Number Of Clinical Events Research Articles

Budget Impact Analysis of Dapagliflozin in Treating Patients With Heart Failure With Reduced Ejection Fraction From the Perspective of Malaysian Public Healthcare System

PurposeThis is a budget impact analysis that compared the scenario of treating heart failure with reduced ejection fraction (HFrEF) using dapagliflozin plus standard of care (SoC) versus a scenario without dapagliflozin, from the perspective of Ministry of Health (MOH) Malaysia over a 5-year time horizon. MethodsA Microsoft Excel-based cost calculator was developed for such comparison. The estimated size of eligible population, uptake rates for dapagliflozin, as well as costs related to drugs, clinical events, and adverse events were based on published data, official tariffs, and databases, and expert opinion. Clinical data from the DAPA-HF trial were used to inform efficacy and safety inputs (i.e., hospitalization for heart failure (hHF), cardiovascular death, and adverse events). Results were reported as total annual and cumulative costs (in 2023 Malaysian Ringgits [RM], United States Dollars [USD], and European Union Euros, [EUR]; with exchange rates of 1 USD = RM 4.40 and 1 EUR = RM 4.90]), as well as the number of clinical events. Sensitivity and scenario analyses were also conducted. FindingsThe base-case analysis estimated that over a five-year period, the adoption of dapagliflozin for HFrEF treatment would result in a cumulative cost-saving of RM 2.6 million (USD 0.6 million/EUR 0.5 million), representing a 0.3% reduction in costs, driven primarily by reduced expenditure on hHF. Moreover, dapagliflozin treatment would lead to 731 fewer hHF and 366 fewer cardiovascular deaths. Sensitivity and scenario analyses revealed that the results were most sensitive to assumptions regarding loop diuretic requirements and the cost of dapagliflozin. Although cost savings or a net-zero balance were projected for the first four years, an anticipated 2.5% annual increase in dapagliflozin uptake in the longer term would lead to additional costs for the MOH, starting from the fifth year. ImplicationsIncorporating dapagliflozin into the SoC can improve health outcomes for HFrEF patients and may generate cost savings, potentially easing the economic strain of HFrEF management on Malaysia's public healthcare system in the short term. Nonetheless, a modest increase in budget should be anticipated as more patients gain access to the treatment over time.

Polypharmacy, anticholinergic burden and drug-drug interaction assessment in people with four-class-resistant HIV: data from the PRESTIGIO registry.

To evaluate polypharmacy, anticholinergic burden (ACB) and drug-drug interactions (DDIs) in people with four-class-resistant HIV (4DR-PWH). We performed a cross-sectional study, including 4DR-PWH from the PRESTIGIO Registry taking at least one non-antiretroviral drug. Polypharmacy was defined as taking five or more non-antiretroviral drugs. ACB was calculated using the ACB scale: 0 = no AC effect, 1-2 = low/moderate risk, ≥3 = high AC risk. Participants' characteristics by ACB score were compared using the Kruskal-Wallis test, and Spearman's correlation coefficient was used to assess linear relationships. DDIs were evaluated using the Liverpool database. Overall, 172 4DR-PLWH were evaluated: 75.6% males, median age 49.9 years (IQR = 45.6-56), 62 (27.1%) on polypharmacy, 124 (72.1%) using a boosting agent and 72 (41.8%) with four or more antiretrovirals. Based on ACB, 128 (74.45%), 33 (19.2%) and 11 (6.4%) had a no, low/moderate and high AC risk, respectively. The most common AC drugs were β-blockers (12.2%), diuretics (8.7%) and antidepressants (8.7%). The high ACB was significantly related to the number of drugs/person (r = 0.33, P < 0.0001) and the number of clinical events (r = 0.222, P = 0.004). Overall, 258 DDIs were found between antiretrovirals and co-medications in 115 (66.8%) PWH, and 14 (8.1%) PWH received contraindicated drug combinations. In 4DR-PWH, polypharmacy, DDIs and the proportion of people with moderate/high AC burden were high. In 4DR-PWH undetectability achievement and maintenance is the priority and use of boosted PIs is common. A strict collaboration (infectious diseases specialists, virologists, pharmacologists) is needed to limit the risk of ACB and DDIs and to explore the advantages of new antiretrovirals.

Routine Pressure Wire Assessment Versus Conventional Angiography in the Management of Patients With Coronary Artery Disease: The RIPCORD 2 Trial.

Measurement of fractional flow reserve (FFR) has an established role in guiding percutaneous coronary intervention. We tested the hypothesis that, at the stage of diagnostic invasive coronary angiography, systematic FFR-guided assessment of coronary artery disease would be superior, in terms of resource use and quality of life, to assessment by angiography alone. We performed an open-label, randomized, controlled trial in 17 UK centers, recruiting 1100 patients undergoing invasive coronary angiography for the investigation of stable angina or non-ST-segment-elevation myocardial infarction. Patients were randomized to either angiography alone (angiography) or angiography with systematic pressure wire assessment of all epicardial vessels >2.25 mm in diameter (angiography+FFR). The coprimary outcomes assessed at 1 year were National Health Service hospital costs and quality of life. Prespecified secondary outcomes included clinical events. In the angiography+FFR arm, the median number of vessels examined was 4 (interquartile range, 3-5). The median hospital costs were similar: angiography, £4136 (interquartile range, £2613-£7015); and angiography+FFR, £4510 (£2721-£7415; P=0.137). There was no difference in median quality of life using the visual analog scale of the EuroQol EQ-5D-5L: angiography, 75 (interquartile range, 60-87); and angiography+FFR, 75 (interquartile range, 60-90; P=0.88). The number of clinical events was as follows: deaths, 5 versus 8; strokes, 3 versus 4; myocardial infarctions, 23 versus 22; and unplanned revascularizations, 26 versus 33, with a composite hierarchical event rate of 8.7% (48 of 552) for angiography versus 9.5% (52 of 548) for angiography+FFR (P=0.64). A strategy of systematic FFR assessment compared with angiography alone did not result in a significant reduction in cost or improvement in quality of life. URL: https://www. gov; Unique identifier: NCT01070771.

Single or triple positivity for antiphospholipid antibodies in “carriers” or symptomatic patients: Untangling the knot

BackgroundAlthough the triple positivity of antiphospholipid antibodies (aPL) is important for classifying high‐risk patients, interpretation of aPL positivity, namely the lupus anticoagulant (LA), anti‐cardiolipin (aCL), and anti‐beta2‐glycoprotein I autoantibodies (aB2GPI) remains challenging for thrombotic risk stratification. ObjectiveTo compare biological and clinical data between triple aPL– and single aCL–positive patients. MethodsOf the 6500 patients assayed for aPL in daily practice within 3 years, we retrospectively analyzed data from 161 patients that were either triple aPL–positive or single aCL–positive with 5 years’ follow‐up for 121 of them. ResultsWhatever triple or single aPL positivity, we found a high prevalence of “carrier” patients (43%), which led us to question the clinical relevance of the triple aPL positivity. This result also justified the need to identify high‐risk profiles. In asymptomatic patients, high risk of thrombotic events is associated with (1) two positive tests for LA or a Rosner Index >27 combined with both aCL‐IgG and aB2GPI‐IgG positivity, (2) persistent single aCL positivity without an associated autoimmune disease. In symptomatic patients, we demonstrated differences in the phenotype of patients and their therapeutic anticoagulation according to the number of positive aPL but we did not find differences in the number of clinical events, recurrence, or relapse, even in the absence of treatment. ConclusionThis study shows that the thrombotic risk does not necessarily increase with the number of positive tests and raises the question of the therapeutic management of single aCL–positive patients.

Are the results of the RATE-AF trial reproducible in daily practice? Clinical outcomes with digoxin vs beta-blocker for heart rate control in permanent atrial fibrillation

Abstract Background There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation (AF), in particular those with coexisting heart failure. In the recent RATE-AF trial that included patients with permanent AF and symptoms of heart failure, treatment with low-dose digoxin or bisoprolol did not result in statistically significant difference in quality of life at 6 months. The purpose of the study was to analyse whether the clinical outcomes may differ among unselected patients with permanent AF treated with digoxin or beta-blocker seen in daily practice. Methods All patients with atrial fibrillation (AF) seen in an academic institution were identified in a database. We examined the clinical course of 8962 consecutive patients with AF seen over a 10-year period. The adverse outcomes were investigated during follow-up and we identified the causes of death. Among them 1,787 patients had the RATE-AF criteria of inclusion (permanent AF, age ≥60 and NYHA ≥2), of whom 512 patients (29%) were treated with beta-blocker alone, 425 (24%) were treated with digoxin alone and 237 (13%) were treated with both a beta-blocker and digoxin. Outcomes in patients treated with beta-blocker alone or digoxin alone were compared after 1:1 propensity-score matching. Results After propensity score matching, 270 patients treated with beta-blocker were matched 1:1 with 270 patients treated with digoxin. In these patients (age 79±8 years, CHA2DS2VASc score 4.0±1.3), 125 deaths were recorded during a follow-up of 2.2±2.7 years (median 1.1, interquartile 0.1–3.5 years, yearly rate of death 10.4%) including 72 cardiovascular deaths (yearly rate 6.0%). Major clinical events (all-cause death, myocardial infarction, ischemic stroke or major bleeding) were recorded in 192 patients (yearly rate 19.1%). In this matched analysis, risk was not statistically significant in the 2 groups for all-cause death (HR 0.95, 95% CI 0.67–1.35 for beta-blocker use vs digoxin use), cardiovascular death (HR 1.23, 95% CI 0.77–1.96 for beta-blocker use vs digoxin use) or major clinical events (HR 0.98, 95% CI 0.74–1.31 for beta-blocker use vs digoxin use). Conclusion Our analysis included more patients and had a longer follow-up than in the RATE-AF trial, resulting in a 10-fold higher number of clinical events. We found that among patients with permanent AF and symptoms of HF, there was no statistically significant difference in the risk of all-cause death, cardiovascular mortality and major clinical events between those treated with digoxin or beta-blocker. Concerns regarding the use of digoxin, such as the narrow therapeutic window and drug interactions, were not issues resulting in worse clinically relevant cardiovascular outcomes with the approach used in the current study. Funding Acknowledgement Type of funding sources: None.

Children’s use of value information is characterized by differential autonomic reactivity during learning

The Marfan syndrome (MFS) patients are highly predisposed to thoracic aortic aneurysm and/or dissection, with virtually every patient having evidence of aortic disease at some point during their lifetime. We conducted a meta-analysis to investigate the efficacy of angiotensin receptor blockers (ARBs) in slowing down the progression of aortic dilatation in MFS patients. PUBMED, EMBASE, and COCHRANE databases were searched for relevant articles published from inception to February 1, 2020. We included randomized clinical trials evaluating the effect of ARBs on aortic root size in patients with MFS with a follow-up period of at least 2.5 years. Seven studies were included with a total of 1,510 patients. Our analysis demonstrated a significantly smaller change in aortic root and ascending aorta dilation in the ARBs treated group when compared with placebo (mean difference 0.68; 95% confidence interval [CI] −1.31 to −0.04; p = 0.04, I2 = 94%, and mean difference −0.13, 95% CI −0.17 to −0.09; p < 0.00001, I2 = 0%, respectively). ARBs as an add-on therapy to beta-blockers resulted in a significantly smaller change in aortic root dilation when compared with the arm without ARBs (mean difference −2.06, 95% CI −2.54 to −1.58; p < 0.00001, I2 = 91%). However, there was no statistically significant difference in the number of clinical events (aortic complications/surgery) observed in the ARBs arm when compared with placebo (Risk ratio of 1.01, 95% CI 0.74 to 1.38; p = 0.94, I2 = 0%). In conclusion, ARBs therapy is associated with a slower progression of aortic root dilation when compared with placebo and as an addition to beta-blocker therapy.

Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa

BackgroundHydroxyurea has proven safety, feasibility, and efficacy in children with sickle cell anemia in sub-Saharan Africa, with studies showing a reduced incidence of vaso-occlusive events and reduced mortality. Dosing standards remain undetermined, however, and whether escalation to the maximum tolerated dose confers clinical benefits that outweigh treatment-related toxic effects is unknown.MethodsIn a randomized, double-blind trial, we compared hydroxyurea at a fixed dose (approximately 20 mg per kilogram of body weight per day) with dose escalation (approximately 30 mg per kilogram per day). The primary outcome was a hemoglobin level of 9.0 g or more per deciliter or a fetal hemoglobin level of 20% or more after 24 months. Secondary outcomes included the incidences of malaria, vaso-occlusive crises, and serious adverse events.ResultsChildren received hydroxyurea at a fixed dose (94 children; mean [±SD] age, 4.6±1.0 years) or with dose escalation (93 children; mean age, 4.8±0.9 years); the mean doses were 19.2±1.8 mg per kilogram per day and 29.5±3.6 mg per kilogram per day, respectively. The data and safety monitoring board halted the trial when the numbers of clinical events were significantly lower among children receiving escalated dosing than among those receiving a fixed dose. At trial closure, 86% of the children in the dose-escalation group had reached the primary-outcome thresholds, as compared with 37% of the children in the fixed-dose group (P<0.001). Children in the dose-escalation group had fewer sickle cell–related adverse events (incidence rate ratio, 0.43; 95% confidence interval [CI], 0.34 to 0.54), vaso-occlusive pain crises (incidence rate ratio, 0.43; 95% CI, 0.34 to 0.56), cases of acute chest syndrome or pneumonia (incidence rate ratio, 0.27; 95% CI, 0.11 to 0.56), transfusions (incidence rate ratio, 0.30; 95% CI, 0.20 to 0.43), and hospitalizations (incidence rate ratio, 0.21; 95% CI, 0.13 to 0.34). Laboratory-confirmed dose-limiting toxic effects were similar in the two groups, and there were no cases of severe neutropenia or thrombocytopenia.ConclusionsAmong children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety. (Funded by the Doris Duke Charitable Foundation and the Cincinnati Children’s Research Foundation; NOHARM MTD ClinicalTrials.gov number, NCT03128515.)

Meta-analysis Examining the Usefulness of Angiotensin Receptor blockers for the Prevention of Aortic Root Dilation in Patients With the Marfan Syndrome

The Marfan syndrome (MFS) patients are highly predisposed to thoracic aortic aneurysm and/or dissection, with virtually every patient having evidence of aortic disease at some point during their lifetime. We conducted a meta-analysis to investigate the efficacy of angiotensin receptor blockers (ARBs) in slowing down the progression of aortic dilatation in MFS patients. PUBMED, EMBASE, and COCHRANE databases were searched for relevant articles published from inception to February 1, 2020. We included randomized clinical trials evaluating the effect of ARBs on aortic root size in patients with MFS with a follow-up period of at least 2.5 years. Seven studies were included with a total of 1,510 patients. Our analysis demonstrated a significantly smaller change in aortic root and ascending aorta dilation in the ARBs treated group when compared with placebo (mean difference 0.68; 95% confidence interval [CI] -1.31 to -0.04; p = 0.04, I2 = 94%, and mean difference -0.13, 95% CI -0.17 to -0.09; p < 0.00001, I2 = 0%, respectively). ARBs as an add-on therapy to beta-blockers resulted in a significantly smaller change in aortic root dilation when compared with the arm without ARBs (mean difference -2.06, 95% CI -2.54 to -1.58; p < 0.00001, I2 = 91%). However, there was no statistically significant difference in the number of clinical events (aortic complications/surgery) observed in the ARBs arm when compared with placebo (Risk ratio of 1.01, 95% CI 0.74 to 1.38; p = 0.94, I2 = 0%). In conclusion, ARBs therapy is associated with a slower progression of aortic root dilation when compared with placebo and as an addition to beta-blocker therapy.

Real-World Data Approaches for Early Detection of Potential Safety and Effectiveness Signals for Generic Substitution: A Metoprolol Extended-Release Case Study.

Real-world spontaneous adverse event reports and administrative health care data were utilized as one part of a multipronged approach to verify surveillance signals related to generic drug formulations. This study used metoprolol succinate extended release as a historic case example from which to develop an analytic framework. The US Food and Drug Administration Adverse Event Reporting System was utilized for disproportionality analyses and to identify outcomes of interest. Claims data were analyzed for generic uptake, proportion of prescriptions with "dispense as written" orders, time to discontinuation or switching, and relative rates of clinical events. Adverse Event Reporting System data showed that the Medical Dictionary for Regulatory Activities terms for product quality were higher for generic metoprolol cases and that a number of clinical events were increased that could be side effects of high or low variability in drug levels. Compared to amlodipine-benazepril, which also had a first-approved generic at the same time, market share data showed that metoprolol succinate had lower utilization and more prescriptions written as dispense as written. Switching and discontinuation were generally higher for metoprolol users compared to amlodipine-benazepril users. Finally, clinical event rates were generally higher for generic versus brand metoprolol but lower for the same comparison for amlodipine-benazepril users. In the claims-based analyses, the 90-day period immediately after generic entry provided stronger signal capture than using the entire study period. This analytic framework can be implemented to actively monitor new generic formulations for potential bioequivalence failures. Signals from these analyses require confirmation (eg, via pharmacometric analyses) to be informative for regulatory action.

Standard pre-travel consultation versus shorter consultation combined with smartphone support: a randomized controlled trial.

Immediate and long-term recalls of a pre-travel consultation are suboptimal. We aimed to assess the role of online consultation for travellers.We randomized travellers into two study groups. In the intervention arm, each traveller was given a short pre-travel consultation of 8-12 minutes, combined with the option of smartphone support before and during the trip. In the control arm, each traveller was given a standard length pre-travel consultation of 18-22 minutes. Endpoints included knowledge about potential risks, travellers' satisfaction, time allocated to each traveller and clinical events.We enrolled 75 patients in the intervention group and 74 patients in the control group. Online consultation was used 33 times, by 24 travellers, both before and during the trip. Important health hazards that were addressed included animal and insect bites (8), treatment of diarrhea (4), malaria prophylaxis (2) and altitude sickness prophylaxis (5). Other consultations consisted mainly of reassurances of worried travellers and provision of data. Knowledge about travel-related risks was higher in the control group before travelling (8.86 ± 1.12 vs 8.34 ± 1.32, P = 0.014), and there was a trend towards higher levels of knowledge also during the trip (8.29 ± 1.35 vs 7.89 ± 1.39, P = 0.06). Travellers' satisfaction before and during the trip was similar in both groups: median 10 (10, 10) in both groups before traveling (P = 0.51) and median 9 (8, 10) in both groups during the trip (P = 0.71). In the intervention group, time allocated to each traveller was <12 minutes. There were no differences in the number of clinical events (P > 0.2 for all comparisons).Online WhatsApp support addressed several important travel-related hazards but, when combined with a shortened pre-travel consultation, was associated with a lower level of knowledge about health risks. Therefore, such smartphone support should augment, rather than replace, pre-travel consultation.

A Rule-Out Strategy Based on High-Sensitivity Troponin and HEART Score Reduces Hospital Admissions

We evaluate whether a combination of a 1-hour high-sensitivity cardiac troponin algorithm and History, ECG, Age, Risk Factors, and Troponin (HEART) score reduces admission rate (primary outcome) and affects time to discharge, health care-related costs, and 30-day outcome (secondary outcomes) in patients with symptoms suggestive of an acute coronary syndrome. This prospective observational multicenter study was conducted before (2013 to 2014) and after (2015 to 2016) implementation of a strategy including level of high-sensitivity cardiac troponin T or I at 0 and 1 hour, combined with the HEART score. Patients with a nonelevated baseline high-sensitivity cardiac troponin level, a 1-hour change in high-sensitivity cardiac troponin T level less than 3 ng/L, or high-sensitivity cardiac troponin I level less than 6 ng/L and a HEART score less than or equal to 3 were considered to be ruled out of having acute coronary syndrome. A logistic regression analysis was performed to adjust for differences in baseline characteristics. A total of 1,233 patients were included at 6 centers. There were no differences in regard to median age (64 versus 63 years) and proportion of men (57% versus 54%) between the periods. After introduction of the new strategy, the admission rate decreased from 59% to 33% (risk ratio 0.55 [95% confidence interval {CI} 0.48 to 0.63]; odds ratio 0.33 [95% CI 0.26 to 0.42]; adjusted odds ratio 0.33 [95% CI 0.25 to 0.42]). The median hospital stay was reduced from 23.2 to 4.7 hours (95% CI of difference -20.4 to -11.4); median health care-related costs, from $1,748 to $1,079 (95% CI of difference -$953 to -$391). The number of clinical events was very low. In this before-after study, clinical implementation of a 1-hour high-sensitivity cardiac troponin algorithm combined with the HEART score was associated with a reduction in admission rate and health care burden, with very low rates of adverse clinical events.

Creating adequate pulsatility with a continuous flow left ventricular assist device: just do it!

Continuous flow left ventricular assist devices (LVADs) have revolutionized the treatment of advanced heart failure; however, as experience with these devices has grown, a number of unanticipated adverse events have emerged. In this study, we review the current literature associating a lack of pulsatility with these events. It is now evident that continuous flow LVAD physiology reflects a spectrum of 'low pulsatile' rather than a truly 'nonpulsatile' state. Thus, the detrimental consequences of nonpulsatile flow noted in early experimental setups may or may not occur in humans supported with continuous flow LVADs. Such studies have demonstrated not only alterations in vascular function and structure during continuous flow LVAD support, but also a clear association of the degree of alterations in vascular, baroreceptor, and sympathetic nervous system function with the degree of actual pulsatility. In addition, a number of clinical events have been linked to continuous flow LVAD physiology, including a decreased extent of ventricular unloading possibly impairing myocardial recovery, hemolysis and device thrombosis, development of aortic insufficiency, and mucosal bleeding. Many of the adverse effects of the current continuous flow LVADs are associated with low pulsatile flow. An evolved understanding of pulsatility as a continuous rather than a binary variable may allow us to incorporate appropriate degrees of pulsatility into the next generation pumps and mitigate these effects.

Nebivolol in chronic heart failure: current evidence and future perspectives

Importance of the field: Chronic activation of the sympathetic nervous system leads to deterioration of cardiovascular function in heart failure patients. In systolic heart failure, β-blockers were proven to be effective in decreasing the number of deaths and improving morbidity. However, β-blockers are a heterogeneous drug group, consisting of agents with different selectivity for adrenergic receptors and/or additional effects in heart or peripheral circulation.Areas covered in the review: We describe the role of the sympathetic nervous system, β-blockers and specifically nebivolol in chronic heart failure.What the reader will gain: Nebivolol is a third-generation β-blocker, with high β1/β2 selectivity. Moreover, it has important vasodilating properties, by stimulating the production of nitric oxide. Smaller studies have already shown beneficial effects of nebivolol treatment on surrogate end points in heart failure patients. The recently published SENIORS (Phase III) study in an elderly heart failure population demonstrated a decreased number of clinical events in patients treated with nebivolol. Importantly, this effect was observed in patients with both impaired and preserved left ventricular systolic function.Take home message: Specific β-blockers may have distinct effects in various subgroups of heart failure patients. So far, nebivolol is the only β-blocker to have been shown effective in elderly heart failure patients, regardless of their left ventricular ejection fraction.

The management of care in setting up an area of health care in the community school

Exploratory nature of this research aims to recognize the causes of problems related to health community school, served in the Division of Educational Guidance and prepare schedule of Health Education to work within an appropriate place: Area of health care in Institute of Culture Technology - ICT in the city of Volta Redonda - RJ. The interest in developing this research was due to a large number of clinical events in the school environment. The approach is quantitative and processing of data through the EpiInfo 3.3.2. The method of data collection will be through a form that all the focus of care performed by nurses to the school community, ie students, staff and relatives attending the ICT. It is intended to establish an area of health care to the clients is preserved in its intimacy, avoiding excessive exposure and embarrassment.

An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage.

Increased demand for oral anticoagulants is overwhelming facilities worldwide, resulting in increasing use of computer assistance. A multicenter clinical endpoint study has been performed to compare the safety and effectiveness of computer-assisted dosage with dosage by experienced medical staff at the same centers. A randomized study of dosage of two commercial computer-assisted dosage programs (PARMA 5 and DAWN AC) vs. manual dosage at 32 centers with an established interest in oral anticoagulation in 13 countries. The aim was to recruit a minimum of 16,000 patient-years randomized to medical staff or computer-assisted dosage. In total, 13,219 patients participated, 6503 patients being randomized to medical staff and 6716 to computer-assisted dosage. The safety and effectiveness of computer-assisted dosage were compared with those of medical staff dosage. In total, 13,052 patients were recruited (18,617 patient-years). International Normalized Ratio (INR) tests numbered 193 890 with manual dosage and 193,424 with computer-assisted dosage. The number of clinical events with computer-assisted dosage was lower (P = 0.1), but in the 3209 patients with deep vein thrombosis/pulmonary embolism, they were reduced by 37 (24%, P = 0.001). Time in target INR range was significantly improved by computer assistance as compared with medical staff dosage at the majority of centers (P < 0.001). The safety and effectiveness of computer-assisted dosage has been demonstrated using two different marketed programs in comparison with experienced medical staff dosage at the centers with established interest in anticoagulation. Significant prevention of clinical events in patients with deep vein thrombosis/pulmonary embolism and the achievement of target INR in all clinical groups has been observed. The reliability and safety of other marketed computer-assisted dosage programs need to be established.

Statins and telomere length: risk assessment and management for coronary heart disease

Cornoary heart disease (CHD) is identified as one of the diseases characterised by biological ageing as one of the important risk factors in several epidemiological studies. Premature biological ageing is distinct from chronological ageing and may predispose the individual to myocardial infarction, atherosclerosis and CHD in particular. The mean telomere length serves as a marker for the biological age at the cellular level, with shorter telomeres defining the increased biological age. Telomere length, therefore, correlates with the risk of CHD and atherosclerosis. Statins serve as the drugs of obvious choice based on their well established efficacy and safety profiles for the treatment of CHD and associated atherosclerosis. A present clinical study states that the treatment with a statin is associated with a reduction in the number of clinical events but only in individuals with increased risk based on their telomere length. This suggests a positive relationship of telomere length with the risk of CHD and, therefore, would help clinicians to categorise the patient populations based on their leucocyte telomere length for treatment with statins.

Design of Randomized Controlled Trials

A major factor in the rapid advance of medical science over the past 50 years has been the development and refinement of the clinical research method known as the randomized controlled trial (RCT). A clinical trial is defined as a prospective scientific experiment that involves human subjects in whom treatment is initiated for the evaluation of a therapeutic intervention. In an RCT, each patient is assigned to receive a specific treatment intervention by a chance mechanism. Nothing more clearly indicates the key role of an RCT in modern clinical research than the placement of this specific research method at the top of the list of levels of evidence in evidence-based medicine.1 According to this classification, significant results of an RCT are more definitive than any other type of clinical research information. The purpose of this article is to present an overview of the design of RCTs. Some of the principles of a high-quality study, such as the use of randomization, placebos, and double-blind designs are well known. Other principles such as stratification, use of a decision-making structure, and statistical power are known by many investigators but are not universally recognized or fully understood. These features plus others that indicate the design of a high-quality RCT are discussed. A companion article on the conduct and evaluation of RCTs will appear in a future issue of this journal. One of the most easily recognized aspects of a well-designed and conducted clinical trial is the apparent clarity of the research mechanism evident in its published report. Alternatively, one of the more common problems with a published clinical trial is the apparent “design by committee” in which different members of a protocol team have different goals. Because a clinical trial is a resource-intensive undertaking, many investigators feel that the study should attempt to …

Association of QRS duration and outcomes after myocardial infarction: the VALIANT trial

Prolongation of the QRS duration has been shown to be associated with adverse outcomes among heart failure (HF) patients. The association of QRS duration with clinical outcomes in the post-myocardial infarction (MI) setting is less well defined. To assess the prognostic significance of QRS duration prolongation on initial electrocardiogram after acute MI. QRS duration was measured in 403 patients with MI complicated by left ventricular dysfunction, signs or symptoms of HF, or both, who were enrolled in the Valsartan in Acute Myocardial Infarction (VALIANT) echo study. The cohort was divided into quartiles of QRS duration (<75 ms, 75-88 ms, 89-108 ms, >108 ms). The number of clinical events were determined and compared across the groups. Increasing QRS duration is associated with a higher incidence of HF, sudden death (SD), and cardiovascular (CV) death (P-trend <0.05) but not with stroke or recurrent MI. The univariate relative risks for HF, SD, and CV death with increasing QRS duration quartiles were 1.31 (95% CI, 1.06-1.64), 1.57 (95% CI, 1.03-2.40), and 1.31 (95% CI, 1.03-1.66), respectively, but QRS duration did not remain independently predictive of adverse outcome after adjusting for the 10 most predictive baseline covariates. Baseline end-diastolic and end-systolic volumes were larger and ejection fraction was lower in the higher QRS quartile groups. Prolonged QRS duration, even within the normal range, is associated with larger ventricular volumes, reduced systolic function, and an increased risk for development of HF, SD, and CV death after MI but appears to be a marker, rather than an independent predictor, for increased risk.

Candesartan Cilexetil

The addition of candesartan cilexetil (Atacand, Amias, Blopress, Kenzen, Ratacand) to standard therapy for chronic heart failure (CHF) provided important clinical benefits at little or no additional cost in France, Germany and the UK, according to a detailed economic analysis focusing on major cardiovascular events and prospectively collected resource-use data from the CHARM-Added and CHARM-Alternative trials in patients with CHF and left ventricular (LV) systolic dysfunction. Results of a corresponding cost-effectiveness analysis showed that candesartan cilexetil was either dominant over placebo or was associated with small incremental costs per life-year gained, depending on the country and whether individual trial or pooled data were used. Preliminary data from a US cost-effectiveness analysis based on CHARM data also showed favourable results for candesartan cilexetil. Two cost-effectiveness analyses of candesartan cilexetil in hypertension have been published, both conducted in Sweden. Data from the SCOPE trial in elderly patients with hypertension, which showed a significant reduction in nonfatal stroke with candesartan cilexetil-based therapy versus non-candesartan cilexetil-based treatment, were incorporated into a Markov model and an incremental cost-effectiveness ratio of euro12 824 per QALY gained was calculated (2001 value). Another modelled cost-effectiveness analysis of candesartan cilexetil was based on the ALPINE trial, in which the incidence of new-onset diabetes was significantly lower in patients with newly diagnosed hypertension who were randomised to candesartan cilexetil (with or without felodipine) than among those who received hydrochlorothiazide (with or without atenolol). Although candesartan cilexetil was dominant over hydrochlorothiazide, the ALPINE cost-effectiveness analysis relied on a small number of clinical events and did not evaluate the incremental cost of candesartan cilexetil per life-year or QALY gained. In conclusion, despite some inherent limitations, economic analyses incorporating CHARM data and conducted primarily in Europe have shown that candesartan cilexetil appears to be cost effective when added to standard CHF treatment in patients with CHF and compromised LV systolic function. The use of candesartan cilexetil as part of antihypertensive therapy in elderly patients with elevated blood pressure was also deemed to be cost effective in a Swedish analysis, primarily resulting from a reduced risk of nonfatal stroke (as shown in the SCOPE study); however, the generalisability of results to other contexts has not been established. Cost-effectiveness analyses comparing candesartan cilexetil with ACE inhibitors or other angiotensin receptor blockers in CHF or hypertension are lacking, and results reported for candesartan cilexetil in a Swedish economic analysis of ALPINE data focusing on outcomes for diabetes require confirmation and extension.

Mono-organic versus Multi-organic Involvement in Primary Antiphospholipid Syndrome

The prevalence of mono-organic and multi-organic involvement during long-term follow-up in patients with primary antiphospholipid syndrome (pAPS) was investigated. We studied 60 pAPS patients followed up at least 5 years. Patients with associated systemic lupus erythematosus were excluded. All patients received oral anticoagulant therapy. A diagnosis of mono-organic involvement was considered when one organ was affected exclusively, and multi-organic involvement was considered when two or more organs became affected during follow-up. Average age at diagnosis was 32.9 +/- 12.4 years, 40 subjects were female and 20 male, and mean disease evolution totaled 11.5 +/- 4.5 years. The mean number of clinical events was 3.75 +/- 1.87. Among patients, immunoglobulin G anticardiolipin (IgM aCL) titers totaled 50 +/- 40.3 IgG phospholipid units, and IgM aCL titers totaled 47.3 +/- 35.4 IgM phospholipid units. The most frequent clinical manifestations at study onset were deep venous thrombosis, stroke, pulmonary thromboembolism, fetal loss, and pre-eclampsia. At the beginning of follow-up, 46 patients had mono-organic involvement and 14 had multi-organic involvement (P = 0.0001). In contrast, at the end of the study, only 8 patients still had mono-organic involvement, leading to deep venous thrombosis (n = 3), stroke (n = 3), and retinal thrombosis (n = 2) (P = 0.0001). Kaplan-Meier analysis showed that the probability of remaining with mono-organic involvement decreased throughout the cumulative years, especially during the first 3. The hazard risk ratio for developing multi-organic involvement was 1.47 patients per year. In conclusion, PAPS is a chronic disorder with unpredictable clinical course and multi-organic involvement, especially during the first years. The conversion to multi-organic involvement supports the concept that pAPS is a systemic autoimmune disease.