The 2013 guidelines of the American College of Cardiology and the American Heart Association (ACC-AHA) for the treatment of cholesterol expand the indications for statin therapy for the prevention of ...cardiovascular disease.
Using data from the National Health and Nutrition Examination Surveys of 2005 to 2010, we estimated the number, and summarized the risk-factor profile, of persons for whom statin therapy would be recommended (i.e., eligible persons) under the new ACC-AHA guidelines, as compared with the guidelines of the Third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program, and extrapolated the results to a population of 115.4 million U.S. adults between the ages of 40 and 75 years.
As compared with the ATP-III guidelines, the new guidelines would increase the number of U.S. adults receiving or eligible for statin therapy from 43.2 million (37.5%) to 56.0 million (48.6%). Most of this increase in numbers (10.4 million of 12.8 million) would occur among adults without cardiovascular disease. Among adults between the ages of 60 and 75 years without cardiovascular disease who are not receiving statin therapy, the percentage who would be eligible for such therapy would increase from 30.4% to 87.4% among men and from 21.2% to 53.6% among women. This effect would be driven largely by an increased number of adults who would be classified solely on the basis of their 10-year risk of a cardiovascular event. Those who would be newly eligible for statin therapy include more men than women and persons with a higher blood pressure but a markedly lower level of low-density lipoprotein cholesterol. As compared with the ATP-III guidelines, the new guidelines would recommend statin therapy for more adults who would be expected to have future cardiovascular events (higher sensitivity) but would also include many adults who would not have future events (lower specificity).
The new ACC-AHA guidelines for the management of cholesterol would increase the number of adults who would be eligible for statin therapy by 12.8 million, with the increase seen mostly among older adults without cardiovascular disease. (Funded by the Duke Clinical Research Institute and others.).
Many young adults with moderate hyperlipidemia do not meet statin treatment criteria under the new American Heart Association/American College of Cardiology cholesterol guidelines because they focus ...on 10-year cardiovascular risk. We evaluated the association between years of exposure to hypercholesterolemia in early adulthood and future coronary heart disease (CHD) risk.
We examined Framingham Offspring Cohort data to identify adults without incident cardiovascular disease to 55 years of age (n=1478), and explored the association between duration of moderate hyperlipidemia (non-high-density lipoprotein cholesterol ≥ 160 mg/dL) in early adulthood and subsequent CHD. At median 15-year follow-up, CHD rates were significantly elevated among adults with prolonged hyperlipidemia exposure by 55 years of age: 4.4% for those with no exposure, 8.1% for those with 1 to 10 years of exposure, and 16.5% for those with 11 to 20 years of exposure (P<0.001); this association persisted after adjustment for other cardiac risk factors including non-high-density lipoprotein cholesterol at 55 years of age (hazard ratio, 1.39; 95% confidence interval, 1.05-1.85 per decade of hyperlipidemia). Overall, 85% of young adults with prolonged hyperlipidemia would not have been recommended for statin therapy at 40 years of age under current national guidelines. However, among those not considered statin therapy candidates at 55 years of age, there remained a significant association between cumulative exposure to hyperlipidemia in young adulthood and subsequent CHD risk (adjusted hazard ratio, 1.67; 95% confidence interval, 1.06-2.64).
Cumulative exposure to hyperlipidemia in young adulthood increases the subsequent risk of CHD in a dose-dependent fashion. Adults with prolonged exposure to even moderate elevations in non-high-density lipoprotein cholesterol have elevated risk for future CHD and may benefit from more aggressive primary prevention.
Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, ...several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications.
We generated Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. Treatment increased mean survival by 1.6 years.
This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease.
http://www.clinicaltrials.gov. Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747.
The Role of Physicians in the Era of Predictive Analytics Sniderman, Allan D; D'Agostino, Sr, Ralph B; Pencina, Michael J
JAMA : the journal of the American Medical Association,
2015-Jul-07, Volume:
314, Issue:
1
Journal Article
To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the ...associations of key modifiable CHD risk factors-specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking-with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age.
Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non-high-density lipoprotein cholesterol (non-HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed.
Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non-HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non-HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to <130 mm Hg or lowering low-density lipoprotein cholesterol by 30% would be expected to lower a baseline 10-year CHD risk of 10.7% to 7.0 and 8.0, respectively (absolute risk reductions: 3.7% and 2.7%, respectively). Prognostic performance decreases with age (C indices for age groups 45-54, 55-64, 65-74, 75-84 are 0.75, 0.72, 0.66, and 0.62, respectively), whereas absolute risk reductions increase (SBP: 1.1%, 2.3%, 5.4%, 10.3%, respectively; non-HDL-C: 1.1%, 2.0%, 3.7%, 5.9%, respectively).
Although individual modifiable CHD risk factors contribute only modestly to prognostic performance, our models indicate that eliminating or controlling these individual factors would lead to substantial reductions in total population CHD events. Metrics used to judge importance of risk factors should be tailored to the research objectives.
Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA yielding the farnesylated aberrant protein progerin. Without ...progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation.
Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial.
No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (P<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%; P=0.001) and femoral (0% to 12%; P=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%; P=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial.
Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid.
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.
Marked reductions in cardiovascular disease (CVD) morbidity and mortality have occurred in the United States over the last 50 years. We tested the hypothesis that the relative burden of CVD ...attributable to diabetes mellitus (DM) has increased over the past 5 decades.
Participants aged 45 to 64 years from the Framingham Heart Study, who attended examinations in an "early" time period (1952 to 1974), were compared with those who attended examinations in a later time period (1975 to 1998). The risk of CVD events (n=133 among those with and 1093 among those without DM) attributable to DM in the 2 time periods was assessed with Cox proportional hazards models; population attributable risk of DM as a CVD risk factor was calculated for each time period. The age- and sex-adjusted hazard ratio for DM as a CVD risk factor was 3.0 (95% CI, 2.3 to 3.9) in the earlier time period and 2.5 (95% CI, 1.9 to 3.2) in the later time period. The population attributable risk for DM as a CVD risk factor increased from 5.4% (95% CI, 3.8% to 6.9%) in the earlier time period to 8.7% (95% CI, 5.9% to 11.4%) in the later time period (P for attributable risk ratio=0.04), although multivariable adjustment resulted in attenuation of these findings (P=0.12); most of these observations were found among men.
The proportion of CVD attributable to DM has increased over the past 50 years in Framingham. These findings emphasize the need for increased efforts to prevent DM and to aggressively treat and control CVD risk factors among those with DM.
The metabolic syndrome may be a common phenotype increasing risk for type 2 diabetes and cardiovascular disease. We assessed the prevalence and characteristics of the metabolic syndrome among ...population-based samples of 3,224 white subjects attending Framingham Offspring Study (FOS) exam 5 (1991-1995) and 1,081 non-Hispanic white and 1,656 Mexican-American subjects attending the San Antonio Heart Study (SAHS) phase II follow-up exam (1992-1996). Subjects were approximately 50% women, aged 30-79 years, without diabetes, and classified with the metabolic syndrome according to criteria for obesity, dyslipidemia, hyperglycemia, and hypertension proposed by the Third Report of the National Cholesterol Education Program's Adult Treatment Panel (ATP III) or the World Health Organization (WHO). We used regression models to estimate rates across ethnic groups and to assess the association of the metabolic syndrome with insulin resistance and predicted 10-year coronary heart disease (CHD) risk. Among FOS white subjects, the age- and sex-adjusted prevalence of the metabolic syndrome was 24% by both ATP III and WHO criteria; among SAHS non-Hispanic white subjects, 23 and 21%, respectively; and among SAHS Mexican-American subjects, 31 and 30%. Rates were highest among Mexican-American women (ATP III, 33%) and lowest among white women (21%). Subjects with the metabolic syndrome by ATP III criteria had higher age-, sex-, and ethnicity-adjusted levels of fasting insulin (11.3 micro U/ml), homeostasis model assessment of insulin resistance (2.7), and predicted CHD risk (11.8%) than those without the syndrome (5.9 micro U/ml, 1.3, and 6.4%, respectively; all P = 0.0001); differences were similar using WHO criteria. We conclude that the metabolic syndrome typically affects 20-30% of middle-aged adults in the U.S. By any criteria, subjects with the metabolic syndrome are more insulin resistant and at increased predicted risk for CHD versus those without the metabolic syndrome.
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