Interim monitoring in a treatment strategy trial with a composite primary endpoint

Abstract Background A de-escalation of P2Y12-inhibitor treatment guided by platelet function testing (PFT) has been identified as a safe and alternative treatment strategy in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). However, no specific data are available on the efficacy of such strategy in patients with high atherothrombotic risk (ATR). Purpose To investigate the safety and efficacy of guided de-escalation of P2Y12-inhibitor treatment in patients with low- vs. high-ATR. Methods The TROPICAL-ACS trial randomized 2,610 biomarker-positive ACS patients 1:1 to either conventional treatment with prasugrel for 12 months (control group) or to a PFT guided de-escalation treatment strategy (guided de-escalation group). The primary endpoint was defined as the composite of cardiovascular mortality (CVM), myocardial infarction (MI), stroke, and clinically overt bleeding (bleeding ≥ grade 2 according to the BARC criteria). The ischemic endpoint was defined as the composite of CVM, MI or stroke. We used semi-parametric Cox regression analysis and interaction testing to assess the effect of low- vs. high-ATR on the primary and ischemic endpoints. High-ATR was defined as one of the following: (i) age ≥65 years or (ii) age <65 and either history of peripheral artery disease or at least two of the following risk-factors: diabetes mellitus, current smoking or renal dysfunction. Results Patients with high- (n=990) versus low-ATR (n=1,620) exhibited a higher risk for the primary endpoint (11.0% vs. 6.7%; HR 1.67; 95% CI 1.28–2.18; p<0.001). Guided de-escalation was non-inferior to conventional treatment for the primary endpoint in both patients with high- (10.5% vs. 11.5%; pnon-inferiority = 0.029; Figure 1A) and low-ATR (5.6% vs. 7.7%; pnon-inferiority=0.001; Figure 1B). Moreover, there was no significant interaction in the prognostic value of guided de-escalation between high- and low-ATR groups for both the primary (HR 0.90 [0.61–1.32]; p=0.586 in patients with high-ART vs. 0.71 [0.48–1.04; p=0.082 in patients with low-ATR; pinteraction= 0.394) and combined ischemic endpoints (HR 0.83 [0.44–1.56]; p=0.567 in patients with high-ATR vs. 0.68 [0.35–1.34]; p=0.262 in patients with low-ATR; pinteraction =0.666). Kaplan-Meier curves Conclusion A guided DAPT de-escalation strategy appears to be safe and effective in ACS patients regardless of the atherothrombotic risk. Further studies are needed for refining antiplatelet treatment strategies in ACS patients with varying levels of atherothrombotic risk. Acknowledgement/Funding Klinikum der Universität München, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.

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Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia

10.1101/2020.06.17.20134031 ◽

2020 ◽

Cited By ~ 4

Author(s):

Francesco Salton ◽

Paola Confalonieri ◽

Pierachille Santus ◽

Sergio Harari ◽

Raffaele Scala ◽

...

Keyword(s):

Primary Endpoint ◽

Low Dose ◽

Research Question ◽

Invasive Mechanical Ventilation ◽

Rapid Improvement ◽

Clinical Trial Registration ◽

Multicenter Observational Study ◽

Randomized Controlled Studies ◽

High Dependency ◽

Composite Primary Endpoint

AbstractBackgroundIn hospitalized patients with COVID-19 pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism.Research QuestionWill early prolonged methylprednisolone (MP) treatment accelerate disease resolution, decreasing the need for ICU and mortality?Study Design and MethodsWe conducted a multicenter, observational study to explore the association between exposure to prolonged, low-dose, MP treatment and need for ICU referral, intubation or death within 28 days (composite primary endpoint) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels.ResultsFindings are reported as MP (n=83) vs. control (n=90). The composite primary endpoint was met by 19 vs. 40 [adjusted hazard ratio (HR) 0.41; 95% confidence interval (CI): 0.24-0.72]. Transfer to ICU and need for invasive MV was necessary in 15 vs. 27 (p=0.07) and 14 vs. 26 (p=0.10), respectively. By day 28, the MP group had fewer deaths (6 vs. 21, adjusted HR=0.29; 95% CI: 0.12-0.73) and more days off invasive MV (24.0 ± 9.0 vs. 17.5 ± 12.8; p=0.001). Study treatment was associated with rapid improvement in PaO2:FiO2 and CRP levels. The complication rate was similar for the two groups (p=0.84).InterpretationIn patients with severe COVID-19 pneumonia, early administration of prolonged MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Randomized controlled studies are needed to confirm these findings.Clinical trial registrationClinicalTrials.gov. Identifier: NCT04323592.

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189 Long-term outcomes of early-onset myocardial infarction with non-obstructive coronary artery disease

European Heart Journal Supplements ◽

10.1093/eurheartj/suab140.030 ◽

2021 ◽

Vol 23 (Supplement_G) ◽

Author(s):

Giulia Magnani ◽

Serena Bricoli ◽

Maddalena Ardissino ◽

Giuseppe Maglietta ◽

Adam Nelson ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Primary Endpoint ◽

Early Onset ◽

Coronary Revascularization ◽

Obstructive Coronary Artery Disease ◽

Fatal Stroke ◽

Artery Disease ◽

Composite Primary Endpoint

Abstract Aims Data regarding long-term prognosis of MINOCA are very limited and conflicting. Methods and results The Italian Genetic Study on early-onset MI enrolled 2000 patients who had a first MI before they were 45. The median follow-up was 19.9 years, the equivalent of 39 535 person-years. The composite primary endpoint was cardiovascular (CV) death, non-fatal MI, and non-fatal stroke (MACE); the secondary endpoint was rehospitalization for coronary revascularization. MINOCA was experienced by 317 patients (15.9%). The risk of MACE was not significantly different between MINOCA patients and those with obstructive coronary artery disease (MICAD, 27.8% vs. 37.5%; adj. HR: 0.79, 95% CI: 0.57–1.09; P = 0.15, Figure 1). There was no between-group difference in the rate of non-fatal MI (17.3% vs. 25.4%; adj. HR: 0.76, 95% CI: 0.52–1.13; P = 0.18), non-fatal ischaemic stroke (9.5% vs. 3.7%; adj. HR: 1.79, 95% CI: 0.87–3.70; P = 0.12), or all-cause mortality (14.1% vs. 20.7%; adj. HR: 0.73, 95% CI: 0.43–1.25; P = 0.26), but the rates of CV death (6.2% vs. 8.4%; adj. HR: 0.26, 95% CI: 0.08–0.86; P = 0.03) and coronary revascularization (6.7% vs. 27.7%; HR: 0.27, 95% CI: 0.15–0.47; P < 0.001) were lower in the MINOCA group. Conclusions MINOCA is frequent in early-onset MI patients and is not benign with a long-term risk of MACE and overall mortality not significantly different from that of the MICAD patients. 189 Figure 1 Composite primary endpoint of CV death, non-fatal MI, and non-fatal stroke

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Conflicts of interest in randomized controlled trials reported in neurosurgical journals

Journal of Neurosurgery ◽

10.3171/2019.5.jns183560 ◽

2020 ◽

Vol 133 (3) ◽

pp. 855-864 ◽

Cited By ~ 1

Author(s):

Victor E. Staartjes ◽

Anita M. Klukowska ◽

Elena L. Sorba ◽

Marc L. Schröder

Keyword(s):

Randomized Controlled Trials ◽

Primary Endpoint ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Critical Role ◽

External Support ◽

Controlled Trials ◽

Randomized Controlled ◽

Primary Endpoints ◽

Composite Primary Endpoint

OBJECTIVERandomized controlled trials (RCTs) form the basis of today’s evidence-based approach to medicine, and play a critical role in guidelines and the drug and device approval process. Conflicts of interest (COIs) are commonplace in medical research, but little is known about their influence. The authors aimed to evaluate the extent and influence of COIs in recent RCTs published in core neurosurgical journals using a cross-sectional analysis.METHODSThrough review of 6 general neurosurgical journals, all interventional RCTs published from January 2009 to January 2019 were identified. Because it is difficult to objectively assess study outcome, the authors opted for a strict rating approach based on the statistical significance of unambiguously reported primary endpoints, and the reported statistical protocol.RESULTSA total of 129 RCTs met the inclusion criteria. During the study period, the Journal of Neurosurgery published the largest number of RCTs (n = 40, 31%). Any potential COI was disclosed by 57%, and a mean of 12% of authors had a personal COI. Nonfinancial industry involvement was reported in 10%, while 31% and 20% received external support and sponsoring, respectively. Study registration was reported by 56%, while 51% of studies were blinded. Registration showed an increasing trend from 17% to 76% (p < 0.001). The median randomized sample size was 92 (interquartile range 50–153), and 8% were designed to investigate noninferiority or equality. Sixty-three RCTs (49%) unambiguously reported a primary endpoint, of which 13% were composite primary endpoints. In 43%, study outcome was positive, which was associated with a noninferiority design (31% vs 3%, p = 0.007) and a composite primary endpoint (46% vs 9%, p = 0.002). Potential COIs were not significantly associated with study positivity (69% vs 59%, p = 0.433). In the multivariate analysis, only a composite primary endpoint remained predictive of a positive study outcome (odds ratio 6.34, 95% confidence interval 1.51–33.61, p = 0.017).CONCLUSIONSThis analysis provides an overview of COIs and their potential influence on recent trials published in core neurosurgical journals. Reporting of primary endpoints, study registration, and uniform disclosure of COIs are crucial to ensure the quality of future neurosurgical randomized trials. COIs do not appear to significantly influence the outcome of randomized neurosurgical trials.

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1108: Treatment Strategy Improves the in Vivo Stone Comminution Efficiency and Reduces Renal Tissue Injury During Shock Wave Lithotripsy

The Journal of Urology ◽

10.1016/s0022-5347(18)35264-9 ◽

2005 ◽

Vol 173 (4S) ◽

pp. 300-301

Author(s):

Michaella E. Maloney ◽

Pei Zhong ◽

Charles G. Marguet ◽

Yufeng F. Zhou ◽

Jeffrey C. Sung ◽

...

Keyword(s):

Shock Wave ◽

Treatment Strategy ◽

Shock Wave Lithotripsy ◽

Tissue Injury ◽

Renal Tissue

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1115: The Effect of Treatment Strategy on Stone Comminution Efficiency in Shock Wave Lithotripsy

The Journal of Urology ◽

10.1016/s0022-5347(18)38352-6 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 294-294

Author(s):

Yufeng Zhou ◽

Charles G. Marguet ◽

Michaella E. Maloney ◽

Franklin H. Cocks ◽

Glenn M. Preminger ◽

...

Keyword(s):

Shock Wave ◽

Treatment Strategy ◽

Shock Wave Lithotripsy ◽

Effect Of Treatment

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Auricular vagal nerve stimulation in peripheral arterial disease patients

VASA ◽

10.1024/0301-1526/a000660 ◽

2017 ◽

Vol 46 (6) ◽

pp. 462-470 ◽

Cited By ~ 3

Author(s):

Gerald Hackl ◽

Andreas Prenner ◽

Philipp Jud ◽

Franz Hafner ◽

Peter Rief ◽

...

Keyword(s):

Primary Endpoint ◽

Nerve Stimulation ◽

Short Form ◽

Therapeutic Option ◽

Arterial Disease ◽

Walking Distance ◽

Control Group ◽

Sf 36 ◽

Peripheral Arterial ◽

Double Blinded

Abstract. Background: Auricular nerve stimulation has been proven effective in different diseases. We investigated if a conservative therapeutic alternative for claudication in peripheral arterial occlusive disease (PAD) via electroacupuncture of the outer ear can be established. Patients and methods: In this prospective, double-blinded trial an ear acupuncture using an electroacupuncture device was carried out in 40 PAD patients in Fontaine stage IIb. Twenty patients were randomized to the verum group using a fully functional electroacupuncture device, the other 20 patients received a sham device (control group). Per patient, eight cycles (1 cycle = 1 week) of electroacupuncture were performed. The primary endpoint was defined as a significantly more frequent doubling of the absolute walking distance after eight cycles in the verum group compared to controls in a standardized treadmill testing. Secondary endpoints were a significant improvement of the total score of the Walking Impairment Questionnaire (WIQ) as well as improvements in health related quality of life using the Short Form 36 Health Survey (SF-36). Results: There were no differences in baseline characteristics between the two groups. The initial walking distance significantly increased in both groups (verum group [means]: 182 [95 % CI 128–236] meters to 345 [95 % CI 227–463] meters [+ 90 %], p < 0.01; control group [means]: 159 [95 % CI 109–210] meters to 268 [95 % CI 182–366] meters [+ 69 %], p = 0.01). Twelve patients (60 %) in the verum group and five patients (25 %) in controls reached the primary endpoint of doubling walking distance (p = 0.05). The total score of WIQ significantly improved in the verum group (+ 22 %, p = 0.01) but not in controls (+ 8 %, p = 0.56). SF-36 showed significantly improvements in six out of eight categories in the verum group and only in one of eight in controls. Conclusions: Electroacupuncture of the outer ear seems to be an easy-to-use therapeutic option in an age of increasingly invasive and mechanically complex treatments for PAD patients.

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