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The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials.

AIMS: The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. METHODS AND RESULTS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98). CONCLUSION: In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not.

Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis.

BACKGROUND: It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. METHODS AND RESULTS: We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.81-0.86 per 1 standard deviation increment), as were apoA-I levels (HR, 0.79; 95% CI, 0.72-0.82). This association was also observed among patients achieving on-statin low-density lipoprotein cholesterol levels <50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR, 0.98; 95% CI, 0.94-1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR, 0.93; 95% CI, 0.90-0.97). CONCLUSIONS: Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low low-density lipoprotein cholesterol. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.

The "New Deadly Quartet" for cardiovascular disease in the 21st century: obesity, metabolic syndrome, inflammation and climate change: how does statin therapy fit into this equation?

Despite population-based improvements in cardiovascular risk factors, such as blood pressure, cholesterol and smoking, cardiovascular disease still remains the number-one cause of mortality in the United States. In 1989, Kaplan coined the term "Deadly Quartet" to represent a combination of risk factors that included upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension [Kaplan in Arch Int Med 7:1514-1520, 1989]. In 2002, the third report of the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP III) essentially added low HDL-C criteria and renamed this the "metabolic syndrome." [The National Cholesterol Education Program (NCEP) in JAMA 285:2486-2497, 2001] However, often forgotten was that a pro-inflammatory state and pro-thrombotic state were also considered components of the syndrome, albeit the panel did not find enough evidence at the time to recommend routine screening for these risk factors [The National Cholesterol Education Program (NCEP) in JAMA 285:2486-2497, 2001]. Now over a decade later, it may be time to reconsider this deadly quartet by reevaluating the roles of obesity and subclinical inflammation as they relate to the metabolic syndrome. To complete this new quartet, the addition of increased exposure to elevated levels of particulate matter in the atmosphere may help elucidate why this cardiovascular pandemic continues, despite our concerted efforts. In this article, we will summarize the evidence, focusing on how statin therapy may further impact this new version of the "deadly quartet".

Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis.

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.govNCT01594333) 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.

The evolution or revolution of statin therapy in primary prevention: where do we go from here?

CHD morbidity and mortality rates have more than halved since their peak in the 1960s and 1970s. This trend is a result of many factors; however, primary prevention provides the bulk of this benefit. Despite this tremendous progress, cardiovascular disease remains the major cause of death and this trend is projected to persist given the continuous growth in those aged 65 years or greater. Although statin therapy has been a main contributor to a primary prevention strategy, there is still controversy about exposing a large healthy population to long-term statin therapy. Advocates contend the mortality benefits from an aggressive statin approach would remove heart disease from its perch as the greatest killer of Americans and stroke mortality would drop from third to fifth place. Those advocating a much more conservative approach contend the data are not available to expose a healthy population to lifelong statin therapy given limited data on mortality, potential adverse events, and considerable costs. Given these opposing views, this summary of the evolution of statin therapy for the primary prevention of cardiovascular disease will review the major factors fueling this debate.

Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.

CONTEXT: The associations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB) levels with the risk of cardiovascular events among patients treated with statin therapy have not been reliably documented. OBJECTIVE: To evaluate the relative strength of the associations of LDL-C, non-HDL-C, and apoB with cardiovascular risk among patients treated with statin therapy. DESIGN: Meta-analysis of individual patient data from randomized controlled statin trials in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. DATA SOURCES: Relevant trials were identified by a literature search updated through December 31, 2011. Investigators were contacted and individual patient data were requested and obtained for 62,154 patients enrolled in 8 trials published between 1994 and 2008. DATA EXTRACTION: Hazard ratios (HRs) and corresponding 95% CIs for risk of major cardiovascular events adjusted for established risk factors by 1-SD increase in LDL-C, non-HDL-C, and apoB. RESULTS: Among 38,153 patients allocated to statin therapy, 158 fatal myocardial infarctions, 1678 nonfatal myocardial infarctions, 615 fatal events from other coronary artery disease, 2806 hospitalizations for unstable angina, and 1029 fatal or nonfatal strokes occurred during follow-up. The adjusted HRs for major cardiovascular events per 1-SD increase were 1.13 (95% CI, 1.10-1.17) for LDL-C, 1.16 (95% CI, 1.12-1.19) for non-HDL-C, and 1.14 (95% CI, 1.11-1.18) for apoB. These HRs were significantly higher for non-HDL-C than LDL-C (P = .002) and apoB (P = .02). There was no significant difference between apoB and LDL-C (P = .21). CONCLUSION: Among statin-treated patients, on-treatment levels of LDL-C, non-HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non-HDL-C than for LDL-C and apoB.

Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.

BACKGROUND: Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes. METHODS: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009, for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ transplants or who needed haemodialysis. We used the I(2) statistic to measure heterogeneity between trials and calculated risk estimates for incident diabetes with random-effect meta-analysis. FINDINGS: We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% CI 1.02-1.17), with little heterogeneity (I(2)=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150-852) patients with statins for 4 years resulted in one extra case of diabetes. INTERPRETATION: Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. FUNDING: None.

Cardiovascular Disease as a Result of the Interactions Between Obesity, Climate Change, and Inflammation: The COCCI Syndemic.

Obesity and climate change conspire to create an environment in which subclinical vascular inflammation leads to progressive atherosclerosis, which contributes to the number 1 cause of global mortality: cardiovascular disease. The syndemic model requires 2 or more diseases or contributors to disease (such as obesity and climate change) clustering within a specific population in addition to the associated societal and social factors, ultimately creating an environment supportive of a greater adverse interaction. This article explores the syndemic of obesity and climate change as a driver for cardiovascular disease.

Public Health and Interprofessional Education as Critical Components in the Evolution of Osteopathic Medical Education.

Public health and interprofessional education (IPE) are included among the osteopathic core competencies and Entrustable Professional Activities that should be reflected in osteopathic medical curricula. Cognizant of the importance of these 2 areas, Touro University College of Osteopathic Medicine-CA (TUCOM) has developed initiatives to advance them on campus as well as within its academic curriculum. The authors acknowledge the importance of incorporating public health content into osteopathic medicine as well as expanding IPE in the health professions as part of a larger project to impart a unique identity and relevance to osteopathic medical education at TUCOM. The authors describe TUCOM's public health and IPE initiatives and outcomes in the context of current and future relevance for osteopathic medicine. Future directions to assess the quality and impact of these programs that may be of value for other colleges of osteopathic medicine are also discussed.

Fundamentals for an Osteopathic Obesity Designed Study: The Effects of Education on Osteopathic Medical Students' Attitudes Regarding Obesity.

CONTEXT: Obesity is a major health concern in the United States, and its prevalence continues to rise. Although it is a common health issue, many people, including health care professionals, are biased against people with obesity. OBJECTIVE: To determine whether a comprehensive obesity curriculum presented to students in medical school can positively influence their attitudes toward obesity. METHODS: The study was designed around a comprehensive educational obesity curriculum at Touro University College of Osteopathic Medicine-CA, involving the classes of 2013 through 2018. A survey to assess student attitudes toward obesity was distributed to first-year students before the curriculum, directly after completion, and each year after until graduation (graduating classes of 2015 through 2018). Second- and third-year medical students in 2011 (graduating classes of 2014 and 2013), who did not complete the curriculum, were given an examination to establish baseline values and served as the control group. The obesity curriculum consisted of lectures delivered during the first and second year of medical school and case study simulations during the third year. Knowledge gained from the curriculum was assessed with a multiple-choice examination, and bias was assessed using the Fat Phobia Scale. RESULTS: A total of 718 first- through fourth-year students were included. Students who completed the first year of the obesity curriculum (n=528) showed significantly greater medical knowledge regarding obesity-related epidemiology, pathogenesis, biochemistry, pathophysiology, and metabolic factors; nutrition, diet, physical activity, self-control, and behavior modification; pharmacologic and nonpharmacologic interventions; and associated chronic disorders, based on their multiple-choice examination scores compared with the control group. The examination scores indicated significant increases in medical knowledge compared with the precurriculum cohort after the curriculum (OMS I students: 130 [72.4%]; 133 [92.6%]; 133 [91.1%]; 132 [89.0%]; vs control: 105 [47.2%]; 134 [52.6%], respectively [P<.01]). In all 4 years observed, there was a significant reduction in bias among first-year medical students after obesity curriculum (before: 3.65, 3.76, 3.57, 3.61, and after: 3.47, 3.38, 3.34, 3.37, respectively) (P<.05). The reduction in bias was also significantly sustained throughout the fourth year. CONCLUSION: A comprehensive obesity curriculum throughout medical school resulted in an improvement in students' attitudes toward and knowledge of obesity.

Conversion of Sugar to Fat: Is Hepatic de Novo Lipogenesis Leading to Metabolic Syndrome and Associated Chronic Diseases?

Epidemiologic studies suggest a link between excess sugar consumption and obesity, fatty liver disease, metabolic syndrome, and type 2 diabetes mellitus. One important pathway that may link these metabolic diseases to sugar consumption is hepatic conversion of sugar to fat, a process known as de novo lipogenesis (DNL). Mechanistic studies have shown that diets high in simple sugars increase both DNL and liver fat. Importantly, removal of sugar from diets of children with obesity for only 9 days consistently reduced DNL and liver fat and improved glucose and lipid metabolism. Although the sugar and beverage industries continue to question the scientific evidence linking high-sugar diets to metabolic diseases, major health organizations now make evidence-based recommendations to limit consumption of simple sugars to no more than 5% to 10% of daily intake. Clear recommendation about moderating sugar intake to patients may be an important nonpharmacologic tool to include in clinical practice.

Plasma homocysteine concentration, statin therapy, and the risk of first acute coronary events.

BACKGROUND: Elevated homocysteine levels are associated with increased coronary risk, and it has been suggested that homocysteine screening may provide a method to identify high-risk patients for aggressive primary prevention. METHODS AND RESULTS: Homocysteine was measured at baseline and after 1 year among 5569 participants in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a randomized trial of lovastatin in the primary prevention of acute coronary events. The effects of homocysteine, LDL cholesterol, and lovastatin on risk were assessed over 5.2 years of trial follow-up. Median baseline homocysteine levels were significantly higher among study participants who subsequently had acute coronary events compared with those who did not (12.1 versus 10.9 micro;mol/L, P<0.001). The relative risks of future events from lowest (referent) to highest quartile of homocysteine were 1.0, 1.6, 1.6, and 2.2 (P<0.001). These effects were similar among those allocated to lovastatin and those allocated to placebo and were modestly attenuated after adjustment for other traditional risk factors. As predicted, the subgroup of participants with elevated LDL cholesterol and elevated homocysteine levels were at high risk and benefited greatly from statin therapy (relative risk, 0.46; 95% CI, 0.29 to 0.75; number needed to treat=26). However, in contrast to findings in this trial for C-reactive protein, homocysteine evaluation did not help to define low LDL subgroups with different responses to lovastatin therapy. CONCLUSIONS: Although homocysteine predicted future coronary events in AFCAPS/TexCAPS, we found little evidence that homocysteine evaluation provided an improved method to target statin therapy among those with low-to-normal LDL cholesterol levels.

Implications from the Air Force/Texas Coronary Atherosclerosis Prevention Study for the Adult Treatment Panel III guidelines.

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) first reported its results in 1998, before the 2001 publication of the National Cholesterol Education Program-Adult Treatment Panel III guidelines (NCEP-ATP III) and 2004 update. Our objective was to investigate the impact of these guidelines on the AFCAPS/TexCAPS cohort. The main outcome measures were the event rates of first acute major coronary events (AMCEs), which were reduced 39% by lovastatin (95% confidence interval [CI] 21% to 53%, p <0.001) in the 65% of the cohort eligible for drug therapy and by 34% (95% CI -9% to 60%, p = 0.108) in the remaining 35% for whom drug therapy was considered optional. The evaluation of other guideline components included a 44% (95% CI 27% to 58%, p <0.001) reduction in AMCEs in subjects with baseline high-density lipoprotein cholesterol <40 mg/dl and a 41% (95% CI 19% to 57%) reduction in AMCEs in subjects with the metabolic syndrome. In the recent update, patients who had a moderately high risk of coronary heart disease and a baseline low-density lipoprotein cholesterol level of 100 to 130 mg/dl could be considered for therapy with a medication to lower the low-density lipoprotein cholesterol level to <100 mg/dl. A total of 334 subjects (5.1%) were in this group, in whom lovastatin reduced the risk of AMCEs by 68% (95% CI 12% to 88%, p = 0.027). However, 21% of the AMCEs were missed by the guidelines. Metabolic syndrome was noted in 48% of these subjects and may help define those in whom treatment with a medication is now considered optional. In conclusion, the ability of the ATP III guidelines and its update has markedly improved our ability to define coronary heart disease risk; however, other components of the guidelines, such as non-high-density lipoprotein cholesterol and the optional low-density lipoprotein cholesterol target goal of <100 mg/dl, still require additional evaluation.

C-reactive protein: a new risk assessment tool for cardiovascular disease.

Recent research has focused on the use of high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, in the detection of patients at increased risk for cardiovascular disease. Several prospective studies have demonstrated that hs-CRP is an independent predictor of future risk for cardiovascular events among healthy individuals, as well as among patients with acute coronary syndromes. In addition, because half of all cardiovascular events occur in persons with low to average levels of low-density lipoprotein cholesterol, hs-CRP may aid in identifying patients at high risk for a first cardiovascular event who might otherwise be missed by lipid screening alone. Thus, hs-CRP is a potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. The Centers for Disease Control and Prevention and the American Heart Association have therefore proposed joint guidelines for the use of hs-CRP in determining cardiovascular disease risk. The author reviews numerous studies examining the prognostic value of hs-CRP and outlines ongoing efforts to assess the effect of statin therapy in healthy individuals with low levels of low-density lipoprotein cholesterol and high levels of hs-CRP.