Individual Patient Risk Profile Research Articles

Routine Invasive Versus Conservative Management Strategies in Acute Coronary Syndrome: Time for a “Hybrid” Approach

The acute coronary syndrome is most often caused by plaque rupture and can result in a variety of clinical conditions. There are two general strategies (early invasive versus conservative) currently employed in the treatment of unstable angina or non-ST elevation myocardial infarction. Pooled data from recent clinical trials have demonstrated that high-risk patients benefit from a routine or early invasive approach while certain low-risk subgroups have similar outcomes with a conservative approach. Most patients in the USA are treated aggressively given advances in technology and the relative ease of interventional therapy. The routine invasive approach, however, remains controversial and has important limitations that are not well identified in trials. Furthermore, data from trials are difficult to interpret given their relevance to contemporary practice in today's cost conscious, health care environment. The decision to pursue an invasive or conservative approach should be based upon an individual patient's risk profile, and the level of medical therapy should be based on the underlying pathophysiology. The best strategy incorporates aggressive anti-atherosclerotic therapy with early risk stratification and invasive therapy when appropriate-the so-called hybrid approach. Identifying plaque rupture helps identify patients that would benefit from potent antiplatelet, antithrombotic, and anti-inflammatory therapies, and further insight into the natural history of coronary artery disease coupled with continued advances in diagnostic and interventional approaches will hopefully help guide long-term primary and secondary management.

Anaesthesia or sedation for MRI in children

The purpose of this review is to focus on recent literature about sedation or anaesthesia in paediatric MRI. Special features of the MRI working environment, recent studies about sedation or anaesthesia, and success rates and risk profiles in this setting are presented. Finally, information for physicians to decide between sedation or anaesthesia in individual situations is presented. Owing to advances in MRI and its crucial role in the diagnosis of various diseases, deep sedation or anaesthesia for MRI in children is requested increasingly. According to current guidelines maximum patient safety and welfare has to be ensured. Recently different sedation regimens comparing effectiveness, safety and outcome have been published. Chloral hydrate, pentobarbital and midazolam are unfavourable for MRI sedation. Dexmedetomidine appears to be convenient for sedation in patients without cardiac risk. Propofol can be effectively used for sedation or anaesthesia in the presence of anaesthesiologists or paediatric intensivists. General anaesthesia should be preferred in preterm or small children as safety and success are predictable. The MRI unit is a work station where all processes have to be well planned and staff trained to guarantee maximum patient safety, superior quality of imaging and economic needs. For optimal performance trained, experienced and certified personnel, appropriate drugs for the individual patient risk profile and sufficient monitoring equipment are essential.

Acquired thrombotic risk factors in the critical care setting

Acquired thrombotic risk factors include a variety of noninherited clinical conditions that can predispose an individual to an increased risk for venous thromboembolism. For patients in a critical care setting, certain acquired risk factors represent chronic conditions that the patients may have had before the current acute illness (e.g., malignancy, various cardiovascular risk factors, certain medications), whereas others may be directly related to the reason the patient is in an intensive care unit or the patient's management there (e.g., postoperative state, trauma, indwelling vascular access, certain medications). Optimal thromboprophylactic strategies depend on individual patient risk profiles including an assessment of the specific clinical setting. Treatment for patients with acquired thrombotic risk factors includes anticoagulant therapy and, if possible, resolution of the acquired risk factor(s). Heparin-induced thrombocytopenia represents a unique clinical situation in which all sources of heparin must be discontinued and the patient started on an alternative anticoagulant (e.g., a direct thrombin inhibitor) in the acute setting. The duration of anticoagulant therapy would vary depending on the specific clinical setting.

Prognostic Modeling of Individual Patient Risk and Mortality Impact of Ischemic and Hemorrhagic Complications

Both ischemic and hemorrhagic complications increase mortality rate in acute coronary syndromes. Their frequency and relative importance vary according to individual patient risk profiles. We sought to develop prognostic models for the risk of myocardial infarction (MI) and major bleeding to assess their impact on risk of death and to examine the manner in which alternative antithrombotic regimens affect these risks in individual patients. The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial randomized 13 819 patients with acute coronary syndrome to heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. By logistic regression, there were 5 independent predictors of MI within 30 days (n=705; 5.1%) and 8 independent predictors of major bleeding (n=645; 4.7%), only 2 of which were common to both event types. In a covariate-adjusted, time-updated Cox regression model, both MI and major bleeding significantly affected subsequent mortality rate (hazard ratios, 2.7 and 2.9, respectively; both P<0.001). Treatment with bivalirudin versus heparin plus a glycoprotein IIb/IIIa inhibitor was associated with a nonsignificant 8% increase in MI and a highly significant 50% decrease in major bleeding. Given the individual patient risk profiles and the fact that bivalirudin prevented approximately 6 major bleeds for each MI that might occur from its use, the estimated reduction in bleeding was greater than the estimated increase in MI by bivalirudin alone rather than heparin plus a glycoprotein IIb/IIIa inhibitor for nearly all patients. Consideration of the individual patient risk profile for MI and major bleeding and the relative treatment effects of alternative pharmacotherapies permits personalized decision making to optimize therapy of patients with acute coronary syndrome. clinicaltrials.gov Identifier: NCT00093158.

Verbesserung der Arzneimitteltherapiesicherheit in Deutschland: Allianz von Staat und Ärzteschaft

According to a multitude of international studies the safety of general drug treatment practice is not up to standard. It has been demonstrated that about 50% of adverse drug reactions are avoidable and that their main cause are medication errors. Such errors have often been related to dosing and non-consideration of contraindications and the individual patient's risk profile. In order to resolve this unacceptable situation pharmacovigilance has to be strengthened. Pharmacovigilance in this context does not only imply the assessment and collection of adverse drug reactions, but also the communication of treatment risks to the medical community as well as to pharmacists and patients, and the development and implementation of intelligent electronic prescribing systems. The Federal Government of Germany in co-operation with the Drug Commission of the German Medical Association has decided on a bunch of about 40 single measures to enhance drug safety in this country. This project was issued in November 2007 by the Federal Ministry of Health. The Drug Commission will be responsible for the co-ordination of any future actions.

A New Logistic Regression Approach for the Evaluation of Diagnostic Test Results

The value of a dichotomous diagnostic test is often described in terms of sensitivity, specificity, and likelihood ratios (LRs). Although it is known that these test characteristics vary between subgroups of patients, they are generally interpreted, on average, without considering information on patient characteristics, such as clinical signs and symptoms, or on previous test results. This article presents a reformulation of the logistic regression model that allows to calculate the LRs of diagnostic test results conditional on these covariates. The proposed method starts with estimating logistic regression models for the prior and posterior odds of disease. The regression model for the prior odds is based on patient characteristics, whereas the regression model for the posterior odds also includes the diagnostic test of interest. Following the Bayes theorem, the authors demontsrate that the regression model for the LR can be derived from taking the differences between the regression coefficients of the 2 models. In a clinical example, they demonstrate that the LRs of positive and negative test results and the sensitivity and specificity of the diagnostic test varied considerably between patients with different risk profiles, even when a constant odds ratio was assumed. The proposed logistic regression approach proves an efficient method to determine the performance of tests at the level of the individual patient risk profile and to examine the effect of patient characteristics on diagnostic test characteristics.

Benefit-Risk Assessment of Sirolimus in Renal Transplantation

Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.

Survival after oesophagectomy for cancer of the oesophagus.

Formerly an inevitably fatal disease, oesophageal cancer today has predictable chances for cure. The recent literature and authors' own experiences in the surgical management of oesophageal cancer was reviewed to identify factors associated with improved survival after oesophagectomy. Currently reported overall 5-year-survival rates are reaching 40% and more in patients who have had an oesophagectomy performed with curative intention. The reasons for improved survival after surgical resection are multifactorial in nature: decreased postoperative mortality and morbidity (due to improved patient selection, surgical technique and perioperative management), the use of tailored surgical strategies (adopted to the histological tumour type, tumour location, stage of disease and the individual patient's risk profile), and multimodality treatment in patients with locally advanced disease. The prognosis of patients who have had oesophagectomy for oesophageal cancer has markedly improved during the past decades. With improved long-term survival after oesophagectomy, postoperative quality of life gains importance as an additional parameter of outcome after oesophageal cancer surgery.

Epidemiological assessment of drug-induced disease

Adverse reactions are a potential concern for physicians when they prescribe or recommend drugs. Epidemiological principles, when combined with clinical judgment, can be of help in this situation, starting with an appreciation of the strengths and weaknesses of different sources of information on adverse reactions--clinical trials, case reports, and formal epidemiological studies. The latter studies generally provide the most comprehensive information on the risks of serious adverse drug reactions. An understanding of the different types of risk estimates, relative and absolute, is also needed--we stress the value of the absolute risk as the best measure of the impact of an adverse reaction. Rare serious reactions, although striking, have little impact on individual risk, whereas more common reactions, even with much lower fatality rates, are more likely to lead to adverse outcomes for patients. The importance of balancing risks and benefits, taking into account all the information about an individual patient's risk profile, is also highlighted.

Risk assessment in recent clinical trials in sepsis/SIRS: lessons learned and future directions

This presentation reviews recent evidence that the design and analysis of clinical trials in sepsis could be improved by using individualized sepsis specific risk assessments. These individual patient risk profiles are derived from independent databases. They describe patients on a continuum of risk. They have correlated very closely to mortality outcomes in recent clinical trials. These individual risk assessments can improve the interpretation of trial data by controlling for potentially confounding patient risk factors, thereby permitting the signal or impact from novel therapy to be more precisely determined. When these individual risk assessments are combined with data on the degree of the host's specific inflammatory response they may eventually lead to the development of specific patient profiles to describe where immunotherapy is appropriate and other situations where it may either not be indicated or pose a risk. This relationship needs further investigation, however, before it can be confirmed. Changes in the acute physiology score can also hold substantial promise as an alternative endpoint for clinical trials. Therapies which significantly and consistently reduce the APS during the initial days of sepsis in small, early exploratory Phase I and II trials may be excellent candidates for investigation in larger Phase III studies.