Hillege, H.L.

A method for the early health technology assessment of novel biomarker measurement in primary prevention programs (Article)

2012-10-15T00:00:00Z

Many promising biomarkers for stratifying individuals at risk of developing a chronic disease or subsequent complications have been identified. Research into the potential cost-effectiveness of applying these biomarkers in actual clinical settings has however been lacking. Investors and analysts may improve their venture decision making should they have indicative estimates of the potential costs and effects associated with a new biomarker technology already at the early stages of its development. To assist in obtaining such estimates, this paper presents a general method for the early health technology assessment of a novel biomarker technology. The setting considered is that of primary prevention programs where initial screening to select high-risk individuals eligible for a subsequent intervention occurs, for example, prevention of type 2 diabetes. The method is based on quantifying the health outcomes and downstream healthcare consumption of all individuals who get reclassified as a result of moving from a screening variant based on traditional risk factors to a screening variant based on traditional risk factors plus a novel biomarker. As these individuals form well-defined subpopulations, a combination of disease progression modeling and sensitivity analysis can be used to perform an initial assessment of the maximum increase in screening cost for which the use of the new biomarker technology is still likely to be cost effective.

ADDIS: A decision support system for evidence-based medicine (Article)

2012-10-15T00:00:00Z

Clinical trials are the main source of information for the efficacy and safety evaluation of medical treatments. Although they are of pivotal importance in evidence-based medicine, there is a lack of usable information systems providing data-analysis and decision support capabilities for aggregate clinical trial results. This is partly caused by unavailability (i) of trial data in a structured format suitable for re-analysis, and (ii) of a complete data model for aggregate level results. In this paper, we develop a unifying data model that enables the development of evidence-based decision support in the absence of a complete data model. We describe the supported decision processes and show how these are implemented in the open source ADDIS software. ADDIS enables semi-automated construction of meta-analyses, network meta-analyses and benefit-risk decision models, and provides visualization of all results.

Deficiencies in the transfer and availability of clinical trials evidence: A review of existing systems and standards (Article)

2012-09-04T00:00:00Z

Background: Decisions concerning drug safety and efficacy are generally based on pivotal evidence provided by clinical trials. Unfortunately, finding the relevant clinical trials is difficult and their results are only available in text-based reports. Systematic reviews aim to provide a comprehensive overview of the evidence in a specific area, but may not provide the data required for decision making. Methods: We review and analyze the existing information systems and standards for aggregate level clinical trials information from the perspective of systematic review and evidence-based decision making. Results: The technology currently used has major shortcomings, which cause deficiencies in the transfer, traceability and availability of clinical trials information. Specifically, data available to decision makers is insufficiently structured, and consequently the decisions cannot be properly traced back to the underlying evidence. Regulatory submission, trial publication, trial registration, and systematic review produce unstructured datasets that are insufficient for supporting evidence-based decision making. Conclusions: The current situation is a hindrance to policy decision makers as it prevents fully transparent decision making and the development of more advanced decision support systems. Addressing the identified deficiencies would enable more efficient, informed, and transparent evidence-based medical decision making.

Multicriteria benefit-risk assessment using network meta-analysis (Article)

2012-04-01T00:00:00Z

Objective: To enable multicriteria benefit-risk (BR) assessment of any number of alternative treatments using all available evidence from a network of clinical trials. Study Design and Setting: We design a general method for multicriteria decision aiding with criteria measurements from Mixed Treatment Comparison (MTC) analyses. To evaluate the method, we apply it to BR assessment of four second-generation antidepressants and placebo in the setting of a published peer-reviewed systematic review. Results: The analysis without preference information shows that placebo is supported by a wide range of possible preferences. Preference information provided by a clinical expert showed that although treatment with antidepressants is warranted for severely depressed patients, for mildly depressed patients placebo is likely to be the best option. It is difficult to choose between the four antidepressants, and the results of the model indicate a high degree of uncertainty. Conclusions: The designed method enables quantitative BR analysis of alternative treatments using all available evidence from a network of clinical trials. The preference-free analysis can be useful in presenting the results of an MTC considering multiple outcomes.

Usefulness of thrombus aspiration for the treatment of coronary stent thrombosis (Article)

2011-12-15T00:00:00Z

Current treatment for coronary stent thrombosis (ST) often lacks satisfactory results and clinical outcome is poor. We investigated the impact of manual thrombus aspiration during percutaneous coronary intervention (PCI) on myocardial reperfusion and clinical outcome in patients with angiographically proved ST. We interrogated our PCI registry for patients with a first stent placement from January 2002 through May 2010 who had undergone an emergency repeated PCI procedure and systematically reviewed coronary angiograms and hospital records for evidence of ST. We identified 113 patients with ST. Thrombus aspiration was used in 51 patients and 62 patients received conventional PCI. Histopathologic analysis of thrombus aspirates was performed in 6 patients. Use of thrombus aspiration predicted postprocedure Thrombolysis In Myocardial Infarction grade 3 flow (odds ratio 3.16, 95% confidence interval 1.22 to 8.17, p = 0.018) and myocardial blush grade 2/3 (odds ratio 3.20, 95% confidence interval 1.20 to 8.55, p = 0.020) after multivariable adjustment with bootstrap model selection. Distal embolization was lower in the thrombus aspiration group compared to the conventional PCI group (14% vs 37%, p = 0.017). In most patients, aspirated thrombus was large and contained platelet and erythrocyte components at histopathologic analysis. Mortality in the thrombus aspiration group and conventional PCI group was 9.8% versus 16% at 30 days (p = 0.351) and 12% versus 21% at 1 year (p = 0.220), respectively. In conclusion, use of manual thrombus aspiration in patients with ST was associated with greater epicardial and microvascular myocardial reperfusion. In addition, mortality was lower in patients treated with thrombus aspiration, although not statistically significant.

Comparison of the temporal release pattern of copeptin with conventional biomarkers in acute myocardial infarction (Article)

2011-12-01T00:00:00Z

Background Early detection of acute myocardial infarction (AMI) using cardiac biomarkers of myocardial necrosis remains limited since these biomarkers do not rise within the first hours from onset of AMI. We aimed to compare the temporal release pattern of the C-terminal portion of provasopressin (copeptin) with conventional cardiac biomarkers, including creatine kinase isoenzyme (CK-MB), cardiac troponin T (cTnT), and high-sensitivity cTnT (hs-cTnT), in patients with ST-elevation AMI. Methods We included 145 patients undergoing successful primary percutaneous coronary intervention (PCI) for a first ST-elevation AMI presenting within 12 h of symptom onset. Blood samples were taken on admission and at four time points within the first 24 h after PCI. Results In contrast to all other markers, copeptin levels were already elevated on admission and were higher with a shorter time from symptom onset to reperfusion and lower systolic blood pressure. Copeptin levels peaked immediately after symptom onset at a maximum of 249 pmol/L and normalized within 10 h. In contrast, CK-MB, cTnT, and hs-cTnT peaked after 14 h from symptom onset at a maximum of 275 U/L, 5.75 lg/L, and 4.16 lg/L, respectively, and decreased more gradually. Conclusions Copeptin has a distinct release pattern in patients with ST-elevation AMI, peaking within the first hour after symptom onset before conventional cardiac biomarkers and falling to normal ranges within the first day. Further studies are required to determine the exact role of copeptin in AMI suspects presenting within the first hours after symptom onset.

Pediatric pulmonary hypertension in the Netherlands: Epidemiology and characterization during the period 1991 to 2005 (Article)

2011-10-18T00:00:00Z

BACKGROUND-: Incidence and prevalence rates for pediatric pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are unknown. This study describes the nationwide epidemiological features of pediatric PH in the Netherlands during a 15-year period and the clinical course of pediatric PAH. METHODS AND RESULTS-: Two registries were used to retrospectively identify children (0-17 years) with PH. Overall, 3263 pediatric patients were identified with PH due to left heart disease (n=160; 5%), lung disease/hypoxemia (n=253; 8%), thromboembolic disease (n=5; <1%), and transient (n=2691; 82%) and progressive (n=154; 5%) PAH. Transient PAH included persistent PH of the newborn and children with congenital heart defects (CHD) and systemic-to-pulmonary shunt, in whom PAH resolved after successful shunt correction. Progressive PAH mainly included idiopathic PAH (n=36; iPAH) and PAH associated with CHD (n=111; PAH-CHD). Pulmonary arterial hypertension associated with CHD represented highly heterogeneous subgroups. Syndromes were frequently present, especially in progressive PAH (n=60; 39%). Survival for PAH-CHD varied depending on the subgroups, some showing better and others showing worse survival than for iPAH. Survival of children with Eisenmenger syndrome appeared worse than reported in adults. For iPAH and PAH-CHD, annual incidence and point prevalence averaged, respectively, 0.7 and 4.4 (iPAH) and 2.2 and 15.6 (PAH-CHD) cases per million children. Compared to studies in adults, iPAH occurred less whereas PAH-CHD occurred more frequently. CONCLUSIONS-: Pediatric PH is characterized by various age-specific diagnoses, the majority of which comprise transient forms of PAH. Incidence of pediatric iPAH is lower whereas incidence of pediatric PAH-CHD is higher than reported in adults. Pediatric PAH-CHD represents a heterogeneous group with highly variable clinical courses.

Response to letter regarding article, "intracoronary versus intravenous administration of abciximab in patients with st-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with thrombus aspiration: The comparison of intracoronary versus intravenous abciximab administration during emergency reperfusion of st-segment elevation myocardial infarction (Article)

2011-08-23T00:00:00Z

Culprit vessel only versus multivessel and staged percutaneous coronary intervention for multivessel disease in patients presenting with ST-segment elevation myocardial infarction: A pairwise and network meta-analysis (Article)

2011-08-09T00:00:00Z

Objectives: The purposes of this study were to investigate whether, in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD), percutaneous coronary intervention (PCI) should be confined to the culprit or also nonculprit vessels and, when performing PCI for nonculprit vessels, whether it should take place during primary PCI or staged procedures. Background: A significant percentage of STEMI patients have MVD. However, the best PCI strategy for nonculprit vessel lesions is unknown. Methods: Pairwise and network meta-analyses were performed on 3 PCI strategies for MVD in STEMI patients: 1) culprit vessel only PCI strategy (culprit PCI), defined as PCI confined to culprit vessel lesions only; 2) multivessel PCI strategy (MV-PCI), defined as PCI of culprit vessel as well as <1 nonculprit vessel lesions; and 3) staged PCI strategy (staged PCI), defined as PCI confined to culprit vessel, after which <1 nonculprit vessel lesions are treated during staged procedures. Prospective and retrospective studies were included when research subjects were patients with STEMI and MVD undergoing PCI. The primary endpoint was short-term mortality. Results: Four prospective and 14 retrospective studies involving 40,280 patients were included. Pairwise meta-analyses demonstrated that staged PCI was associated with lower short- and long-term mortality as compared with culprit PCI and MV-PCI and that MV-PCI was associated with highest mortality rates at both short- and long-term follow-up. In network analyses, staged PCI was also consistently associated with lower mortality. Conclusions: This meta-analysis supports current guidelines discouraging performance of multivessel primary PCI for STEMI. When significant nonculprit vessel lesions are suitable for PCI, they should only be treated during staged procedures.

A stochastic multicriteria model for evidence-based decision making in drug benefit-risk analysis (Article)

2011-05-30T00:00:00Z

Drug benefit-risk (BR) analysis is based on firm clinical evidence regarding various safety and efficacy outcomes. In this paper, we propose a new and more formal approach for constructing a supporting multi-criteria model that fully takes into account the evidence on efficacy and adverse drug reactions. Our approach is based on the stochastic multi-criteria acceptability analysis methodology, which allows us to compute the typical value judgments that support a decision, to quantify decision uncertainty, and to compute a comprehensive BR profile. We construct a multi-criteria model for the therapeutic group of second-generation antidepressants. We assess fluoxetine and venlafaxine together with placebo according to incidence of treatment response and three common adverse drug reactions by using data from a published study. Our model shows that there are clear trade-offs among the treatment alternatives.

Associations between cardiovascular parameters and uteroplacental Doppler (blood) flow patterns during pregnancy in women with congenital heart disease: Rationale and design of the Zwangerschap bij Aangeboren Hartafwijking (ZAHARA) II study (Article)

2011-02-01T00:00:00Z

Background: Previous research has shown that women with congenital heart disease (CHD) are more susceptible to cardiovascular, obstetric, and offspring events. The causative pathophysiologic mechanisms are incompletely understood. Inadequate uteroplacental circulation is an important denominator in adverse obstetric events and offspring outcome. The relation between cardiac function and uteroplacental perfusion has not been investigated in women with CHD. Moreover, the effects of physiologic changes on pregnancy-related events are unknown. In addition, long-term effects of pregnancy on cardiac function and exercise capacity are scarce. Methods: Zwangerschap bij Aangeboren Hartafwijking (ZAHARA) II, a prospective multicenter cohort study, investigates changes in and relations between cardiovascular parameters and uteroplacental Doppler flow patterns during pregnancy in women with CHD compared to matched healthy controls. The relation between cardiovascular parameters and uteroplacental Doppler flow patterns and the occurrence of cardiac, obstetric, and offspring events will be investigated. At 20 and 32 weeks of gestation, clinical, neurohumoral, and echocardiographic evaluation and fetal growth together with Doppler flow measurements in fetal and maternal circulation are performed. Maternal evaluation is repeated 1 year postpartum. Implications: By identifying the factors responsible for pregnancy-related events in women with CHD, risk stratification can be refined, which may lead to better pre-pregnancy counseling and eventually improve treatment of these women.

Intracoronary versus intravenous administration of abciximab in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with thrombus aspiration: The comparison of intracoronary versus intravenous abciximab administration during emergency reperfusion of ST-segment elevation myocardial infarction (CICERO) Trial (Article)

2010-12-21T00:00:00Z

Background- Administration of the glycoprotein IIb/IIIa inhibitor abciximab is an effective adjunctive treatment strategy during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Although small-scale studies have suggested beneficial effects of intracoronary over intravenous administration of abciximab, this has not been investigated in a medium-scale randomized clinical trial. Methods and results- A total of 534 ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention with thrombus aspiration within 12 hours of symptom onset were randomized to either an intracoronary or an intravenous bolus of abciximab (0.25 mg/kg). Patients were pretreated with aspirin, heparin, and clopidogrel. The primary end point was the incidence of restored myocardial reperfusion, defined as complete ST-segment resolution. Secondary end points included myocardial reperfusion as assessed by myocardial blush grade, enzymatic infarct size, and major adverse cardiac events at 30 days. The incidence of complete ST-segment resolution was similar in the intracoronary and intravenous groups (64% versus 62%; P=0.562). However, the incidence of myocardial blush grade 2/3 was higher in the intracoronary group than in the intravenous group (76% versus 67%; P=0.022). Furthermore, enzymatic infarct size was smaller in the intracoronary than in the intravenous group (P=0.008). The incidence of major adverse cardiac events was similar in both groups (5.5% versus 6.1%; P=0.786). Conclusions- In ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention with thrombus aspiration, intracoronary administration of abciximab compared with intravenous administration does not improve myocardial reperfusion as assessed by ST-segment resolution. However, intracoronary administration is associated with improved myocardial reperfusion as assessed by myocardial blush grade and a smaller enzymatic infarct size.

Outcome of Pediatric Patients With Pulmonary Arterial Hypertension in the Era of New Medical Therapies (Article)

2010-07-01T00:00:00Z

Little is known about the effects of "second-generation drugs" (prostanoids, endothelin receptor antagonists, 5-phosphodiesterase inhibitors) in children with pulmonary arterial hypertension (PAH). This study describes the outcome of a national cohort of children with PAH in an era when these drugs became available. From 1993 to 2008, 52 consecutive children with idiopathic PAH (n = 29) or systemic-to-pulmonary shunt-associated PAH (n = 23) underwent baseline and follow-up assessments. Treatment was initiated depending on functional class, acute pulmonary vasoreactivity response, and drug availability. Observed survival was evaluated depending on time of diagnosis in relation to second-generation drug availability and subsequently compared to calculated predicted survival. Children for whom second-generation drugs were available had improved survival compared to their predicted survival (1-, 3-, and 5-year survival rates 93%, 83%, and 66% vs 79%, 61%, and 50%, respectively). However, this improved survival was observed only in patients for whom second-generation drugs became available during their disease course. No improved survival was observed in patients for whom drugs were available already at diagnosis. Baseline variables associated with decreased survival included higher functional class, higher pulmonary-to-systemic arterial pressure ratio, lower cardiac index, and higher serum levels of N-terminal pro-brain natriuretic peptide and uric acid. After start of second-generation drugs, functional class, 6-minute walking distance, and N-terminal pro-brain natriuretic peptide improved but gradually decreased after longer follow-up. In conclusion, survival of pediatric PAH seemed improved since the introduction of second-generation drugs only in selected patients for whom these drugs became available during their disease course. Start of second-generation drugs initially induced clinical improvements, but these effects decreased after longer follow-up.

Differential associations between renal function and "modifiable" risk factors in patients with chronic heart failure. (Article)

2009-02-01T00:00:00Z

BACKGROUND: Reduced glomerular filtration rate (GFR) is strongly associated with reduced survival in patients with chronic heart failure (CHF). Our aim was to determine different pathophysiologic markers that are associated with reduced renal function in CHF. METHODS AND RESULTS: We studied 86 patients with CHF (58+/-12 years, 78% male). GFR and renal blood flow (RBF) were determined by (125)I-Iothalamate and (131)I-Hippuran clearances. Filtration fraction (FF) was calculated. We determined haemoglobin levels, endothelial function, inflammatory status, plasma renin activity (PRA) and N-terminal pro brain natriuretic peptide (NT-proBNP). Urinary albumin excretion (UAE) was measured in 24 h urine. Mean GFR was 74+/-28 ml/min/1.73 m(2). GFR was strongly related to RBF (r=0.915, P<0.001), FF (r=0.546, P<0.001), but only weakly to endothelial function and PRA. In multivariate analysis, RBF (r=0.938, P < 0.001), FF (r=0.786, P < 0.001) and haemoglobin levels (r= -0.520, P<0.001) were independently associated with GFR. UAE was mainly dependent on RBF (r= -0.401, P < 0.001) and increased exponentially with decreasing RBF. RBF was mainly associated with NT-proBNP (r= -0.561, P<0.001) and PRA (r= -0.422, P<0.001). CONCLUSION: Reduced GFR is mainly dependent of decreased RBF in patients with CHF. Endothelial function and neurohormonal activation showed only mild associations with GFR. NT-proBNP showed a strong relationship with RBF, and may be used as a marker of reduced renal perfusion.

Meeting report: ESC forum on drug eluting stents European heart house, Nice, 27-28 September 2007 (Article)

2009-01-01T00:00:00Z

Measurement of coronary calcium scores or exercise testing as initial screening tool in asymptomatic subjects with ST-T changes on the resting ECG: An evaluation study (Article)

2007-07-13T00:00:00Z

Background: Asymptomatic subjects at intermediate coronary risk may need diagnostic testing for risk stratification. Both measurement of coronary calcium scores and exercise testing are well established tests for this purpose. However, it is not clear which test should be preferred as initial diagnostic test. We evaluated the prevalence of documented coronary artery disease (CAD) according to calcium scores and exercise test results. Methods: Asymptomatic subjects with ST-T changes on a rest ECG were selected from the population based PREVEND cohort study and underwent measurement of calcium scores by electron beam tomography and exercise testing. With calcium scores ≥10 or a positive exercise test, myocardial perfusion imaging (MPS) or coronary angiography (CAG) was recommended. The primary endpoint was documented obstructive CAD (≥50% stenosis). Results: Of 153 subjects included, 149 subjects completed the study protocol. Calcium scores ≥400, 100-399, 10-99 and <10 were found in 16, 29, 18 and 86 subjects and the primary endpoint was present in 11 (69%), 12 (41%), 0 (0%) and 1 (1%) subjects, respectively. A positive, nondiagnostic and negative exercise test was present in 33, 27 and 89 subjects and the primary endpoint was present in 13 (39%), 5 (19%) and 6 (7%) subjects, respectively. Receiver operator characteristics analysis showed that the area under the curve, as measure of diagnostic yield, of 0.91 (95% CI 0.84-0.97) for calcium scores was superior to 0.74 (95% CI 0.64-0.83) for exercise testing (p = 0.004). Conclusion: Measurement of coronary calcium scores is an appropriate initial non-invasive test in asymptomatic subjects at increased coronary risk.

High plasma cholesteryl ester transfer protein levels may favour reduced incidence of cardiovascular events in men with low triglycerides (Article)

2007-04-01T00:00:00Z

Aims: High cholesteryl ester transfer protein (CETP) concentrations are associated with increased risk of cardiovascular disease (CVD) in subjects with high triglycerides. We determined the relationship of plasma CETP with incident CVD in a population with relatively low triglycerides. Methods and results: A nested case-control study was performed in men participating in the prospective PREVEND study, after exclusion of CVD, diabetes mellitus, and lipid-lowering drugs use at baseline. Plasma CETP was measured in 111 men who developed a cardiovascular event (cases) during follow-up and in 116 controls who remained free of CVD. Fasting total cholesterol (P < 0.001) and triglycerides (P < 0.001) were higher, HDL cholesterol was lower (P = 0.001), but CETP was similar in cases and controls (P = 0.39). Cox proportional hazards regression analysis showed that CVD risk tended to be lower with higher plasma CETP after adjustment for age and lipids (hazard ratio 0.84; 95% CI 0.69-1.03, P = 0.10). Plasma CETP was lower in cases than in controls (P = 0.05) with triglycerides ≤ 1.38 mmol/L (median), but not with higher triglycerides. The age-adjusted hazard ratio for CVD was 0.46 (95% CI 0.24-0.90) in men with triglycerides ≤ 1.38 mmol/L and CETP > 2.26 mg/L (median) compared with men with similarly low triglycerides and CETP ≤ 2.26 mg/L. With higher triglycerides, the hazard ratio for CVD was similar in both CETP categories. Conclusion: Relatively high plasma CETP may favour reduced CVD risk in the context of low triglycerides.

Angioscopic versus angiographic detection of intimal dissection and intracoronary thrombus (Article)

1994-01-01T00:00:00Z

OBJECTIVES: This study was undertaken to compare coronary angioscopy with angiography for the detection of intimal dissection and intracoronary thrombus. BACKGROUND. It has been demonstrated previously that coronary angioscopy provides more intravascular detail than cineangiography. Both imaging methods have to be compared directly to assess the additional diagnostic value of angioscopy. METHODS. The angiograms and videotapes of 52 patients who had undergone angioscopy were reviewed independently by two observers unaware of other findings. Classic angiographic definitions were used for dissection and thrombus. Angioscopic dissection was defined as visible cracks or fissures on the lumen surface or mobile protruding structures that are contiguous with the vessel wall. Angioscopic thrombus was defined as a red, white or mixed red and white intraluminal mass. RESULTS. Angiography and angioscopy were in agreement in 40.4% of cases in the absence of thrombus and in 11.5% in the presence of thrombus. No fewer than 25 (48.1%) angioscopically observed thrombi remained undetected at angiography. With angioscopy as the standard, although the specificity of angiography for thrombus was 100%, sensitivity was very low at 19%. Angioscopic dissection was present in 40 patients (76.9%) versus angiographic dissection in 15 patients (28.8%). With regard to dissection, there was no correlation between the two imaging methods (r phi = 0.15, p = 0.29). CONCLUSIONS. Coronary angiography underestimates the presence of intracoronary thrombus. Angioscopy and angiography are complementary techniques for detecting and grading intimal dissections.