Event-driven Trials Research Articles

Effect of SGLT2 Inhibitors on Discontinuation of Renin-angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are foundational therapy for CKD but are underused, in part because they are frequently withheld and not restarted due to hyperkalemia, AKI, or hospitalization. Consequently, ensuring persistent use of ACE inhibitors and ARBs in CKD has long been a major clinical priority. In this joint analysis of the CREDENCE and DAPA-CKD trials, the relative risk of discontinuation of ACE inhibitors and ARBs was reduced by 15% in patients randomized to sodium-glucose cotransporter 2 (SGLT2) inhibitors. This effect was more pronounced in patients with urine albumin:creatinine ratio ≥1000 mg/g, for whom the absolute benefits of these medications are the greatest. These findings indicate that SGLT2 inhibitors may enable better use of ACE inhibitors and ARBs in patients with CKD. Strategies to enable persistent use of renin-angiotensin system (RAS) blockade to improve outcomes in CKD have long been sought. The effect of SGLT2 inhibitors on discontinuation of RAS blockade has yet to be evaluated. We conducted a joint analysis of canagliflozin and renal events in diabetes with established nephropathy clinical evaluation (CREDENCE) and dapagliflozin and prevention of adverse outcomes in CKD (DAPA-CKD), two randomized, double-blind, placebo-controlled, event-driven trials of SGLT2 inhibitors in patients with albuminuric CKD. The main outcome was time to incident temporary or permanent discontinuation of RAS blockade, defined as interruption of an ACE inhibitor or ARB for at least 4 weeks or complete cessation during the double-blind on-treatment period. Cox regression analyses were used to estimate the treatment effects from each trial. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled with fixed effects meta-analysis to obtain summary treatment effects, overall and across key subgroups. During median follow-up of 2.2 years across both trials, 740 of 8483 (8.7%) patients discontinued RAS blockade. The relative risk for discontinuation of RAS blockade was 15% lower in patients randomized to receiving SGLT2 inhibitors (HR, 0.85; 95% CI, 0.74 to 0.99), with consistent effects across trials ( P -heterogeneity = 0.92). The relative effect on RAS blockade discontinuation was more pronounced among patients with baseline urinary albumin:creatinine ratio ≥1000 mg/g (pooled HR, 0.77; 95% CI, 0.63 to 0.94; P -heterogeneity = 0.009). In patients with albuminuric CKD with and without type 2 diabetes, SGLT2 inhibitors facilitate the use of RAS blockade. ClinicalTrials.gov, NCT02065791 and NCT03036150 . This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_11_21_JASN0000000000000248.mp3.

SGLT-2 inhibitors improve cardiovascular and renal outcomes in patients with CKD: a systematic review and meta-analysis

The effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors on cardiovascular and renal outcomes has not been systematically reviewed across baseline kidney function groups. We conducted a systematic review and meta-analysis of randomized control trials (RCTs) with SGLT-2 inhibitors in patients with and without CKD. We performed a PubMed/Medline search of randomized, placebo-controlled, event-driven outcome trials of SGLT-2 inhibitors versus active or placebo control in patients with and without diabetes from inception to November 2022. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 (PROSPERO registration CRD4202016054). The primary outcome was cardiovascular death. Secondary outcomes included hospitalization for heart failure, major adverse cardiovascular events, CKD progression, all-cause mortality, treatment discontinuation, and acute kidney injury (AKI). The relative risk (RR) was estimated using a random-effects model. Twelve RCTs were included in this meta-analysis (89,191 patients, including 38,949 with eGFR < 60 ml/min/1.73m2). Use of an SGLT-2 inhibitor in patients with CKD was associated with a lower incidence of cardiovascular death (RR 0.87; 95% CI 0.79–0.95) and of heart failure (RR 0.67; 95% CI 0.61–0.75), compared with placebo. Heart failure risk reduction with SGLT-2 inhibitors was larger among patients with CKD compared with patients without CKD (RR for the interaction 0.87, 95% CI 0.75–1.02, and p-value for interaction 0.08). SGLT-2 inhibitors were associated with a lower incidence of CKD progression among patients with pre-existing CKD: RR 0.77 (95% CI 0.68–0.88), compared with placebo. Among patients with CKD, a lower risk of AKI (RR 0.82; 95% CI 0.72–0.93) and treatment discontinuation was seen with SGLT-2 inhibitors compared with placebo. SGLT-2 inhibitors offer substantial protection against cardiovascular and renal outcomes in patients with CKD. These results strongly advocate in favor of using them in patients with CKD and keeping them as kidney function declines.

#3807 HEART FAILURE IN ASCEND-ND AND ASCEND-D

Abstract Background and Aims Heart failure (HF) is a common cardiovascular (CV) complication in chronic kidney disease (CKD) [1]. Two CV outcome trials (ASCEND-ND [NCT02876835][2] and ASCEND-D [NCT02879305][3]) have provided the principal assessment of CV risk with daprodustat in CKD: both studies showed noninferiority of daprodustat to erythropoiesis-stimulating agent (ESA). Here, we examined the risk of HF in daprodustat-treated patients in the ASCEND-ND and ASCEND-D trials. Method The Phase 3, open-label, randomised, event-driven ASCEND trials investigated oral, once-daily daprodustat vs injectable ESA in patients with anaemia of CKD not on (ASCEND-ND) or on (ASCEND-D) dialysis. Time-to-first adjudicated major adverse CV event (MACE) was the primary CV endpoint. Time-to-first MACE or hospitalisation for heart failure (HHF) was a key secondary endpoint; the composite of time-to-first adjudicated MACE + HHF was assessed as a principal secondary endpoint, and time-to-first HHF alone as an additional secondary endpoint. To better understand HF-specific outcomes, post-hoc analyses accounting for competing risk of death were conducted via the composite endpoint of all-cause mortality (ACM) + HHF – more typically employed to evaluate HF-specific outcomes and to assess “hospitalisation-free survival”. Post-hoc subgroup analyses of patients identified as having a baseline HF history were also conducted. Results Overall, 3872 and 2964 patients were randomised in ASCEND-ND and ASCEND-D, respectively. All key prespecified and post-hoc CV endpoints in ASCEND-ND and ASCEND-D are shown in the Table, and the composite endpoint of ACM + HHF is shown in the Figure. In summary, for components of MACE for daprodustat vs ESA, respectively, ACM events were similar between treatment arms in both studies: ASCEND ND: 11.6% vs 12.2%; ASCEND-D: 14.8% vs 14.6%. For HHF alone in both studies, event rates for daprodustat vs ESA, respectively, were: 7.2% vs 5.9% (hazard ratio [HR] 95% confidence interval [CI] = 1.22 [0.95, 1.56]) in ASCEND ND; and 7.5% vs 6.8% (HR [95% CI] = 1.10 [0.84, 1.45]) in ASCEND-D. In post-hoc analyses using the composite endpoint of ACM + HHF in ASCEND-ND, the event rate for daprodustat was 20.3% (n = 393/1937), and the event rate for ESA was 19.0% (n = 368/1935) (HR [95% CI] = 1.09 [0.94, 1.26]). More HHF events were observed in patients with a history of HF (daprodustat: 20.4% [n = 54/265]; ESA: 13.4% [n = 34/254]). In ASCEND-D, ACM + HHF events were similar for daprodustat (24.4% [n = 363/1487]) and ESA (24.8% [n = 366/1477]; HR [95% CI] = 0.98 [0.85, 1.14]). In this composite endpoint in patients with a history of HF in ASCEND-D, there were also more HHF events in those treated with daprodustat (18% [n = 47/267]) vs ESA (13% [n = 32/254]), but there were fewer deaths with daprodustat (21% [n = 56/267]) than ESA (28% [n = 71/254]). For subgroup analyses of daprodustat vs ESA, the proportion of patients with a history of HF at baseline was greater in ASCEND-D (18.0% vs 17.2%) than ASCEND-ND (13.7% vs 13.1%). Incidence of MACE + HHF was similar between treatment arms in both studies. Conclusion Our findings showed that there was a higher HHF risk in daprodustat-treated patients who had a history of HF compared to ESA-treated patients. While HF risk was similar between treatments in patients on dialysis (ASCEND-D) when combining ACM + HHF in a post-hoc analysis, the risk remained numerically higher for daprodustat vs ESA in patients not on dialysis (ASCEND-ND). The underlying mechanism responsible for these observations and differences is not known, although patients with advanced CKD and comorbid HF who are not on dialysis are recognised to be at underlying risk of HF decompensation.

P.67 Development and evaluation of a time to event endpoint for clinical trials in Duchenne muscular dystrophy (DMD)

Event-driven clinical trials, commonly used in oncology, offer several benefits over continuous outcome measures: i) each patient is assessed individually, ii) after the event has occurred, patients can receive therapy without breaking the blind. This study aimed to develop a time-to-event outcome measure for the North Star Ambulatory Assessment (NSAA) corresponding to clinically meaningful disease progression in DMD. Three candidate definitions based on changes in NSAA were investigated: A) Loss of 3 NSAA total score points; B) Loss of 2 distinct NSAA items; C) Loss of 3 NSAA points or loss of 2 NSAA items. To evaluate these definitions, 619 DMD patients with expected decline in motor function (baseline rise from supine ≥5 seconds) were studied from 3 clinical trial placebo arms and 4 natural history studies. At baseline, mean age was 9.3 years (range: 6-18yrs), mean NSAA total score was 22 (range:12-34); 63% were receiving prednisone, 37% deflazacort, and 0.4% no steroids. For each definition, median time to progression was 11.0, 14.0 and 8.3 months, respectively, based on Kaplan-Meier analyses. As a measure of prognostic validity, a progression event during the first year of follow-up was associated with significantly shorter time to loss of ambulation, with hazard ratios of 2.5, 6.5 and 3.2, respectively (all p<0.05), based on landmark analyses. Stability of the progression definitions varied, with approximately 10%, 19% and 12%, respectively, regaining their baseline level of function within a year. Definition A exhibited a favorable combination of event rate, prognostic validity, and stability. A hypothetical, well-powered, randomized, event-driven trial based on endpoint A and enrolling 160 DMD patients over a period of 9 months would require an expected duration of 10, 14, or 25 months to detect treatment effects delaying progression by 13.0, 8.4 or 5.4 months, respectively. Thus, event-driven trials may be viable for drug development in ambulatory DMD.

General independent censoring in event-driven trials with staggered entry.

Randomized clinical trials with time-to-event endpoints are frequently stopped after a prespecified number of events has been observed. This practice leads to dependent data and nonrandom censoring, which can in general not be solved by conditioning on the underlying baseline information. In case of staggered study entry, matters are complicated substantially. The present paper demonstrates that the study design at hand entails general independent censoring in the counting process sense, provided that the analysis is based on study time information only. To illustrate that the filtrations must not use abundant information, we simulated data of event-driven trials and evaluated them by means of Cox regression models with covariates for the calendar times. The Breslow curves of the cumulative baseline hazard showed considerable deviations, which implies that the analysis is disturbed by conditioning on the calendar time variables. A second simulation study further revealed that Efron's classical bootstrap, unlike the (martingale-based) wild bootstrap, may lead to biased results in the given setting, as the assumption of random censoring is violated. This is exemplified by an analysis of data on immunotherapy in patients with advanced, previously treated nonsmall cell lungcancer.

Statistical inference for state occupation and transition probabilities in non-Markov multi-state models subject to both random left-truncation and right-censoring

The Aalen-Johansen estimator generalizes the Kaplan-Meier estimator for independently left-truncated and right-censored survival data to estimate the transition probability matrix of a time-inhomogeneous Markov model with finite state space. Such multi-state models have a wide range of applications for modelling complex courses of a disease over the course of time, but the Markov assumption may often be in doubt. If censoring is entirely unrelated to the multi-state data, it has been suggested that the Aalen-Johansen estimator, standardized by the initial empirical distribution of the multi-state model, still consistently estimates the state occupation probabilities. Recently, this approach has been extended to transition probabilities using landmarking, which is, inter alia, useful for dynamic prediction. However, there have been recent concerns about the mathematical arguments leading to the former result. These findings are complemented in three ways. Firstly, a rigorous proof of consistency of the Aalen-Johansen estimator for state occupation probabilities, on which also correctness of the landmarking approach hinges, is presented correcting and simplifying the earlier result. Secondly, delayed study entry is a common phenomenon in observational studies, and the earlier results are extended to multi-state data also subject to left-truncation. Thirdly, the rigorous proof is suggestive of wild bootstrap resampling. Studying wild bootstrap is motivated by the fact that it is desirable to have a technique that works for models where left-truncation and right-censoring need not be entirely random, then requiring a Markov assumption, and that may still perform reasonably with non-Markov models subject to random left-truncation and right-censoring. The developments for left-truncation are motivated by a prospective observational study on the occurrence and the impact of a multi-resistant infectious organism in patients undergoing surgery. Both the real data example and simulation studies are presented. The case for wild bootstrapping is illustrated for event-driven trials, where the data are censored once a prespecified number of events have been observed.

A unified approach to power and sample size determination for log-rank tests under proportional and nonproportional hazards.

Log-rank tests have been widely used to compare two survival curves in biomedical research. We describe a unified approach to power and sample size calculation for the unweighted and weighted log-rank tests in superiority, noninferiority and equivalence trials. It is suitable for both time-driven and event-driven trials. A numerical algorithm is suggested. It allows flexible specification of the patient accrual distribution, baseline hazards, and proportional or nonproportional hazards patterns, and enables efficient sample size calculation when there are a range of choices for the patient accrual pattern and trial duration. A confidence interval method is proposed for the trial duration of an event-driven trial. We point out potential issues with several popular sample size formulae. Under proportional hazards, the power of a survival trial is commonly believed to be determined by the number of observed events. The belief is roughly valid for noninferiority and equivalence trials with similar survival and censoring distributions between two groups, and for superiority trials with balanced group sizes. In unbalanced superiority trials, the power depends also on other factors such as data maturity. Surprisingly, the log-rank test usually yields slightly higher power than the Wald test from the Cox model under proportional hazards in simulations. We consider various nonproportional hazards patterns induced by delayed effects, cure fractions, and/or treatment switching. Explicit power formulae are derived for the combination test that takes the maximum of two or more weighted log-rank tests to handle uncertain nonproportional hazards patterns. Numerical examples are presented for illustration.

Predicting study duration in clinical trials with a time-to-event endpoint.

In event-driven clinical trials comparing the survival functions of two groups, the number of events required to achieve the desired power is usually calculated using the Freedman formula or the Schoenfeld formula. Then, the sample size and the study duration derived from the required number of events are considered; however, their combination is not uniquely determined. In practice, various combinations are examined considering the enrollment speed, study duration, and the cost of enrollment. However, effective methods for visually representing their relationships and evaluating the uncertainty in study duration are insufficient. We developed a graphical approach for examining the relationship between sample size and study duration. To evaluate the uncertainty in study duration under a given sample size, we also derived the probability density function of the study duration and a method for updating the probability density function according to the observed number of events (ie, information time). The proposed methods are expected to improve the operation and management of clinical trials with a time-to-event endpoint.

Crossover and Repeated Randomization in Event Driven Trials for HIV Prevention: Addressing the Impact of Heterogeneity in Risk in the Trial Design

Abstract The availability of effective Pre-Exposure Prophylaxis (PrEP) for HIV introduces new challenges for testing novel on-demand, user-controlled HIV prevention products, including lower placebo arm incidence and increased between-participant variability in HIV risk. In this paper, we discuss how low HIV incidence may result in longer trials in which the variability in participants' risk may impact the estimate of risk reduction. We introduce a measure of per-exposure efficacy that may be more relevant than the population level reduction in incidence for on demand products and explore alternatives to the parallel arm design that could target better this parameter of interest: the crossover and the re-randomization designs. We propose three different ways in which crossover and re-randomization of intervention assignments could be implemented in event-driven trials. We evaluate the performance of these designs through a simulation study, finding that they allow for better estimation and higher power than the traditional event-driven parallel arm design. We conclude by discussing future work, practical challenges and ethical considerations that need to be addressed to take these designs closer to implementation.

Incidence of total hip and total knee replacements from the prospective epidemiologic risk factor study: considerations for event driven clinical trial design

BackgroundOsteoarthritis (OA) leads to joint failure and total joint replacement (TJR, either hip (H) or knee (K)). Worsening of pain and joint space narrowing are believed to be surrogates for joint failure; however, we hypothesize that TJR, as a reflection of joint failure, can be used as an endpoint in event-driven clinical trials within a reasonable duration. We explored the incidence of TJR in the Prospective Epidemiologic Risk Factor (PERF I) study.MethodsA total of 5855 Danish postmenopausal women aged 49–88 enrolled in the PERF I study during 1999–2001 (baseline). Three-, six- and twelve-year follow-up data from the Danish National Patient Registry was collected, including occurrence of TJR and OA diagnosis. At baseline the women were asked whether they had OA.ResultsThe women with a TJR diagnosis before or after baseline were on average 1 year older (p < 0.001) and heavier (p < 0.001), compared to women with no TJR. The 3-, 6- and 12-year cumulative incidences were 1.1, 2.4 and 6.0% for TKR, and 2.1, 4.4 and 9.3% for THR. For those with an OA diagnosis at baseline the respective incidences were 2.7, 5.6 and 11.7% and 3.9, 7.2 and 13.6%ConclusionsWithin 3, 6 or 12 years TJR incidences were double for women with an OA diagnosis compared to the all-comer population. TJRs are frequent amongst elderly women with OA and it is, therefore, feasible to conduct event-driven clinical trials where TJR is the endpoint demonstrating clinical benefit of a novel disease-modifying OA drug (DMOAD).

Empagliflozin in heart failure patients with reduced ejection fraction: a randomized clinical trial (Empire HF)

BackgroundData from recent cardiovascular outcome trials in patients with type 2 diabetes (T2D) suggest that sodium-glucose cotransporter 2 (SGLT2) inhibitors can prevent development of heart failure (HF) and prolong life in patients without HF. Ongoing event-driven trials are investigating whether the same effect is present in patients with well-defined HF. The mechanism behind the effect of SGLT2 inhibitors in patients with T2D and the potential effect in patients with overt HF is presently unknown.MethodsThis is a randomized, double-blinded, placebo-controlled, parallel group, clinical trial including HF patients with reduced left ventricular ejection fraction (HFrEF) with an ejection fraction ≤ 40% on optimal therapy recruited from specialized HF clinics in Denmark. The primary aim is to investigate the effect of the SGLT2 inhibitor empagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP). Secondary endpoints include cardiac biomarkers, function and hemodynamics, metabolic and renal parameters, daily activity level, and quality of life. Patients are assigned 1:1 to 90 days treatment with empagliflozin 10 mg daily or placebo. Patients with T2D are required to be on recommended doses of anti-glycemic therapy with a hemoglobin A1c (HbA1c) of 6.5–10.0% (48–86 mmol/mol). To show a between-group difference in the change of NT-proBNP of 30%, a total of 189 patients will be included.DiscussionThe Empire HF trial will elucidate the effects and modes of action of empagliflozin in HFrEF patients with and without T2D and provide important mechanistic data which will complement ongoing event-driven trials.Trial registrationClinicaltrialsregister.eu, EudraCT Number 2017-001341-27. Registered on 29 May 2017.ClinicalTrials.gov, NCT03198585. Registered on 26 June 2017.

Hierarchical Testing of a Primary and a Secondary Endpoint in a Group Sequential Design With Different Information Times

ABSTRACTWe consider a confirmatory clinical trial where a primary and a secondary endpoints are tested hierarchically to control the family-wise error rate at level α. The trial uses a group sequential design with an interim and a final analysis. When the information times at the interim analysis are the same for the primary and the secondary hypotheses, it has been shown in the literature that the secondary hypothesis has to be tested using a group sequential boundary at a level no more than α. In many event-driven trials, however, the information times are usually different because of different event rates for the two endpoints. The information times may also be different for a noninferiority hypothesis and a superiority hypothesis due to different analysis sets. We consider this general setup and derive a sharp upper bound on the probability of rejecting the secondary hypothesis at an interim and a final analysis. This bound suggests that the secondary boundary can be refined so that the group sequential design can be tested at a significance level greater than α while still controlling the family-wise error rate at level α. We carry out a simulation study to illustrate the power gain by using the refined boundary for different choices of boundaries for the two hypotheses. The proposed approach is illustrated in two oncology clinical trials with more than two analyses.

Blinded sample size reestimation in event-driven clinical trials: Methods and an application in multiple sclerosis.

Motivated by a recently completed trial in secondary progressive multiple sclerosis, we developed blinded sample size reestimation procedures for clinical trials with time‐to‐event endpoint and assessed their properties in simulation studies. Assuming independent right‐censoring and proportional hazards for the two treatment groups, we considered event‐driven designs with fixed number of events, which guarantees the power to be at a desired level under a certain alternative. We develop reestimation procedures based on parametric models and show that these maintain the expected duration of the trial at a target length in flexible follow‐up designs across a range of nuisance parameter values by adjusting the number of patients recruited into the trial based on blinded nuisance parameter estimates. Furthermore, we provide convincing evidence from a simulation study that such procedures proposed do not inflate the type I error rate in any practically relevant way, thereby satisfying the standards set by relevant international guidelines. Inspired by practical application of these procedures, we outline a number of extensions including methods for extrapolating the observed survival curve beyond the interim time point, application of reestimation procedures to interval censored data, and situations in which a confirmation of event is required leading to a certain lag time.

Incidence of Total Joint Replacements from the Prospective Epidemiologic Risk Factor Study: Considerations for Event Driven Clinical Trial Design

Background: Osteoarthritis (OA) leads to joint failure and total joint replacement (TJR, either hip (H) or knee (K)). Worsening of pain and joint space narrowing are believed to be surrogates for joint failure; however, we hypothesize that TJR, as a reflection of joint failure, can be used as an endpoint in event-driven clinical trials within a reasonable duration. We explored the incidence of TJR in the Prospective Epidemiologic Risk Factor (PERF I) study. Methods: A total of 5,855 Danish postmenopausal women aged 49-88 enrolled in the PERF I study during 1999-2001 (baseline). Three-, six- and twelve-year follow-up data from the Danish National Patient Registry was collected, including occurrence of TJR and OA diagnosis. At baseline the women were asked whether they had OA. Findings: The TJR women were on average 1 year older (p<0.001) and heavier (p<0.001), compared to women with no TJR in the follow-up period. The 3-, 6- and 12-year cumulative incidences were 1.1, 2.4 and 6.0% for TKR, and 2.1, 4.4 and 9.3% for THR. For those with an OA diagnosis at baseline the respective incidences were 2.7, 5.6 and 11.7% and 3.9, 7.2 and 13.6%. Interpretation: Within 3, 6 or 12 years TJR incidences were double for women with an OA diagnosis compared to the all-comer population. TJRs are frequent amongst elderly women with OA and it is, therefore, feasible to conduct event-driven clinical trials where TJR is the endpoint demonstrating clinical benefit of a novel disease-modifying OA drug (DMOAD). Funding Statement: The Danish Research Foundation funded the PERF I study. Declaration of Interests: Bager is employed at ProScion. Karsdal, Bihlet, Thudium, Byrjalsen and Bay-Jensen are employed at Nordic Bioscience. Karsdal, Bihlet, and Bay-Jensen holds stocks in Nordic Bioscience. Ethics Approval Statement: The PERF I study was carried out in accordance with applicable regulatory and ethical guidelines, and the study protocol was approved by the local ethics committees. All participants signed an informed consent.

Cardiovascular Event Hazards over Time in TECOS

Background: Event accumulation patterns in event-driven trials inform forecasting of trial size and duration. It is hypothesized that trials enrol a healthier cohort who have lower early cardiovascular (CV) event rates that increase during follow-up as surviving patients age and accumulate comorbidities. We present hazard rate patterns for incident CV events in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Methods: Using adjudicated endpoints from the intention-to-treat population, Weibull models show whether hazards for these CV events were increasing (shape parameter&amp;gt;1), decreasing (&amp;lt;1), or constant (=1) over time: MACE-4 composite (CV death, nonfatal myocardial infarction [NFMI], nonfatal stroke [NFSt], and unstable angina hospitalization [UA]); fatal (F) or NFMI, F/NFSt, UA, CV death, all-cause mortality (ACM), and heart failure hospitalization (HF). Results: The Figure shows hazard rate over time. Weibull shape point estimates (95% CI) were MACE-4 0.96 (0.92, 1.01); ACM 1.14 (1.08, 1.21); CV death 1.(1.01, 1.16); F/NFMI 0.96 (0.89, 1.03); F/NFSt 0.93 (0.85, 1.03); UA 0.90 (0.79, 1.01); HF 0.98 (0.90, 1.08). Annual event rates (per 100 pt-years) were CV death: 1.5, 1.6, 2.0, 1.9, 2.7; ACM: 2.1, 2.3, 2.8, 3.0, 3.8. Conclusions: Hazard rates were constant for all events except CV death and ACM, which had small significant increased risk over time. Our findings may inform the planning and conduct of future trials in diabetes. Disclosure M. Bethel: Research Support; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Merck Serono. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca. Other Relationship; Self; Sanofi. Consultant; Self; Theracos, Inc.. Research Support; Self; GlaxoSmithKline plc. H. Sourij: Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Novo Nordisk A/S, Amgen Inc., Sanofi, MSD K.K.. Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH, MSD K.K., GI Dynamics Inc.. S.R. Stevens: None. Y. Lokhnygina: None. R.D. Lopes: Consultant; Self; Bayer AG, Boehringer Ingelheim GmbH. Other Relationship; Self; Bristol-Myers Squibb Company. Consultant; Self; Daiichi Sankyo Company, Limited. Other Relationship; Self; GlaxoSmithKline plc., Medtronic. Consultant; Self; Merck &amp; Co., Inc.. Other Relationship; Self; Pfizer Inc.. A. Adler: None. D.K. McGuire: Consultant; Self; AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Pfizer Inc., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi-Aventis, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Lexicon Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Esperion Therapeutics. E. Peterson: Research Support; Self; Merck &amp; Co., Inc.. Consultant; Self; Merck &amp; Co., Inc.. Research Support; Self; AstraZeneca. Consultant; Self; AstraZeneca. R.R. Holman: Research Support; Self; AstraZeneca, Merck &amp; Co., Inc., Bayer AG. Advisory Panel; Self; Elcelyx Therapeutics, Inc., Novartis AG, Novo Nordisk A/S. Other Relationship; Self; Bayer AG. Advisory Panel; Self; Merck &amp; Co., Inc.. Other Relationship; Self; AstraZeneca.

Attrition in NRG Oncology's Radiation-Based Clinical Trials

To determine individual, organizational, and protocol-specific factors associated with attrition in NRG Oncology's radiation-based clinical trials. This retrospective analysis included 27,443 patients representing 134 NRG Oncology's radiation-based clinical trials .trials with primary efficacy results published from 1985-2011. Trials were separated on the basis of the primary endpoint (fixed time vs event driven). The cumulative incidence approach was used to estimate time to attrition, and cause-specific Cox proportional hazards models were used to assess factors associated with attrition. Most patients (69%) were enrolled in an event-driven trial (n=18,809), while 31% were enrolled in a fixed-time trial (n=8634). Median follow-up time for patients enrolled in fixed-time trials was 4.1months and 37.2months for patients enrolled in event-driven trials. Fixed time trials with a duration < 6 months had a 5 month attrition rate of 4.3% (95% confidence interval [CI]: 3.4%, 5.5%) and those with a duration ≥ 6 months had a 1 year attrition rate of 1.6% (95% CI: 1.2, 2.1). Event-driven trials had 1- and 5-year attrition rates of 0.5% (95% CI: 0.4%, 0.6%) and 13.6% (95% CI: 13.1%, 14.1%), respectively. Younger age, female gender, and Zubrod performance status >0 were associated with greater attrition as were enrollment by institutions in the West and South regions and participation in fixed-time trials. Attrition in clinical trials can have a negative effect on trial outcomes. Data on factors associated with attrition can help guide the development of strategies to enhance retention. These strategies should focus on patient characteristics associated with attrition in both fixed-time and event-driven trials as well as in differing geographic regions of the country.

Trial Duration and Risk Reduction in Combination Therapy Trials for Pulmonary Arterial Hypertension: A Systematic Review

Relative risk (RR) and number needed-to-treat (NNT) are frequently time-dependant measures. We performed a systematic review and meta-analysis to assess whether trial duration influenced the relative and absolute risk of worsening in randomized controlled trials (RCTs) comparing combination therapy (CT) of pulmonary arterial hypertension (PAH)-specific therapies vs monotherapy (MT). We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to September 2016) for RCTs assessing CT compared with MT in PAH. The primary outcome was the risk of clinical worsening. We assessed whether trial duration correlated with RR and NNT using weighted meta-regression with mixed effects. Changes in NNT overtime were also assessed using data from long-term event-driven trials. There were 3,801 patients throughout 15 studies included. The RR for clinical worsening positively correlated with trial duration (R2= 0.67, P= .0002), whereas the NNT did not (mean NNT, 7; R2= 0.02; P= .65). Among long-term event-driven trials, the mean NNT progressively decreased until 52weeks of follow-up, being stable thereafter. Conversely, the mean RR progressively increased from approximately 0.40 at week 16 to approximately 0.68 at week104. Absolute risk reduction of clinical worsening was relatively constant beyond 6 to 12months of treatment in clinical trials comparing CT with MT in PAH. These results question the need for CT trials of very long duration in PAH.

Can LDL cholesterol be too low? Possible risks of extremely low levels.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

Combination therapy in pulmonary arterial hypertension: recent accomplishments and future challenges.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive increase in pulmonary vascular resistance, ultimately leading to right heart failure and death. Throughout the past 20 years, numerous specific pharmacologic agents, including phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostaglandins, and more recently, soluble guanylate cyclase stimulators and selective IP prostacyclin receptor agonist, have emerged for the treatment of PAH. Early clinical trials were typically of short-term duration, comparing the effects of PAH-targeted therapies versus placebo and using exercise tolerance as the primary endpoint in most trials. A meta-analysis of these trials documented a reduction in short-term mortality of ∼40% with monotherapy. More recently, we have witnessed a progressive shift in PAH study designs using longer event-driven trials comparing the effects of upfront and sequential combination therapy on clinical worsening that is perceived as a more clinically relevant outcome measure. Recent meta-analyses also documented that combination therapy significantly reduced the risk of clinical worsening by ∼35% compared with monotherapy alone.In this review article, we will discuss the evolution of treatments and clinical trial design in the field of PAH over the past decades with a special focus on combination therapy and its current role in the management of PAH. We will also detail unresolved questions regarding the future of PAH patients’ care and the challenges of future clinical trials.

Steps forward in the treatment of pulmonary arterial hypertension: latest developments and clinical opportunities.

Pulmonary arterial hypertension (PAH) is a chronic disease that results in narrowing of the small pre-capillary pulmonary arteries leading to elevation of pulmonary artery pressure and pulmonary vascular resistance, subsequent right ventricular failure, and if unchecked, death. Advances in the treatment of PAH over the last two decades have markedly improved survival. These improvements reflect a combination of changes in treatments, improved patient care strategies, and varying disease phenotypes in the PAH population. Currently approved therapies for PAH are directed at the recognized abnormalities within the pulmonary vasculature and include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin pathway agents. Most of these drugs have been approved on the basis of short-term trials that mainly demonstrated improvements in exercise capacity. More recently, long-term, event-driven trials of novel drugs have been performed, demonstrating new efficacy parameters. There have also been exciting advances in the understanding of right heart failure pathophysiology in PAH that have the potential to inspire the development of right ventricular targeted therapy and continued discoveries in the heterogeneity of disease and response to treatment has great potential for developing more 'personalized' therapeutic options. In this article, we review the current available data regarding the management of PAH, with an emphasis on the pharmacologic therapies and discussion of novel therapeutic directions for the treatment of this fatal disease.