VIOLET Trial: High-Dose Vitamin D3 for Critically Ill

violet trial vitamin d

VIOLET Trial Summary

The VIOLET trial was a phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the effects of early vitamin D3 supplementation in critically ill patients with vitamin D deficiency who were at high risk for death. Vitamin D deficiency is a common and potentially reversible factor contributing to morbidity and mortality in this patient population.

The trial enrolled a total of 1360 patients who were found to be vitamin D-deficient during point-of-care screening and were randomized within 12 hours of admission to the intensive care unit. The eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or a matched placebo. The primary endpoint of the study was 90-day all-cause, all-location mortality.

Among the randomized patients, 1078 had confirmed baseline vitamin D deficiency (25-hydroxyvitamin D level <20 ng per milliliter [50 nmol per liter]) and were included in the primary analysis. The mean level of 25-hydroxyvitamin D at day 3 was significantly higher in the vitamin D group (46.9±23.2 ng per milliliter [117±58 nmol per liter]) compared to the placebo group (11.4±5.6 ng per milliliter [28±14 nmol per liter]).

However, the administration of high-dose enteral vitamin D3 did not result in a significant advantage over placebo in terms of 90-day mortality. The mortality rate at 90 days was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients), with a difference of 2.9 percentage points (95% confidence interval [CI], -2.1 to 7.9; P=0.26). There were no clinically important differences observed between the treatment groups in secondary clinical, physiological, or safety endpoints. The severity of vitamin D deficiency at baseline did not affect the relationship between treatment assignment and mortality.

In conclusion, early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo in terms of 90-day mortality or other nonfatal outcomes in critically ill patients with vitamin D deficiency. Despite significantly increasing vitamin D levels, there were no significant clinical benefits observed. Further studies may be needed to explore alternative approaches or populations that could potentially benefit from vitamin D supplementation in the critical care setting.

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VISION Trial: Lutetium-177–PSMA-617 for Metastatic Prostate Cancer

The VISION trial was a phase 3 international, open-label study that aimed to evaluate the efficacy of Lutetium-177 (177Lu)–PSMA-617, a radioligand therapy, in patients with metastatic castration-resistant prostate cancer (mCRPC). This type of cancer remains fatal despite recent advancements, and prostate-specific membrane antigen (PSMA) is highly expressed in mCRPC.

The trial enrolled patients who had previously received treatment with at least one androgen-receptor–pathway inhibitor and one or two taxane regimens and had PSMA-positive gallium-68 (68Ga)–labeled PSMA-11 positron-emission tomographic–computed tomographic scans. The patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 in addition to protocol-permitted standard care or standard care alone. Chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs were excluded from the protocol-permitted standard care. The primary endpoints were imaging-based progression-free survival and overall survival, with key secondary endpoints including objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were monitored up to 30 days after the last dose and prior to subsequent anticancer treatment.

Between June 2018 and mid-October 2019, a total of 831 out of 1179 screened patients were randomized. The baseline characteristics of the patients were well-balanced between the two groups, and the median follow-up period was 20.9 months. The addition of 177Lu-PSMA-617 to standard care significantly prolonged both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio, 0.62; 95% CI, 0.52 to 0.74; P<0.001) compared to standard care alone. All key secondary endpoints, including objective response, disease control, and time to symptomatic skeletal events, favored the 177Lu-PSMA-617 group. The incidence of adverse events of grade 3 or above was higher in the 177Lu-PSMA-617 group compared to the standard care group (52.7% vs. 38.0%), but the quality of life was not adversely affected.

In conclusion, the VISION trial demonstrated that the addition of 177Lu-PSMA-617 to standard care significantly improved imaging-based progression-free survival and overall survival in patients with advanced PSMA-positive mCRPC. Although there was a higher incidence of grade 3 or above adverse events in the 177Lu-PSMA-617 group, the treatment did not negatively impact the patients’ quality of life. This study provides important evidence for the efficacy of radioligand therapy with 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer and PSMA expression.

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VITAL-AF Trial: Screening for AFib

vital af trial atrial fibrillation

VITAL-AF Trial Summary

The VITAL-AF trial aimed to determine whether point-of-care screening with a handheld single-lead ECG device during primary care visits increases the diagnosis of atrial fibrillation (AF) in older adults. The study randomized 16 primary care clinics in a 1:1 ratio, with half implementing AF screening using the AliveCor KardiaMobile device during vital sign assessments, while the other half provided usual care without systematic screening. The participants included were aged 65 years or older, and screening results were communicated to the primary care clinicians during the patient encounters. Diagnostic testing and treatment decisions were made by the clinicians, and new AF diagnoses during the 1-year follow-up were ascertained and adjudicated.

Among the 30,715 patients without prevalent AF at baseline (15,393 in the screening group and 15,322 in the control group), the incidence of new AF diagnoses at 1 year was 1.72% in the screening group and 1.59% in the control group, indicating no significant difference between the two groups (risk difference, 0.13%; 95% confidence interval [CI], -0.16 to 0.42; P=0.38). However, subgroup analyses revealed that in individuals aged 85 years or older, the rate of new AF diagnoses was higher in both the screening and control groups compared to the overall population (5.56% versus 3.76%, respectively; risk difference, 1.80%; 95% CI, 0.18 to 3.30).

When comparing the screening period to the previous year, the difference in newly diagnosed AF between the screening and control groups was slightly larger in the screening group (0.32% versus -0.12%; risk difference, 0.43%; 95% CI, -0.01 to 0.84). However, this difference was not statistically significant. The proportion of individuals with newly diagnosed AF who were initiated on oral anticoagulants was similar in the screening (73.5%) and control (70.8%) arms (risk difference, 2.7%; 95% CI, -5.5 to 10.4).

In conclusion, the VITAL-AF trial did not find evidence to support the use of point-of-care AF screening with a handheld single-lead ECG device during primary care visits to increase the diagnosis of new AF among individuals aged 65 years or older compared to usual care. Although subgroup analyses indicated higher rates of new AF diagnoses in older individuals, overall, the screening intervention did not significantly impact the detection of AF or the initiation of oral anticoagulant treatment. Further research may be necessary to explore the effectiveness of alternative screening strategies or targeted approaches for specific age groups.

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VITAL-DEP Trial: vitamin D and omega-3 FA for depression

vital dep trial

VITAL-DEP Trial Summary

The VITAL-DEP trial aimed to investigate whether long-term supplementation with vitamin D3 could prevent depression in the general adult population. The study included 18,353 adults aged 50 years or older without depression or clinically relevant depressive symptoms at the beginning of the trial. The participants were randomly assigned to receive either vitamin D3 supplementation or a placebo over a 5-year treatment period.

The primary outcomes assessed were the incidence and recurrence of depression or clinically relevant depressive symptoms, as well as changes in mood scores. The results showed that vitamin D3 supplementation did not lead to statistically significant differences compared to the placebo group in terms of depression risk or clinically relevant depressive symptoms (hazard ratio, 0.97). Additionally, there were no significant differences between the groups regarding changes in mood scores over the course of the study.

Among the 18,353 participants, with a mean age of 67.5 years, the median treatment duration was 5.3 years, and 90.5% completed the trial. The risk of depression or clinically relevant depressive symptoms was similar between the vitamin D3 group and the placebo group, with no significant variation in incidence or recurrence. The results did not indicate any significant differences in mood scores over time, with the mean change in the 8-item Patient Health Questionnaire depression scale (PHQ-8) score being negligible.

In conclusion, the VITAL-DEP trial found no evidence to support the use of vitamin D3 supplementation in the prevention of depression among adults aged 50 years or older without clinically relevant depressive symptoms at baseline. The study’s results did not demonstrate a significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms between the vitamin D3 and placebo groups. Furthermore, there were no notable variations in mood scores over the median follow-up period of 5.3 years. Therefore, based on these findings, the use of vitamin D3 supplementation in adults to prevent depression is not supported.

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TAME Trial: Mild Hypercapnia after Cardiac Arrest

tame trial cardiac arrest

TAME Trial Summary

The TAME trial investigated the impact of mild hypercapnia versus normocapnia on neurologic outcomes in adults with coma who were resuscitated after out-of-hospital cardiac arrest. Current guidelines recommend normocapnia, but mild hypercapnia has been suggested to enhance cerebral blood flow and potentially improve neurologic outcomes.

The trial randomly assigned adults admitted to the intensive care unit (ICU) after out-of-hospital cardiac arrest to either 24 hours of mild hypercapnia (target partial pressure of arterial carbon dioxide [Paco2] between 50 and 55 mm Hg) or normocapnia (target Paco2 between 35 and 45 mm Hg) in a 1:1 ratio. The primary outcome assessed was a favorable neurologic outcome at 6 months, defined as a score of 5 or higher on the Glasgow Outcome Scale–Extended, indicating lower moderate disability or better. The secondary outcome measured was death within 6 months.

The trial included a total of 1,700 patients from 63 ICUs in 17 countries, with 847 patients assigned to the mild hypercapnia group and 853 to the normocapnia group. At 6 months, a favorable neurologic outcome occurred in 43.5% of patients in the mild hypercapnia group and 44.6% in the normocapnia group. The relative risk of achieving a favorable neurologic outcome with mild hypercapnia compared to normocapnia was 0.98, with a 95% confidence interval (CI) of 0.87 to 1.11. This result indicated no significant difference between the two groups (P=0.76). Regarding death within 6 months after randomization, it occurred in 48.2% of patients in the mild hypercapnia group and 45.9% in the normocapnia group, with a relative risk of 1.05 (95% CI, 0.94 to 1.16). The incidence of adverse events did not significantly differ between the groups.

In conclusion, the TAME trial found that among patients with coma who were resuscitated after out-of-hospital cardiac arrest, targeted mild hypercapnia did not result in better neurologic outcomes at 6 months compared to targeted normocapnia. There was no significant difference between the two groups in terms of achieving a favorable neurologic outcome or death within 6 months. Furthermore, the incidence of adverse events did not differ significantly between the mild hypercapnia and normocapnia groups. These findings indicate that mild hypercapnia does not confer an advantage over normocapnia in improving neurologic outcomes in this specific patient population. These results have important implications for clinical practice and highlight the need to adhere to current guidelines recommending normocapnia in adults with coma following out-of-hospital cardiac arrest.

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DEVICE Trial: Video versus Direct Laryngoscopy for Tracheal Intubation

device trial

DEVICE Trial Summary

The article discusses the findings of the DEVICE trial, which aimed to determine whether video laryngoscopy increased the likelihood of successful tracheal intubation on the first attempt compared to direct laryngoscopy in critically ill adults.

The trial was conducted at 17 emergency departments and intensive care units (ICUs), involving a multicenter, randomized design. Critically ill adults undergoing tracheal intubation were randomly assigned to either the video-laryngoscope group or the direct-laryngoscope group. The primary outcome assessed was successful intubation on the first attempt, while the occurrence of severe complications during intubation was considered a secondary outcome. Severe complications were defined as severe hypoxemia, severe hypotension, new or increased use of vasopressors, cardiac arrest, or death.

The trial was stopped for efficacy at the preplanned interim analysis. The final analysis included 1,417 patients, with 91.5% of them undergoing intubation performed by an emergency medicine resident or a critical care fellow. The results indicated that successful intubation on the first attempt occurred in 85.1% of patients in the video-laryngoscope group and 70.8% of patients in the direct-laryngoscope group. This represented an absolute risk difference of 14.3 percentage points, with a statistically significant difference between the groups (P<0.001).

Regarding severe complications during intubation, 21.4% of patients in the video-laryngoscope group and 20.9% in the direct-laryngoscope group experienced such complications. The absolute risk difference was 0.5 percentage points, with the 95% confidence interval indicating no significant difference between the two groups (−3.9 to 4.9). Safety outcomes, including esophageal intubation, injury to the teeth, and aspiration, were similar in both groups.

In conclusion, the DEVICE trial demonstrated that among critically ill adults undergoing tracheal intubation in emergency departments or ICUs, the use of a video laryngoscope resulted in a higher incidence of successful intubation on the first attempt compared to the use of a direct laryngoscope. This finding suggests that video laryngoscopy may be a beneficial tool in improving first-attempt intubation success rates in critically ill patients. The study did not show a significant difference in severe complications between the two groups. Safety outcomes were comparable, suggesting that the use of a video laryngoscope does not pose an increased risk of adverse events compared to a direct laryngoscope. These results provide valuable insights for clinicians and highlight the potential advantages of incorporating video laryngoscopy into tracheal intubation procedures for critically ill adults.

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TRAVERSE Trial: CV Safety of Testosterone-Replacement Therapy

TRAVERSE Trial testosterone

TRAVERSE Trial Summary

The abstract highlights the findings of the TRAVERSE trial, which aimed to assess the cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism. The trial sought to determine whether testosterone replacement therapy in this population increased the risk of cardiovascular events.

The inclusion criteria for participants required them to be men between the ages of 45 and 80 with low serum testosterone concentrations (<300 ng/dL), exhibiting at least one sign or symptom of hypogonadism, and having evidence of cardiovascular disease or an increased risk for cardiovascular disease.

Certain exclusion criteria were established, including participants with congenital or acquired hypogonadism for whom long-term placebo therapy would not be appropriate, participants with prostate-specific antigen (PSA) levels exceeding certain thresholds, individuals who had received testosterone therapy in the past six months and were contraindicated for further testosterone therapy, and participants with confirmed testosterone levels below 100 ng/dL, a high body mass index (BMI), elevated hemoglobin A1c (HbA1c) levels, high hematocrit (Hct), reduced estimated glomerular filtration rate (eGFR), and a history of deep vein thrombosis, pulmonary embolism, prostate cancer, or heart failure.

The TRAVERSE trial was a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial. A total of 5,246 men aged 45 to 80 years with preexisting cardiovascular disease or a high risk of cardiovascular disease, symptoms of hypogonadism, and low testosterone levels were enrolled. The participants were randomly assigned to receive daily transdermal 1.62% testosterone gel or placebo gel. The primary cardiovascular safety endpoint was the occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary endpoints included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.

The mean duration of treatment was 21.7 months, with a mean follow-up period of 33.0 months. The results showed that the occurrence of primary cardiovascular endpoint events was similar in both the testosterone group (7.0%) and the placebo group (7.3%). The hazard ratio for the primary endpoint was 0.96, indicating noninferiority of testosterone therapy compared to placebo. Sensitivity analyses also supported these findings. However, the testosterone group did show a higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism.

In conclusion, the TRAVERSE trial demonstrated that testosterone-replacement therapy in men with hypogonadism and preexisting or high-risk cardiovascular disease was noninferior to placebo in terms of major adverse cardiac events. The study found no significant difference in the occurrence of primary or secondary cardiovascular endpoints between the testosterone and placebo groups. However, it should be noted that the testosterone group did show an increased incidence of certain adverse events. Further research and monitoring are necessary to fully understand the cardiovascular safety profile of testosterone-replacement therapy in this population.

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CONVINCE Trial: Hemodiafiltration or Hemodialysis in Kidney Failure

convince trial dialysis

CONVINCE Trial Summary

The abstract discusses the results of the CONVINCE trial, a randomized, controlled study comparing high-dose hemodiafiltration (HDF) with conventional high-flux hemodialysis (HD) in patients with end-stage kidney disease (ESKD). The trial aimed to determine whether high-dose HDF reduces the risk of death in ESKD patients compared to high-flux HD.

Previous studies had suggested potential benefits of high-dose HDF over standard hemodialysis, but more data were needed due to limitations in existing research. The CONVINCE trial was designed as an investigator-initiated, international, multicenter, prospective study to address this gap.

The inclusion criteria for participants required them to be diagnosed with ESKD, receiving HD treatment for at least three months, and likely to achieve high-dose HDF as per the protocol. They also needed to be willing to undergo dialysis sessions of at least four hours, three times a week, and demonstrate an understanding of the study procedures.

Certain exclusion criteria were established, such as severe non-compliance with dialysis procedures, a life expectancy of less than three months, recent HDF treatment, and anticipated living donor kidney transplantation within six months. Other exclusion factors included diseases or medical conditions that could interfere with treatment or increase the risk of complications, participation in conflicting studies, and unavailability for study visits lasting three months or more.

The trial utilized a pragmatic approach and included patients who had been on high-flux HD for at least three months. Participants were randomized into two groups: one receiving high-dose HDF and the other continuing with high-flux HD. The primary outcome assessed was death from any cause, with key secondary outcomes including cause-specific death, composite cardiovascular events, kidney transplantation, and hospitalizations due to all-cause or infection-related reasons.

A total of 1,360 patients were randomized, with 683 in the high-dose HDF group and 677 in the high-flux HD group. The median follow-up period was 30 months. During the trial, the average convection volume for the HDF group was 25.3 liters per session. The analysis revealed that death from any cause occurred in 118 patients (17.3%) in the HDF group and 148 patients (21.9%) in the HD group. The hazard ratio for death was 0.77, indicating a lower risk of death in the high-dose HDF group compared to conventional high-flux HD.

In conclusion, the CONVINCE trial demonstrated that high-dose hemodiafiltration was associated with a reduced risk of death from any cause in patients with kidney failure requiring kidney-replacement therapy. This finding suggests that high-dose HDF may be a more effective treatment option compared to conventional high-flux HD. The results of this trial provide additional data supporting the potential benefits of high-dose HDF in patients with end-stage kidney disease, and further research in this area may be warranted.

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RITA 3 Trial: Interventional vs. Conservative Strategy in UA/NSTEMI

RITA 3 Trial Summary

Background:

  • Current guidelines recommend either an interventional strategy (angiography followed by revascularization) or a conservative strategy (ischemia-driven or symptom-driven angiography) for patients at moderate risk of death from unstable coronary artery disease.
  • The aim was to compare the effectiveness of an interventional strategy versus a conservative strategy in these patients.

Methods:

  • Randomized multicenter trial involving 1810 patients with non-ST-elevation acute coronary syndromes.
  • Mean age of patients was 62 years, with 38% women.
  • Patients were assigned to either an early intervention or conservative strategy.
  • Both groups received enoxaparin as the antithrombin agent.
  • Coprimary endpoints: combined rate of death, non-fatal myocardial infarction, or refractory angina at 4 months; and combined rate of death or non-fatal myocardial infarction at 1 year.
  • Analysis was conducted based on intention to treat.

Findings:

  • At 4 months, the intervention group had a lower incidence of death, myocardial infarction, or refractory angina compared to the conservative group (9.6% vs. 14.5%; risk ratio 0.66, 95% CI 0.51-0.85, p=0.001).
  • The difference was primarily due to a significant reduction in refractory angina in the intervention group.
  • There was no significant difference in the rates of death or myocardial infarction between the two groups at 1 year (7.6% vs. 8.3%; risk ratio 0.91, 95% CI 0.67-1.25, p=0.58).
  • The interventional strategy led to improved angina symptoms and reduced use of antianginal medications (p<0.0001).

Interpretation:

  • In patients with unstable coronary artery disease, an interventional strategy is preferred over a conservative strategy.
  • The interventional approach significantly reduces the incidence of refractory or severe angina without increasing the risk of death or myocardial infarction.
  • Patients benefit from improved angina symptoms and a decreased need for antianginal medications.

Key Takeaways:

  • The RITA 3 trial compared an interventional strategy to a conservative strategy in patients with unstable coronary artery disease.
  • Interventional strategy resulted in a lower incidence of death, myocardial infarction, or refractory angina at 4 months.
  • No significant difference in death or myocardial infarction rates between the two groups at 1 year.
  • The interventional strategy improved angina symptoms and reduced the use of antianginal medications.
  • These findings support the preference for an interventional approach in managing unstable coronary artery disease.

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RESCUE BT2 Trial: Tirofiban for Acute Ischemic Stroke

rescue bt2 trial tirofiban

Summary of the RESCUE BT2 Trial: Tirofiban in Acute Ischemic Stroke

Background:

  • Limited research on the effects of tirofiban, a glycoprotein IIb/IIIa receptor inhibitor, in acute ischemic stroke patients without complete occlusion of large or medium-sized vessels.

Methods:

  • Multicenter trial conducted in China.
  • Enrolled patients with ischemic stroke without vessel occlusion, National Institutes of Health Stroke Scale (NIHSS) score of 5 or more, and at least one moderately to severely weak limb.
  • Eligible patients had different clinical presentations: ineligible for thrombolysis or thrombectomy within 24 hours of last known well; stroke symptom progression 24 to 96 hours after onset; early neurological deterioration after thrombolysis; or no improvement after thrombolysis at 4 to 24 hours.
  • Patients randomized to receive intravenous tirofiban (plus oral placebo) or oral aspirin (100 mg/day plus intravenous placebo) for 2 days, followed by oral aspirin until day 90.
  • Primary efficacy endpoint: excellent outcome (modified Rankin scale score of 0 or 1) at 90 days.
  • Secondary endpoints: functional independence at 90 days, quality-of-life score.
  • Primary safety endpoints: death and symptomatic intracranial hemorrhage.

Inclusion criteria:

  1. Aged 18 years or older.
  2. Various presentations of acute ischemic stroke (AIS) within specific timeframes.
  3. NIHSS score of 5 or more, with at least one limb affected.
  4. No visible occlusion of large or medium intracranial vessels on imaging.
  5. Written informed consent obtained.

Results:

  • 606 patients in the tirofiban group and 571 patients in the aspirin group.
  • Majority had small atherosclerotic infarctions.
  • Excellent outcome (mRS score 0 or 1) at 90 days: 29.1% in the tirofiban group vs. 22.2% in the aspirin group (adjusted risk ratio 1.26; 95% CI 1.04-1.53; p=0.02).
  • Secondary endpoints did not consistently align with the primary analysis.
  • Similar mortality rates in both groups.
  • Symptomatic intracranial hemorrhage incidence: 1.0% in tirofiban group vs. 0% in aspirin group.

Conclusions:

  • In this trial involving patients with recent onset or progressing stroke symptoms and nonoccluded large or medium-sized cerebral vessels, intravenous tirofiban showed a greater likelihood of excellent outcomes compared to low-dose aspirin.
  • Incidence of intracranial hemorrhage was low but slightly higher with tirofiban.

Key Takeaways:

  • Tirofiban, a glycoprotein IIb/IIIa receptor inhibitor, showed promise in improving outcomes for acute ischemic stroke patients without complete vessel occlusion.
  • Tirofiban was associated with a higher likelihood of excellent outcomes compared to aspirin.
  • Incidence of symptomatic intracranial hemorrhage was low but slightly higher with tirofiban.
  • Further research is needed to validate these findings and determine the optimal treatment approach for this patient population.

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