Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.

BACKGROUND: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1ß, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. METHODS: We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point. RESULTS: The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1ß, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo. CONCLUSIONS: Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1ß, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.).

The effects of rosiglitazone on inflammatory biomarkers and adipokines in diabetic, hypertensive patients.

OBJECTIVE: To compare the effects of a 12-week treatment course of a rosiglitazone-based versus a metformin- or glyburide-based strategy on inflammatory biomarkers and adipokine levels in hypertensive, type 2 diabetes patients. METHODS: One hundred three treatment-naive patients or patients on monotherapy with either metformin or glyburide, and a hemoglobin A1C (A1C) ≥7.5%, were randomly assigned to either rosiglitazone add-on (4 mg/day ± titration to 8 mg/day) or a combination of metformin (250 mg twice per day [BID] titrated to 500 BID if A1C ≥7.5% and ≤8.0%; 500 mg BID titrated to 1 g BID if A1C >8.0%) and glyburide (2.5 mg BID titrated to 5 mg BID if A1C ≥7.5% and ≤8.0%; 5 mg BID titrated to 10 mg BID if A1C >8.0%). RESULTS: Rosiglitazone add-on produced significantly greater reductions in high-sensitivity C-reactive protein (2.1 mg/L to 0.9 mg/L) and increases in adiponectin (8.7 mg/mL to 14.8 mg/mL) levels compared with metformin/glyburide (both P<0.005). At close-out, all patients had improved fasting plasma glucose and A1C levels (8.5% to 7.4% and 8.8% to 7.1% for rosiglitazone add-on and metformin-glyburide, respectively [P<0.001 for both arms]) relative to the corresponding baseline values. CONCLUSIONS: The present study demonstrated that in hypertensive, diabetic subjects, a rosiglitazone-based treatment strategy results in favourable changes in inflammatory biomarkers compared with metformin/glyburide.

Effects of ezetimibe add-on to statin therapy on adipokine production in patients with metabolic syndrome and stable vascular disease.

The aim of this study was to determine whether the addition of ezetimibe to ongoing statin therapy in patients with atherosclerosis and metabolic syndrome would favorably affect levels of inflammatory markers and adipokines. Individuals with the metabolic syndrome exhibit higher levels of inflammatory biomarkers and adipokines, which have been implicated in the pathobiology of cardiovascular risk. The impact of the addition of ezetimibe to statin therapy on these proinflammatory mediators is unclear. Fifty patients with metabolic syndrome and concomitant vascular disease receiving stable statin monotherapy, with low-density lipoprotein cholesterol (LDL-C) levels >77.4 mg/dL (>2.0 mM), were treated with ezetimibe 10 mg per day for 12 weeks. The primary study end point was the % change in adiponectin levels from baseline to 12 weeks. Secondary study end points included % changes in the levels of other circulating inflammatory markers, adipokines, and plasma lipids. The addition of ezetimibe to statin therapy resulted in a significant reduction in total cholesterol and LDL-C and the ratio of total cholesterol to high-density lipoprotein cholesterol. However, ezetimibe add-on treatment had no effect on the primary outcome of plasma adiponectin or on any of the secondary outcomes, including leptin, hsCRP, tumor necrosis factor-α, or interleukin-6 concentrations. These observations remained unchanged after adjusting for body mass index and for background statin used. The addition of ezetimibe to stable statin therapy in patients with vascular disease and metabolic syndrome, who were not at guideline recommended LDL-C levels, did not alter adipokine levels after 12 weeks. Short-term add-on with ezetimibe may not be associated with additional inflammatory benefits beyond improvements in cholesterol homeostasis.

Statin effects on LDL and HDL cholesterol in South Asian and white populations.

Inasmuch as statins appear to exhibit altered efficacy in some Asian populations (predominantly East Asian), current lipid guidelines recommend the use of lower statin doses in all Asians. Whether this should also apply to South Asians, a population at high risk for coronary heart disease, remains unclear. The authors evaluated the lipid-modifying effects of statins in South Asian and white patients with established coronary heart disease. Atorvastatin (median dose=20 mg/d in both groups) produced similar decreases in low-density lipoprotein cholesterol (LDL-c) in South Asian (43%) and white (41%) patients and raised high-density lipoprotein cholesterol (HDL-c) by 19% in South Asians and by 12% in whites. Simvastatin (median dose=20 mg/d in both groups) reduced LDL-c by 35% in South Asians and by 37% in whites while raising HDL-c by 12% in both groups. Using a multiple linear regression model (atorvastatin equivalent), the expected decrease in LDL-c for 10 mg atorvastatin and 20 mg atorvastatin was similar between the groups. Results indicate that atorvastatin and simvastatin, at commonly prescribed doses, modulate LDL-c and HDL-c levels to a similar degree in both South Asians and whites with documented coronary heart disease. These findings suggest that South Asian patients may be treated with atorvastatin and simvastatin at doses typically applied to white patients.

Prediction of Familial Hypercholesterolemia in Patients at High Atherosclerotic Cardiovascular Disease Risk Using a Recently Validated Algorithm.

BACKGROUND: The prevalence of heterozygous familial hypercholesterolemia (FH) is 1 of 250 in the general population and approximately 1 of 125 in patients with atherosclerotic cardiovascular disease (ASCVD), yet only a minority are diagnosed. The diagnostic criteria for FH rely on a point system using low-density lipoprotein cholesterol (LDL-C), family history, cutaneous manifestations, and molecular diagnosis. The aim of the present study was to determine the prevalence of FH in the Relating Evidence to Achieve Cholesterol Targets (REACT) registry. METHODS: Patients were enrolled as ASCVD (n = 86) or FH (n = 109) and with an LDL-C level > 3.0 mmol/L despite maximally tolerated statin therapy. FH was diagnosed clinically using a validated clinical application integrating an imputation for baseline (untreated) LDL-C levels. RESULTS: There were 109 men and 86 women with a mean age of 63 ± 12 years. Diabetes (29.7%), hypertension (62.1%), smoking (37.9%), and family history of premature ASCVD (59.5%) were common. On-treatment LDL-C was 4.26 ± 0.94 mmol/L. On the basis of the dose and type of statin ± ezetimibe, imputed baseline LDL-C was 7.04 ± 2.90 mmol/L. A diagnosis of probable/definite FH was found in 54.7%, 49.5%, and 61.5% of patients according to the Simon Broome, Dutch Lipid Clinic Network criteria, and the new Canadian FH definition, respectively. Of note, 40% of patients in the ASCVD inclusion subgroup had probable or definite FH. CONCLUSIONS: Our study reveals that a substantial proportion of patients with ASCVD whose LDL-C levels are > 3.0 mmol/L despite maximally tolerated statins have heterozygous FH. Clinicians should consider using the recently described algorithm to assess the possibility of FH in this high-risk population.

CONTEXTE: La prévalence de l'hypercholestérolémie familiale (HF) hétérozygote est de 1 cas sur 250 dans la population générale et d'environ 1 cas sur 125 chez les patients atteints d'une maladie cardiovasculaire athérosclérotique (MCVAS), pourtant on ne la diagnostique que dans une minorité de cas. Les critères diagnostiques de l'HF reposent sur un système de points utilisant comme paramètres le cholestérol à lipoprotéines de faible densité (C-LDL), les antécédents familiaux, les manifestations cutanées et le diagnostic moléculaire. La présente étude visait à déterminer la prévalence de l'HF parmi les patients répertoriés dans le registre REACT (Relating Evidence to Achieve Cholesterol Targets). MÉTHODOLOGIE: Les patients admis à l'étude étaient considérés comme étant atteints d'une MCVAS (n = 86) ou d'une HF (n = 109) et présentaient un taux de C-LDL > 3,0 mmol/l malgré la prise d'un traitement par statine à la dose maximale tolérée. L'HF a été diagnostiquée sur le plan clinique à l'aide d'une application clinique validée incluant une imputation des taux de C-LDL initiaux (en l'absence de traitement). RÉSULTATS: L'étude comptait 86 femmes et 109 hommes âgés en moyenne de 63 ± 12 ans. Le diabète (29,7 %), l'hypertension (62,1 %), le tabagisme (37,9 %) et les antécédents familiaux de MCVAS prématurée (59,5 %) étaient fréquents. Sous traitement, le taux de C-LDL était de 4,26 ± 0,94 mmol/l. D'après la dose et le type de statine ± ézétimibe administrés, le taux de C-LDL imputé au départ était de 7,04 ± 2,90 mmol/l. Un diagnostic d'HF probable ou certaine a été établi respectivement chez 54,7 %, 49,5 % et 61,5 % des patients selon les critères de Simon Broome et du Dutch Lipid Clinic Network, ainsi que la nouvelle définition canadienne de l'HF. Notons que 40 % des patients dans le sous-groupe d'inclusion de la MCVAS présentaient une HF probable ou certaine. CONCLUSIONS: Notre étude révèle qu'une proportion importante de patients atteints de MCVAS dont les taux de C-LDL sont > 3,0 mmol/l malgré la prise de statines à la dose maximale tolérée présentent une HF hétérozygote. Les cliniciens devraient envisager d'utiliser l'algorithme récemment décrit pour évaluer la présence possible d'une HF dans cette population à haut risque.

Detection of atherosclerotic cardiovascular disease influences the perceived need for aggressive lipid management.

BACKGROUND AND AIMS: Overt atherosclerotic cardiovascular disease (ASCVD) warrants aggressive lipid lowering. Imaging for ambiguous symptoms suggesting ischemia or for clarification of CV risk in asymptomatic individuals often uncovers previously unknown ASCVD. Guidelines do not provide clear recommendations for aggressive lipid lowering in such cases. We explored physicians' perception, as influenced by tests that detect ASCVD, regarding appropriateness of getting to lipid goals and for theoretically accessing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). METHODS: A questionnaire was developed including cases of low to high CV risk, chronic kidney disease (CKD) or type 2 diabetes mellitus (T2DM). Each case was considered with or without angina symptoms and, in turn, whether testing identified previously unknown advanced, early/subclinical or no ASCVD. Synthesis of responses was facilitated by using a scale for perceived appropriateness from 1 (lowest) to 9 (highest). RESULTS: Getting to goal and, if not achieved by statins and/or ezetimibe, accessing PCSK9i was considered appropriate in patients with T2DM with preclinical or advanced ASCVD, patients with moderate or high CV risk and advanced ASCVD, patients with CKD or low CV risk with angina symptoms and advanced ASCVD. For most of the remaining cases adding PCSK9i was considered only possibly appropriate. CONCLUSIONS: Physicians' perception of appropriateness for achieving lipid goals, including access to PCSK9i, is markedly influenced by detection of previously unknown ASCVD. Since these commonly encountered scenarios do not clearly meet current indications for PCSK9i, our data identify pressing areas requiring further research.

Oral Anticoagulation for Stroke Prevention in Canadian Practice: Stroke Prevention and Rhythm Interventions in Atrial Fibrillation (SPRINT-AF) Registry(.).

BACKGROUND: We explored patterns of and factors associated with the use of oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF) in contemporary Canadian practice. METHODS: Phase 1 of the Stroke Prevention and Rhythm Intervention in Atrial Fibrillation (SPRINT-AF) registry was a cross-sectional retrospective study of patients with nonvalvular AF (NVAF). From December 2012-July 2013, 936 consecutive patients with NVAF were enrolled in SPRINT-AF. Of the 782 patients treated with OAC, the proportion treated with warfarin and a new oral anticoagulant (NOAC) was 53.2% and 46.8%, respectively. The rate of OAC use was 90.9% among patients with a CHADS2 (Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack) score ≥ 2. RESULTS: On multivariable analysis, the 2 strongest factors associated with NOAC use (compared with warfarin use) were an improved side effect profile (as perceived by the patient) and improved efficacy (as perceived by the physician) (odds ratio [OR], 0.10; 95% confidence interval [CI], 0.06-0.17; P < 0.01 and OR, 0.52; 95% CI, 0.36-0.76; P < 0.01, respectively). Lower cost was strongly associated with warfarin use (OR, 5.16; 95% CI, 3.49-7.63; P < 0.01). CONCLUSIONS: In this contemporary Canadian AF registry, the rate of guideline-concordant OAC use was high. About half of OAC-treated patients received NOACs. Patient- and physician-driven preferences, such as side effect profile, perceived greater efficacy, and cost, were strong determinants of NOAC use over warfarin use.

Impact of job and marital strain on ambulatory blood pressure results from the double exposure study.

BACKGROUND: Psychosocial stressors such as job strain and marital stress have been associated with a sustained increase in blood pressure (BP). METHODS: We evaluated whether job strain and marital cohesion were associated with ambulatory BP in workers with normal or untreated elevated BP using baseline data from the Double Exposure study. The study population included 248 male and female volunteers who were nonmedicated, employed, and living with a significant other, all for a minimum of 6 months. Blood pressure was measured with an ambulatory BP monitor and participants completed a diary that recorded time during work, spousal contact, and sleep. Job strain and marital cohesion were calculated from the Job Content Questionnaire and the Dyadic Adjustment Scale, respectively. RESULTS: Of the subjects, 54.4% were female with a mean age of 50.8 years (6.6, SD). In all, 21.3% reported job strain. Significant assocations were found between 24-h systolic BP (SBP) and alcohol consumption (P = .033), job strain (P = .007), male gender (P = .004), and age (P = .039) and was inversely associated with exercise (P = .037). An interaction between 24-h SBP, job strain, and marital cohesion was found such that greater marital cohesion was associated with lower SBP in subjects with job strain. CONCLUSIONS: Psychosocial factors may influence the development of early hypertension. This should be clarified by the cohort phase of the Double Exposure study.

Contemporary Management and Control of Uncomplicated Hypertension in Canada: Insight From the Primary Care Audit of Global Risk Management (PARADIGM) Study.

BACKGROUND: Although clinical practice guidelines for the management of hypertension exist in Canada, the rate of contemporary blood pressure (BP) control remains unclear. METHODS: In the Primary Care Audit of Global Risk Management (PARADIGM) study, 3015 healthy, middle-aged Canadians, free of cardiovascular disease (CVD) or diabetes were evaluated. In this analysis, we characterized the CVD risk factors, treatment patterns, and BP control rates in subjects with uncomplicated hypertension. RESULTS: A total of 917 subjects (30.4%) had a diagnosis of hypertension. The median age was 59 ± 8 years. The mean treated systolic/diastolic BP were 134 ± 14 mm Hg/82 ± 9 mm Hg, respectively. CVD risk factors included past/current smoking (35.9%), abdominal obesity (62.5%), and dyslipidemia (59.4%). Using the Framingham Risk Score, 20.4%, 41.0%, and 38.5% of the subjects were at low, intermediate, and high risk, respectively. Of the 88% with treated hypertension, 46.9%, 38.7%, and 14.3% received 1, 2, or ≥3 drugs, respectively. The rate of BP control was 57.4% (systolic BP < 140 and diastolic BP < 90 mm Hg). The rate of BP control was lower in patients prescribed diuretic monotherapy (53.2%) vs those who received angiotensin converting enzyme inhibitor/angiotensin receptor blocker monotherapy (66.5%; P < 0.01). Importantly, BP control deteriorated with increasing Framingham Risk Score, and was lower in patients with metabolic syndrome vs those without (P < 0.00001 for both). CONCLUSIONS: PARADIGM demonstrated that CVD risk factors are prevalent in Canadians with uncomplicated hypertension. BP control was modest (57.4%) and was lowest in patients prescribed diuretic monotherapy and in those at highest CVD risk. Despite the success of national hypertension strategies, enhanced efforts are warranted to improve BP control in Canada.

Primary prevention of cardiovascular disease: global cardiovascular risk assessment and management in clinical practice.

AIMS: For the primary prevention of cardiovascular disease, the Framingham Risk Score (FRS) is the most well-known risk prediction method. However, there are limited data regarding physicians' method of risk assessment and guideline adherence in clinical practice. METHODS AND RESULTS: In the PARADIGM (Primary cARe AuDIt of Global risk Management) study (March 2009-10), 105 primary care physicians across Canada prospectively collected data for 3015 patients (mean age 56 years, 59% men) without known cardiovascular disease, diabetes, or lipid-lowering medications at baseline. For each patient, the treating physician determined their cardiovascular risk, and reported the risk stratification method and subsequent treatment decisions. Kappa statistics assessed the agreement between the study-calculated FRS and the treating physician's reported risk assessment. The FRS was the most commonly reported risk assessment method, but was used in only 34.0% of patients. Regardless of the method used (even if the FRS was reportedly used), there was only fair agreement between the risk stratification as reported by the physician and the study-calculated FRS. Moreover, physicians recommended statin initiation in 92% of all patients that they identified as high risk; however, according to the study-calculated FRS, only 56% of the truly high-risk patients were recommended statin therapy. CONCLUSION: For the primary prevention of cardiovascular disease, these findings indicate a need to improve risk assessment and stratification, as misclassification directly contributes to suboptimal risk factor management in real-world clinical practice. Future studies should establish the optimal risk stratification method with quality improvement strategies for its subsequent implementation. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT00950703; NCT00950703.

Perceptions of Canadian primary care physicians towards cardiovascular risk assessment and lipid management.

BACKGROUND: Cardiovascular (CV) risk stratification remains the cornerstone of preventive cardiology. This study was performed to gain insight into how Canadian primary care physicians (PCPs) incorporate traditional and emerging risk factors in determining risk. METHODS: Using a tested questionnaire, this cross-sectional survey evaluated the perceptions of 846 PCPs (38% response rate) on CV risk assessment, treatment thresholds, and novel biomarkers of vascular risk. RESULTS: Most physicians (74%) perform CV risk assessment in eligible patients annually with 69% using the Framingham Risk Score (FRS). Although 89% of the physicians knew that FRS estimates 10-year risk of coronary heart disease death and myocardial infarction, 30% could not characterize FRS thresholds for high risk. Only 44% correctly used a positive family history to double the FRS. Waist circumference was considered by 79% of the physicians as a vital sign but only 6% reported measuring this routinely. Carotid ultrasound was identified by 55% as the preferred imaging technique for screening in primary prevention. Although 99% had heard of high sensitivity C-reactive protein (hs-CRP), only 49% measured it for the purposes of assessing CV risk and 27% were unsure under what clinical scenarios the test is indicated. CONCLUSIONS: Our survey suggests that FRS is employed by approximately 2/3 of Canadian PCPs for risk stratification. Family history and central obesity are considered important additional CV risk markers. There are substantial knowledge gaps on the appropriate use of family history and hs-CRP in risk stratification, particularly in patients who may not present with hyperlipidemia.