Remote Ischemic Conditioning In Patients Research Articles

Remote Ischemic Conditioning for Intracerebral Hemorrhage (RICH-1): Rationale and Study Protocol for a Pilot Open-Label Randomized Controlled Trial.

Background and rationale: Although many therapies have been investigated for intracerebral hemorrhage (ICH), none have succeeded in improving the functional outcomes. Remote ischemic conditioning (RIC) has been proven to promote hematoma resolution and improve neurological outcomes in an ICH model; whether it is safe and feasible in patients with ICH remains unknown. This trial aims to assess the safety, feasibility, and preliminary efficacy of RIC in patients with ICH and to plan for a phase-2 study.Methods: A proof-of-concept, assessor-blinded, pilot open-label randomized controlled trial will be carried out with patients with ICH within 24–48 h of ictus. All participants will be randomly allocated to the intervention group and the control group with a 1:1 ratio (n = 20) and will be treated with standard managements according to the guidelines. Participants allocated to the intervention group will receive RIC once daily for 7 consecutive days. Cranial computed tomography examinations will be performed at baseline, and on days 3, 7, and 14. Neurological outcomes will be assessed at baseline, and on days 1 to 14, 30, and 90. The primary outcome to be tested is safety. Secondary tested outcomes include changes of hematoma and perihematomal edema volume, incidence of hematoma expansion, functional outcomes, and frequency of adverse events.Discussions: This study will be the first proof-of-concept randomized controlled trial to ascertain the safety, feasibility, and preliminary efficacy of RIC in patients with ICH, results of which will provide parameters for future studies and provide insights into the treatment of ICH.Trial Registration: Clinicaltrials.gov, identifier: NCT03930940.

Abstract WP444: Influencing Factors on the Compliance in Ischemic Stroke Patients Treated With Remote Ischemic Conditioning

Objectives: To investigate the treatment compliance of remote ischemic conditioning in patients with ischemic stroke, and determine its associated influencing factors. Methods: A retrospective survey of ischemic stroke patients treated with remote ischemic conditioning was conducted. Treatment compliance was obtained and analysed in patients with one-year training of remote ischemic conditioning. The influencing factors on patients’ compliance were determined by univariate and multivariate regression analysis. Results: The history of hypertension, the number of follow-ups, and the physiological, psychological and environmental dimensions of the comfort scale were related to patient compliance, out of which the number of follow-ups and physiological comfort were independent influencing factors of compliance (P<0.05). Conclusion: In future researches, if we can comprehensively consider the patient’s efficacy, comfort, compliance and other factors, choose the optimal treatment dose, and improve the RIC nursing process accordingly, then this will provide the basis for clinical implementation and scientific research of RIC.

A multicentre, randomised, sham-controlled trial on REmote iSchemic conditioning In patients with acute STroke (RESIST) - Rationale and study design.

Remote ischaemic conditioning, applied in the prehospital setting and continued in-hospital, may improve functional outcome in patients with acute ischaemic stroke and intracerebral haemorrhage. To evaluate whether combined remote ischaemic per- and postconditioning can improve long-term functional outcome in acute ischaemic stroke and intracerebral haemorrhage patients. Danish multicentre, prospective, randomised, patient-assessor blinded, sham-controlled study. Adult patients with a putative stroke identified prehospital with symptom duration <4 h, who are independent in daily activities will be randomised 1:1 to remote ischaemic conditioning or Sham-remote ischaemic conditioning. The treatment protocol will be five cycles, each consisting of 5 min with a blood pressure cuff inflation and 5 min with a deflated cuff placed on the upper extremity. The cuff pressure for remote ischaemic conditioning will be 200 mmHg-285 mmHg according to the individual systolic blood pressure and 20 mmHg sham-remote ischaemic conditioning during inflation. The study is approved as an acute study and consent is waived in the acute phase.Sample size estimation: For a 7% increased odds for a beneficial shift on the modified Rankin Scale at a significance level of 5% and power of 90%, 1000 patients with a target diagnosis of acute ischaemic stroke and intracerebral haemorrhage and a total of 1500 patients with a prehospital presumed stroke will be included.Study outcomes: The primary outcome will be the modified Rankin Scale score measured at three-month follow-up (analysed using ordinal logistic regression). ClinicalTrials.gov Identifier: NCT03481777.

Influence of Cardiovascular Risk Factors, Comorbidities, Medication Use and Procedural Variables on Remote Ischemic Conditioning Efficacy in Patients with ST-Segment Elevation Myocardial Infarction.

Remote ischemic conditioning (RIC) confers cardioprotection in patients with ST-segment elevation myocardial infarction (STEMI). Despite intense research, the translation of RIC into clinical practice remains a challenge. This may, at least partly, be due to confounding factors that may modify the efficacy of RIC. The present review focuses on cardiovascular risk factors, comorbidities, medication use and procedural variables which may modify the efficacy of RIC in patients with STEMI. Findings of such efficacy modifiers are based on subgroup and post-hoc analyses and thus hold risk of type I and II errors. Although findings from studies evaluating influencing factors are often ambiguous, some but not all studies suggest that smoking, non-statin use, infarct location, area-at-risk of infarction, pre-procedural Thrombolysis in Myocardial Infarction (TIMI) flow, ischemia duration and coronary collateral blood flow to the infarct-related artery may influence on the cardioprotective efficacy of RIC. Results from the on-going CONDI2/ERIC-PPCI trial will determine any clinical implications of RIC in the treatment of patients with STEMI and predefined subgroup analyses will give further insight into influencing factors on the efficacy of RIC.

Remote ischemic conditioning in septic shock (RECO-Sepsis): study protocol for a randomized controlled trial

BackgroundSeptic shock is a major public health problem that is associated with up to 50% mortality. Unfavorable outcomes are mainly attributed to multiple organ failure (MOF) resulting from an uncontrolled inflammatory response and ischemia-reperfusion processes. REmote ischemic COnditioning (RECO) is a promising intervention to prevent ischemia-reperfusion injury. We hypothesize that RECO would reduce the severity of septic shock-induced MOF.Methods/designRECO in septic shock patients (RECO-Sepsis study) is an ongoing, prospective, multicenter, randomized, open-label trial, testing whether RECO, as an adjuvant therapy to conventional treatment in septic shock, decreases the severity of MOF as assessed by the Sequential Organ Failure Assessment (SOFA) score. Adult patients admitted to an intensive care unit with documented or suspected infection, lactatemia > 2 mmol/l, and treated with norepinephrine for less than 12 h are potentially eligible for the study. Non-inclusion criteria are: having expressed the wish not to be resuscitated, contraindication for the use of a brachial cuff on both arms, intercurrent disease with an expected life expectancy of less than 24 h, cardiac arrest, and pregnant or breastfeeding women. After enrollment, patients are randomized (n = 180) 1:1 to receive RECO or no adjunctive intervention. RECO consists of four cycles of cuff inflation to 200 mmHg for 5 min and then deflation to 0 mmHg for another 5 min. RECO is performed at inclusion and repeated 12 and 24 h later. The primary endpoint is the mean daily SOFA score up to day 4 after inclusion. Secondary outcomes include the need for organ support, hospital length of stay, and 90-day mortality.DiscussionResults of this proof-of-concept trial should provide information on the efficacy of RECO in patients with septic shock.Trial registrationClinicalTrials.gov, ID: identifier: NCT03201575. Registered on 28 June 2017.

Safety and Efficacy of Remote Ischemic Conditioning in Patients With Essential Hypertension (SERIC-EH)

Safety and Efficacy of Remote Ischemic Conditioning in Patients With Essential Hypertension (SERIC-EH)

Changes in the Diameter of Retinal Vessels After Remote Ischemic Conditioning in Patients With Type 1 Diabetes

Changes in the Diameter of Retinal Vessels After Remote Ischemic Conditioning in Patients With Type 1 Diabetes

A12271 Which is better for patients treated with primary percutaneous coronary Intervention

Objectives: The aim of present study was to compare ischemic postconditioning (IPC) with remote ischemic conditioning (RIC) in STEMI patients treated with primary PCI, a network meta-analysis was performed using adjusted indirect treatment comparison (AITC) approach. Methods: A search was conducted using electronic database to identify RCTs reported either IPC or RIC in patients with STEMI during pPCI published in any language up to December 2017. Outcomes of interest were enzymatic infarct size, infarct size assessed by cardiac magnetic resonance (CMR), complete ST-segment resolution (cSTR) and cardiac events during follow-up. A network meta-analysis was performed using metan function in STATA version 12.0. Results: Thirty two studies including results of 3067 IPC and RIC patients were identified. Pooled results showed the RIC group was associated with lower enzymatic infarct size (IPC vs. RIC, SMD,0.992; 95%CI, 0.708 to 1.39). Compared with IPC,RIC significantly reduced infarct size evaluated by CMR. (IPC VS.RIC, SMD, 1.104; 95%CI, 0.665 to 1.883).There was a trend toward more cSTR in RIC patients than in IPC subjects (OR, 2.085; 95%CI, 0.76 to 5.768). There was no significant difference in all-cause mortality (OR, 0.32; 95%CI, 0.044to 2.332), reinfarction (OR, 0.631; 95%CI, 0.049 to 8.167) or Target vessel revascularization (TVR) (IPC VS.RIC: OR, 0.23; 95%CI, 0.023 to 2.431) with a mean follow up duration of 14 months among patients treated with RIC compared to IPC. Conclusion: In STEMI patients undergoing pPCI, available evidence from this network meta-analysis suggests RIC was associated with significant lower level of infarct size relative to IPC. However, no significantsuperiority of RIC vs. IPC was found in the present study on incidence of cSTR,all-cause mortality, reinfarct and TVR.

Remote Ischemic Conditioning for Patients With STEMI.

ST-segment elevation myocardial infarction (STEMI) remains a leading cause of death and morbidity, despite declining incidence and improved short-term outcome in many countries. Although mortality declines in developed countries with easy and fast access to optimized treatment, development of heart failure often remains a challenge in survivors and still approaches 10% at 1 year. Rapid admission and acute interventional treatment combined with modern antithrombotic pharmacologic therapy frequently establish complete reperfusion and acutely stabilize the patient, but the reperfusion itself adds further to the damage in the myocardium compromising the long-term outcome. Reperfusion injury is believed to be a significant-if not the dominant-contributor to the net injury resulting from STEMI and has become a major focus of research in recent years. Despite a plethora of pharmacological and mechanical interventions showing consistent reduction of reperfusion injury in experimental models, translation into a clinical setting has been challenging. In patients, attempts to modify reperfusion injury by pharmacological strategies have largely been unsuccessful, and focus is increasingly directed toward mechanical modalities. Remote ischemic conditioning of the heart is achieved by repeated brief interruption of the blood supply to a distant part of the body, most frequently the arm. At present, remote ischemic conditioning is the most promising adjuvant therapy to reduce reperfusion injury in patients with STEMI. In this review, we discuss the results of clinical trials investigating the effect of remote ischemic conditioning in patients admitted with STEMI and potential reasons for its apparent superiority to current pharmacologic adjuvant therapies.

Meta-analysis of remote ischemic conditioning in patients with acute myocardial infarction

Effects of remote ischemic conditioning (RIC) in acute myocardial infarction (AMI) patients remain conflicting. We performed this meta-analysis of randomized clinical trials (RCTs) to evaluate the benefits of the RIC in patients with AMI. Potentially relevant RCTs were identified by searching PubMed, Embase, Cochrane Library, VIP, CNKI, and Wanfang database until November 2016. RCTs evaluating RIC using intermittent limb ischemia-reperfusion in AMI patients were included. Thirteen RCTs were identified and analyzed. Meta-analysis showed that RIC significantly reduced the area under the curve (AUC) of creatine kinase-myocardial band (CK-MB) (standardized mean difference [SMD] −0.29; 95% confidence intervals [CI] −0.44 to −0.14; P = 0.0002) and AUC of troponin T (SMD −0.22; 95% CI −0.37 to −0.08; P = 0.003). Risk ratio (RR) for ≥70% ST-segment resolution favored RIC group than the control group (RR 1.39; 95% CI 1.03–1.86; P = 0.03). RIC also significantly reduced all-cause mortality (RR 0.33; 95%CI 0.17–0.64; P = 0.001). Subgroup analyses on the CK-MB AUC and ST-segment resolution ≥70% rate showed that the effects of RIC appeared to be affected by the limb used, duration of RIC, and clinical setting. RIC may offer cardioprotective effects by improving ST-segment resolution and reducing the infarct size in AMI patients.

The effects of remote ischemic conditioning in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: a meta-analysis.

Timely and successful reperfusion is effective at improving outcome in patients presenting with ST elevation myocardial infarction (STEMI). However, abrupt restoration of blood flow may cause detrimental myocardial reperfusion injury. Remote ischemic conditioning (RIC) is a potent activator of innate protection against ischemia-reperfusion injury. This study assessed remote ischemic conditioning in patients presenting with STEMI treated with primary percutaneous coronary intervention (PCI). Relevant studies were identified through electronic literature search from PubMed, Medline, EMBASE, CNKI, WANFANG, and VIP. Studies published up to December 2015 were eligible for inclusion. RIC was performed by applying consecutive cycles of reocclusion/reperfusion through intermittent upper or lower limb ischemia before, during, or after reperfusion. The outcomes included creatine kinase-MB (CK-MB), ST resolution (STR), and left ventricular ejection fraction (LVEF). The 9 trials allocated 540 patients to perform RIC cycles before, during, or after reperfusion and 533 patients to usual PCI. Statistical analysis indicated that the peak of CK-MB and CK-MB AUC in RIC groups decrease significantly during the first 72 hours after PCI compared with controls (P=0.02 and P<0.01). The STR was significantly improved in RIC patients than in control subjects (P<0.001). LVEF is also improved 7 days after myocardial infarction (P=0.001). However, LVEF was not significantly different between study groups over 1 month (P=0.65). There may be a cardioprotective effect of RIC before, during, or after reperfusion, in the setting of acute STEMI.

Meta-Analysis of Randomized Trials on Remote Ischemic Conditioning During Primary Percutaneous Coronary Intervention in Patients With ST-Segment Elevation Myocardial Infarction

Ischemia/reperfusion injury adversely affects the final infarct size (IS) after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). Few studies have evaluated the role of remote ischemic conditioning (RIC) in reducing ischemia/reperfusion injury. However, the results of these studies were not consistent, and an overview of overall effectiveness of this technique in patients with STEMI is lacking. We conducted this meta-analysis to evaluate the available evidence in literature regarding the application of RIC in patients with STEMI who underwent primary PCI. The authors included randomized trials that studied RIC in patients with STEMI who underwent primary PCI versus no conditioning (standard of care). Final analysis included 8 trials with a total of 1,083 patients. Compared with standard of care alone, RIC was associated with reduced IS assessed by biomarker release (standardized mean difference=-0.23, 95% confidence interval [CI]-0.37 to-0.09; p= 0.001), better rates of ST-segment resolution (54% vs 30%; relative risk [RR] 1.78; 95% CI 1.35 to 2.34; p <0.001), reduced major adverse cardiac and cerebrovascular events (11% vs 20%; RR 0.57; 95% CI 0.39 to 0.83; p= 0.003), and nonsignificant reduction in IS assessed by cardiac imaging (standardized mean difference=-0.15; 95% CI-1.03 to-0.14; p= 0.36). There was no difference in postprocedural Thrombolysis In Myocardial Infarction-III flow between RIC and standard of care groups (86% vs 87%; RR 0.99; 95% CI 0.94 to 1.05; p= 0.81). In conclusion, remote ischemic conditioning may improve cardiovascular outcomes in patients with STEMI who underwent primary PCI evidenced by reduced biomarkers release, major adverse cardiac and cerebrovascular events, and better ST-segment resolution.

Time to Give Up on Cardioprotection? A Critical Appraisal of Clinical Studies on Ischemic Pre-, Post-, and Remote Conditioning.

The mortality from acute myocardial infarction (AMI) remains significant, and the prevalence of post-myocardial infarction heart failure is increasing. Therefore, cardioprotection beyond timely reperfusion is needed. Conditioning procedures are the most powerful cardioprotective interventions in animal experiments. However, ischemic preconditioning cannot be used to reduce infarct size in patients with AMI because its occurrence is not predictable; several studies in patients undergoing surgical coronary revascularization report reduced release of creatine kinase and troponin. Ischemic postconditioning reduces infarct size in most, but not all, studies in patients undergoing interventional reperfusion of AMI, but may require direct stenting and exclusion of patients with >6 hours of symptom onset to protect. Remote ischemic conditioning reduces infarct size in patients undergoing interventional reperfusion of AMI, elective percutaneous or surgical coronary revascularization, and other cardiovascular surgery in many, but not in all, studies. Adequate dose-finding phase II studies do not exist. There are only 2 phase III trials, both on remote ischemic conditioning in patients undergoing cardiovascular surgery, both with neutral results in terms of infarct size and clinical outcome, but also both with major problems in trial design. We discuss the difficulties in translation of cardioprotection from animal experiments and proof-of-concept trials to clinical practice. Given that most studies on ischemic postconditioning and all studies on remote ischemic preconditioning in patients with AMI reported reduced infarct size, it would be premature to give up on cardioprotection.

Abstract 10092: Renal Evidence of Remote Ischemic Conditioning for Elective Coronary Revascularization: A Meta-analysis of 13 Randomized Trials

Background: Several early small trials have concerned about the renal effect of periprocedural remote ischemic conditioning(RIC) in patients with coronary artery disease(CAD), however, negative results were widely obtained. Hence, we sought to summarize the renal evidence of RIC in patients undergoing coronary artery bypass grafting(CABG) or percutaneous coronary intervention(PCI). Methods: A systematic search was performed in Pubmed, Embase, Cochrane library, and scientific sessions of AHA, ACC and ESC (up to April 2015). Randomized controlled trials with data on postoperative acute kidney injury(AKI) during elective coronary revascularization were included. Odds ratio(OR) with 95% confidence interval(CI) was calculated. Random-effect models were used for the potential clinical inconsistency. Publication bias assessment and sensitivity analysis were performed to evaluate the robustness of the results. Results: Thirteen RCTs with a total of 1861 CAD patients were identified and selected. Compared with controls, RIC significantly reduced the incidence of AKI (6.61% vs 11.6%;OR= 0.54; 95% CI, 0.37 to 0.78; P=0.001; I2=8.5%; Figure 1). No evidence of significant publication bias were observed (P=0.784, Begg’s test; P=0.096, Egger’s test). Sensitivity analysis of mortality excluding each included study at one time revealed that most individual study was consisted with the direction and size of the overall effect (All P≥0.01).There was no significant difference between CABG subgroup (9.8% vs 16.6%;OR=0.54;95%CI, 0.32 to 0.92; P=0.02; I2=0.0%) and PCI subgroup(5.3% vs 9.4%;OR=0.54; 95% CI, 0.30 to 1.00;P=0.05; I2=36.5%) (P=1.00 for subgroup difference). Conclusions: Based on the available evidence, RIC provides renal protection by reducing the postprocedural AKI in elective coronary revascularization. Such effect is similar between CABG and PCI.

Using remote ischemic conditioning to reduce acute kidney injury in patients undergoing percutaneous coronary intervention: a meta-analysis

Background and aims:It remains uncertain whether remote ischemic conditioning (RIC) could prevent acute kidney injury (AKI) in patients undergoing percutaneous coronary intervention (PCI). Thus, this meta-analysis aiming to explore the renoprotective role of RIC in patients undergoing PCI was carried out.Methods:PubMed, Web of Science, and Cochrane Library were searched from inception to 31 December 2014 to identify eligible randomized controlled trials. Pooled risk ratio, mean, standard deviation and 95% CI were used to assess the effect by fixed- or random-effect models. Heterogeneity was assessed by the Cochran Q and I 2 statistics.Results:Nine trials were included in this study. RIC decreased the AKI incidence in patients undergoing PCI compared with control individuals (P < 0.001; RR, 0.53; 95% CI, 0.39–0.71; P for heterogeneity = 0.15; heterogeneity χ2 = 13.38; I2 = 33%). Besides, limb conditioning attenuated AKI (P = 0.001; RR, 0.57; 95% CI, 0.41–0.81; P for heterogeneity = 0.13; heterogeneity χ2 = 12.48; I2 = 36%). Remote postconditioning may reduce the AKI incidence (P = 0.03; RR, 0.65; 95% CI, 0.44–0.97; P for heterogeneity = 0.15; heterogeneity χ2 = 5.36; I2 = 44%); remote preconditioning could also play a renoprotective role (P < 0.001; RR, 0.42; 95% CI, 0.27–0.65; P for heterogeneity = 0.31; heterogeneity χ2 = 5.98; I2 = 16%).Conclusions:RIC may not only confer cardioprotection, but also reduce the incidence of AKI in patients undergoing PCI, ultimately leading to better clinical outcomes. RIC may potentially be a powerful approach conferring protection in patients undergoing PCI in future clinical practice. More large-scale trials are required to obtain a more reliable conclusion.

GW25-e2152 Ischemic Postconditioning versus Remote Ischemic Conditioning in Patients Treated with Primary Percutaneous Coronary Intervention: A Bayesian Network Meta-analysis

The aim of present analysis was to compare ischemic postconditioning (IPC) with remote ischemic conditioning (RIPC) in primary percutaneous coronary intervention (pPCI), a network meta-analysis was performed using a Bayesian approach. Published randomized controlled trials included either IPC or

Safety, feasibility, and effect of remote ischemic conditioning in patients undergoing lung transplantation

Primary graft dysfunction (PGD) remains a significant problem after lung transplantation. Data from animal and clinical studies suggest that remote ischemic conditioning (RIC) may reduce ischemia-reperfusion injury in solid organ transplantation. A pilot randomized controlled trial of 60 patients undergoing bilateral sequential lung transplantation assessed the utility of RIC in attenuating PGD. Treated recipients underwent 3 cycles of lower limb ischemic conditioning before allograft reperfusion. The primary outcome measure was a comparison of the partial pressure of arterial oxygen/fraction of inspired oxygen ratio (P/F ratio) between treatment groups. No adverse effects of tourniquet application were observed. The mean lowest P/F ratio during the first 24 hours after transplantation was 271.3 mm Hg in the treatment arm vs 256.1 mm Hg in the control arm (p = 0.46). PGD grade and severity and the rate of acute rejection also showed a tendency to favor the treatment arm. Sub-group analysis demonstrated a significant benefit of treatment in patients with a primary diagnosis of restrictive lung disease, a group at high risk for the development of PGD. RIC was not accompanied by systemic release of high-molecular-weight group box 1. Levels of cytokines, high-molecular-weight group box 1, and endogenous secretory receptor for advanced glycation end products peaked within 2 hours after reperfusion and likely reflected donor organ quality rather than an effect of RIC. RIC did not significantly improve P/F ratios or PGD in this randomized controlled trial. However, encouraging results in this small study warrant a large multicenter trial of RIC in lung transplantation.

Remote Ischemic Conditioning in Patients With Myocardial Infarction Treated With Primary Angioplasty

Background— We have found that remote ischemic conditioning (rIC), adjunctive to primary angioplasty, increases myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI) and extensive myocardial area at risk (AAR). The present substudy aimed to evaluate the short-term effects of rIC on left ventricular (LV) function. Methods and Results— Patients with a first STEMI were randomized to rIC (4 cycles of 5 minutes upper-limb ischemia) during transfer to primary percutaneous coronary intervention (pPCI) (n=123) versus pPCI alone (n=119). Ejection fraction (EF), LV volumes, (2D and 3D echocardiography and myocardial perfusion imaging), and speckle-tracking global longitudinal strain were compared between treatment groups. There was no significant difference in LV function at day 1 (EF-2D, 0.51±0.10 versus 0.49±0.10; P =0.22) and after 30 days (EF-2D, 0.54±0.08 versus 0.53±0.10) between the rIC and the pPCI-alone groups. In patients with extensive AAR ≥35% of LV (n=53), EF after 30 days was higher after rIC than after pPCI alone (EF-2D, 0.51±0.07 versus 0.46±0.09; P =0.05). In patients with anterior infarction (n=97), rIC preserved LV function on day 1 (EF-2D, 0.51±0.11 versus 0.46±0.11; P =0.03) and persistently after 30 days (EF-2D, 0.55±0.08 versus 0.50±0.11; P =0.04; EF-myocardial perfusion imaging, 0.55±0.10 versus 0.49±0.12; P =0.02). These patients had similar AAR, whereas rIC reduced infarct size from 16% to 7% of LV ( P =0.01). Conclusions— Although no significant overall effect was observed, rIC seemed to result in modest improvement in LV function in high-risk patients prone to develop large myocardial infarcts. These results need to be confirmed in larger trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00435266.