Hongjian Zhu

Prognostic Value of Fractional Flow Reserve: Linking Physiologic Severity to Clinical Outcomes

BACKGROUND Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

Sequential monitoring of response-adaptive randomized clinical trials

Clinical trials are complex and usually involve multiple objectives such as controlling type I error rate, increasing power to detect treatment difference, assigning more patients to better treatment, and more. In literature, both response-adaptive randomization (RAR) procedures (by changing randomization procedure sequentially) and sequential monitoring (by changing analysis procedure sequentially) have been proposed to achieve these objectives to some degree. In this paper, we propose to sequentially monitor response-adaptive randomized clinical trial and study its properties. We prove that the sequential test statistics of the new procedure converge to a Brownian motion in distribution. Further, we show that the sequential test statistics asymptotically satisfy the canonical joint distribution defined in Jennison and Turnbull (2000). Therefore, type I error and other objectives can be achieved theoretically by selecting appropriate boundaries. These results open a door to sequentially monitor response-adaptive randomized clinical trials in practice. We can also observe from the simulation studies that, the proposed procedure brings together the advantages of both techniques, in dealing with power, total sample size and total failure numbers, while keeps the type I error. In addition, we illustrate the characteristics of the proposed procedure by redesigning a well-known clinical trial of maternal-infant HIV transmission.

A composite likelihood method for bivariate meta-analysis in diagnostic systematic reviews.

Diagnostic systematic review is a vital step in the evaluation of diagnostic technologies. In many applications, it involves pooling pairs of sensitivity and specificity of a dichotomized diagnostic test from multiple studies. We propose a composite likelihood (CL) method for bivariate meta-analysis in diagnostic systematic reviews. This method provides an alternative way to make inference on diagnostic measures such as sensitivity, specificity, likelihood ratios, and diagnostic odds ratio. Its main advantages over the standard likelihood method are the avoidance of the nonconvergence problem, which is nontrivial when the number of studies is relatively small, the computational simplicity, and some robustness to model misspecifications. Simulation studies show that the CL method maintains high relative efficiency compared to that of the standard likelihood method. We illustrate our method in a diagnostic review of the performance of contemporary diagnostic imaging technologies for detecting metastases in patients with melanoma.

A Unified Family of Covariate-Adjusted Response-Adaptive Designs Based on Efficiency and Ethics

Response-adaptive designs have recently attracted more and more attention in the literature because of its advantages in efficiency and medical ethics. To develop personalized medicine, covariate information plays an important role in both design and analysis of clinical trials. A challenge is how to incorporate covariate information in response-adaptive designs while considering issues of both efficiency and medical ethics. To address this problem, we propose a new and unified family of covariate-adjusted response-adaptive (CARA) designs based on two general measurements of efficiency and ethics. Important properties (including asymptotic properties) of the proposed procedures are studied under categorical covariates. This new family of designs not only introduces new desirable CARA designs, but also unifies several important designs in the literature. We demonstrate the proposed procedures through examples, simulations, and a discussion of related earlier work.

Optimal Adenosine Stress for Maximum Stress Perfusion, Coronary Flow Reserve, and Pixel Distribution of Coronary Flow Capacity by Kolmogorov-Smirnov Analysis.

Background— Different adenosine stress imaging protocols have not been systemically validated for absolute myocardial perfusion and coronary flow reserve (CFR) by positron emission tomography, where submaximal stress precludes assessing physiological severity of coronary artery disease. Methods and Results— In 127 volunteers, serial rest–stress positron emission tomography scans using rubidium-82 with various adenosine infusion protocols identified (1) the protocol with maximum stress perfusion and CFR, (2) test–retest precision in same subject, (3) stress perfusion and CFR after adenosine compared with dipyridamole, (4) heterogeneity of coronary flow capacity combining stress perfusion and CFR, and (5) potential relevance for patients with risk factors or coronary artery disease. The adenosine 6-minute infusion with rubidium-82 injection at 3 minutes caused CFR that was significantly 15.7% higher than the 4-minute adenosine infusion with rubidium-82 injection at 2 minutes and significantly more homogeneous by Kolmogorov–Smirnov analysis for histograms of 1344 pixel range of perfusion in paired positron emission tomographies. In a coronary artery disease cohort separate from volunteers of this study, compared with the 3/6-minute protocol, the 2/4-minute adenosine protocol would potentially have changed 332 of 1732 (19%) positron emission tomographies at low-risk physiological severity CFR ≥2.3 to CFR <2.0, thereby implying high-risk quantitative severity potentially appropriate for interventions but because of suboptimal stress of the 2/4 protocol in some patients. Conclusions— The 6-minute adenosine infusion with rubidium-82 activation at 3 minutes produced CFR that averaged 15.7% higher than that in the 2/4-minute protocol, thereby potentially providing essential information for personalized management in some patients.

Assessing protocol adherence in a clinical trial with ordered treatment regimens: Quantifying the pragmatic, randomized optimal platelet and plasma ratios (PROPPR) trial experience.

BACKGROUND Medication dispensing errors are common in clinical trials, and have a significant impact on the quality and validity of a trial. Therefore, the definition, calculation and evaluation of such errors are important for supporting a trials conclusions. A variety of medication dispensing errors can occur. In this paper, we focus on errors in trials where the intervention includes multiple therapies that must be given in a pre-specified order that varies across treatment arms and varies in duration. METHODS The Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial was a Phase III multi-site, randomized trial to compare the effectiveness and safety of 1:1:1 transfusion ratios of plasma and platelets to red blood cells with a 1:1:2 ratio. In this trial, these three types of blood products were to be transfused in a pre-defined order that differed by treatment arm. In this paper, we present approaches from the PROPPR trial that we used to define and calculate the occurrence of out of order blood transfusion errors. We applied the proposed method to calculate protocol adherence to the specified order of transfusion in each treatment arm. RESULTS Using our proposed method, protocol adherence was greater in the 1:1:1 group than in the 1:1:2 group (96% vs 93%) (p<0.0001), although out of order transfusion errors in both groups were low. Final transfusion ratios of plasma to platelets to red blood cells for the 1:1:1 ratio group was 0.93:1.32:1, while the transfusion ratio for the 1:1:2 ratio group was 0.48:0.48:1. CONCLUSIONS Overall, PROPPR adherence to blood transfusion order pre-specified in the protocol was high, and the required order of transfusions for the 1:1:2 group was more difficult to achieve. The approaches proposed in this manuscript were useful in evaluating the PROPPR adherence and are potentially useful for other trials where a specific treatment orders with varying durations must be maintained.

Regional Artery Specific Thresholds Of Quantitative Myocardial Perfusion By PET Associated With Reduced MI and Death After Revascularization In Stable CAD

Because randomized coronary revascularization trials in stable coronary artery disease (CAD) have shown no reduced myocardial infarction (MI) or mortality, the threshold of quantitative myocardial perfusion severity was analyzed for association with reduced death, MI, or stroke after revascularization within 90 d after PET. Methods: In a prospective long-term cohort of stable CAD, regional, artery-specific, quantitative myocardial perfusion by PET, coronary revascularization within 90 d after PET, and all-cause death, MI, and stroke (DMS) at 9-y follow-up (mean ± SD, 3.0 ± 2.3 y) were analyzed by multivariate Cox regression models and propensity analysis. Results: For 3,774 sequential rest–stress PET scans, regional, artery-specific, severely reduced coronary flow capacity (CFC) (coronary flow reserve ≤ 1.27 and stress perfusion ≤ 0.83 cc/min/g) associated with 60% increased hazard ratio for major adverse cardiovascular events and 30% increased hazard of DMS that was significantly reduced by 54% associated with revascularization within 90 d after PET (P = 0.0369), compared with moderate or mild CFC, coronary flow reserve, other PET metrics or medical treatment alone. Depending on severity threshold for statistical certainty, up to 19% of this clinical cohort had CFC severity associated with reduced DMS after revascularization. Conclusion: CFC by PET provides objective, regional, artery-specific, size–severity physiologic quantification of CAD severity associated with high risk of DMS that is significantly reduced after revascularization within 90 d after PET, an association not seen for moderate to mild perfusion abnormalities or medical treatment alone.

Implementing optimal allocation in clinical trials with multiple endpoints

Modern clinical trials are often complex, with multiple competing objectives and multiple endpoints. Such trials should be both ethical and efficient. In this paper, we overcome the obstacles introduced by the large number of unknown parameters and the possible correlations between the multiple endpoints. We obtain the optimal allocation proportions for the following two optimization problems: (1) maximizing the power of the test of homogeneity with a fixed sample size, and (2) minimizing the expected weighted number of failures with a fixed power. Further, we implement these optimal allocations through response-adaptive randomization procedures. Our theoretical results provide the foundation for the implementation and further investigation of the procedure, and our numerical studies demonstrate its ability to achieve diverse objectives.

Accuracy of Voltage Signal Measurement During Radiofrequency Delivery Through the SMARTTOUCH Catheter

Current methods for measuring voltage during radiofrequency (RF) ablation (RFA) necessitate turning off the ablation catheter. If voltage could be accurately read without signal attenuation during RFA, turning off the catheter would be unnecessary, allowing continuous ablation. We evaluated the accuracy of the Thermocool SMARTTOUCH catheter for measuring voltage while RF traverses the catheter.

Statistical inference for response adaptive randomization procedures with adjusted optimal allocation proportions

ABSTRACT Seamless phase II/III clinical trials have attracted increasing attention recently. They mainly use Bayesian response adaptive randomization (RAR) designs. There has been little research into seamless clinical trials using frequentist RAR designs because of the difficulty in performing valid statistical inference following this procedure. The well-designed frequentist RAR designs can target theoretically optimal allocation proportions, and they have explicit asymptotic results. In this paper, we study the asymptotic properties of frequentist RAR designs with adjusted target allocation proportions, and investigate statistical inference for this procedure. The properties of the proposed design provide an important theoretical foundation for advanced seamless clinical trials. Our numerical studies demonstrate that the design is ethical and efficient.