCRP (>3 mg/l) at baseline. Only the 38% of CSX patients who had elevated baseline hsCRP demonstrated lower peak MBF and correspondingly, decreased CFR. Of note, those patients with CSX who did not have elevated levels of hsCRP showed no difference in corrected CFR compared with the control group, despite an incidence of ST-segment depression during adenosine infusion that was not significantly different from that of high hsCRP CSX patients. These results thus reinforce previous observations (15–17) that Inflammation is associated with impaired coronary vasoreactivity, and in the appropriate patient population, may be a better marker for poor outcomes associated with diffuse and/or microvascular CAD than conventional assessments for ischemia. To date, no clinical trial has yet proven that directly reducing Inflammation lowers Cardiovascular event rates. However, 2 large-scale hard outcome trials have now been launched to address this issue. In the first, the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial, post-myocardial infarction patients with elevated CRP are being randomly allocated to placebo or to the interleukin (IL)-1β inhibitor canakinumab (18). In the second, the CIRT (Cardiovascular Inflammation Reduction Trial) study, funded by the National Heart, Lung, and Blood Institute, similar post-myocardial infarction patients with either diabetes or metabolic syndrome are being randomly allocated to placebo or to low-dose methotrexate (19). Both trials provide a unique opportunity to assess whether CFR might provide a simple noninvasive method to predict which patients best respond to targeted anti-inflammatory interventions. For example, with regard to IL-1β, previous work has suggested that the ability of statins to improve measures of coronary blood flow and endothelial dysfunction (20,21) is modified among carriers of a specific genetic polymorphism that reduces IL-1β expression (22). Further, short-term inhibition of IL-1 activity with the IL-1 receptor antagonist anakinra in rheumatoid arthritis patients without perfusion abnormalities has been shown to improve echocardiographic measures of left ventricular myocardial deformation (by speckle tracking) and CFR (by Doppler flow velocity in the left anterior descending artery [LAD]) (23). With regard to low-dose methotrexate, the use of this common systemic anti-inflammatory agent in early rheumatoid arthritis has been found to reduce clinical scores of disease severity and improve CFR (as measured by echo Doppler flow velocity in the LAD), without effect on common carotid intima-medial thickness (24). As such, PET imaging substudies embedded in CANTOS and CIRT would provide not only an opportunity to investigate the clinical utility of CFR as a marker of subsequent vascular risk, but would also allow for a direct evaluation of 2 anti-inflammatory therapies on changes in coronary vascular function over time.
Jeffrey A Sparks - One of the best experts on this subject based on the ideXlab platform.
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pulmonary adverse events in patients receiving low dose methotrexate in the randomized double blind placebo controlled Cardiovascular Inflammation reduction trial
Arthritis & Rheumatism, 2020Co-Authors: Jeffrey A Sparks, Paul M Ridker, Nina P Paynter, Robert J Glynn, Paul F Dellaripa, Daniel H SolomonAbstract:OBJECTIVE We previously reported that low-dose methotrexate (MTX) was associated with an increased risk of pulmonary adverse events (AEs) in a large randomized, placebo-controlled trial. Herein, we report details on the predictors and severity of pulmonary AEs. METHODS We conducted a prespecified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial. Adults with known Cardiovascular disease and diabetes/metabolic syndrome were randomly allocated to receive low-dose MTX (target dose 15-20 mg/week) or placebo after a 6-8-week open-label run-in phase in which all patients received low-dose MTX. Individuals with systemic inflammatory diseases were excluded. Pulmonary AEs were adjudicated in a blinded manner. We described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs in patients receiving low-dose MTX. RESULTS A total of 2,391 subjects were randomized to receive low-dose MTX and 2,395 to receive placebo. There were 13 severe pulmonary AEs (0.5%) and 7 cases of possible pneumonitis (0.3%) in the low-dose MTX group, compared to 8 (0.3%) and 1 (<0.1%), respectively, in the placebo group. Among those randomized to receive low-dose MTX, risk factors for any pulmonary AE included female sex (hazard ratio [HR] 1.69 versus male sex [95% confidence interval (95% CI) 1.16-2.45]), white race (HR 2.35 versus other race [95% CI 1.03-5.36]), and insulin use (HR 1.60 versus non-use [95% CI 1.11-2.30]). The only risk factor for severe pulmonary AEs was older age at baseline (HR 1.09 per year increase [95% CI 1.02-1.16]). CONCLUSION In this large placebo-controlled trial, pulmonary AEs, including possible pneumonitis, were uncommon but were more likely to occur in those randomized to receive low-dose MTX. White race, older age, male sex, and insulin use were associated with an increased risk of pulmonary AEs in those receiving low-dose MTX.
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investigating methotrexate toxicity within a randomized double blinded placebo controlled trial rationale and design of the Cardiovascular Inflammation reduction trial adverse events cirt ae study
Seminars in Arthritis and Rheumatism, 2017Co-Authors: Jeffrey A Sparks, Medha Barbhaiya, Elizabeth W Karlson, Susan Y Ritter, Soumya RaychaudhuriAbstract:Abstract Background The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of Cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. Design CIRT will randomize up to 7000 participants with Cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15–20mg/week) or placebo for an average follow-up period of 3–5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. Summary CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with Cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice.
Daniel H Solomon - One of the best experts on this subject based on the ideXlab platform.
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adverse effects related to methotrexate polyglutamate levels adjudicated results from the Cardiovascular Inflammation reduction trial
Rheumatology, 2021Co-Authors: Jacob Selhub, Paul M Ridker, Paul F Jacques, Nina P Paynter, Jean G Macfadyen, Robert J Glynn, Daniel H SolomonAbstract:Objectives Methotrexate is widely used at low dosages (LD-MTX) for non-oncologic indications and is associated with a variety of adverse effects (AEs). We sought to determine whether concentrations of the active metabolite, MTX polyglutamates (MTX-PGs) 1-5, correlate with AEs. Method We examined data from the LD-MTX arm of the randomized double-blind Cardiovascular Inflammation Reduction Trial (CIRT). All AEs were blindly adjudicated and monitoring laboratories were tested centrally. The MTX-PGs 1-5 were assessed in one reference laboratory using liquid chromatography-tandem mass spectrometry. Based on prior literature, MTX-PGs 3-5 were chosen as the exposure of interest and quartiles of MTX-PGs 3-5 were assessed for their relationship with all AEs and each pre-specified category of AE using adjusted Cox proportional hazards regression. Results Of the 2391 subjects randomized to LD-MTX, MTX-PG levels were available for 1319 subjects (median dosage 16.1 mg/week) from the 8 month visit. We followed these subjects for a median of 2.2 years [interquartile range (IQR) 1.5-2.9]. Higher MTX-PG3-5 levels were related to an increased risk of anaemia [compared with quartile 1 (Q1); hazard ratio (HR) for Q4 1.27 (95% CI 0.98, 1.65), P for trend = 0.05] and a decreased risk of thrombocytopenia [HR for Q4 0.52 (95% CI 0.32, 0.84), P for trend = 0.05]. MTX-PG3-5 levels >134 nmol/l were associated with an increased risk of liver abnormalities [HR 1.36 (95% CI 1.08, 1.72)]. Conclusions Higher MTX- PG3-5 levels were modestly associated with LD-MTX AEs, including anaemia and liver function abnormalities, but a reduced risk of thrombocytopenia and haemorrhage. Clinical trial registration NCT01594333.
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pulmonary adverse events in patients receiving low dose methotrexate in the randomized double blind placebo controlled Cardiovascular Inflammation reduction trial
Arthritis & Rheumatism, 2020Co-Authors: Jeffrey A Sparks, Paul M Ridker, Nina P Paynter, Robert J Glynn, Paul F Dellaripa, Daniel H SolomonAbstract:OBJECTIVE We previously reported that low-dose methotrexate (MTX) was associated with an increased risk of pulmonary adverse events (AEs) in a large randomized, placebo-controlled trial. Herein, we report details on the predictors and severity of pulmonary AEs. METHODS We conducted a prespecified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial. Adults with known Cardiovascular disease and diabetes/metabolic syndrome were randomly allocated to receive low-dose MTX (target dose 15-20 mg/week) or placebo after a 6-8-week open-label run-in phase in which all patients received low-dose MTX. Individuals with systemic inflammatory diseases were excluded. Pulmonary AEs were adjudicated in a blinded manner. We described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs in patients receiving low-dose MTX. RESULTS A total of 2,391 subjects were randomized to receive low-dose MTX and 2,395 to receive placebo. There were 13 severe pulmonary AEs (0.5%) and 7 cases of possible pneumonitis (0.3%) in the low-dose MTX group, compared to 8 (0.3%) and 1 (<0.1%), respectively, in the placebo group. Among those randomized to receive low-dose MTX, risk factors for any pulmonary AE included female sex (hazard ratio [HR] 1.69 versus male sex [95% confidence interval (95% CI) 1.16-2.45]), white race (HR 2.35 versus other race [95% CI 1.03-5.36]), and insulin use (HR 1.60 versus non-use [95% CI 1.11-2.30]). The only risk factor for severe pulmonary AEs was older age at baseline (HR 1.09 per year increase [95% CI 1.02-1.16]). CONCLUSION In this large placebo-controlled trial, pulmonary AEs, including possible pneumonitis, were uncommon but were more likely to occur in those randomized to receive low-dose MTX. White race, older age, male sex, and insulin use were associated with an increased risk of pulmonary AEs in those receiving low-dose MTX.
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rationale and design of the Cardiovascular Inflammation reduction trial a test of the inflammatory hypothesis of atherothrombosis
American Heart Journal, 2013Co-Authors: Brendan M Everett, Nina P Paynter, Jean G Macfadyen, Daniel H Solomon, Aruna D Pradhan, Elaine Zaharris, Milan Gupta, Michael Clearfield, Peter LibbyAbstract:Background Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of Inflammation will reduce the occurrence of adverse Cardiovascular outcomes is not known. Design The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.gov NCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and Cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants. Summary CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent Inflammation. If low-dose methotrexate reduces Cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and Cardiovascular death.
Soumya Raychaudhuri - One of the best experts on this subject based on the ideXlab platform.
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investigating methotrexate toxicity within a randomized double blinded placebo controlled trial rationale and design of the Cardiovascular Inflammation reduction trial adverse events cirt ae study
Seminars in Arthritis and Rheumatism, 2017Co-Authors: Jeffrey A Sparks, Medha Barbhaiya, Elizabeth W Karlson, Susan Y Ritter, Soumya RaychaudhuriAbstract:Abstract Background The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of Cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. Design CIRT will randomize up to 7000 participants with Cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15–20mg/week) or placebo for an average follow-up period of 3–5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. Summary CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with Cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice.
Frédéric Jaisser - One of the best experts on this subject based on the ideXlab platform.
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Beneficial Effects of Mineralocorticoid Receptor Pathway Blockade against Endothelial Inflammation Induced by SARS-CoV-2 Spike Protein
'MDPI AG', 2021Co-Authors: Eva Jover, Lara Matilla, Mattie Garaikoetxea, Amaya Fernández-celis, Pieter Muntendam, Frédéric Jaisser, Patrick Rossignol, Natalia López-andrésAbstract:Background: Vascular endothelial cells activation and dysfunction mediate Inflammation and abnormal coagulation in COVID-19 patients. Mineralocorticoid receptor (MR) signaling and its downstream target Galectin-3 (Gal-3) are known to mediate Cardiovascular Inflammation and might be involved in the pathogenesis of COVID-19 complications. Accordingly, we aimed to investigate the potential beneficial effects of MR antagonism and Gal-3 inhibition on the inflammatory response induced by SARS-CoV-2 Spike protein in human aortic endothelial cells (HAECs). Methods: HAECs were treated with recombinant SARS-COV2 Spike (S) protein. MR antagonists (namely spironolactone and eplerenone) or the Gal-3 inhibitor G3P-01 were supplemented before and after S protein challenge. HAECs supernatants were assessed by ELISA or Western blotting. Results: HAECs treated with recombinant S protein resulted in enhanced secretion of inflammatory molecules (interleukin-6, monocyte chemoattractant protein-1, interleukin-18, interleukin-27, and interferon-γ) as well as in the thrombosis marker plasminogen activator inhibitor (PAI)-1. This was prevented and reversed by both MR antagonists and G3P-01. Conclusions: These findings indicate that MR/Gal-3 pathway blockade could be a promising option to reduce endothelial Inflammation in SARS-CoV-2 infection
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endothelial cell mineralocorticoid receptors turning Cardiovascular risk factors into Cardiovascular dysfunction
Hypertension, 2014Co-Authors: Iris Z Jaffe, Frédéric JaisserAbstract:See related article, pp 1033–1040 Clinically, mineralocorticoid receptor (MR) antagonists are widely prescribed for the treatment of hypertension and heart failure because of their diuretic action in aldosterone-sensitive distal nephron. Clinical trials of MR antagonism in patients with various degrees of heart failure severity have also demonstrated a pronounced reduction of Cardiovascular mortality in MR antagonist–treated patients.1 The underlying mechanisms of these Cardiovascular benefits are still debated and are probably diverse. Potential beneficial effects of MR antagonism on extracellular matrix remodeling, arrhythmia susceptibility, coronary flow reserve, Cardiovascular Inflammation, and vascular function have all been suggested. Indeed, the vasculature has been recently highlighted as a primary target of aldosterone and MR antagonists. MR is expressed in human vascular endothelial cells (ECs) and smooth muscle cells as is the 11β-HSD2 enzyme that allows for selective aldosterone versus cortisol activation of MR. The effects of MR activation on vascular reactivity in healthy humans remains controversial because of conflicting results from clinical studies with many demonstrating a constrictive response and some showing vascular relaxation.2 Discrepancies may be due to differences in the vascular health of study participants as well as differences in study design. However, when patients with underlying Cardiovascular diseases are studied, the data are consistent with MR activation promoting increased systemic vascular resistance and reduced forearm blood flow and MR antagonism improving endothelium-dependent vasodilatation, independent of changes in blood pressure. The aggregate of data supports that, in healthy vessels, acute MR activation may evoke endothelium-dependent, NO-mediated vasodilatation, whereas, in the presence of endothelial dysfunction, vascular injury, or high vascular oxidative stress (as in patients with Cardiovascular risk factors or heart …