Bisphosphonates for cardiovascular risk reduction: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Bisphosphonates might be effective in reducing cardiovascular events due to their ability to reduce calcification in arterial walls. We aimed to investigate the effects of treatment with bisphosphonates on the prevention of atherosclerotic processes and cardiovascular disease. METHODS: Pubmed, Embase and the Cochrane Library were systematically reviewed by two independent investigators for randomized controlled studies published up to January 2016, in which the effect of bisphosphonates on arterial wall disease, cardiovascular events, cardiovascular mortality or all-cause mortality were reported. There was no restriction for the type of population used in the trials. Random-effects models were used to calculate the pooled estimates. RESULTS: 61 trials reporting the effects of bisphosphonates on the outcomes of interest were included. Bisphosphonates had beneficial effects on arterial wall disease regarding arterial calcification (pooled mean percentage difference of 2 trials -11.52 (95% CI -16.51 to -6.52, p < 0.01, I(2) 13%), but not on arterial stiffness (pooled mean percentage difference of 2 trials -2.82; 95% CI -10.71-5.07; p = 0.48, I(2) 59%). No effect of bisphosphonate treatment on cardiovascular events was found (pooled RR of 20 trials 1.03; 95% CI 0.91-1.17, I(2) 16%), while a lower risk for cardiovascular mortality was observed in patients treated with bisphosphonates (pooled RR of 10 trials 0.81; 95% CI 0.64-1.02; I(2) 0%) although not statistically significant. Patients treated with bisphosphonates had a reduced risk of all-cause mortality (pooled RR of 48 trials 0.90; 95% CI 0.84-0.98; I(2) 53%). CONCLUSIONS: In this systematic review and meta-analysis it is shown that bisphosphonates reduce arterial wall calcification but have no effect on arterial stiffness or on cardiovascular events. Bisphosphonates tend to reduce the risk of cardiovascular mortality and reduce all-cause mortality in various patient groups, including osteoporosis and cancer patients.

The relation between the presence of cardiovascular disease and vascular risk factors in offspring and the occurrence of new vascular events in their parents already at high vascular risk.

BACKGROUND: For parents at high risk for cardiovascular events, presence of cardiovascular disease or risk factors in their offspring may be an indicator of their genetic load or exposure to (unknown) risk factors and might be related to the development of new or recurrent vascular events. METHODS: In 4,267 patients with vascular disease, hypertension, diabetes, or hypercholesterolemia enrolled in the SMART cohort, the presence of cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, smoking, or overweight) and cardiovascular disease (coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysm) was assessed in their 10,564 children. The relation between presence of cardiovascular disease or cardiovascular risk factors in their offspring and new or recurrent vascular events was determined by Cox proportional hazard analyses. RESULTS: Of the patients, 506 (12%) had offspring with cardiovascular disease, hypertension, hypercholesterolemia, or diabetes. Smoking in offspring was present in 1,972 patients (46%), and overweight in 845 patients (20%). During a median follow-up of 7.0 years (interquartile range 3.7-10.4), the composite outcome of myocardial infarction (MI), stroke, or vascular mortality occurred in 251 patients. Patients with offspring with cardiovascular disease, hypertension, hypercholesterolemia, or diabetes had an increased risk of vascular mortality (hazard ratio [HR] 2.9, 95% CI 1.2-7.1), MI (HR 1.6, 95% CI 1.1-2.5), and the composite outcome (HR 1.5, 95% CI 1.1-2.2). Diabetes in offspring was related to an increased risk of the composite outcome (HR 2.7, 95% CI 1.5-5.0), MI (HR 3.3, 95% CI 1.7-6.6), and vascular mortality (HR 3.4, 95% CI 0.8-14.8). Smoking and overweight in offspring were not related to increased vascular risk in parents. CONCLUSIONS: Presence of cardiovascular disease, hypertension, hypercholesterolemia, and diabetes in offspring, with diabetes mellitus being the most contributing cardiovascular risk factor, is related to an increased risk of developing new or subsequent vascular events in patients already at high vascular risk.

Prevalence and risk of cardiovascular risk factors and events in offspring of patients at high vascular risk and effect of location of parental vascular disease.

BACKGROUND: Offspring of patients with cardiovascular disease are at increased risk of developing cardiovascular events. We evaluated whether prevalence of risk factors in offspring of patients with increased cardiovascular risk is higher compared with the general population and whether the risk of cardiovascular events and prevalence of cardiovascular risk factors in offspring is dependent on parental vascular disease location. METHODS: Of 4270 patients enrolled in the SMART cohort we assessed after a follow-up of 7 years (IQR 4-8) the presence of cardiovascular risk factors and disease in their 10,572 children by questionnaire. The SMART patients had symptomatic vascular disease (coronary artery disease (CAD) (n = 1826), cerebrovascular disease (CVD) (n = 637), peripheral artery disease (PAD) (n = 275), abdominal aortic aneurysm (AAA) (n = 98), polyvascular disease (≥ 2 vascular manifestations) (n = 371)) or risk factors (hypercholesterolemia, diabetes, hypertension) (n = 1063). The prevalence of risk factors in offspring was compared with the general population and stratified for parental vascular disease location. The relation between parental vascular disease location and cardiovascular events in offspring was determined by Poisson regression. RESULTS: The offspring had higher prevalence of in particular hypercholesterolemia and hypertension compared with the general population, irrespective of the parental vascular disease location. Higher risks of cardiovascular events compared with offspring of patients without manifest vascular disease were observed in offspring of patients with CAD (PR 1.8, 95%CI 0.9-3.4), CVD (PR 2.4, 95%CI 1.2-4.8), PAD (PR 2.8, 95%CI 1.3-6.4), polyvascular disease (PR 2.5, 95%CI 1.2-5.2), but not with AAA (PR 1.7, 95%CI 0.5-6.1). CONCLUSIONS: In offspring from patients with cardiovascular disease or risk factors, the prevalence of traditional risk factors was higher compared with the general population, independent of the location of vascular disease of the parent. Offspring of patients with PAD had the highest risk of developing vascular disease.

Incremental value of a genetic risk score for the prediction of new vascular events in patients with clinically manifest vascular disease.

BACKGROUND: Several genetic markers are related to incidence of cardiovascular events. We evaluated whether a genetic risk score (GRS) based on 30 single-nucleotide-polymorphisms associated with coronary artery disease (CAD) can improve prediction of 10-year risk of new cardiovascular events in patients with clinical manifest vascular disease. METHODS: In 5742 patients with symptomatic vascular disease enrolled in the SMART study, we developed Cox regression models based on the SMART Risk Score (SRS) and based on the SRS plus the GRS in all patients, in patients with a history of acute arterial thrombotic events and in patients with a history of more stable atherosclerosis and without CAD. The discriminatory ability was expressed by the c-statistic. Model calibration was evaluated by calibration plots. The incremental value of adding the GRS was assessed by net reclassification index (NRI) and decision curve analysis. RESULTS: During a median follow-up of 6.5 years (IQR4.0-9.5), the composite outcome of myocardial infarction, stroke, or vascular death occurred in 933 patients. Hazard ratios of GRS ranging from 0.86 to 1.35 were observed. The discriminatory capacity of the SRS for prediction of 10-year risk of cardiovascular events was fairly good (c-statistic 0.70, 95%CI 0.68-0.72), similar to the model based on the SRS plus the GRS. Calibration of the models based on SRS and SRS plus GRS was adequate. No increase in c-statistics, categorical NRIs and decision curves was observed when adding the GRS. The continuous NRI improved only in patients with stable atherosclerosis (0.14, 95%CI 0.03-0.25), increasing further excluding patients with a history of CAD (0.21, 95%CI 0.06-0.36). CONCLUSIONS: In patients with symptomatic vascular disease, a GRS did not improve risk prediction of 10-year risk of cardiovascular events beyond clinical characteristics. The GRS might improve risk prediction of first vascular events in the subgroup of patients with a history of stable atherosclerosis.

Parental history and the risk of subsequent vascular events in patients with clinically manifest vascular disease: the effects of sex of the parent and vascular disease location.

BACKGROUND: Parental history of cardiovascular disease is a risk factor for first vascular events. It is unknown whether this also holds for subsequent events in patients with vascular disease. Also, the role of the location of parental vascular disease and the sex of the affected parent is unidentified. METHODS: In a cohort of 4529 patients with symptomatic vascular disease enrolled in the Second Manifestations of Arterial Disease (SMART) Study, the relation between parental cardiovascular history under the age of sixty, sex of the parent, location of parental vascular disease (heart, brain, lower extremities) and subsequent myocardial infarction (MI), stroke, vascular death and peripheral artery disease (PAD) was determined by Cox-proportional hazard analyses. RESULTS: During a median follow-up of 4.9 years (interquartile range 2.5-7.0), MI was experienced by 220 patients, stroke by 112, PAD by 297, whereas 371 patients died. A positive parental history of cardiovascular disease, without knowledge of vascular disease location and sex of that particular parent, was not associated with subsequent events (HR1.0; 95%CI 0.8-1.3). For specific types of parental history regarding sex and vascular location, having a father with a history of PAD was related to an increased risk of incident PAD (HR3.1; 95%CI 2.1-4.6). CONCLUSIONS: A positive parental history of cardiovascular disease without information about vascular disease location and sex does not increase the risk of recurrent vascular events in patients with symptomatic vascular disease. Vascular patients with a father with PAD have an increased risk of subsequent peripheral artery disease compared with vascular patients without such a family history.

Low accuracy of tumor markers for diagnosing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 patients.

CONTEXT: The assessment of tumor markers for diagnosing pancreatic neuroendocrine tumors (pNET) in multiple endocrine neoplasia type 1 (MEN1) patients is advised in the current guidelines but has never been validated for this purpose. OBJECTIVE: The objective of the study was to assess the diagnostic accuracy of chromogranin A (CgA), pancreatic polypeptide (PP), and glucagon for pNET in MEN1. DESIGN: This was a diagnostic study. SETTING: The study was conducted at Dutch university medical centers from 2008 to 2011, representing 90% of the total Dutch MEN1 population. PATIENTS AND METHODS: Patients for whom data on tumor markers in combination with the reference standard (ie, radiological imaging) were available between 2008 and 2011 were included. The reference standard for the presence of pNET was pathology or detection on magnetic resonance imaging, computed tomography, or endoscopic ultrasound confirmed on subsequent imaging, irrespective of modality at follow-up. MAIN OUTCOME MEASURES: The area under the receiver-operating characteristic curve (AUC), positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, sensitivity, and specificity were calculated for each marker. RESULTS: For the analysis of PP, CgA, and glucagon, 73, 81, and 94 patients were available, respectively. The AUC for CgA was 0.48 [95% confidence interval (CI) 0.35-0.61] with a sensitivity 0.33 and a specificity 0.73; the AUC for glucagon was 0.58 (95% CI 0.46-0.70) with a sensitivity 0.43 and a specificity 0.73; and the AUC for PP was 0.64 (95% CI 0.50-0.77) with a sensitivity 0.36 and a specificity 0.74. Age, imaging modality, tumor size, and number did not influence the outcomes. CONCLUSION: The diagnostic accuracy of the tumor markers CgA, PP, and glucagon for pNET in MEN1 is low.