Surrogate end points in secondary analyses of cardiovascular trials

A surrogate end point is one that is used as a substitute for a clinical end point of more direct interest, usually for reasons of practicality, and that is expected to predict clinical benefit. Surrogate end points play a critical role in the advancement of all medical research, and cardiovascular (CV) research in particular. However, the relationship between a surrogate end point and its clinical end point is usually complex, and there are many examples where results based on surrogates have proved to be misleading. Secondary analyses of existing clinical trial data are likely to involve surrogate end points, if only because clinical end points will have been extensively studied as part of the primary analysis of a trial large enough to collect useful clinical end point data. Validation of a surrogate end point is a laudable goal for a secondary analysis of a large clinical end point trial (or meta-analysis of multiple smaller trials), and the result may be an important new tool for further study of a class of compounds in a particular disease context. Secondary analyses using surrogate end points may also provide new insight into disease or treatment mechanism, but as with any surrogate end point analysis, the results can mislead, and the existing literature is heavy on application and light on methodology. Surrogate end points often substitute efficiency for clarity, and while many interesting and potentially informative secondary analyses of CV trials will involve surrogates, results are likely to be ambiguous and should be interpreted with care.     

European Bone Marrow Working Group trial on reproducibility of World Health Organization criteria to discriminate essential thrombocythemia from prefibrotic primary myelofibrosis

Background

The World Health Organization classification of myeloproliferative neoplasms discriminates between essential thrombocythemia and the prefibrotic phase of primary myelofibrosis. This discrimination is clinically relevant because essential thrombocythemia is associated with a favorable prognosis whereas patients with primary myelofibrosis have a higher risk of progression to myelofibrosis or blast crisis.

Design and Methods

To assess the reproducibility of the classification, six hematopathologists from five European countries re-classified 102 non-fibrotic bone marrow trephines, obtained because of sustained thrombocytosis.

Results

Consensus on histological classification defined as at least four identical diagnoses occurred for 63% of the samples. Inter-observer agreement showed low to moderate kappa values (0.28 to 0.57, average 0.41). The percentage of unclassifiable myeloproliferative neoplasms rose from 2% to 23% when minor criteria for primary myelofibrosis were taken into account. In contrast, the frequency of primary myelofibrosis dropped from 23% to 7%, indicating that the majority of patients with a histological diagnosis of primary myelofibrosis did not fulfill the complete criteria for this disease. Thus, over 50% of cases in this series either could not be reproducibly classified or fell into the category of unclassifiable myeloproliferative neoplasms.

Conclusions

World Health Organization criteria for discrimination of essential thrombocythemia from prefibrotic primary myelofibrosis are poorly to only moderately reproducible and lead to a higher proportion of non-classifiable myeloproliferative neoplasms than histology alone.     

Die Proktokolektomie bei Colitis ulcerosa

Background

The coloproctomucosectomy (CPM) is the procedure of the choice for the surgical treatment of ulcerative colitis (UC). In cases with pronounced immunosuppression (IS), a 3-step (3S) procedure [i.e., subtotal colectomy and ileal pouch-anal anastomosis (IPAA) and finally ileostomy reconstruction] is often selected. Fewer perioperative complications can be expected compared to the 2-step (2S) procedure; however, an additional in-hospital stay and surgical intervention are necessary. The aim of the present study was to compare both approaches using the clinical outcome of our patients undergoing IPAA to determine efficacy of these two concepts.

Patients and methods

From 1997–2010, a total of 225 patients were operated using a 2S or 3S IPAA procedure. Clinical outcomes were evaluated based on the number of surgical steps for the ileoanal pouch procedure and IPAA. The survey was performed within the scope of prospective study.

Results

Of the 225 patients with CPM, 66 were excluded due to a diagnosis other than UC (familial adenomatous polyposis, indeterminate colitis, Crohn’s disease) and patients with permanent ILS procedures without the possibility or wish for an IPAA (n?=??54). Included were 71 patients with 2S (w?=?30, m?=?41) and 34 patients with 3S procedures (w?=?21, m?=?13). Compared to the 2S procedure, the 3S procedure was shown to have shorter operation times (246 versus 296 min; p??=?0.05), shorter hospital stays (15.5 versus 24.6 days; p?=?0.05), shorter intensive care unit stays (3.3 versus 7.2 days; p?=?0.05), and fewer major complications (5.9?% versus 22.5?%; p?=?0.035). Patients with 3S procedures had a higher BMI (26.2 versus 23.1 kg/m²; p?=?0.05) and fewer required IS (10?% vs. 62?%; p?<?0.05).

Conclusion

The decision for a 3S procedure in UC and pronounced IS is advisable and justified. Using a 3S procedure, immunosuppression and its influence on perioperative morbidity are thus reduced. The IPAA can be performed with shorter operation times, shorter hospital stays and fewer major complications.     

Therapierefraktäre chronisch entzündliche Darmerkrankungen

Surgery for inflammatory bowel disease under immunosuppressant drugs is a widely discussed topic. Because therapeutic concepts have significantly changed, almost no patient is currently without an immunosuppressant or biologic agent prior to surgery. However, the data whether biological agents and immunosuppressant are a risk factor are very inconsistent. Concerning Crohn’s disease, monotherapy with immunosuppressants or biological agents seems to have no negative influence on the postoperative results. In contrast, however, for ulcerative colitis more publications recognise biologic agents and immunosuppressants as a single therapy as a risk factor for infections. To reduce the general risk, all risk factors have to be reduced. In Crohn’s disease, nutritional status must be optimised, corticoids should be reduced, biological agents and immunosuppressant drugs should be stopped, protection of an eventual anastomosis by a stoma. For ulcerative colitis in high-risk patients, a three-stage restaurative proctocolectomy is favoured to a one- or two-staged proctocolectomy.     

Error propagation in calculated ratios

BACKGROUND: Calculated quantities that combine results of multiple laboratory tests have become popular for screening, risk evaluation, and ongoing care in medicine. Many of these are ratios. In this paper, we address the specific issue of propagated random analytical error in calculated ratios. METHODS: Standard error propagation theory is applied to develop an approximate formula for the mean, standard deviation (SD), and coefficient of variation (CV) of the ratio of two independent, normally distributed random variables. A method of mathematically modeling the problem by random simulations to validate these formulas is proposed and applied. Comparisons are made with the commonly quoted formula for the CV of a ratio. RESULTS: The approximation formula for the CV of a ratio R=X/Y of independent Gaussian random variables developed herein has an absolute percentage error less than 4% for CVs of less than 20% in Y. In contrast the commonly quoted formula has a percentage error of up to 16% for CVs of less than 20% in Y. CONCLUSION: The usual formula for the CV of a ratio functions well when the CV of the denominator is less than 10% but for larger CVs, the formula proposed here is more accurate. Random analytical error in calculated ratios may be larger than clinicians and laboratorians are aware. The magnitude of the propagated error needs to be considered when interpreting calculated ratios in the clinical laboratory, especially near medical decision limits where its effect may lead to erroneous conclusions.