Prediction of individualized lifetime benefit from cholesterol lowering, blood pressure lowering, antithrombotic therapy, and smoking cessation in apparently healthy people.

AIMS: The benefit an individual can expect from preventive therapy varies based on risk-factor burden, competing risks, and treatment duration. We developed and validated the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model for the estimation of individual-level 10 years and lifetime treatment-effects of cholesterol lowering, blood pressure lowering, antithrombotic therapy, and smoking cessation in apparently healthy people. METHODS AND RESULTS: Model development was conducted in the Multi-Ethnic Study of Atherosclerosis (n = 6715) using clinical predictors. The model consists of two complementary Fine and Gray competing-risk adjusted left-truncated subdistribution hazard functions: one for hard cardiovascular disease (CVD)-events, and one for non-CVD mortality. Therapy-effects were estimated by combining the functions with hazard ratios from preventive therapy trials. External validation was performed in the Atherosclerosis Risk in Communities (n = 9250), Heinz Nixdorf Recall (n = 4177), and the European Prospective Investigation into Cancer and Nutrition-Netherlands (n = 25 833), and Norfolk (n = 23 548) studies. Calibration of the LIFE-CVD model was good and c-statistics were 0.67-0.76. The output enables the comparison of short-term vs. long-term therapy-benefit. In two people aged 45 and 70 with otherwise identical risk-factors, the older patient has a greater 10-year absolute risk reduction (11.3% vs. 1.0%) but a smaller gain in life-years free of CVD (3.4 vs. 4.5 years) from the same therapy. The model was developed into an interactive online calculator available via www.U-Prevent.com. CONCLUSION: The model can accurately estimate individual-level prognosis and treatment-effects in terms of improved 10-year risk, lifetime risk, and life-expectancy free of CVD. The model is easily accessible and can be used to facilitate personalized-medicine and doctor-patient communication.

Prevalence and Prognostic Implications of Coronary Artery Calcification in Low-Risk Women: A Meta-analysis.

Importance: The role of coronary artery calcium (CAC) testing for guiding preventive strategies among women at low cardiovascular disease (CVD) risk based on the American College of Cardiology and American Heart Association CVD prevention guidelines is unclear. Objective: To assess the potential utility of CAC testing for CVD risk estimation and stratification among low-risk women. Design, Setting, and Participants: Women with 10-year atherosclerotic CVD (ASCVD) risk lower than 7.5% from 5 large population-based cohorts: the Dallas Heart Study (United States), the Framingham Heart Study (United States), the Heinz Nixdorf Recall study (Germany), the Multi-Ethnic Study of Atherosclerosis (United States), and the Rotterdam Study (the Netherlands). The 5 cohorts were selected based on the availability of CAC data in a sizable group of low-risk women from the general population together with the long detailed follow-up data. Across the cohorts, events were assessed from the date of CAC scan (performed from 1998 through 2006) until January 1, 2012; January 1, 2014; or March 6, 2015. Fixed-effects meta-analysis was conducted to combine the results of the 5 studies. Exposures: CAC score by computed tomography. Main Outcomes and Measures: Main outcome was incident ASCVD, including nonfatal myocardial infarction, coronary heart disease (CHD) death, and stroke. Association of CAC with ASCVD was examined using Cox proportional hazards models. To assess whether CAC was associated with improved ASCVD risk predictions beyond the traditional risk factors, the C statistic and the continuous net reclassification improvement (cNRI) index were calculated. Results: Among 6739 women with low ASCVD risk from the 5 studies, mean age ranged from 44 to 63 years and CAC was present in 36.1%. Across the cohorts, median follow-up ranged from 7.0 to 11.6 years. A total of 165 ASCVD events occurred (64 nonfatal myocardial infarctions, 29 CHD deaths, and 72 strokes), with the ASCVD incidence rates ranging from 1.5 to 6.0 per 1000 person-years. Compared with the absence of CAC (CAC = 0), presence of CAC (CAC >0) was associated with an increased risk of ASCVD (incidence rates per 1000 person-years, 1.41 for CAC absence vs 4.33 for CAC presence; difference, 2.92 [95% CI, 2.02-3.83]; multivariable-adjusted hazard ratio, 2.04 [95% CI, 1.44-2.90]). The addition of CAC to traditional risk factors improved the C statistic from 0.73 (95% CI, 0.69-0.77) to 0.77 (95% CI, 0.74-0.81) and provided a cNRI of 0.20 (95% CI, 0.09-0.31) for ASCVD prediction. Conclusions and Relevance: Among women at low ASCVD risk, CAC was present in approximately one-third and was associated with an increased risk of ASCVD and modest improvement in prognostic accuracy compared with traditional risk factors. Further research is needed to assess the clinical utility and cost-effectiveness of this additional accuracy.

Left atrial size quantification using non-contrast-enhanced cardiac computed tomography - association with cardiovascular risk factors and gender-specific distribution in the general population: the Heinz Nixdorf Recall study.

BACKGROUND: Left atrial (LA) size is associated with cardiovascular mortality and morbidity. Once cardiac computed tomography (CT) is performed, information on LA size is readily available without additional contrast media or radiation exposure. PURPOSE: To determine the association of CT-derived LA area and body surface area-adjusted (BSA) LA index with cardiovascular risk factors and describe age- and gender-specific normative values in a general population cohort. MATERIAL AND METHODS: This study included 3945 participants (mean age, 59 ± 8 years; 53% women) from the community-based Heinz Nixdorf Recall Study. LA area in an axial image at the level of the mitral valve was quantified from non-contrast-enhanced electron-beam CT by manual delineations of the boundaries of the LA with exclusion of subjects with prevalent cardiovascular disease. Definition of normative values was performed in subjects without predictors of LA enlargement. RESULTS: LA quantification was feasible in all subjects. Men had larger LA size (1856 mm(2) vs. 1677 mm(2), P < 0.0001), while after adjustment for BSA, this effect was inverted (910 mm(2)/m(2) vs. 933 mm(2)/m(2) for men and women, P < 0.0001). Determinants of body size were major predictors of LA size (body mass index [BMI]: R(2) = 0.195, BSA: R(2 )= 0.216, both P < 0.0001). Blood pressure was associated with LA size (parameter-estimate [95% confidence interval] = 51.0 (4.9-57.1) mm(2)/10 mmHg for systolic, 31.4 (25.4-37.4) mm(2)/5 mmHg for diastolic blood pressure, 214.6 (186.9-242.3) mm(2) for antihypertensive medication, P < 0.0001 for all). Cholesterol levels, lipid-lowering therapy, and diabetes were associated with LA in univariable analysis, however, correlations were low (r(2 )≤ 0.026). Current smoking was associated with reduced LA size (-115.9 [-149.0 - -82.8] mm(2), P < 0.0001). In multivariable regression, BMI, blood pressure, antihypertensive medication, and smoking remained associated with LA size (P < 0.005). CONCLUSION: Non-contrast-enhanced cardiac CT enables LA quantification with body size, hypertension, and smoking status being predictors of LA size.

Update of the effect estimates for common variants associated with carotid intima media thickness within four independent samples: The Bonn IMT Family Study, the Heinz Nixdorf Recall Study, the SAPHIR Study and the Bruneck Study.

Carotid intima media thickness (cIMT) is a marker for subclinical atherosclerosis. The most recent genome-wide association meta-analysis (GWAMA) from the CHARGE consortium identified four genomic regions showing either significant (ZHX2, APOC1, PINX1) or suggestive evidence (SLC17A4) for an association. Here we assess these four cIMT loci in a pooled analysis of four independent studies including 5446 individuals by providing updated unbiased effect estimates of the cIMT association signals. The pooled estimates of our four independent samples pointed in the same direction and were similar to those of the GWAMA. When updating the independent second stage replication results from the earlier CHARGE GWAMA by our estimates, effect size estimates were closer to those of the original CHARGE discovery. A fine-mapping approach within a ±50 kb region around each lead SNP from CHARGE revealed 27 variants with larger estimated effect sizes than the lead SNPs but only three of them showed a r(2) > 0.40 with these respective lead SNPs from CHARGE. Some variants are located within potential functional loci.

Use of aspirin combinations with caffeine and increasing headache frequency: a prospective population-based study.

Combinations of analgesics with caffeine have been discussed as bearing a risk for headache chronicity. We investigated whether aspirin with caffeine (ASA+) increases headache frequency compared with aspirin alone in migraine, tension-type headache (TTH), and migraine + TTH (MigTTH). The population-based German Headache Consortium Study, which included participants aged 18 to 65 years, collected information about headache and analgesics at baseline (2003-2007, t0, response rate: 55.2%), first follow-up after 1.87 ± 0.39 years (t1, 37.2%), and second follow-up after 3.26 ± 0.60 years (t2, 38.8%). We included participants with headache at t0, aspirin intake, ASA+ or no analgesics at t0 and t2, and known headache frequency. Linear regression was used to estimate changes of headache frequency (Δt2-t0) and 95% confidence intervals depending on analgesic intake, stratified by headache subtypes, adjusting for sex, age, analgesics at t1, changes of headache frequency at t1, drinking, smoking, body mass index, education, headache frequency at t0. Of 509 participants (56.0% women, 42.0 ± 11.8 years [mean ± SD]), 45.2% reported aspirin intake (41.3 ± 10.9 years, 59.6% women, headache days at t0: 2.8 ± 3.1 d/mo, t2: 3.6 ± 4.1 d/mo), 11.8% ASA+ intake (46.0 ± 9.8 years, 73.3%, t0: 4.8 ± 6.1 d/mo, t2: 5.3 ± 5.1 d/mo), and 43.0% no analgesics (41.6 ± 13.1 years, 47.5%, t0: 3.8 ± 6.2 d/mo, t2: 5.3 ± 6.6 d/mo). There was no increase in headache frequency in participants with ASA+ intake compared with aspirin (adjusted, all headache: -0.34 d/mo [95% confidence intervals: -2.50 to 1.82], migraine: -1.36 d/mo [-4.76 to 2.03], TTH: -0.57 d/mo [-4.97 to 3.84], MigTTH: 2.46 d/mo [-5.19 to 10.10]) or no analgesics (all headache: -2.24 d/mo [-4.54 to 0.07], migraine: -3.77 d/mo [-9.22 to 1.68], TTH: -4.68 d/mo [-9.62 to 0.27]; MigTTH: -3.22 d/mo [-10.16 to 3.71]). In our study, ASA+ intake did not increase headache frequency compared with aspirin or no analgesics.

Association of computed tomography-derived left ventricular size with major cardiovascular events in the general population: the Heinz Nixdorf recall study.

OBJECTIVE: To investigate the relationship between LV size as determined by non-contrast enhanced cardiac CT with incident cardiovascular disease in the general population free of clinical cardiovascular disease. METHODS: LV axial area was quantified from non-contrast CT in axial, end-diastolic images at a mid-ventricular slice in participants from the population-based Heinz Nixdorf recall study, free of cardiovascular disease (n=3926, 59±8years, 53%female). LV size index (LVI) was defined as the quotient of LV area and body surface area. Major CV events (coronary events, stroke, CV death) were assessed during follow-up. Association of LVI with events was assessed using Cox regression analysis in unadjusted and multivariable adjusted models. RESULTS: During 8.0±1.5years of follow-up, 219 subjects developed a major CV event. Those with events had larger LVI at baseline (2258±352 vs. 2149±276 mm2/m2, p<0.0001). In univariate analysis, increase of LVI by 1 standard deviation was associated with 40% higher risk of events (HR(95%CI):1.41(1.26-1.59), p<0.0001). Associations remained statistically significant after adjustment for CV risk factors (1.24(1.10-1.40), p=0.0007) and when further adjusting for CAC (1.21(1.07-1.37), p=0.003). There was a trend towards stronger association for subjects with low CAC-score (CAC<100:1.41(1.16-1.71), p=0.0005, CAC≥100:1.24(1.06-1.44), p=0.006) in univariate analysis which persisted after multivariable adjustment (CAC<100: 1.41(1.14-1.73), p=0.001, CAC≥100: 1.12(0.96-1.31), p=0.16). CONCLUSION: CT-derived LV size is associated with incident major CV events independent of traditional risk factors and CAC-score in a population-based cohort and may improve the prediction of hard events especially in subjects with low CAC-scores.

Association of computed tomography-derived left atrial size with major cardiovascular events in the general population: the Heinz Nixdorf Recall Study.

BACKGROUND: Echocardiography based data suggests that left atrial (LA) size is associated with cardiovascular morbidity and mortality. Once non-contrast cardiac CT is performed for prevention purposes, information on the LA is readily available. We aimed to determine whether LA area from non-contrast cardiac CT is associated with incident major cardiovascular (CV) events, independent of CV risk factors and coronary artery calcium (CAC), based on a general population cohort. METHODS: Subjects aged 45-75 years without prevalent CV disease from the population-based Heinz Nixdorf Recall Study were enrolled between 2000 and 2003. LA area at the level of the mitral valve was quantified from non-contrast cardiac CT. Major CV events (coronary event, stroke, CV death) were assessed during follow-up. The association of LA with events was assessed using Cox regression analysis. RESULTS: Overall, 3958 subjects (59.2 ± 7.7 years, 53% female) were included. Mean LA area was 17.64 ± 4.22 cm(2) (range: 7.16-44.13 cm(2)). During 8.0 ± 1.5 years of follow-up, 221 major CV events occurred. In univariate analysis, increase of LA size by 1 standard deviation was associated with nearly 50% excess events (HR (95%CI): 1.48 (1.32-1.65)), which remained significant after adjustment for CV risk factors (HR (95%CI): 1.25 (1.09-1.43)) and when additionally adjusting for CAC (HR (95%CI): 1.22 (1.07-1.40)). Associations for LA size were similar for each endpoint and again independent of risk factors and CAC (coronary event: HR (95%CI): 1.21 (1.01-1.45); stroke: 1.31 (1.05-1.63); CV death: 1.33 (1.03-1.71)). CONCLUSION: LA size is associated with incident major CV events independent of risk factors and CAC-score. Once cardiac CT imaging is performed, assessment of LA size may complement information of this imaging modality.

B-type natriuretic peptide: distribution in the general population and the association with major cardiovascular and coronary events--the Heinz Nixdorf Recall Study.

BACKGROUND: A B-type natriuretic peptide (BNP) threshold of 100 pg/ml is used in practice for identification of heart failure, but data about the "normal" distribution of BNP in a large population in primary prevention are rare. We aimed to characterize the BNP distribution in a healthy subset of a population-based cohort and to evaluate the association of elevated BNP levels with major events. METHODS: In a first step, we determined gender-specific distribution and 90th percentiles of BNP in participants who were at baseline free from known determinants of increased BNP, i.e. cardiovascular disease, hypertension or chronic kidney disease. Consecutively, the association of BNP levels above these 90th percentiles with subsequent cardiovascular and coronary events was assessed in the entire cohort. RESULTS: In the BNP-normal sub-sample (n = 1,639), we defined gender-specific 90th percentile of BNP (31.3 pg/ml for men, 45.5 pg/ml for women). From overall 3,697 subjects (mean age 59.4, 52.4 % female), 194 subjects developed a major cardiovascular event and 122 myocardial infarction during a mean follow-up period of 8.0 ± 1.5 years. The 90th percentiles derived from the normal subset as threshold showed strong associations with major events in the entire cohort even after adjusting for traditional risk factors: hazard ratio (95% CI): 1.86 (1.37; 2.53), p < 0.0001 for cardiovascular, and 1.77 (1.19; 2.62), p = 0.005 for coronary events. CONCLUSION: The gender-specific 90th percentile of BNP (31 pg/ml for males and 45 pg/ml for females) obtained from a BNP-normal sub-sample is associated with incident major cardiovascular and coronary events, suggesting that even BNP values lower than 100 pg/ml could imply prognostic information in the general population.