Antiphospholipid Syndrome Clinical Research Task Force report

The Antiphospholipid Syndrome (APS) Clinical Research Task Force (CRTF) was one of six Task Forces developed by the 13(th) International Congress on Antiphospholipid Antibodies (aPL) organization committee with the purpose of: a) evaluating the limitations of APS clinical research and developing guidelines for researchers to help improve the quality of APS research; and b) prioritizing the ideas for a well-designed multicenter clinical trial and discussing the pragmatics of getting such a trial done. Following a systematic working algorithm, the Task Force identified five major issues that impede APS clinical research and the ability to develop evidence-based recommendations for the management of aPL-positive patients: (1) aPL detection has been based on partially or non-standardized tests, and clinical (and basic) APS research studies have included patients with heterogeneous aPL profiles with different clinical event risks; (2) clinical (and basic) APS research studies have included a heterogeneous group of patients with different aPL-related manifestations (some controversial); (3) thrombosis and/or pregnancy risk stratification and quantification are rarely incorporated in APS clinical research; (4) most APS clinical studies include patients with single positive aPL results and/or low-titer aPL ELISA results; furthermore, study designs are mostly retrospective and not population based, with limited number of prospective and/or controlled population studies; and (5) lack of the understanding the particular mechanisms of aPL-mediated clinical events limits the optimal clinical study design. The Task Force recommended that there is an urgent need for a truly international collaborative approach to design and conduct well-designed prospective large-scale multi-center clinical trials of patients with persistent and clinically significant aPL profiles. An international collaborative meeting to formulate a good research question using 'FINER' (Feasible; Interesting; Novel; Ethical; and Relevant) criteria took place in November 2010.     

Pulmonary embolism: diagnostic algorithms.

In 90% of cases the clinical suspicion of pulmonary embolism (PE) is raised by clinical signs and symptoms, while in only 10% of cases PE is suspected on the basis of electrocardiographic, arterial blood gas analysis or radiological findings. The combination of clinical signs and symptoms and the results of first-level diagnostic tests (electrocardiography, gas analysis and chest X-ray) allows a fairly accurate classification of patients with "clinical suspicion of PE" into three categories of clinical (or pre-test) probability: low, intermediate and high. The clinical diagnosis of PE is very often inaccurate making the use of additional tests, including imaging techniques, mandatory. The choice and the combination (= diagnostic algorithms) of second- and third-level diagnostic tests (D-dimer, venous ultrasound, echocardiography, lung scintigraphy, helical computed tomography and pulmonary angiography) depend primarily on the clinical conditions of patients and their pre-test probability. We propose two diagnostic algorithms: 1) a diagnostic algorithm for patients with clinically suspected PE and critical clinical conditions (unstable patients), 2) a diagnostic algorithm for patients with clinically suspected PE and non-critical clinical conditions (hemodynamically stable patients).     

Clinical excellence in cardiology

A recent study identified 7 domains of clinical excellence on the basis of interviews with "clinically excellent" physicians at academic institutions in the United States: (1) communication and interpersonal skills, (2) professionalism and humanism, (3) diagnostic acumen, (4) skillful negotiation of the health care system, (5) knowledge, (6) taking a scholarly approach to clinical practice, and (7) having passion for clinical medicine. What constitutes clinical excellence in cardiology has not previously been defined. The author discusses clinical excellence in cardiology using the framework of these 7 domains and also considers the additional domain of clinical experience. Specific aspects of the domains of clinical excellence that are of greatest relevance to cardiology are highlighted. In conclusion, this discussion characterizes what constitutes clinical excellence in cardiology and should stimulate additional discussion of the topic and an examination of how the domains of clinical excellence in cardiology are related to specific patient outcomes.     

A three-page Standard Protocol to Evaluate Rheumatoid Arthritis (SPERA) for efficient capture of essential data from patients and health professionals in standard clinical care and clinical research

A Standard Protocol to Evaluate Rheumatoid Arthritis (SPERA) has been developed to collect essential data from patients and health professionals to assess, monitor, and document change in standard clinical care and clinical research. Three one-page forms are completed by a health professional assessor, which can be completed at baseline for use at all future visits: (1) clinical features of rheumatoid arthritis (RA); (2) medications taken; and (3) a 42-joint count. The patient also completes a patient questionnaire, and a radiographic scoring sheet can also be included for a comprehensive database. The 15-20 minutes involved in completing the SPERA generally add efficiency to subsequent visits in standard clinical care. Collection of additional information for clinical care and/or clinical research is also possible. The SPERA is presented not as an optimal format but rather as an example of a possible approach to develop a common format for core clinical data to be collected in standard clinical care.     

Clinical screening for HIV in a health centre setting in urban Kenya: an entry point for voluntary counselling, HIV testing and early diagnosis of HIV infection?

A study was conducted among patients attending a public health centre in Nairobi, Kenya in order to (a) verify the prevalence of HIV, (b) identify clinical risk factors associated with HIV and (c) determine clinical markers for clinical screening of HIV infection at the health centre level. Of 304 individuals involved in the study,107(35%) were HIV positive. A clinical screening algorithm based on four clinical markers, namely oral thrush, past or present TB, past or present herpes zoster and prurigo would pick out 61 (57%) of the 107 HIV-positive individuals. In a resource-poor setting, introducing a clinical screening algorithm for HIV at the health centre level could provide an opportunity for targeting voluntary counselling and HIV testing, and early access to a range of prevention and care interventions.     

Lipoprotein(a) is an independent risk factor for cardiovascular disease in hemodialysis patients.

BACKGROUND. Although serum lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis in the general population and Lp(a) levels are increased in hemodialysis patients, an association of Lp(a) with the risk of clinical events attributed to atherosclerosis has not been established in the chronic hemodialysis patient population. We therefore determined the association between Lp(a) levels and the risk of clinical events of presumed atherosclerotic etiology in a prospective study of an outpatient hemodialysis population. METHODS AND RESULTS. Lp(a) was measured by radioimmunoassay in a baseline cardiovascular disease risk assessment in a consecutive series of 129 hemodialysis patients. The relation between baseline Lp(a) and clinical events of presumed atherosclerotic etiology was determined during 48 months of follow-up. Hemodialysis patients had a median Lp(a) concentration that was approximately four times as high as the median Lp(a) concentration in normal controls and twice as high as the levels in controls with angiographic evidence of coronary artery disease [median Lp(a), 38.4 versus 16.9 mg/dl; p less than 0.001]. Baseline Lp(a) levels were no different in participants with or with no history of a previous clinical event at the time of the baseline examination. However, baseline Lp(a) concentration (p less than 0.001) and a history of atherosclerotic clinical events (p = 0.001) were associated with clinical events during the period of follow-up. In contrast, baseline serum total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol, age, gender, race, or duration of hemodialysis were unrelated to this risk in the prospective study. Stepwise multiple logistic regression analysis demonstrated that serum Lp(a) concentration (p = 0.001) and the presence of a previous clinical event (p = 0.004) were the only independent contributors to the risk of a clinical event during the period of follow-up. CONCLUSIONS. Lp(a) is an independent risk factor for clinical events attributed to atherosclerotic cardiovascular disease in patients receiving chronic hemodialysis treatment of end-stage renal disease.     

Should contemporary rheumatoid arthritis clinical trials be more like standard patient care and vice versa?

The information used by rheumatologists when delivering care to patients with rheumatoid arthritis (RA) is derived mainly from two sources: randomised controlled clinical trials and experience in clinical care. However, these two sources differ significantly because (a) the extensive inclusion and exclusion criteria result in clinical trial participants being recruited from only a minority of patients seen in standard clinical care; (b) assessments in clinical trials are conducted according to standard quantitative measures and indices, while standard clinical care of most patients with RA is generally conducted empirically, without collection of any quantitative data other than laboratory tests to estimate prognosis and document change in status; and (c) although baseline databases of various clinical trials (and observational studies) are 60-90% identical in content, they are not standardised and therefore not amenable to direct comparisons. Strategies to promote similarities between clinical trials and standard clinical care in patients with RA may include: more generalised inclusion criteria; incorporation of quantitative measurement into standard care, easily accomplished by asking each patient to complete a simple questionnaire at each visit to a rheumatologist; and consensus among rheumatologists for databases with standard content and format in clinical care and research involving patients with RA.     

How to Develop and Implement a Specialized Heart Failure with Preserved Ejection Fraction Clinical Program

Heart failure with preserved ejection fraction (HFpEF), a highly prevalent and complex clinical syndrome with high morbidity and mortality, is often unrecognized and not optimally treated. Clinical trials for HFpEF have been plagued by low enrollment, and clinicians often approach HFpEF patients with “therapeutic nihilism” given the perceived lack of available therapies based on the disappointing results of these prior trials. Due to these challenges, we have pioneered the successful creation of dedicated, specialized HFpEF clinical programs. Here, we discuss (1) the rationale for the development of a specialized HFpEF clinical program; (2) strategies for the systematic identification of HFpEF patients; (3) a standardized diagnostic and therapeutic approach; (4) validation of the HFpEF clinical program paradigm; (5) staffing and reimbursement considerations; (6) HFpEF clinical trial enrollment; and (7) challenges and future directions for HFpEF clinical programs. We conclude that it is feasible to create HFpEF clinical programs that fulfill the major unmet need of identifying and caring for patients with HFpEF. These clinics are essential for confirming the HFpEF diagnosis, providing standardized treatment, and facilitating clinical trial enrollment. It is our hope that the information provided here will encourage others to establish their own specialized HFpEF programs, thereby allowing for comprehensive care for these complex patients.     

A new clinical model in pulmonary embolism and its correlation with V/P scan results.

The study was prospectively designed to assess the correlation between a new clinical model empirically developed for acute pulmonary embolism (PE) and ventilation/perfusion (V/P) scan results. One hundred sixty consecutive patients with suspected acute PE underwent clinical evaluation before V/P scintigraphy. The clinical probability of PE was categorized according to a structured clinical model empirically developed as low, intermediate, or high, and the results were compared with those of V/P scintigraphy. Forty, 61, and 59 patients were classified as low, intermediate, and high clinical probability, respectively. Seventy-five percent (30/40) of the patients with low clinical probability were also of low scintigraphic probability or had a normal result (r(s): 0.39, p=0.000); 28% (17/61) of the patients with intermediate clinical probability demonstrated intermediate scintigraphic probability (r(s): 0.20, p=0.012); and 68% (40/59) of the patients with high clinical probability were also of high scintigraphic probability (r(s): 0.43, p=0.000). Overall, the correlation of two scoring systems was statistically significant (r(s): 0.39, p=0.000). Unilateral leg swelling (p=0.027), syncope or near syncope (p=0.002), amputation of a hilar artery (p=0.007), and electrocardiographic signs of right ventricular overload (p=0.000) prevailed in patients with high scintigraphic probability. "Syncope-near syncope or hemodynamic collapse" PLUS "electrocardiographic signs of right ventricular overload or hypoxemia" combination had the most significant correlation with a high scintigraphic probability (r(s): 0.31; p=0.000). In conclusion, the new clinical model empirically developed was significantly successful to provide comparable results with V/P scan. This consistency was particularly prominent in patients with low or high clinical probability for PE.     

Formal decision aids in gastroenterology--results of a survey]

Formal decision aids such as scores, decision-trees and expert systems, are recommended for supporting research and daily clinical work. In the field for gastroenterology it is unknown, to which degree these tools are accepted and applied in clinical routine. We therefore conducted a mail survey in order to find out whether clinical gastroenterologists know, use or want formal decision-aids. To all clinical members of a german gastroenterological scientific society (Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten, n = 584) an information leaflet and a questionnaire was sent. The form contained questions about use, knowledge and requests with respect to decision-aids in gastroenterology and concerning the attitude to computerized decision-aids in general. 584 clinicians received the questionnaire, 215 sent it back for analysis (39%). Formal decision-aids were used by half of the survey participants (56%), mainly three scores (Child-Pugh, Best and other indices for inflammatory bowel disease, Ranson) and four classifications (TNM, Forrest, Savary-Miller, Paquet). Computer-based formal decision-aids (e.g. expert systems) were used by a minority. Clinicians, who applied formal decision-aids stated more frequently a request for further decision-aids (72%) than those who did not (46%). A considerable part of the survey participants believed that computerized decision-aids will come into clinical routine (52%) and will improve education (37%) and clinical practice (35%). 88% were convinced, that decision-aids should be tested in controlled clinical trials before a clinical use can be recommended. There is a discrepancy between propagation of formal decision-aids and it's clinical use. Only a few scores and classifications are used in clinical routine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Infliximab in treatment of Crohn''s disease: the Milan experience

BACKGROUND: Efficacy of infliximab in treatment of patients with moderate-to-severe refractory and fistulizing Crohn's disease has been shown in controlled clinical trials. Moreover, audit data from North America and North Europe have confirmed efficacy in clinical practice comparable to that in clinical trials. AIM: To report clinical experience using infliximab in treatment of Crohn's disease in Italy, comparing efficacy and safety with those reported in clinical trials and other published series. PATIENTS AND METHODS: The study population comprised 63 patients (31 males and 32 females, median age 33 years) treated with infliximab for refractory/inflammatory (31 patients) and/or fistulizing Crohn's disease (32 patients). All patients received an infusion of infliximab at a dose of 5 mg/kg at weeks 0, 2 and 6. After the first infusion, clinical and laboratory assessments were repeated at weeks 2, 6 and 10. For refractory inflammatory Crohn's disease, clinical remission was defined as a Crohn's Disease Activity Index of < or = 150 at each scheduled visit, clinical response as a reduction in the Crohn's Disease Activity Index score of > or = 70 points in comparison to baseline. For fistulizing Crohn's disease, a complete response was defined as closure of any draining fistulae at week 10. A fistula was defined as closed when it no longer drained despite gentle finger pressure. A partial response was defined as reduction in number, size or drainage of fistulae, at the same visit. RESULTS: According to an intention-to-treat evaluation on the 31 patients with refractory/inflammatory Crohn's disease, at week 2, 42.5% (14 patients) had a clinical response and 31.3% of patients (10 patients) were in clinical remission. At week 10 (4 weeks after the end of third infusion), 80.6% (25 patients) had a clinical response and 71% (22 patients) were in clinical remission and 14/19 (74%) had discontinued steroid treatment. Of the 32 patients with fistulizing Crohn's Disease, 15 (46.9%) had a complete response, 8 (25%) a partial response, and 9 (28.1%) no response at week 10 check-up. The incidence of side-effects was low (16%) and not influenced by concurrent immunomodulatory therapy. CONCLUSION: The present experience with infliximab in clinical practice confirms its efficacy, in particular in inflammatory/refractory Crohn's disease and its safety, at least, in short-term follow-up.     

Is cardiac MRI an effective test for arrhythmogenic right ventricular cardiomyopathy diagnosis?

AIM:To evaluate the referrals with suspected arrhythmogenic right ventricular cardiomyopathy(ARVC)and compare cardiac MR(cMR)findings against clinical diagnosis.METHODS:A retrospective analysis of 114(age range16 to 83,males 55%and females 45%)patients referred for cMR with a suspected diagnosis of ARVC between May 2006 and February 2010 was performed after obtaining institutional approval for service evaluation.Reasons for referral including clinical symptoms and family history of sudden death,electrocardiogram and echo abnormalities,cMR findings,final clinical diagnosis and information about clinical management were obtained.The results of cMR were classified as major,minor,non-specific or negative depending on both functional and tissue characterisation and the cMR results were compared against the final clinical diagnosis.RESULTS:The most common reasons for referral included arrhythmias(30%)and a family history of sudden death(20%).Of the total cohort of 114 patients:4 patients(4%)had major cMR findings for ARVC,13patients(11%)had minor cMR findings,2 patients had non-specific cMR findings relating to the right ventricle and 95 patients had a negative cMR.Of the 4 patients who had major cMR findings,3(75%)had a positive clinical diagnosis.In contrast,of the 13 patients who had minor cMR findings,only 2(15%)had a positive clinical diagnosis.Out of the 95 negative patients,clinical details were available for 81 patients and none of them had ARVC.Excluding the 14 patients with no clinical data and final diagnosis,the sensitivity of the test was 100%,specificity 87%,positive predictive value29%and the negative predictive value 100%.CONCLUSION:CMR is a useful tool for ARVC evaluation because of the high negative predictive value as the outcome has a significant impact on the clinical decision-making.     

Endomyocardial biopsy: experience with 156 patients

Transcatheter endomyocardial biopsy (EMB) is a well known technique but its clinical value is still controversial. Our experience in the first 156 patients studied, in whom 182 EMB were performed, is reported and particular attention is given to the clinical value of the biopsy. Complications were observed in 7 patients and left ventricular EMB appeared to be more complicated (2/23) than right ventricular EMB (5/159). The clinical value of EMB was well documented (63.5%) in patients with congestive heart failure and a dilated heart (group 1) in whom a fairly high presence of myocarditis (17.5%), in different stages, was observed (13/74 patients). In patients with congestive failure and a restrictive/constrictive physiology (group 2), with angina and normal coronary arteries (group 3) and with acute advanced atrio-ventricular block and young age (group 5) the clinical value of EMB was good (85.7%, 58.3% and 60.6% respectively). The clinical value of EMB was on the contrary poor in patients with idiopathic ventricular arrhythmias (group 4) and in an heterogeneous group of patients (group 7), where EMB was mainly performed to exclude myocarditis. EMB had no clinical value in patients with aortic or mitral incompetence (group 6) studied according to a research protocol. EMB is a safe procedure which provides useful clinical informations in more than 50% of patients studied. The fairly high incidence of myocarditis (25 out of 156 patients studied) and the protean clinical presentations of the disease are stressed.     

The lessons learned from randomized clinical trials of GERD.

Despite the huge number of randomized controlled clinical trials published on gastro-oesophageal reflux disease, the translation of the information gathered into clinical practice is rather limited. The aim of this article is to summarize the results of pivotal randomized controlled clinical trials and review articles on reflux disease and evaluate to what extent their results can be applied to current clinical practice. We reviewed the most relevant randomized controlled clinical trials and reviews since the publication of the first randomized controlled clinical trial on reflux oesophagitis (1978) to date. Six areas were explored, namely: (1) diagnostic "entry" criteria, (2) efficacy parameters, (3) duration of therapy, (4) degree of antisecretory effect, (5) placebo effect, (6) follow-up data. Gastro-oesophageal reflux disease is now the most frequent upper GI disorder treated by gastroenterologists in Europe and North America. There is still a dearth of information regarding the natural history of the disease. The types of information generated through randomized controlled clinical trials have had only limited applicability to routine clinical practice. In the future, large cooperative databases accumulating the clinical histories of a great variety of gastro-oesophageal reflux disease patients may help to provide us with the much needed insights into the natural history of this common disorder.     

Conflicting clinical trials and the uncertainty of treating mild hypertension

Recommendations to treat patients with mild hypertension are based principally on six randomized clinical trials conducted in three countries between 1964 and 1979. To determine whether the methods and results of these randomized clinical trials justify the current therapeutic policy, a clinical epidemiologic analysis of the data was performed focusing on (1) clinical versus statistical significance, (2) clinical heterogeneity of patients' baseline state, (3) suitable management of the untreated control patients, and (4) choice of outcome events. This analysis suggested that the results of available studies are better suited to public health decisions (number of cardiovascular deaths prevented nationwide) than personal health decisions (whether treatment does more good than harm for individual patients), and that current evidence does not justify a uniform policy of treating all asymptomatic patients with mild hypertension.     

Improving outcomes for pulmonary vascular disease

Recognizing the importance of improving lung health through lung disease research, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of multidisciplinary experts for the following purpose: (1) to review the current scientific knowledge underlying the basis for treatment of adults and children with pulmonary vascular diseases (PVDs); (2) to identify gaps, barriers, and emerging scientific opportunities in translational PVD research and the means to capitalize on these opportunities; (3) to prioritize new research directions that would be expected to affect the clinical course of PVDs; and (4) to make recommendations to the NHLBI on how to fill identified gaps in adult and pediatric PVD clinical research. Workshop participants reviewed experiences from previous PVD clinical trials and ongoing clinical research networks with other lung disorders, including acute respiratory distress syndrome, chronic obstructive lung disease, and idiopathic pulmonary fibrosis, as well. Bioinformatics experts discussed strategies for applying cutting-edge health information technology to clinical studies. Participants in the workshop considered approaches in the following broad concept areas: (1) improved phenotyping to identify potential subjects for appropriate PVD clinical studies; (2) identification of potential new end points for assessing key outcomes and developing better-designed PVD clinical trials; and (3) the establishment of priorities for specific clinical research needed to advance care of patients with various subsets of PVDs from childhood through adulthood. This report provides a summary of the objectives and recommendations to the NHLBI concentrating on clinical research efforts that are needed to better diagnose and treat PVDs.     

The value of clinical findings in the detection of normal pressure hydrocephalus

We conducted a retrospective study of 627 individuals with dementia to determine whether clinical characteristics could identify individuals with normal pressure hydrocephalus (NPH) on computed tomography (CT) brain scanning. Fifty (8%) individuals had classical clinical characteristics of NPH: dementia, urinary incontinence, and gait disturbance. When this clinical trial was present, 12% of individuals had NPH on CT scan; when absent, only 3% had NPH. The clinical findings identified individuals with a 4-fold increase (p less than .001) of NPH on CT scan. Of the 50 individuals with the clinical trial, 6 had both clinical and CT scan findings consistent with NPH; 2 of these had shunt surgery, and 1 improved clinically. None of the 577 individuals without clinical findings had shunt surgery performed, including those with CT scan abnormalities consistent with NPH. We conclude that clinical characteristics can be used to identify individuals who need CT scanning for detection of NPH.     

Comparison between clinical evaluation and ultrasonography in detecting hydrarthrosis of the knee

OBJECTIVE: To assess the validity of the clinical detection of knee hydrarthrosis compared to ultrasonography (US). To assess the differences of results for both clinical and US tests when they are done by independent investigators. To assess the effect of a previous clinical evaluation on the US diagnosis. METHOD: The clinical and US examinations were scored using a 3 point scale. In 50 symptomatic patients, 82 knees underwent clinical and US evaluations by the same physician. Two independent observers clinically and echographically tested 22 other knees (11 patients). Finally, in another series of 20 knees (10 patients), the first investigator performed clinical testing before the US evaluation, while the other did the US with no previous clinical evaluation. RESULTS: Between the clinical and US evaluations, agreement was moderate (kappa = 0.508), but statistically significant (p<0.001). The relationship between the 2 investigators for clinical evaluation was slightly weaker (kappa = 0.446, p = 0.032). Possible (score 1) or definite (score 2) clinical knee hydrarthrosis sensitivity was 79/100% and specificity 25/78%, respectively. In contrast, US studies from 2 independent observers were strongly related (kappa = 0.902) and were not modified by a previous clinical evaluation. CONCLUSION: Clinical knee hydrarthrosis detection is less accurate and reproducible than US detection.     

The prevalence and incidence of clinical and asymptomatic Lyme borreliosis in a population at risk

A past history of clinical Lyme borreliosis and the 6-month incidence of clinical and asymptomatic Lyme borreliosis was studied prospectively in a high-risk population. In the spring, blood samples were drawn from 950 Swiss orienteers, who also answered a questionnaire. IgG anti-Borrelia burgdorferi antibodies were detected by ELISA. Positive IgG antibodies were seen in 248 (26.1%), in contrast to 3.9%-6.0% in two groups of controls (n = 101). Of the orienteers, 1.9%-3.1% had a past history of definite or probable clinical Lyme borreliosis. Six months later a second blood sample was obtained from 755 participants, 558 (73.9%) of whom were seronegative initially; 45 (8.1%) had seroconverted from negative to positive. Only 1 (2.2%) developed clinical Lyme borreliosis. Among all participants, the 6-month incidence of clinical Lyme borreliosis was 0.8% (6/755) but was much higher (8.1%) for asymptomatic seroconversion (45/558). In conclusion, positive Lyme serology was common in Swiss orienteers, but clinical disease occurred infrequently.