Prospective Randomized Open Blinded Endpoint Research Articles

Safety and efficacy of fluoxetine in post-stroke anxiety-A pilot prospective randomized open blinded endpoint (PROBE) study.

The prevalence of post-stroke anxiety (PSA) is reported to be 20%-25%. There is insufficient evidence on the efficacy of antidepressants for treating anxiety in such patients. This Prospective Randomized Open Blinded Endpoint (PROBE) study was designed to assess the safety and efficacy of fluoxetine in PSA. In this single-center pilot study conducted in India, post-stroke patients (between 1 to 6months) were randomized to fluoxetine (intervention group: 20mg/day for 12weeks) or standard medical care (control group). The primary outcome was improvement in the Hamilton Anxiety Rating Scale (HAM-A) at 12weeks. The secondary outcomes were anxiety remission (>50% improvement in HAM-A), modified Rankin Scale (mRS), Barthel Index (BI), quality of life (SF-36), and Hamilton Depression Rating Scale (HAM-D). A linear regression analysis was done for determinants of HAM-A to account for baseline differences in the intervention and control groups. A total of 60 patients were randomized: (30: intervention, 30: control). The overall prevalence of post-stroke anxiety among participants in the study was 50.8%, and 31.5% experienced both anxiety and depression. The average HAM-A score at baseline was 11, and average follow-up score at study conclusion was 4. There was similar improvement in the HAM-A score at 12weeks post-randomization in the intervention and control groups [fluoxetine: -8.0 (95% CI = -11.0 to -4.0); control: -7.0 (95% CI = -9.5 to -4.0); P = 0.91]. Likewise, there was no significant difference between intervention and control groups at 12weeks post-randomization on the mRS, BI, SF-36, or HAM-D. There were no serious adverse events in either group during the study. Fluoxetine and standard medical care had comparable improvement in HAM-A in post-stroke patients with mild anxiety at 12weeks. Further study of the pharmacological treatment of post-stroke patients with more severe anxiety is needed. CTRI/2018/12/016568.

ChatGPT-4 and wearable device assisted Intelligent Exercise Therapy for co-existing Sarcopenia and Osteoarthritis (GAISO): a feasibility study and design for a randomized controlled PROBE non-inferiority trial.

Sarcopenia and osteoarthritis are prevalent age-related diseases that mutually exacerbate each other, creating a vicious cycle that worsens both conditions. Exercise is key to breaking this detrimental cycle. Facing increasing demand for rehabilitation services within this patient demographic, ChatGPT-4 and wearable device may increase the availability, efficiency and personalization of such health care. To evaluate the clinical efficacy and cost-effectiveness of a rehabilitation system implemented on mobile platforms, utilizing the integration of ChatGPT-4 and wearable devices. The study design is a prospective randomized open blinded end-point (PROBE) non-inferiority trial. 278 patients diagnosed with osteoarthritis and sarcopenia will be recruited and randomly assigned to the intervention group and the control group. In the intervention group patients receive mobile phone-based rehabilitation service where ChatGPT-4 generates personalized exercise therapy, and wearable device guides and monitor the patient to implement the exercise therapy. Traditional clinic based face-to-face exercise therapy will be prescribed and implemented in the control group. All patients will receive three-months exercise therapies following the frequency, intensity, type, time, volume and progression (FITT-VP) principle. The patients will be assessed at baseline, one month, three months, and six months after initiation. Outcome measures will include ROM, gait patterns, Visual Analogue Scale (VAS) for pain assessment, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS) for functional assessment, Short-Form Health Survey 12 (SF-12) for quality of life, Minimal Clinically Important Difference (MCID), Patient Acceptable Symptom State (PASS), and Substantial Clinical Benefit (SCB) for clinically significant measures. A rehabilitation system combining the capabilities of ChatGPT-4 and wearable devices potentially enhance the availability and efficiency of professional rehabilitation services, thus enhancing the therapeutic outcomes for a substantial population concurrently afflicted with sarcopenia and osteoarthritis.

Ramipril After Transcatheter Aortic Valve Implantation in Patients Without Reduced Ejection Fraction: The RASTAVI Randomized Clinical Trial.

Patients with aortic stenosis may continue to have an increased risk of heart failure, arrhythmias, and death after successful transcatheter aortic valve implantation. Renin-angiotensin system inhibitors may be beneficial in this setting. We aimed to explore whether ramipril improves the outcomes of patients with aortic stenosis after transcatheter aortic valve implantation. PROBE (Prospective Randomized Open, Blinded Endpoint) was a multicenter trial comparing ramipril with standard care (control) following successful transcatheter aortic valve implantation in patients with left ventricular ejection fraction >40%. The primary end point was the composite of cardiac mortality, heart failure readmission, and stroke at 1-year follow-up. Secondary end points included left ventricular remodeling and fibrosis. A total of 186 patients with median age 83 years (range 79-86), 58.1% women, and EuroSCORE-II 3.75% (range 3.08-4.97) were randomized to receive either ramipril (n=94) or standard treatment (n=92). There were no significant baseline, procedural, or in-hospital differences. The primary end point occurred in 10.6% in the ramipril group versus 12% in the control group (P=0.776), with no differences in cardiac mortality (ramipril 1.1% versus control group 2.2%, P=0.619) but lower rate of heart failure readmissions in the ramipril group (3.2% versus 10.9%, P=0.040). Cardiac magnetic resonance analysis demonstrated better remodeling in the ramipril compared with the control group, with greater reduction in end-systolic and end-diastolic left ventricular volumes, but nonsignificant differences were found in the percentage of myocardial fibrosis. Ramipril administration after transcatheter aortic valve implantation in patients with preserved left ventricular function did not meet the primary end point but was associated with a reduction in heart failure re-admissions at 1-year follow-up. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03201185.

Abstract 26: An Effective mHealth Intervention to Close the Guideline-to-Practice Gap in Hypertension Treatment: mGlide RCT

Background: Suboptimal HTN control is a widespread problem particularly among minorities and socioeconomically disadvantaged groups. Objective: To determine if a mobile health (mHealth) intervention facilitating an active partnership between inter-professional care teams (including pharmacists) and patients improves HTN control in patients with uncontrolled HTN. Methods: mGlide is an NIH-funded, 2-arm RCT evaluating HTN control between a mHealth intervention (mGlide) vs. state-of-clinical-care (comparison) groups using a PROBE (Prospective Randomized Open Blinded End-point) design. Table 1 shows intervention components. High CVD risk patients with uncontrolled HTN identified by EHR query were randomized 1:1 to either mGlide or to comparison for a 6-month intervention followed by a 6-month observation period. Recruitment sites include primary care clinics and specialty stroke service in an integrated health system, community clinics (CC) and federally qualified health centers (FQHC). The FQHC and CC serve low income and minority (Hmong and Latino) patients. The primary aim tested clinical effectiveness of mGlide in reducing SBP at 6 months. Secondary outcomes include resource utilization, adverse events and medication side-effects. Results: Recruitment started in 2019. N=395 participants enrolled by August 2023. The pandemic impacted enrollment; however enrollment recovered after vaccine availability (Figure). Primary outcome was available in March 2024 on everyone except in those lost to follow-up (n=38; 9.6%). We used multiple imputation for those missing 6 month SBP. Baseline mean SBP was 143.2 vs. 143.6 mm Hg in mGlide vs. comparison. The intervention led to better HTN control (Table 2). Mean 6-month SBP was 128.1 (mGlide) vs. 134 mm Hg (comparison). Adjusting for baseline SBP and study strata, 6-month mean SBP was 5.7 mm Hg (95% CI 2.9-8.4; p = 0.0001) lower in mGlide vs. comparison. The odds of HTN control defined as “alive and SBP < 130 mm Hg”, was 60% higher in the mGlide arm (OR 1.6; 95% CI 1.03-2.48; p=0.035). There was one death in each study arm. The mGlide arm had fewer ER visits (16% vs. 25%; p=0.024), fewer hospitalizations (7% vs. 13%; p=0.044) and more medication side effects (39% vs. 26%, p=0.008). Conclusions: An inexpensive mHealth intervention that used the patient’s own phone (Table 1) was implemented in diverse health systems and significantly reduced SBP and was associated with less resource utilization at 6 months (Table 2).

Tenecteplase, 0.4 mg/kg, in Moderate and Severe Acute Ischemic Stroke: A Pooled Analysis of NOR-TEST and NOR-TEST 2A.

Background The optimal dose of tenecteplase in acute ischemic stroke remains to be defined. We present a pooled analysis of the 2 NOR-TESTs (Norwegian Tenecteplase Stroke Trials) exploring the efficacy and safety of tenecteplase, 0.4 mg/kg. Methods and Results We retrospectively reviewed 2 PROBE (Prospective Randomized Open, Blinded End-point) trials, NOR-TEST and NOR-TEST 2A. Patients were randomized to either tenecteplase, 0.4 mg/kg, or alteplase, 0.9 mg/kg. The primary end point was favorable functional outcome at 3 months (modified Rankin Scale score, 0-1) or return to baseline if prestroke modified Rankin Scale score was 2. Secondary end points included favorable functional and clinical outcome and safety data. The pooled analysis includes patients with National Institutes of Health Stroke Scale score ≥6 from both trials and an additional post hoc analysis of patients with National Institutes of Health Stroke Scale score ≤5 from NOR-TEST. The per-protocol analysis contains 483 patients, of whom 235 were assigned to tenecteplase and 248 were assigned to alteplase. In per-protocol analysis, functional outcome was better in the alteplase arm with cutoff modified Rankin Scale score of 2 (odds ratio [OR], 0.52 [95% CI, 0.33-0.80]; P=0.003) and expressed by ordinal shift analysis (OR, 1.64 [95% CI, 1.17-2.28]; P=0.004). Mortality at 3 months was higher in the tenecteplase arm (OR, 2.48 [95% CI, 1.20-5.10]; P=0.01). Mortality and intracranial hemorrhage rates were higher in the severe stroke group randomized to tenecteplase, whereas these rates were similar for alteplase and tenecteplase in moderate and mild stroke. Conclusions Tenecteplase, 0.4 mg/kg, is unsafe in moderate and severe stroke, and the risk of death and intracranial hemorrhage probably increases with stroke severity. A lower tenecteplase dose should be tested in future trials. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01949948, NCT03854500.

Gait pattern after electromechanically-assisted gait training with the Hybrid Assistive Limb and conventional gait training in sub-acute stroke rehabilitation-A subsample from a randomized controlled trial.

Electromechanically-assisted gait training has been introduced in stroke rehabilitation as a means to enable gait training with a large number of reproducible and symmetrical task repetitions, i.e. steps. However, few studies have evaluated its impact on gait pattern functions. This study includes persons with no independent ambulation function at the start of a 4-week neurorehabilitation period in the sub-acute phase after stroke. The primary aim of the study was to evaluate whether the addition of electromechanically-assisted gait training to conventional training resulted in better gait pattern function than conventional training alone. The secondary aim was to identify correlations between overall gait quality and standardized clinical assessments. Seventeen patients with no independent ambulation function who participated in a Prospective Randomized Open Blinded End-point study in the sub-acute phase after stroke were randomized into two groups; one group (n = 7) to undergo conventional training only (CONV group) and the other group (n = 10) to undergo conventional training with additional electromechanically-assisted gait training (HAL group). All patients were assessed with 3D gait analysis and clinical assessments after the 4-week intervention period. Overall gait quality as per the Gait Profile Score (GPS), as well as kinematic, and kinetic and other spatiotemporal metrics were collected and compared between intervention groups. Correlations between biomechanical and clinical outcomes were evaluated. Both the CONV and HAL groups exhibited similar gait patterns with no significant differences between groups in any kinematic, kinetic parameters or other spatiotemporal metrics. The GPS for the paretic limb had a median (IQR) of 12.9° (7.8°) and 13.4° (4.3°) for the CONV and HAL groups, respectively (p = 0.887). Overall gait quality was correlated with independence in walking, walking speed, movement function and balance. We found no added benefit in gait pattern function from the electromechanically-assisted gait training compared to the conventional training alone. This finding raises new questions about how to best design effective and optimal post-stroke rehabilitation programs in patients with moderate to severe gait impairments to achieve both independent walking and optimal gait pattern function, and about which patients should be in focus in further studies on the efficacy of electromechanically-assisted gait training. The study was retrospectively registered at ClinicalTrials.gov, identifier (NCT02410915) on April 2015.

Effect of Individualized Versus Standardized Blood Pressure Management During Endovascular Stroke Treatment on Clinical Outcome: A Randomized Clinical Trial.

Optimal blood pressure (BP) management during endovascular stroke treatment is not well established. We studied whether an individualized approach for managing BP during endovascular stroke treatment gives a better clinical outcome than an approach with standardized systolic BP targets. The INDIVIDUATE study (Individualized Blood Pressure Management During Endovascular Treatment of Acute Ischemic Stroke Under Procedural Sedation) is a randomized clinical trial with a prospective randomized open blinded end point (PROBE) design. Patients were recruited between October 1, 2020 and July 7, 2022 at a single center at a tertiary care university hospital. Patients were eligible, when they were suffering from acute ischemic stroke of the anterior circulation with occlusions of the internal carotid artery and middle cerebral artery and a National Institutes of Health Stroke Scale score of ≥8 receiving endovascular stroke treatment in procedural sedation. The intervention consists of an individualized BP management strategy, where preinterventional baseline systolic BP (SBP) values are used as intraprocedural BP targets. As a control, the standard treatment aims to maintain the intraprocedural SBP between 140 and 180 mm Hg. The main prespecified outcome is the proportion of favorable functional outcomes 90 days after stroke, defined as a modified Rankin Scale score of 0 to 2. Two hundred fifty patients were enrolled and included in the analysis, mean (SD) age was 77 (12) years, 142 (57%) patients were women, and mean (SD) National Institutes of Health Stroke Scale score on admission was 17 (5.2). In all, 123 (49%) patients were treated with individualized and 127 (51%) with standard BP management. Mean (SD) intraprocedural SBP was similar in the individualized versus standard BP management group (157 [19] versus 154 [18] mm Hg; P=0.16). The rate of favorable functional outcome after 3 months was not significantly different between the individualized versus the standard BP management group (25% versus 24%; adjusted odds ratio, 0.81 [95% CI, 0.41-1.61]; P=0.56). Among patients treated with endovascular stroke treatment due to an acute ischemic stroke of the anterior circulation, no significant difference was seen between the individualized BP management strategy, where intraprocedural SBP was targeted to baseline values, and the standardized regimen of targeting SBP between 140 and 180 mm Hg. URL: https://www. gov; Unique identifier: NCT04578288.

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stage IB3 and IIA2): study protocol of the LAUNCH 3 trial

BackgroundCervical cancer is and will remain to be an important health problem in China, especially with an increasing proportion of younger patients who has more specific needs. In China, surgery to remove tumor burden followed by postoperative treatment with radiotherapy and chemotherapy based on clinicopathologic factors may be the best choice for stages IB3 and IIA2 patients. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology. The current trial is designed to evaluate whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stages IB3 and IIA2) patient survival under stringent operation standards and consistent surgical oncologic principles. This paper reports the rationale, design, and implementation of the trial.Methods/designThis is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 1104 patients with stage IB3 and IIA2 cervical cancer will be enrolled over a period of 3 years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed up for at least 5 years. The primary end point will be 5-year overall survival, and secondary endpoints include 5-year progression-free survival, recurrence, and quality of life measurements.DiscussionThe study results will provide more convincing evidence-based information for stages IB3 and IIA2 cervical cancer patients and their gynecologic cancer surgeons in their choice of surgical method.Trial registrationClinicalTrials.gov, NCT04939831, retrospectively registered on 25 June 2021.

Tenecteplase to Replace Alteplase? Comparing Thrombolytic Therapies for Acute Ischemic Stroke: June 2023 Annals of Emergency Medicine Journal Club.

Tenecteplase to Replace Alteplase? Comparing Thrombolytic Therapies for Acute Ischemic Stroke: June 2023 Annals of Emergency Medicine Journal Club.

Efficacy and Safety of Automated Antiseptic Lavage and Suctioning of Oral, Oropharyngeal, and Subglottic Secretions (Vapcare) Among Ventilated Patients with COVID-19 Developing VentilatorAssociated Events During Hospitalization: A Prospective Randomized Open Blinded End-Point Study

Background: Globally, invasive mechanical ventilation is one of the many methods relied on by intensivists to treat patients diagnosed with COVID-19. In this population, substandard oral care and secretion management permit the colonization of pathogens in the oral cavity and aspiration of these microbeladen secretions is the leading cause of ventilator-associated pneumonia (VAP). This study was conducted to analyze the effects of VapCare, an automated and intelligent secretion clearance and oral hygiene management system for VAP prevention, compared to the manual process.

Comparison of the Efficacy of Platelet-Rich Plasma (PRP) and Local Corticosteroid Injection in Periarthritis Shoulder: A Prospective, Randomized, Open, Blinded End-Point (PROBE) Study.

BackgroundPeriarthritis or frozen shoulder, also called adhesive capsulitis, is characterized by stiffness and pain along with gradual loss of active and passive movement in the glenohumeral joint. More than 2-5% of the population suffers from periarthritis with a higher incidence in the age group of 40-60 years. The various treatment modalities used for its management include simple physiotherapy, short-wave therapy, ultrasonic therapy, transcutaneous electrical nerve stimulation, hydrotherapy, analgesics, intra-articular injections, manipulation under general anesthesia (MUA), and surgical management. The application of intra-articular steroid injection has been a common and efficacious option in rapidly diminishing shoulder pain and disability. Some recent studies reported a better outcome using platelet-rich plasma (PRP) injections in frozen shoulder cases. Hence, this randomized controlled trial was conducted to compare the efficacy of intra-articular injections of PRP and triamcinolone in patients of shoulder periarthritis in a population from the eastern region of IndiaMethodologyA total of 60 patients with periarthritis shoulder were allocated into two groups after randomization. Group A received 2 mL autologous PRP, and Group B received 2 mL of triamcinolone (40 mg/mL) intra-articular injection. Patients were followed up on the 4th week, 12th week, and 24th week. The assessment of pain and function using the visual analog scale (VAS) score and the Disabilities of Arm, Shoulder, and Hand (DASH) score, respectively, was done at each follow-up. The primary analyses of both primary and secondary outcomes were conducted in the intention-to-treat (ITT) population. SPSS version 24 (IBM Corp., Armonk, NY, USA) was used for data analysis.ResultsThe mean VAS score in the PRP and triamcinolone groups was 14.33 ± 3.79 and 31.63 ± 7.62, respectively (p = 0.0001) after 24 weeks. The mean DASH score in the PRP and triamcinolone groups was 18.08 ± 8.08 and 31.76 ± 3.63, respectively (p = 0.0001), which shows significant improvement in both pain and disability scores in the PRP group after 24 weeks.ConclusionsThe triamcinolone group showed better short-term outcomes whereas PRP showed better long-term outcomes in reducing pain and disability scores in terms of VAS and DASH scores.

A multicenter noninferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stage IA1 with LVSI, IA2): study protocol of the LAUNCH 1 trial

BackgroundA retrospective study and a randomized controlled trial published in a high quality journal in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology, therefore this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stage IA1 with LVSI, IA2) patient survival under stringent operation standards and consistent tumor-free technique. This paper reports the rationale, design, and implementation of the trial.MethodsThis is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 690 patients with stage IA1 (with intravascular), and IA2 cervical cancer will be enrolled over a period of three years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed-up for at least five years. The primary endpoint will be 5-year progression-free survival. Secondary endpoints will include 5-year overall survival rates, recurrence rates, operation time, intraoperative blood loss, surgery-related complications, and quality of life.DiscussionThe results of the trial will provide valuable evidence for guiding clinical decision of choosing appropriate treatment strategies for stage IA1 (LVSI) and stage IA2 cervical cancer patients.Trial registrationClinicalTrials.gov (NCT04934982, Registered on 22 June 2021).

A multicenter non-inferior randomized controlled study comparing the efficacy of laparoscopic versus abdominal radical hysterectomy for cervical cancer (stages IB1, IB2, and IIA1): study protocol of the LAUNCH 2 trial

BackgroundA retrospective study and a randomized controlled trial published in late 2018 have shown that laparoscopic radical hysterectomy (RH) was associated with worse survival than abdominal RH among patients with early-stage cervical cancer. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology; therefore, this conclusion is pivotal. The current trial is designed to reconfirm whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stages IB1, IB2, and IIA1) patient survival under stringent operation standards and consistent surgical oncologic principles.Methods/designThis is an investigator-initiated, Prospective, Randomized, Open, Blinded End-point (PROBE)-controlled non-inferiority trial. A total of 780 patients with stage IB1, IB2, and IIA1 cervical cancer will be enrolled over a period of 3 years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed up for at least 5 years. The primary endpoint will be 5-year progression-free survival, and secondary endpoints include 5-year overall survival, recurrence, and quality of life measurements.DiscussionThe debate on laparoscopic versus abdominal RH is still ongoing, and high-quality evidences are needed to guide clinical practice. The study results will provide more convincing evidence-based information for early-stage cervical cancer patients and their gynecologic cancer surgeons in their choice of surgical method.Trial registrationClinicalTrials.govNCT04929769. Registered on 18 June 2021

Design of a pragmatic clinical trial embedded in the Electronic Health Record: The VA's Diuretic Comparison Project

BackgroundRecent US guidelines recommend chlorthalidone over other thiazide-type diuretics for the treatment of hypertension based on its long half-life and proven ability to reduce CVD events. Despite recommendations most clinicians prescribe hydrochlorothiazide (HCTZ) over chlorthalidone (CTD). No randomized controlled data exist comparing these two diuretics on cardiovascular outcomes. MethodsThe Diuretic Comparison Project (DCP) is a multicenter, two-arm, parallel, Prospective Randomized Open, Blinded End-point (PROBE) trial testing the primary hypothesis that CTD is superior to HCTZ in the prevention of non-fatal CVD events and non-cancer death. Patients with hypertension taking HCTZ 25 or 50 mg were randomly assigned to either continue their current HCTZ or switch to an equipotent dose of CTD. The primary outcome is time to the first occurrence of a composite outcome consisting of a non-fatal CVD event (stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, or hospitalization for acute heart failure) or non-cancer death. The trial randomized 13,523 patients at 72 VA medical centers. The study is conducted by a centralized research team with site procedures embedded in the electronic health record and all data collected through administrative claims data, with no study related visits for participants. The trial will have 90% power to detect an absolute reduction in the composite event rate of 2.4%. ResultsEnrollment ended in November 2021. There are 4128 participting primary care providers and 16,595 patients individually consented to participate, 13,523 of whom were randomized. ConclusionsDCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients. Clinical trial registrationNCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].

Fresh lemon juice supplementation for the prevention of recurrent stones in calcium oxalate nephrolithiasis: A pragmatic, prospective, randomised, open, blinded endpoint (PROBE) trial

SummaryBackgroundStandard diet with normal calcium and reduced animal proteins and salt content reduces stone recurrence in calcium oxalate nephrolithiasis. Whether lemon juice supplementation further reduces recurrence rate is unknown.MethodsIn this single-centre, prospective, randomised, open, blinded endpoint trial (Clinical Trials gov NCT01217372) we evaluated the effects of fresh lemon juice supplementation (60 mL twice daily) versus no supplementation, on time to stone recurrence in 203 patients with recurrent idiopathic calcium oxalate nephrolithiasis who were all prescribed a standard diet. Patients were included between July 2009 and March 2017 at the Nephrology Unit of the Papa Giovanni XXIII hospital in Bergamo, Italy. Time to stone recurrence at 2 years of follow-up was the primary outcome. Analyses were by intention-to-treat.FindingsDuring two years of follow-up 21 of 100 patients randomised to lemon juice supplementation and 32 of 103 controls randomised to no supplementation had stone recurrence [HR (95% CI): 0·62 (0·35–1·07), p = 0·089]. Patient adherence to lemon juice supplementation, however, progressively decreased from 68% at one-year to 48% at two-year follow-up. At explorative analyses restricted at one-year follow-up, ten patients with supplementation versus 22 controls had stone recurrence [0·43 (0·20–0·89), p = 0·028]. After adjustment by age, sex and normo or hypocitraturia, the HR (95%) was still significant [0·45 (0·20–0·93), p = 0·036]. At six months, 24 hour urinary sodium excretion decreased by 8·60±65·68 mEq/24 h in patients receiving lemon juice supplementation and increased by 3·88±64·78 mEq/24 h in controls. Changes significantly differed between groups (p = 0·031). This difference was subsequently lost. Treatment was safe. In patients with lemon juice supplementation gastrointestinal disorders were more frequent (p<0·001). Renal and urinary tract disorders were similar between groups (p = 0·103).InterpretationExplorative analyses suggest that fresh lemon juice supplementation to standard diet might prevent stone recurrence in patients with calcium-oxalate nephrolithiasis. However, treatment effect was likely reduced by progressively declining adherence to lemon juice supplementation.FundingThis study received no funding.

Improving Outcomes After Stroke: From Stroke Units to Mobile Stroke Units.

A proactive clinical approach to stroke care improved functional outcomes with implementation of specialized in-hospital stroke units, urgently delivered systemic thrombolysis, mechanical thrombectomy and most recently with mobile stroke units deployed in the field. An 18% absolute difference in outcomes as a shift across all modified Rankin Scale strata at 3 months in the recent Berlin study may not be explained by just 8.8% more patients treated within the golden hour for thrombolytic treatment from symptom onset. These findings parallel the findings in the largest controlled multi-center BEST-MSU trial (Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit) to date. A shortcoming in blinding of the investigators to the mode of transportation is similar to blinding to the endovascular treatment in PROBE (Prospective Randomized Open, Blinded End-Point) design used in thrombectomy trials. A faster access to stroke experts and brain imaging in the field for all patients suspect of stroke regardless symptom nature, severity, duration or resolution delivered by mobile stroke units is likely the reason for improved outcomes akin the impact observed in the initial multidisciplinary approach to in-hospital stroke units and reperfusion therapies delivery.

Central blood pressure lowering effect of telmisartan-rosuvastatin single-pill combination in hypertensive patients combined with dyslipidemia: A pilot study.

This multicenter, phase 4, Prospective Randomized Open, Blinded End‐point (PROBE) study aimed to evaluate safety and efficacy of telmisartan/rosuvastatin single‐pill combination (SPC) therapy on lowering central blood pressure (BP) compared with telmisartan monotherapy in hypertensive patients with dyslipidemia in Korea. Study was terminated earlier than planned due to COVID‐19 pandemic, thus should be considered as a pilot study. Among 125 patients who met the inclusion criteria of hypertension and dyslipidemia (defined as 10‐year Atherosclerotic Cardiovascular Disease risk score over 5%), 80 patients went through 4‐week single‐group run‐in period with telmisartan 40–80 mg, then randomized to telmisartan 80 mg + rosuvastatin (10 or 20 mg) SPC group or telmisartan 80 mg monotherapy group. The central/brachial BP, brachial‐ankle pulse wave velocity (baPWV), and augmentation index (AIx) were assessed at baseline and 16 weeks later. Mean brachial SBP changed from 135.80 ± 14.22 mmHg to 130.69 ± 13.23 mmHg in telmisartan/rosuvastatin group and from 134.37 ± 12.50 mmHg to 133.75 ± 12.30 mmHg in telmisartan monotherapy group without significant difference (between‐group difference p = .149). Mean central SBP were reduced significantly in the telmisartan/rosuvastatin group with change from 126.72 ± 14.44 mmHg to 121.56 ± 14.56 mmHg while telmisartan monotherapy group showed no significant change (between‐group difference p = .028). BaPWV changed from 1672.57 ± 371.72 m/s to 1591.75 ± 272.16 m/s in telmisartan/rosuvastatin group and from 1542.85 ± 263.70 m/s to 1586.12 ± 297.45 m/s in telmisartan group with no significance (between‐group difference p = .078). Change of AIx had no significant difference (between‐group difference p = .314). Both groups showed excellent compliance rate of 96.9 ± 4.5% with no significant difference in adverse rate. Telmisartan/rosuvastatin SPC therapy was more effective in lowering central BP compared with the telmisartan monotherapy. The results of this study showed benefit of additive statin therapy in hypertensive patients combined with dyslipidemia.

Penile Hemodynamic Response to Phosphodiesterase Type V Inhibitors after Cavernosal Sparing Inflatable Penile Prosthesis Implantation: A Prospective Randomized Open-Blinded End-Point (PROBE) Study.

Forceful corporal dilatation amidst penile prosthesis implantation may injure cavernosal arteries compromising penile vasculature. In this study, we aimed to compare the conventional and cavernosal sparing techniques regarding cavernosal artery preservation. Overall, 33 patients underwent inflatable penile prosthesis implantation with Coloplast Titan Touch® three-piece inflatable penile implants. 16 patients had conventional implantations with serial vigorous dilatations, while 17 patients were implanted with the cavernosal sparing technique, consisting of a single minimal corporal dilatation after an intraoperative intracavernosal injection (ICI) of Alprostadil. Postoperatively, a penile duplex Doppler ultrasound study was performed. Whenever a cavernosal artery was spared and thus successfully probed, its hemodynamics were studied before and after an oral administration of a phosphodiesterase type 5 inhibitor (PDE5i). A cavernosal artery was successfully probed in 16/17 (94%) of patients in the cavernosal sparing group compared to 5/16 (31%) of patients in the conventional group with a significant statistical difference (P=0.001). This demonstrated that the cavernosal sparing technique was superior to the conventional approach in preserving the cavernosal artery (odds ratio 35.2, 95% IC 3.5–344.2; P=0.0022). Whenever a cavernosal artery could be probed, its hemodynamic responsiveness was also preserved. This trial is registered with NCT03733860.

The beneficial effect over 3 years by pictorial information to patients and their physician about subclinical atherosclerosis and cardiovascular risk: Results from the VIPVIZA randomized clinical trial

ObjectiveNon-adherence to guidelines and preventive measures is a major challenge, particularly so to obtain long-term adherence to lifestyle changes and recommended medication. The objective was to investigate if pictorial information regarding subclinical carotid atherosclerosis provided to individuals and physicians gave sustained effects on cardiovascular risk beyond the previously reported effect after 1 year and up to 3 years. MethodsA Prospective Randomized Open Blinded End-point (PROBE) trial. Within a CVD prevention program in Västerbotten County, Sweden, 3532 healthy individuals aged 40, 50 or 60 years were enrolled and 1:1 randomized to intervention (n = 1749; pictorial information with additional prevention materials to participants and physicians) or control group (n = 1783; no pictorial information to participants and physicians). Preventive measures were managed within primary care. Participants were investigated at baseline during 2013–2016 and at follow-up after 1 and 3 years. ResultsA beneficial effect on cardiovascular risk was observed at 3-year follow-up; Framingham Risk Score (FRS) was 13.38 for the intervention group and 14.08 for the control group (p = 0.047) and SCORE was 1.69 vs. 1.82 (p = 0.022). The effect observed at 1-year was sustained over 3 years after adjustment for sex and education and more pronounced among participants with a severe atherosclerotic picture at baseline. ConclusionsThis study provides evidence of sustained beneficial effects on the adherence to prevention guidelines over 3 years of pictorial information about subclinical carotid atherosclerosis, resulting in lower cardiovascular risk regardless of sex and educational level. Direct visualization of the underlying still subclinical atherosclerotic disease, rather than just indirect information about risk factors and statistical risk of future myocardial infarction, stroke and death, is one way to tackle the problem of non-adherence to prevention of cardiovascular diseases.

A randomized ablation-based atrial fibrillation rhythm control versus rate control trial in patients with heart failure and high burden atrial fibrillation: The RAFT-AF trial rationale and design

Heart failure (HF) and atrial fibrillation (AF) are 2 cardiac conditions that are increasing in prevalence and incidence. The 2 conditions frequently coexist, and are associated with increased morbidity and mortality. Catheter ablation of AF has been successfully performed in patients with HF, with an improvement in HF and AF, when compared to amiodarone, but further data is required to compare this to rate control. ObjectivesThe primary objective is to determine whether AF treated by catheter ablation, with or without antiarrhythmic drugs reduces all-cause mortality and hospitalizations for HF as compared with rate control in patients with HF and a high burden AF. MethodsThis is a multi-center prospective randomized open blinded endpoint (PROBE) study. Patients with NYHA class II-III HF (HF with reduced ejection fraction (<35%) or HF with preserved ejection fraction), and high burden AF are included in the trial. Patients are randomized to either rate control or catheter ablation-based AF rhythm control in a 1:1 ratio. Patients in the rate control group receive optimal HF therapy and rate control measures to achieve a resting hazard ratio (HR) < 80 bpm and 6-minute walk HR < 110 bpm. Patients randomized to catheter ablation-based AF rhythm control group receive optimal HF therapy and one or more aggressive catheter ablation, which include PV antral ablation and LA substrate ablation with or without adjunctive antiarrhythmic drug. The primary outcome is a composite of all-cause mortality and hospitalization for heart failure defined as an admission to a health care facility. The sample size is 600. Enrolment has been completed.