Michael Schemper

A note on quantifying follow-up in studies of failure time

In a recent review of survival analyses published in cancer journals, Altman et al [l] found that about half of the papers did not include any summary of followup time. Only 31% of those papers that did report median follow-up specified the method used to compute it. Independently of Altman et al [I], we have surveyed articles in three medical journals-Journal of Clinical Oncology, Annals of Internal Medicine, and Nao England Journal of Medicine-within a 6-month period (January-June 1994) and identified 70 that used survival analysis. Among these, 47 (67%) included a statement regarding duration of follow-up, but 24 did not specify the method used to quantify followup (usually median follow-up). Among the 23 other articles, methods employed were (1) follow-up based only on censored times (14 articles); (2) specification of a minimum follow-up time (5 articles); (3) times from entry to death or last contact (1 article); (4) times from entry to end-of-study date (1 article); (5) other methods (2 articles). Median sample size in the surveyed articles was 236 (range 30-8331), and the median proportion of censoring was 60% (range 3-96%). This note shows that values of median follow-up may differ substantially depending on the method used. Results of survival analysis apply to the time frame in whichmost of the individuals were observed. In particular, standard analytical methods for survival data, such as the log-rank test 121, the generalized Wilcoxon test [3], or the proportional hazards model 141, estimate average effects [51 for the observed response times and test those effects for significance. Thus the current reporting of follow-up is unsatisfactory. The following methods have been used or suggested. We assume a medical study with staggered entry of all individuals between times T,, and T,, and analysis of the available data at a final end-of-study time, TX. For each individual i (1 G i s n), we observe the time of entry into the study, t,,, and the final recorded date, t2,. If tli is the date of death, the status indicator, Si, assumes a value of 1. For

Predictors of Outcome in Severe, Asymptomatic Aortic Stenosis

BACKGROUND Whether to perform valve replacement in patients with asymptomatic but severe aortic stenosis is controversial. Therefore, we studied the natural history of this condition to identify predictors of outcome. METHODS During 1994, we identified 128 consecutive patients with asymptomatic, severe aortic stenosis (59 women and 69 men; mean [+/-SD] age, 60+/-18 years; aortic-jet velocity, 5.0+/-0.6 m per second). The patients were prospectively followed until 1998. RESULTS Follow-up information was available for 126 patients (98 percent) for a mean of 22+/-18 months. Event-free survival, with the end point defined as death (8 patients) or valve replacement necessitated by the development of symptoms (59 patients), was 67+/-5 percent at one year, 56+/-5 percent at two years, and 33+/-5 percent at four years. Five of the six deaths from cardiac disease were preceded by symptoms. According to multivariate analysis, only the extent of aortic-valve calcification was an independent predictor of outcome, whereas age, sex, and the presence or absence of coronary artery disease, hypertension, diabetes, and hypercholesterolemia were not. Event-free survival for patients with no or mild valvular calcification was 92+/-5 percent at one year, 84+/-8 percent at two years, and 75+/-9 percent at four years, as compared with 60+/-6 percent, 47+/-6 percent, and 20+/-5 percent, respectively, for those with moderate or severe calcification. The rate of progression of stenosis, as reflected by the aortic-jet velocity, was significantly higher in patients who had cardiac events (0.45+/-0.38 m per second per year) than those who did not have cardiac events (0.14+/-0.18 m per second per year, P<0.001), and the rate of progression of stenosis provided useful prognostic information. Of the patients with moderately or severely calcified aortic valves whose aortic-jet velocity increased by 0.3 m per second or more within one year, 79 percent underwent surgery or died within two years of the observed increase. CONCLUSIONS In asymptomatic patients with aortic stenosis, it appears to be relatively safe to delay surgery until symptoms develop. However, outcomes vary widely. The presence of moderate or severe valvular calcification, together with a rapid increase in aortic-jet velocity, identifies patients with a very poor prognosis. These patients should be considered for early valve replacement rather than have surgery delayed until symptoms develop.

Outcome of Watchful Waiting in Asymptomatic Severe Mitral Regurgitation

Background— The management of asymptomatic severe mitral regurgitation remains controversial. The aim of this study was to evaluate the outcome of a watchful waiting strategy in which patients are referred to surgery when symptoms occur or when asymptomatic patients develop left ventricular (LV) enlargement, LV dysfunction, pulmonary hypertension, or recurrent atrial fibrillation. Methods and Results— A total of 132 consecutive asymptomatic patients (age 55±15 years, 49 female) with severe degenerative mitral regurgitation (flail leaflet or valve prolapse) were prospectively followed up for 62±26 months. Patients underwent serial clinical and echocardiographic examinations and were referred for surgery when the criteria mentioned above were fulfilled. Overall survival was not statistically different from expected survival either in the total group or in the subgroup of patients with flail leaflet. Eight deaths were observed. Thirty-eight patients developed criteria for surgery (symptoms, 24; LV criteria, 9; pulmonary hypertension or atrial fibrillation, 5). Survival free of any indication for surgery was 92±2% at 2 years, 78±4% at 4 years, 65±5% at 6 years, and 55±6% at 8 years. Patients with flail leaflet tended to develop criteria for surgery slightly but not significantly earlier. There was no operative mortality. Postoperative outcome was good with regard to survival, symptomatic status, and postoperative LV function. Conclusions— Asymptomatic patients with severe degenerative mitral regurgitation can be safely followed up until either symptoms occur or currently recommended cutoff values for LV size, LV function, or pulmonary hypertension are reached. This management strategy is associated with good perioperative and postoperative outcome but requires careful follow-up.

Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis

Background—Recently, statins and angiotensin-converting enzyme inhibitors (ACEIs) have been shown to slow aortic valve calcium accumulation. Although several studies also suggest that statins may reduce the hemodynamic progression of aortic stenosis (AS), no data are available for ACEIs or the combination of both. Methods and Results—A total of 211 consecutive patients (aged 70±10 years, 104 females) with native AS, defined by a peak velocity >2.5 m/s (valve area 0.84±0.23 cm2, mean gradient 42±19 mm Hg), with normal left ventricular function and no other significant valvular lesion who were examined between 2000 and 2002 and who had 2 echocardiograms separated by at least 6 months were included. Of these, 102 patients were treated with ACEIs, 50 patients received statins, and 32 patients received both. Hemodynamic progression of AS was assessed and related to medical treatment. Annualized increase in peak aortic jet velocity for the entire study group was 0.32±0.44 m · s−1 · y−1. Progression was significantly lower in patients treated with statins (0.10±0.41 m · s−1 · y−1) than in those who were not (0.39±0.42 m · s−1 · y−1; P<0.0001). This effect was observed both in mild-to-moderate and severe AS. ACEI use, however, did not significantly affect hemodynamic progression (P=0.29). Furthermore, ACEIs had no additional effect on AS progression when given in combination with statins (0.11±0.42 versus 0.08±0.43 m · s−1 · y−1 for combination versus statin only; P=0.81). Cholesterol levels did not correlate with hemodynamic progression either in the group receiving statins or in the group that did not. Conclusions—ACEIs do not appear to slow AS progression. However, statins significantly reduce the hemodynamic progression of both mild-to-moderate and severe AS, an effect that may not be related to cholesterol lowering.

Natural History of Very Severe Aortic Stenosis

Background— We sought to assess the outcome of asymptomatic patients with very severe aortic stenosis. Methods and Results— We prospectively followed 116 consecutive asymptomatic patients (57 women; age, 67±16 years) with very severe isolated aortic stenosis defined by a peak aortic jet velocity (AV-Vel) ≥5.0 m/s (average AV-Vel, 5.37±0.35 m/s; valve area, 0.63±0.12 cm2). During a median follow-up of 41 months (interquartile range, 26 to 63 months), 96 events occurred (indication for aortic valve replacement, 90; cardiac deaths, 6). Event-free survival was 64%, 36%, 25%, 12%, and 3% at 1, 2, 3, 4, and 6 years, respectively. AV-Vel but not aortic valve area was shown to independently affect event-free survival. Patients with an AV-Vel ≥5.5 m/s had an event-free survival of 44%, 25%, 11%, and 4% at 1, 2, 3, and 4 years, respectively, compared with 76%, 43%, 33%, and 17% for patients with an AV-Vel between 5.0 and 5.5 m/s (P<0.0001). Six cardiac deaths occurred in previously asymptomatic patients (sudden death, 1; congestive heart failure, 4; myocardial infarction, 1). Patients with an initial AV-Vel ≥5.5 m/s had a higher likelihood (52%) of severe symptom onset (New York Heart Association or Canadian Cardiovascular Society class >II) than those with an AV-Vel between 5.0 and 5.5 m/s (27%; P=0.03). Conclusions— Despite being asymptomatic, patients with very severe aortic stenosis have a poor prognosis with a high event rate and a risk of rapid functional deterioration. Early elective valve replacement surgery should therefore be considered in these patients.

Metabolic disorders in severe abdominal sepsis: glutamine deficiency in skeletal muscle.

The metabolic profiles of 14 patients with prolonged abdominal sepsis were analysed on the second day after laparotomy. The profiles of survivors were compared with those of non-survivors who died one to five days after the time of evaluation due to uncontrollable multiple organ failure. In the non-surviving patients plasma glucose and glucagon levels were significantly higher than in surviving patients. The plasma concentrations of phosphoserine, cysteine, valine, phenylalanine, and 3-methylhistidine were found to be significantly increased in non-survivors and their muscle tissue showed significantly decreased concentrations of glutamine, proline and lysine with increases in valine and leucine. A correct classification of non-survivors and survivors could be obtained from the plasma and muscle amino acid concentrations, the highest discriminant power being from muscle glutamine. In severe sepsis metabolic changes correlate with the outcome of the patients, and amino acid metabolism seems to be characterised by low concentrations of muscle glutamine and high levels of the branched chain amino acids possibly indicating an inhibited intracellular glutamine formation in muscle tissue.

Explained variation for logistic regression.

Different measures of the proportion of variation in a dependent variable explained by covariates are reported by different standard programs for logistic regression. We review twelve measures that have been suggested or might be useful to measure explained variation in logistic regression models. The definitions and properties of these measures are discussed and their performance is compared in an empirical study. Two of the measures (squared Pearson correlation between the binary outcome and the predictor, and the proportional reduction of squared Pearson residuals by the use of covariates) give almost identical results, agree very well with the multiple R2 of the general linear model, have an intuitively clear interpretation and perform satisfactorily in our study. For all measures the explained variation for the given sample and also the one expected in future samples can be obtained easily. For small samples an adjustment analogous to Radj2 in the general linear model is suggested. We discuss some aspects of application and recommend the routine use of a suitable measure of explained variation for logistic models.

Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by organized thromboemboli that obstruct the pulmonary vascular bed. Although CTEPH is a serious complication of acute symptomatic pulmonary embolism in 4% of cases, signs, symptoms and classical risk factors for venous thromboembolism are lacking. The aim of the present study was to identify medical conditions conferring an increased risk of CTEPH. We performed a case-control-study comparing 109 consecutive CTEPH patients to 187 patients with acute pulmonary embolism that was confirmed by a high probability lung scan. Splenectomy (odds ratio=13, 95% CI 2.7-127), ventriculo-atrial (VA-) shunt for the treatment of hydrocephalus (odds ratio=13, 95% CI 2.5-129) and chronic inflammatory disorders, such as osteomyelitis and inflammatory bowel disease (IBD, odds ratio=67, 95% CI 7.9-8832) were associated with an increased risk of CTEPH.

Statistical evaluation of epiluminescence microscopy criteria for melanocytic pigmented skin lesions

BACKGROUND Epiluminescence microscopy (ELM) is a noninvasive technique by which the clinical diagnosis of pigmented skin lesions (PSL) can be improved. Many ELM criteria have been described, but their significance in the differential diagnosis of PSL has not yet been established. OBJECTIVE The purpose of this study was to determine the value of ELM criteria in the differential diagnosis of PSL. METHODS Two hundred one melanocytic PSL (61 common nevi, 60 dysplastic nevi, and 80 melanomas) were investigated with ELM for the presence of certain ELM criteria; their significance was determined by calculating the odds ratios. RESULTS Individual ELM criteria have different weights of significance in the differential diagnosis of melanocytic PSL. Selected patterns of ELM criteria adjusted to the distinct types of PSL considerably improve the diagnostic accuracy of melanocytic PSL. CONCLUSION The prevalence of certain distinct ELM criteria in a given melanocytic PSL has statistical value in differential diagnosis.

High-Density Lipoprotein and the Risk of Recurrent Venous Thromboembolism

Background— High-density lipoprotein (HDL) protects against arterial atherothrombosis, but it is unknown whether it protects against recurrent venous thromboembolism. Methods and Results— We studied 772 patients after a first spontaneous venous thromboembolism (average follow-up 48 months) and recorded the end point of symptomatic recurrent venous thromboembolism, which developed in 100 of the 772 patients. The relationship between plasma lipoprotein parameters and recurrence was evaluated. Plasma apolipoproteins AI and B were measured by immunoassays for all subjects. Compared with those without recurrence, patients with recurrence had lower mean (±SD) levels of apolipoprotein AI (1.12±0.22 versus 1.23±0.27 mg/mL, P<0.001) but similar apolipoprotein B levels. The relative risk of recurrence was 0.87 (95% CI, 0.80 to 0.94) for each increase of 0.1 mg/mL in plasma apolipoprotein AI. Compared with patients with apolipoprotein AI levels in the lowest tertile (<1.07 mg/mL), the relative risk of recurrence was 0.46 (95% CI, 0.27 to 0.77) for the highest-tertile patients (apolipoprotein AI >1.30 mg/mL) and 0.78 (95% CI, 0.50 to 1.22) for midtertile patients (apolipoprotein AI of 1.07 to 1.30 mg/mL). Using nuclear magnetic resonance, we determined the levels of 10 major lipoprotein subclasses and HDL cholesterol for 71 patients with recurrence and 142 matched patients without recurrence. We found a strong trend for association between recurrence and low levels of HDL particles and HDL cholesterol. Conclusions— Patients with high levels of apolipoprotein AI and HDL have a decreased risk of recurrent venous thromboembolism.