Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib.

Ibrutinib is a Bruton tyrosine kinase inhibitor approved for the treatment of patients with relapsed refractory chronic lymphocytic leukemia (RR-CLL). We describe the characteristics, causes of discontinuation, and outcomes in patients who discontinued treatment with ibrutinib. One hundred twenty-seven patients were enrolled in various clinical trials of ibrutinib, with or without rituximab, at our center. Thirty-three (26%) patients have discontinued ibrutinib to date. The majority of those patients had high-risk features: 94% with unmutated immunoglobulin heavy chain variable gene rearrangement, 58% with del(17p) by fluorescence in situ hybridization, and 54% with a complex karyotype. Causes of discontinuation were disease transformation (7), progressive CLL (7), stem cell transplantation (3), adverse events (11), serious adverse events/deaths (3), and miscellaneous reasons (2). Twenty five patients (76%) died after discontinuing ibrutinib; the median overall survival was 3.1 months after discontinuation. Most patients with RR-CLL who discontinued ibrutinib early were difficult to treat and had poor outcomes.

'Charting a new course for prostate cancer' - currying favor for docetaxel in hormone-sensitive metastatic prostate cancer.

Docetaxel has an established role in the treatment of metastatic castrate-resistant prostate cancer. A number of recent treatments have been shown to improve the survival outcomes for this group of patients and many with improved toxicity profiles, bringing the role of docetaxel into question. We discuss the results and implications of the CHAARTED study that demonstrated a significant improvement in overall survival with docetaxel in metastatic hormone-sensitive prostate cancer.

Increased mortality after transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis and low ejection fraction: a meta-analysis of 6898 patients.

BACKGROUND: There is conflicting evidence regarding the safety and efficacy of transcatheter aortic valve implantation (TAVI) procedures in patients with severe aortic stenosis and low left ventricular ejection fraction (EF). The primary aim of this study was to determine the impact of TAVI on short- and long-term mortality in patients with low EF (EF <50%); the secondary aim was to analyze the impact of TAVI procedure on EF recovery in the same setting of patients. METHODS AND RESULTS: Twenty-six studies enrolling 6898 patients with severe aortic stenosis undergoing TAVI procedure were included in the meta-analysis and analyzed for 30-day, 6-month and 1-year all-cause and cardiovascular mortality; a further meta-analysis was also performed in patients with low EF to assess EF changes post TAVI. In low EF patients, both all-cause and cardiovascular short- and long-term mortality were significantly higher when compared to patients with normal EF (30-day-all-cause mortality: 0.13; 95% confidence interval [CI]: 0.01 to 0.25, I(2)=49.65, Q=21.85; 1-year-all-cause mortality: 0.25; 95% [CI]: 0.16 to 0.34, I(2)=25.57, Q=16.12; 30-day-cardiovascular mortality: 0.03; 95% [CI]: -0.31 to 0.36, I(2)=66.84, Q=6.03; 1-year-cardiovascular mortality: 0.29; 95% [CI]: 0.12 to 0.45, I(2)=0.00, Q=1.88). Nevertheless, in low EF patients TAVI was associated with a significant recovery of EF, which started at discharge and proceeded up to 1-year-follow-up. CONCLUSIONS: Patients with low EF severe aortic stenosis have higher mortality following TAVI compared to normal EF patients, despite a significant and sustained improvement in EF.

Blinded versus unblinded covariate selection in confirmatory survival trials.

Adjustment for covariates and specification of the correct covariate set are important issues in the analysis of clinical trials. Edwards (1999) proposes a model selection approach where the model is chosen on the final data set, which remains blinded for treatment group allocation. We investigate this method for time-to-event endpoints and compare its performance to variable selection within an adaptive design. This adaptive design integrates the methods of Schäfer and Müller (2001) and Keiding et al. (1987) and allows variable selection on the unblinded data during an interim analysis. Monte Carlo simulation shows that Edwards' method-though blinded-outperforms the adaptive method in terms of ability to select the survival relevant covariates and power. The application of the methods is illustrated by a clinical trial example.

Is early ventricular dysfunction or dilatation associated with lower mortality rate in adult severe sepsis and septic shock? A meta-analysis.

INTRODUCTION: Reversible myocardial depression occurs early in severe sepsis and septic shock. The question of whether or not early ventricular depression or dilatation is associated with lower mortality in these patients remains controversial. Most studies on this topic were small in size and hence lacked statistical power to answer the question. This meta-analysis attempted to answer the question by increasing the sample size via pooling relevant studies together. METHODS: PubMed, Embase (and Medline) databases and conference abstracts were searched to July 2012 for primary studies using well-defined criteria. Two authors independently screened and selected studies. Eligible studies were appraised using defined criteria. Additional information was sought the corresponding authors if necessary. Study results were pooled using random effects models. Standardized mean differences (SMD) between survivor and non-survivor groups were used as the main effect measures. RESULTS: A total of 62 citations were found. Fourteen studies were included in the analysis. The most apparent differences between the studies were sample sizes and exclusion criteria. All studies, except four pre-1992 studies, adopted the Consensus definition of sepsis. Altogether, there were >700 patients available for analysis of the left ventricle and >400 for the right ventricle. There were no significant differences in left ventricular ejection fractions, right ventricular ejection fractions, and right ventricular dimensions between the survivor and non-survivor groups. When indexed against body surface area or body height, the survivors and non-survivors had similar left ventricular dimensions. However, the survivors had larger non-indexed left ventricular dimensions. CONCLUSION: This meta-analysis failed to find any evidence to support the view that the survivors from severe sepsis or septic shock had lower ejection fractions. However, non-indexed left ventricular dimensions were mildly increased in the survivor group but the indexed dimensions were similar between the groups. Both survivors and non-survivors had similar right ventricular dimensions.

Lost in follow-up rates in TRACER, ATLAS ACS 2, TRITON and TRA 2P trials: challenging PLATO mortality rates.

CONTEXT: Extreme rates of vascular and all-cause mortality especially in the clopidogrel arm of the Platelet Inhibition and Patient Outcomes (PLATO) non-USA cohort raise concerns of data integrity, and call for independent verification of vital records in the national death registries. Four recent acute coronary syndrome (ACS) trials: Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER), Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome (ATLAS-ACS 2), Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON), and the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P), provide a valuable opportunity to match lost in follow-up (LIFU) with mortality rates among similar ACS studies. OBJECTIVE: To compare the LIFU from PLATO, TRACER, ATLAS-ACS 2, TRITON-TIMI 38 and TRA 2P trials. RESULTS: The disturbingly high (8.9%-14.7%) LIFU in PLATO was no match to LIFU in TRACER (0.1%), ATLAS ACS 2 (0.3%), TRITON (0.1%) and TRA 2P (0.1%). In fact, such an astronomical (49-147 fold higher) PLATO LIFU rate should result in less mortality compared to the other ACS trials since no event can be reported or adjudicated if the patient has been lost. Adjusting LIFU rate revealed that vascular (5.55%) and all cause (6.05%) mortality in PLATO was even more disparate than in TRACER (3.2% and 4.9%), ATLAS-ACS 2 (4.1% and 4.5%), TRITON-TIMI 38 (2.4% and 3.2%) and TRA 2P (3.0% and 5.3%) control arms, respectfully. Moreover, the incomplete CV follow-up in the ATLAS ACS 2 trial was later revealed to be around 12%, which lead to the rejection of rivaroxaban for the treatment of ACS. PLATO's LIFU rate was just as high, if not higher, than seen in ATLAS ACS 2. CONCLUSIONS: The chance to die in PLATO far exceeds the mortality risks observed in the clopidogrel arms of four recent ACS trials, which becomes especially evident after adjustment for LIFU rates among trials. Astronomical LIFU numbers are not likely to be responsible for the PLATO mortality paradox, providing additional justification for an independent audit of the PLATO presumably deceased clopidogrel cohort.

Brain natriuretic peptide for prediction of mortality in patients with sepsis: a systematic review and meta-analysis.

INTRODUCTION: Early identification of septic patients at high risk of dying remains a challenge. The prognostic role of brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) in septic patients remains controversial. The purpose of this systematic review and meta-analysis was to investigate the value of elevated BNP or NT-proBNP in predicting mortality in septic patients. METHODS: PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched (up to February 18, 2011). Studies were included if they had prospectively collected data on all-cause mortality in adult septic patients with either plasma BNP or NT-proBNP measurement. Studies that failed to construct a 2 × 2 table of results were excluded. Two authors independently determined the validity of included studies and extracted data. RESULTS: 12 studies with a total of 1,865 patients were included. Elevated natriuretic peptides were significantly associated with increased risk of mortality (odds ratio (OR) 8.65, 95% confidence interval (CI) 4.94 to 15.13, P < 0.00001). The association was consistent for BNP (OR 10.44, 95% CI 4.99 to 21.58, P < 0.00001) and NT-proBNP (OR 6.62, 95% CI 2.68 to 16.34, P < 0.0001). The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 79% (95% CI 75 to 83), 60% (95% CI 57 to 62), 2.27 (95% CI 1.83 to 2.81) and 0.32 (95% CI 0.22 to 0.46), respectively. CONCLUSIONS: Our results suggested that an elevated BNP or NT-proBNP level may prove to be a powerful predictor of mortality in septic patients. Future larger and more adequately powered prospective studies are warranted to clarify the assay standardization, the optimal cut-off, and the prognostic value of BNPs in conjunction with other biomarkers.

Power comparison of summary measure, mixed model, and survival analysis methods for analysis of repeated-measures trials.

In two-group repeated-measures studies, a traditional statistical approach is to base analysis directly on the observed continuous measurements, using either summary measures or a mixed linear model. In some medical studies, however, an alternate approach has been taken: Declare the occurrence of an "event" when the sequence of measurements crosses a prespecified threshold, and compare the groups with respect to time to event using the log-rank test. This approach is appealing to clinicians, but clearly involves a loss of information and therefore statistical efficiency. The aim of this article is to quantify the degree of power loss in the context of the random line model. We also compare the summary measures approach to the random line approach. In regard to the efficiency loss with the survival analysis approach, we find that the loss ranges, depending on the location of the threshold, from moderate to dramatic. Using an optimally weighted log-rank test in place of the standard log-rank test leads to minimal gain in efficiency. In regard to analysis based on the original continuous measurements, for testing the slope a weighted summary measure appears to be the best overall choice, whereas for testing the intercept the maximum likelihood (ML) approach is typically much more efficient than the summary measures approach, although the efficiency of the ML approach can be compromised in studies with a small number of observation timepoints. These results have obvious implications for the choice of study design and analysis.

Current misconception 3: that subgroup-specific trial mortality results often provide a good basis for individualising patient care.

Misconceptions and ill-founded theories can arise in all areas of science. However, the apparent accessibility of many epidemiology findings and popular interest in the subject can lead to additional misunderstandings. The article below is the third in an occasional series of short editorials highlighting some current misinterpretations of epidemiological findings. Invited authors will be given wide scope in judging the prevalence of the misconception under discussion. We hope that this series will prove instructive to cancer researchers in other disciplines as well as to students of epidemiology. Adrian L Harris and Leo Kinlen.

The independent and combined risk of diabetes and non-endstage renal impairment in non-ST-segment elevation acute coronary syndromes.

OBJECTIVES: To assess the effect of renal impairment (RI) and diabetes (DM) on outcomes in non-ST-segment elevation acute coronary syndromes (NSTE-ACS). METHODS: Data were pooled from 13,126 patients in five NSTE-ACS TIMI trials (TIMI 11A and B, TIMI 12, OPUS-TIMI 16, and TACTICS-TIMI 18). Patients were divided based on DM status and RI (none, mild, or moderate if the glomerular filtration rate (GFR, ml/min/1.73 m(2)) was > or = 90, 60-89 and 30-59 respectively). RESULTS: Patients with DM and moderate RI (n=609) were older and had more prior MI (p<0.01 for all) than other subgroups. Compared with no RI/DM (n=3,832), the 12-month adjusted risks of death, MI, and death/MI increased with advancing RI and were highest with DM and moderate RI (H.R. 1.7, (1.2-2.4), p=0.002; H.R. 2.0 (1.5-2.6), p<0.001; and H.R. 1.7 (1.3-2.2), p<0.001 respectively). These events were also increased with DM and mild RI (H.R. 1.4, (1.0-1.9), p=0.06, H.R. 1.4 (1.1-1.8), p=0.006 and H.R. 1.3 (1.1-1.7), p=0.007 respectively) but not with 1) mild or moderate RI without DM or 2) DM without RI. The interaction terms for RI and DM in their association with MI and death/MI were significant. CONCLUSIONS: In the absence of DM, RI and in the absence of RI, DM did not increase the risk of MI or death/MI. However, the combination of RI and DM was associated with a particularly high risk of MI and death/MI suggesting that attention to preserving renal function may be of particular benefit for reducing cardiovascular risk in diabetic patients.

Estimation of the marginal survival time in the presence of dependent competing risks using inverse probability of censoring weighted (IPCW) methods.

In medical studies, there is interest in inferring the marginal distribution of a survival time subject to competing risks. The Kyushu Lipid Intervention Study (KLIS) was a clinical study for hypercholesterolemia, where pravastatin treatment was compared with conventional treatment. The primary endpoint was time to events of coronary heart disease (CHD). In this study, however, some subjects died from causes other than CHD or were censored due to loss to follow-up. Because the treatments were targeted to reduce CHD events, the investigators were interested in the effect of the treatment on CHD events in the absence of causes of death or events other than CHD. In this paper, we present a method for estimating treatment group-specific marginal survival curves of time-to-event data in the presence of dependent competing risks. The proposed method is a straightforward extension of the Inverse Probability of Censoring Weighted (IPCW) method to settings with more than one reason for censoring. The results of our analysis showed that the IPCW marginal incidence for CHD was almost the same as the lower bound for which subjects with competing events were assumed to be censored at the end of all follow-up. This result provided reassurance that the results in KLIS were robust to competing risks.

Under-smoothed kernel confidence intervals for the hazard ratio based on censored data.

In cancer clinical trials, it is often of interest in estimating the ratios of hazard rates at some specific time points during the study from two independent populations. In this paper, we consider nonparametric confidence interval procedures for the hazard ratio based on kernel estimates for the hazard rates with under-smoothing bandwidths. Two methods are used to derive the confidence intervals: one based on the asymptotic normality of the ratio of the kernel estimates for the hazard rates in two populations and another through Fieller's Theorem. The performances of the proposed confidence intervals are evaluated through Monte-Carlo simulations and applied to the analysis of data from a clinical trial on early breast cancer.

[Drug trials in humans. Risks in the light of the London catastrophe]. / Arzneimitteltestung am Menschen. Die Risiken im Licht der Katastrophe von London.

London's first-in-man drug trial with the monoclonal anti-CD28 antibody TGN1412 used for the treatment of oncological and autoimmune diseases resulted in a disaster with life-threatening adverse events in the volunteers triggered by an unexpected cytokine storm. Potential mistakes and consequences from this trial are highlighted in the general context of drug development and its risks. Risks in drug testing are not only found for high risk substances, such as TGN1412, or in the critical first-in-man phase, but can sometimes be detected only in later phases of the clinical testing, such as the phase 3 submission studies, or even after market authorization, as for example was the case in the cyclooxygenase-2-inhibitor rofecoxib (Vioxx) used for the treatment of rheumatic diseases and acute pain. Regulatory requirements to minimize risks in drug trials, however, have improved substantially over the last decades. Moreover, in light of the London incident these are being continuously modified with great diligence.