Validation of Methods to Control for Immortal Time Bias in a Pharmacoepidemiologic Analysis of Renin–Angiotensin System Inhibitors in Type 2 Diabetes

Background

Pharmacoepidemiologic analysis can confirm whether drug efficacy in a randomized controlled trial (RCT) translates to effectiveness in real settings. We examined methods used to control for immortal time bias in an analysis of renin–angiotensin system (RAS) inhibitors as the reference cardioprotective drug.

Methods

We analyzed data from 3928 patients with type 2 diabetes who were recruited into the Hong Kong Diabetes Registry between 1996 and 2005 and followed up to July 30, 2005. Different Cox models were used to obtain hazard ratios (HRs) for cardiovascular disease (CVD) associated with RAS inhibitors. These HRs were then compared to the HR of 0.92 reported in a recent meta-analysis of RCTs.

Results

During a median follow-up period of 5.45 years, 7.23% (n = 284) patients developed CVD and 38.7% (n = 1519) were started on RAS inhibitors, with 39.1% of immortal time among the users. In multivariable analysis, time-dependent drug-exposure Cox models and Cox models that moved immortal time from users to nonusers both severely inflated the HR, and time-fixed models that included immortal time deflated the HR. Use of time-fixed Cox models that excluded immortal time resulted in a HR of only 0.89 (95% CI, 0.68–1.17) for CVD associated with RAS inhibitors, which is closer to the values reported in RCTs.

Conclusions

In pharmacoepidemiologic analysis, time-dependent drug exposure models and models that move immortal time from users to nonusers may introduce substantial bias in investigations of the effects of RAS inhibitors on CVD in type 2 diabetes.Key words: cardiovascular disease, immortal time bias, renin–angiotensin system inhibitors, time-dependent Cox model, cancer, type 2 diabetes     

Effectiveness of home blood pressure monitoring, Web communication, and pharmacist care on hypertension control: a randomized controlled trial

Beverly B. Green, MD, MPH; Andrea J. Cook, PhD; James D. Ralston, MD, MPH; Paul A. Fishman, PhD; Sheryl L. Catz, PhD; James Carlson, PharmD; David Carrell, PhD; Lynda Tyll, RN, MS; Eric B. Larson, MD, MPH; Robert S. Thompson, MD

JAMA. 2008;299(24):2857-2867.

Context  Treating hypertension decreases mortality and disability from cardiovascular disease, but most hypertension remains inadequately controlled.

Objective  To determine if a new model of care that uses patient Web services, home blood pressure (BP) monitoring, and pharmacist-assisted care improves BP control.

Design, Setting, and Participants  A 3-group randomized controlled trial, the Electronic Communications and Home Blood Pressure Monitoring study was based on the Chronic Care Model. The trial was conducted at an integrated group practice in Washington state, enrolling 778 participants aged 25 to 75 years with uncontrolled essential hypertension and Internet access. Care was delivered over a secure patient Web site from June 2005 to December 2007.

Interventions  Participants were randomly assigned to usual care, home BP monitoring and secure patient Web site training only, or home BP monitoring and secure patient Web site training plus pharmacist care management delivered through Web communications.

Main Outcome Measures  Percentage of patients with controlled BP (<140/90 mm Hg) and changes in systolic and diastolic BP at 12 months.

Results  Of 778 patients, 730 (94%) completed the 1-year follow-up visit. Patients assigned to the home BP monitoring and Web training only group had a nonsignificant increase in the percentage of patients with controlled BP (<140/90 mm Hg) compared with usual care (36% [95% confidence interval {CI}, 30%-42%] vs 31% [95% CI, 25%-37%]; P = .21). Adding Web-based pharmacist care to home BP monitoring and Web training significantly increased the percentage of patients with controlled BP (56%; 95% CI, 49%-62%) compared with usual care (P < .001) and home BP monitoring and Web training only (P < .001). Systolic BP was decreased stepwise from usual care to home BP monitoring and Web training only to home BP monitoring and Web training plus pharmacist care. Diastolic BP was decreased only in the pharmacist care group compared with both the usual care and home BP monitoring and Web training only groups. Compared with usual care, the patients who had baseline systolic BP of 160 mm Hg or higher and received home BP monitoring and Web training plus pharmacist care had a greater net reduction in systolic BP (–13.2 mm Hg [95% CI, –19.2 to –7.1]; P < .001) and diastolic BP (–4.6 mm Hg [95% CI, –8.0 to –1.2]; P < .001), and improved BP control (relative risk, 3.32 [95% CI, 1.86 to 5.94]; P<.001).

Conclusion  Pharmacist care management delivered through secure patient Web communications improved BP control in patients with hypertension.

Trial Registration  clinicaltrials.gov Identifier: NCT00158639

     

心肺移植患者巨细胞病毒耐更昔洛韦基因突变研究

目的　建立并应用人巨细胞病毒 (HCMV)行列探针检测 (LiPA)技术 ,快速检测心肺移植患者HCMV耐更昔洛韦 (GCV)基因突变。方法　以HCMV UL97基因为靶序列 ,设计 13条特异性寡核苷酸探针 ,用Nested PCR扩增目的基因 ,LiPA技术检测与耐药有关的碱基突变。并对Nested PCR产物平行做直接序列测定 ,与LiPA结果比较。结果　 16例心肺移植患者 ,LiPA技术检测发现 4例患者存在HCMV UL97基因突变 ,突变分别发生在编码子 5 2 0 ,5 95及 6 0 3,与直接序列测定比较 ,两者完全吻合。结论　长期应用GCV预防及治疗HCMV感染可以诱导病毒耐药 ,LiPA技术可作为检测HCMV基因突变的一种有效手段。     

A clinical trial of anti-idiotype therapy for B cell malignancy

Eleven patients with B lymphocytic malignancy were treated with mouse monoclonal anti-idiotype antibodies. All but one of the patients in this study had received extensive prior treatment with conventional lymphoma therapy. All antibodies were prepared against, and uniquely reactive with, the patient's own tumor. Ten patients were treated with a single antibody, but one patient received three antibodies concurrently. The treatment protocol initially used an escalating dose schedule that was intended to evaluate toxicity, pharmacokinetics and, eventually, to achieve appreciable levels of free mouse antibody in the circulation. The last two patients received substantial initial doses. Tumor sampling was performed before and during therapy to evaluate tissue penetration by antibody. None of the patients had serum paraproteins by routine clinical testing, but six had idiotype protein detectable by a sensitive immunoassay at levels greater than 1 microgram/mL, two of which were greater than 200 micrograms/mL. Plasmapheresis was capable of reducing these levels temporarily. However, the presence of serum idiotype increased the requirement for mouse antibody to achieve tumor penetration. Another obstacle to treatment was immune response to mouse Ig, which occurred in five of the 11 patients. Once an immune response had begun, further infusions of antibody were not capable of reaching the tumor or inducing tumor regression and were associated with toxicity. Our initial patient remains in an unmaintained complete remission 42 months after receiving antibody. Five of ten additional patients have had objective remissions that were also clinically significant. However, these remissions were not complete and were of relatively short duration. This therapy shows promise as an alternative modality for the treatment of B cell malignancy. Further study will be needed to determine the mechanisms of the antitumor effect and to improve the clinical results.     

The product of the protooncogene c-src is modified during the cellular response to platelet-derived growth factor.

We have observed a modification of the cellular protein kinase pp60c-src, elicited in murine 3T3 fibroblasts by platelet-derived growth factor (PDGF). The modification occurred rapidly after addition of PDGF to the culture medium and was first detected as a reduction in the electrophoretic mobility of a portion of the pp60c-src molecules. A similarly modified form of the viral homologue pp60v-src occurs in vivo in the absence of stimulation by PDGF. The occurrence of modified forms of both pp60c-src and pp60v-src was associated with a novel phosphorylation at tyrosine in the amino-terminal domains of the proteins. The time-course and dose-response for this modification of pp60c-src paralleled PDGF-induced increases in phosphorylation of pp36, a major cellular substrate for several tyrosine-specific protein kinases. In parallel experiments, treatment of cells with PDGF increased the kinase activity of pp60c-src in an immunocomplex assay. These results suggest pp60c-src may play a role in the mitogenic response to PDGF.     

A mutation affecting the latency-associated peptide of TGFbeta1 in Camurati-Engelmann disease enhances osteoclast formation in vitro

Camurati-Engelmann disease (CED) is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. CED is caused by various missense mutations in the TGFB1 gene that encodes TGFbeta1, the most common of which is an arginine-cysteine amino acid change at codon 218 (R218C) in the latency-associated peptide domain of TGFbeta1. We studied osteoclast formation in vitro from peripheral blood mononuclear cells obtained from three related CED patients harboring the R218C mutation, in comparison with one family-based and several unrelated controls. Osteoclast formation was enhanced approximately 5-fold (P < 0.001) and bone resorption approximately 10-fold (P < 0.001) in CED patients, and the increase in osteoclast formation was inhibited by soluble TGFbeta type II receptor. Total serum TGFbeta1 levels were similar in affected and unaffected subjects, but concentrations of active TGFbeta1 in conditioned medium of osteoclast cultures was higher in the three CED patients than in the unaffected family member. We concluded that the R218C mutation increases TGFbeta1 bioactivity and enhances osteoclast formation in vitro. The activation of osteoclast activity noted here is consistent with clinical reports that have shown biochemical evidence of increased bone resorption as well as bone formation in CED.     

Physiologic anterior subluxation: case report of occurrence at C5 to C6 and C6 to C7 spinal levels

Physiologic anterior subluxation is a phenomenon that is common to the upper pediatric cervical spine and characterized by the normal forward displacement of one cervical vertebra relative to the subjacent one. Physiologic anterior subluxation can be seen in children in the setting of trauma, when it must be distinguished from pathologic subluxation. Physiologic anterior subluxation has not been reported at lower cervical spinal levels (C 5 to C 6 or C 6 to C 7 ). This is a report of physiologic anterior subluxation at C 5 to C 6 and C 6 to C 7 spinal levels distinguished from pathologic subluxation in a 9-year-old child evaluated in the acute setting after cervical spine injury.     

Prevention of transfusion-induced graft-versus-host disease in dogs by ultraviolet irradiation

Ten dogs were given 9.2 Gy of total body irradiation and autologous bone marrow infusion followed by ten daily transfusions of leukocytes for a total of 11.5 to 36.2 (median, 18.8) x 10(8)/kg obtained via leukapheresis from histoincompatible unrelated donors. Four dogs were given unirradiated leukocytes, and all developed graft-versus-host disease (GVHD). In contrast, only two of three dogs given leukocytes irradiated with 20 mJ/cm2 of ultraviolet (UV) light (200 to 300 nm), and none of three dogs given leukocytes irradiated with 1,000 mJ/cm2 developed GVHD. These data indicate that UV irradiation abrogates the alloreactive potential of transfused leukocytes, and suggest that UV irradiation can be used to prevent the development of transfusion- induced GVHD.     

Management of Glucocorticoid-Induced Osteoporosis

This review summarizes the available evidence-based data that form the basis for therapeutic intervention and covers the current status of glucocorticoid-induced osteoporosis (GIOP) management, regulatory requirements, and risk-assessment options. Glucocorticoids are known to cause bone loss and fractures, yet many patients receiving or initiating glucocorticoid therapy are not appropriately evaluated and treated. An European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis workshop was convened to discuss GIOP management and to provide a report by a panel of experts. An expert panel reviewed the available studies that discussed approved therapeutic agents, focusing on randomized and controlled clinical trials reporting on bone mineral density and/or fracture risk of at least 48?weeks' duration. There is no evidence that GIOP and postmenopausal osteoporosis respond differently to treatments. The FRAX algorithm can be adjusted according to glucocorticoid dose. Available antiosteoporotic therapies such as bisphosphonates and teriparatide are efficacious in GIOP management. Several other agents approved for the treatment of postmenopausal osteoporosis may become available for GIOP. It is advised to stop antiosteoporotic treatment after glucocorticoid cessation, unless the patient remains at increased risk of fracture. Calcium and vitamin D supplementation as an osteoporosis-prevention measure is less effective than specific antiosteoporotic treatment. Fracture end-point studies and additional studies investigating specific subpopulations (pediatric, premenopausal, or elderly patients) would strengthen the evidence base and facilitate the development of intervention thresholds and treatment guidelines.