Annemarie M.J. Wassink

Estimating treatment effects for individual patients based on the results of randomised clinical trials.

Objectives To predict treatment effects for individual patients based on data from randomised trials, taking rosuvastatin treatment in the primary prevention of cardiovascular disease as an example, and to evaluate the net benefit of making treatment decisions for individual patients based on a predicted absolute treatment effect. Setting As an example, data were used from the Justification for the Use of Statins in Prevention (JUPITER) trial, a randomised controlled trial evaluating the effect of rosuvastatin 20 mg daily versus placebo on the occurrence of cardiovascular events (myocardial infarction, stroke, arterial revascularisation, admission to hospital for unstable angina, or death from cardiovascular causes). Population 17 802 healthy men and women who had low density lipoprotein cholesterol levels of less than 3.4 mmol/L and high sensitivity C reactive protein levels of 2.0 mg/L or more. Methods Data from the Justification for the Use of Statins in Prevention trial were used to predict rosuvastatin treatment effect for individual patients based on existing risk scores (Framingham and Reynolds) and on a newly developed prediction model. We compared the net benefit of prediction based rosuvastatin treatment (selective treatment of patients whose predicted treatment effect exceeds a decision threshold) with the net benefit of treating either everyone or no one. Results The median predicted 10 year absolute risk reduction for cardiovascular events was 4.4% (interquartile range 2.6-7.0%) based on the Framingham risk score, 4.2% (2.5-7.1%) based on the Reynolds score, and 3.9% (2.5-6.1%) based on the newly developed model (optimal fit model). Prediction based treatment was associated with more net benefit than treating everyone or no one, provided that the decision threshold was between 2% and 7%, and thus that the number willing to treat (NWT) to prevent one cardiovascular event over 10 years was between 15 and 50. Conclusions Data from randomised trials can be used to predict treatment effect in terms of absolute risk reduction for individual patients, based on a newly developed model or, if available, existing risk scores. The value of such prediction of treatment effect for medical decision making is conditional on the NWT to prevent one outcome event. Trial registration number Clinicaltrials.gov NCT00239681.

The metabolic syndrome: metabolic changes with vascular consequences

Despite criticism regarding its clinical relevance, the concept of the metabolic syndrome improves our understanding of both the pathophysiology of insulin resistance and its associated metabolic changes and vascular consequences. Free fatty acids (FFA) and tumour necrosis factor‐alpha (TNF‐α) play prominent roles in the development of insulin resistance by impairing the intracellular insulin signalling transduction pathway. Obesity is an independent risk factor for cardiovascular disease and strongly related to insulin resistance. In case of obesity, FFAs and TNF‐α are produced in abundance by adipocytes, whereas the production of adiponectin, an anti‐inflammatory adipokine, is reduced. This imbalanced production of pro‐ and anti‐inflammatory adipokines, as observed in adipocyte dysfunction, is thought to be the driving force behind insulin resistance. The role of several recently discovered adipokines such as resistin, visfatin and retinol‐binding protein (RBP)‐4 in the pathogenesis of insulin resistance is increasingly understood. Insulin resistance induces several metabolic changes, including hyperglycaemia, dyslipidaemia and hypertension, all leading to increased cardiovascular risk. In addition, the dysfunctional adipocyte, reflected largely by low adiponectin levels and a high TNF‐α concentration, directly influences the vascular endothelium, causing endothelial dysfunction and atherosclerosis. Adipocyte dysfunction could therefore be regarded as the common antecedent of both insulin resistance and atherosclerosis and functions as the link between obesity and cardiovascular disease. Targeting the dysfunctional adipocyte may reduce the risk for both cardiovascular disease and the development of type 2 diabetes. Although lifestyle intervention remains the cornerstone of therapy in improving insulin sensitivity and its associated metabolic changes, medical treatment might prove to be important as well.

Metabolic syndrome and the risk of new vascular events and all-cause mortality in patients with coronary artery disease, cerebrovascular disease, peripheral arterial disease or abdominal aortic aneurysm

AIMS To investigate the vascular risk associated with Metabolic Syndrome (MetS) according to different clinical criteria with subsequent vascular events and all-cause mortality in patients with coronary artery disease, cerebrovascular disease, peripheral artery disease or abdominal aortic aneurysm and to examine whether patients with MetS at treatment goals for systolic blood pressure (SBP) or low density lipoprotein-cholesterol (LDL-c) level are still at elevated risk. METHODS AND RESULTS Prospective study of 3196 patients with a history or recent diagnosis of clinically manifest vascular disease. During a median follow-up of 3.2 years (interquartile range 1.4-5.4 years), 331 patients died and 373 patients experienced a first vascular event. National Cholesterol Education Program (NCEP) and revised NCEP (NCEP-R)-defined MetS were related to increased risk of vascular events [HR - hazard ratio 1.50 (95% CI - confidence interval 1.22-1.84) and 1.50 (1.22-1.87)] and all-cause mortality [HR 1.49(1.20-1.84) and 1.43 (1.14-1.78)]. Results were similar in the 2472 patients without type 2 diabetes (DM2) and localization of vascular disease; SBP-category (<140 or > or =140 mmHg) or LDL-category (<2.5 or > or =2.5 mmol/L) did not affect this relation. CONCLUSION In patients with various manifestations of atherosclerosis, presence of NCEP and NCEP-R-defined MetS is associated with increased risk of cardiovascular events and all-cause mortality, independently of the presence of DM2. This risk is significantly higher than the risk associated with International Diabetes Federation-defined MetS. Also in patients at treatment goals for SBP (<140 mmHg) or LDL-c (<2.5 mmol/L) according to current guidelines, presence of NCEP-R-defined MetS points to a higher vascular risk.

Aspirin for primary prevention of vascular events in women: individualized prediction of treatment effects.

AIMS To identify women who benefit from aspirin 100 mg on alternate days for primary prevention of vascular events by using treatment effect prediction based on individual patient characteristics. METHODS AND RESULTS Randomized controlled trial data from the Womens Health Study were used to predict treatment effects for individual women in terms of absolute risk reduction for major cardiovascular events (i.e. myocardial infarction, stroke, or cardiovascular death). Predictions were based on existing risk scores, i.e. Framingham (FRS), and Reynolds (RRS), and on a newly developed prediction model. The net benefit of different aspirin treatment-strategies was compared: (i) treat no one, (ii) treat everyone, (iii) treatment according to the current guidelines (i.e. selective treatment of women >65 years of age or having >10% FRS), and (iv) prediction-based treatment (i.e. selective treatment of patients whose predicted treatment effect exceeds a given decision threshold). The predicted reduction in 10-year absolute risk for major cardiovascular events was <1% in 97.8% of 27 939 study subjects when based on the refitted FRS, in 97.0% when based on the refitted RRS, and in 90.0% when based on the newly developed model. Of the treatment strategies considered, only prediction-based treatment using the newly developed model and selective treatment of women >65 years of age yielded more net benefit than treating no one, provided that the 10-year number-willing-to-treat (NWT) to prevent one cardiovascular event was above 50. CONCLUSION Aspirin was ineffective or even harmful in the majority of patients. Age was positively related to treatment effect, whereas current smoking and baseline risk for cardiovascular events were not. When the NWT is 50 or lower, the aspirin treatment strategy that is associated with optimal net benefit in primary prevention of vascular events in women is to treat none.

Development and validation of a prediction rule for recurrent vascular events based on a cohort study of patients with arterial disease: the SMART risk score

Objectives To enable risk stratification of patients with various types of arterial disease by the development and validation of models for prediction of recurrent vascular event risk based on vascular risk factors, imaging or both. Design Prospective cohort study. Setting University Medical Centre. Patients 5788 patients referred with various clinical manifestations of arterial disease between January 1996 and February 2010. Main outcome measures 788 recurrent vascular events (ie, myocardial infarction, stroke or vascular death) that were observed during 4.7 (IQR 2.3 to 7.7) years’ follow-up. Results Three Cox proportional hazards models for prediction of 10-year recurrent vascular event risk were developed based on age and sex in addition to clinical parameters (model A), carotid ultrasound findings (model B) or both (model C). Clinical parameters were medical history, current smoking, systolic blood pressure and laboratory biomarkers. In a separate part of the dataset, the concordance statistic of model A was 0.68 (95% CI 0.64 to 0.71), compared to 0.64 (0.61 to 0.68) for model B and 0.68 (0.65 to 0.72) for model C. Goodness-of-fit and calibration of model A were adequate, also in separate subgroups of patients having coronary, cerebrovascular, peripheral artery or aneurysmal disease. Model A predicted <20% risk in 59% of patients, 20–30% risk in 19% and >30% risk in 23%. Conclusions Patients at high risk for recurrent vascular events can be identified based on readily available clinical characteristics.

Insulin resistance increases the occurrence of new cardiovascular events in patients with manifest arterial disease without known diabetes. the SMART study.

BackgroundInsulin resistance is accompanied by a cluster of metabolic changes, often referred to as metabolic syndrome. Metabolic syndrome is associated with an increased cardiovascular risk in patients with manifest arterial disease. We investigated whether insulin resistance is associated with an increased risk for cardiovascular events in patients with manifest arterial disease without known diabetes and whether this can be explained by the components of the metabolic syndrome or by inflammation.MethodsProspective cohort study in 2611 patients with manifest arterial disease without known diabetes. Homeostasis model of insulin resistance (HOMA-IR) was used to quantify insulin resistance. The relation of HOMA-IR with cardiovascular events (vascular death, myocardial infarction or stroke) and all cause mortality was assessed with Cox regression analysis. In additional models adjustments were performed for the single components constituting the metabolic syndrome and for inflammation.ResultsHOMA-IR increases with the number of metabolic syndrome components (mean HOMA-IR ± SD in groups with 0, 1, 2, 3, 4 and 5 metabolic syndrome components: 1.4 ± 0.7; 1.8 ± 1.2; 2.4 ± 1.5; 3.1 ± 1.8; 4.0 ± 2.6; and 5.6 ± 3.6 respectively). High HOMA-IR was independently associated with an increased risk of cardiovascular events (tertile 2 vs. 1 HR 1.92; 95%CI 1.20-3.08) (tertile 3 vs.1 HR 1.78; 95%CI 1.10-2.89) and with all cause mortality (tertile 2 vs. 1 HR 1.80; 95%CI 1.04-3.10) (tertile 3 vs.1 HR 1.56; 95%CI 0.88-2.75). These relations were not influenced by the individual components of metabolic syndrome or by inflammation.ConclusionsIn patients with manifest arterial disease without known diabetes, insulin resistance increases with the number of metabolic syndrome components, and elevated insulin resistance increases the risk of new cardiovascular events.

Metabolic syndrome and incidence of type 2 diabetes in patients with manifest vascular disease

Risk reduction in patients with clinically manifest vascular disease focuses on preventing new vascular events and not on prevention of type 2 diabetes. However, given the common pathophysiological pathways involved in the development of atherosclerosis and type 2 diabetes, it is probable that people with atherosclerotic vascular disease have an elevated risk of type 2 diabetes. The present prospective cohort study investigated the incidence of type 2 diabetes and the effect of the presence of metabolic syndrome on the incidence of type 2 diabetes in 4,022 patients with clinically manifest atherosclerosis, included in the study from September 1996 to June 2006. Patients who died (n=456), who were lost to follow-up (n=84) and those with diabetes at baseline (n=558) were excluded, leaving 2,924 patients for analysis. The incidence of diabetes was assessed by questionnaire (self-reported diabetes). During 13,726 person-years of follow-up (median follow-up 4.3 years, range 2.4–7.0 years), there were 152 type 2 diabetes cases (5.2%), corresponding to an incidence rate of 11.1 (95% CI 9.4–13.0) per 1,000 person-years. Patients with metabolic syndrome were at increased risk of incident type 2 diabetes compared to those without metabolic syndrome, with an adjusted hazard ratio of 5.7 (95% CI 3.7–8.9) for Revised National Cholesterol Education Program, 6.0 (4.1–9.0) for National Cholesterol Education Program and 4.0 (2.7–6.1) for International Diabetes Federation definitions of metabolic syndrome. Of all metabolic syndrome components, abdominal obesity was most strongly associated with incident type 2 diabetes (94% higher risk of type 2 diabetes for 1 standard deviation (11.3 cm) increase in waist circumference). In conclusion, patients with manifest atherosclerosis are at high risk of developing type 2 diabetes. Metabolic syndrome identifies those at the highest risk and is an easy to use clinical tool. Abdominal obesity is a strong individual predictor of type 2 diabetes. Patients with manifest atherosclerosis and metabolic syndrome may derive particular benefit from lifestyle interventions focusing on weight reduction.

The risk of resting heart rate on vascular events and mortality in vascular patients

BACKGROUND Resting heart rate (RHR) reflects sympathetic nerve activity and is independently related to the occurrence of cardiovascular events and death in healthy subjects, patients with coronary artery disease (CAD) and patients with cardiovascular risk factors. We investigated and compared the risk of RHR on the occurrence of cardiovascular events and death in patients with CAD, cerebrovascular disease (CVD), peripheral arterial disease (PAD) or abdominal aortic aneurysm (AAA). METHODS Data were used from a prospective cohort study of 4272 patients with manifest vascular disease: CAD (n=2244), CVD (n=930), PAD (n=823) or AAA (n=275). RHR was obtained at baseline from an electrocardiogram. The median follow-up time was 4.4 (interquartile range 2.1-7.4) years. The relation between RHR and the occurrence of cardiovascular events and death was estimated by Cox proportional hazard analyses. RESULTS Each increase in RHR of 10 beats/min was related to an increased risk for all-cause mortality (hazard ratio (HR) 1.14; 95% confidence interval (CI) 1.07-1.21) and vascular mortality (HR 1.15; 95% CI 1.06-1.25), but not for myocardial infarction (HR 1.03; 95% CI 0.94-1.14) or ischemic stroke (HR 1.05; 95% CI 0.92-1.20). The relation between an increased RHR and increased risk for all-cause mortality was present irrespective of beta-blocker use and irrespective of the location of vascular disease: CAD (HR 1.23; 95% CI 1.05-1.44), CVD (HR 1.18; 95% CI 1.05-1.33) and PAD/AAA (HR 1.10; 95% CI 1.01-1.20). CONCLUSIONS Elevated RHR is associated with increased risk for mortality but not for myocardial infarction or stroke in patients with manifest vascular diseases irrespective of location of vascular disease.

Increased visceral adipose tissue is associated with increased resting heart rate in patients with manifest vascular disease.

Abdominal obesity is characterized by sympathetic nerve activation (SNA), probably mediated by elevated insulin and leptin levels. Resting heart rate (RHR) is a marker of sympathetic tone, and independently associated with cardiovascular events and death in various populations. We investigated and quantified the relation between visceral adipose tissue (VAT) and RHR in patients with vascular disease. In 3,723 patients with manifest vascular disease, visceral and subcutaneous fat tissue was measured with ultrasonography. RHR was obtained from an electrocardiogram (ECG). The association between quartiles of VAT and RHR was quantified using linear regression analysis with adjustments for potential confounding factors. Separate analyses were performed for men and women and for location of vascular disease. Visceral fat was categorized into sex‐pooled quartiles (Q) ranging from 2.7–8.0 cm in Q1 (reference) to 9.4–20.6 cm in Q4. High visceral fat thickness was associated with increased RHR, in men (Q4 vs. Q1, β = 4.36; 95% confidence interval (CI) = 3.11–5.61) and women (β = 1.48; 95% CI = −0.70 to 3.66), after full adjustment. Waist circumference and BMI had a significant relation with RHR in men (β = 3.51; 95% CI = 2.21–4.81 and β = 2.80; 95% CI = 1.51–4.08, respectively) but these relations were smaller and not significant in women (β = 0.71; 95% CI = −1.44 to 2.85 and β = 0.24; 95% CI = −1.90 to 2.37, respectively). There was no relation between subcutaneous fat and RHR in men and women. The relation between visceral fat and RHR was similar in patients with different locations of vascular diseases. Increased visceral fat is associated with increased RHR in male and female patients with vascular disease, independent of the location.

Aldosterone, atherosclerosis and vascular events in patients with stable coronary artery disease

BACKGROUND AND AIMS Plasma aldosterone has been associated with all-cause and cardiovascular mortality in high-risk cardiovascular populations, including patients with heart failure, myocardial infarction and high-risk coronary artery disease (CAD) patients. In the present study, we evaluated the association of plasma aldosterone levels with vascular events in a large prospective cohort of stable CAD patients recruited in an outpatient setting. Moreover, we investigated the relationship between aldosterone and atherosclerotic burden. METHODS AND RESULTS Baseline plasma aldosterone levels were measured in 2699 subjects with CAD (mean age 60 ± 10 years, 82% male). During a median follow-up of 4.7 years, 308 (11%) patients died, of which 203 were from a vascular cause. Vascular endpoints of myocardial infarction, ischemic stroke or vascular death occurred in 355 (13%) patients. Multivariable Cox regression analysis was performed, adjusting for multiple confounders. Aldosterone (median 96 pg/mL, interquartile range 70-138 pg/mL, normal range 58-362 pg/mL) was independently associated with major vascular events (hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.13-2.15) and vascular mortality (HR 1.95, 95% CI 1.27-3.00). By multivariable regression analysis, aldosterone was also associated with the presence of atherosclerosis in additional vascular territories (cerebrovascular disease and/or peripheral artery disease) (p=0.026). CONCLUSIONS In patients with stable coronary artery disease, plasma aldosterone is independently associated with the risk of major vascular events and vascular mortality and with atherosclerotic burden.