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.
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.
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:
Aged 18 years or older.
Various presentations of acute ischemic stroke (AIS) within specific timeframes.
NIHSS score of 5 or more, with at least one limb affected.
No visible occlusion of large or medium intracranial vessels on imaging.
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.
Early control of elevated blood pressure is crucial for acute intracerebral hemorrhage (ICH) treatment.
The INTERACT 3 trial aimed to assess the impact of a goal-directed care bundle on outcomes for patients with acute spontaneous ICH.
The care bundle included protocols for early intensive blood pressure lowering and management algorithms for hyperglycemia, pyrexia, and abnormal anticoagulation.
Conducted in nine low-income and middle-income countries and one high-income country.
Hospitals eligible if they lacked consistent ICH-specific protocols and were willing to implement the care bundle.
Patients aged ≥18 years with imaging-confirmed spontaneous ICH within 6 hours of symptom onset included.
Exclusion criteria: Secondary ICH due to structural abnormalities, previous thrombolysis, or anticipated non-adherence.
Findings:
144 hospitals in ten countries participated, with 22 withdrawals before patient enrollment.
10,857 patients screened, with 3,821 excluded.
Modified intention-to-treat population: 7,036 patients enrolled at 121 hospitals.
Care bundle group: 3,221 patients; Usual care group: 3,815 patients.
Primary outcome data available for 2,892 patients in the care bundle group and 3,363 patients in the usual care group.
Primary Outcome:
Likelihood of poor functional outcome lower in care bundle group (common odds ratio 0.86; 95% CI 0.76-0.97; p=0.015).
Favourable shift in modified Rankin scale (mRS) scores observed in the care bundle group across sensitivity analyses.
Patients in the care bundle group had fewer serious adverse events compared to the usual care group (16.0% vs. 20.1%; p=0.0098).
Interpretation:
Implementation of the care bundle protocol for early intensive blood pressure lowering and other management algorithms resulted in improved functional outcomes for acute ICH patients.
Hospitals are encouraged to incorporate this approach into clinical practice as part of active management for acute ICH.
Trial Information:
Registered at ClinicalTrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787).
Trial completed, providing robust evidence for the efficacy of the care bundle approach in acute ICH management.
Key Takeaways:
Early control of elevated blood pressure is crucial for acute intracerebral hemorrhage treatment.
Implementing a care bundle protocol improved functional outcomes for patients with acute spontaneous intracerebral hemorrhage.
The care bundle included protocols for early intensive blood pressure lowering and management algorithms for hyperglycemia, pyrexia, and abnormal anticoagulation.
Hospitals should consider incorporating this approach into their clinical practice to enhance management of acute intracerebral hemorrhage.
Introduction: The ELAN trial aimed to investigate the optimal timing of initiating direct oral anticoagulants (DOACs) in individuals with atrial fibrillation (AF) who had experienced an acute ischemic stroke. The study compared early anticoagulation (initiated within 48 hours or on day 6-7 after stroke) with later anticoagulation (initiated on day 3-4, day 6-7, or day 12-14 after stroke). The primary outcome was a composite measure of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization.
Methods: The trial was conducted at 103 sites across 15 countries. Key features of the study design included:
Participants: Individuals with acute ischemic stroke confirmed by imaging or by persistent focal neurological deficit presumed to be of ischemic origin, along with a diagnosis of AF.
Randomization: Participants were randomly assigned in a 1:1 ratio to either early anticoagulation or later anticoagulation.
Primary Outcome: The primary outcome measure was the composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization.
Secondary Outcomes: Secondary outcomes included individual components of the primary outcome at both 30 and 90 days.
Apologies for the oversight. Here are the inclusion and exclusion criteria for the ELAN trial:
Inclusion Criteria:
Written informed consent according to country-specific details.
Age: ≥18 years.
Acute ischemic stroke confirmed by MRI or CT scan (tissue-based definition) or by sudden focal neurological deficit of presumed ischemic origin that persisted beyond 24 hours and a normal non-contrast CT scan.
Permanent, persistent, or paroxysmal spontaneous atrial fibrillation (AF) previously known or diagnosed during the index hospitalization.
Agreement of the treating physician to prescribe DOACs.
Exclusion Criteria:
Atrial fibrillation due to reversible causes (e.g., thyrotoxicosis, pericarditis, recent surgery, myocardial infarct).
Valvular disease requiring surgery.
Mechanical heart valve(s).
Moderate or severe mitral stenosis (other valvular diseases and biological valves are eligible).
AF and conditions other than AF that require anticoagulation, including therapeutic dose of low-molecular-weight heparin or heparin (infratherapeutic anticoagulation at ischemic stroke onset is not an exclusion criterion).
Contraindications to DOACs.
Please note that these criteria were used to select eligible participants for the trial.
Results: A total of 2,013 participants were enrolled in the trial, with 1,006 assigned to early anticoagulation and 1,007 to later anticoagulation. The majority of participants had minor or moderate strokes. The primary outcome occurred in 2.9% of the early-treatment group and 4.1% of the later-treatment group by 30 days. Recurrent ischemic stroke was observed in 1.4% of the early-treatment group and 2.5% of the later-treatment group by 30 days, and in 1.9% and 3.1% respectively by 90 days. Symptomatic intracranial hemorrhage occurred in 0.2% of participants in both groups by 30 days.
Conclusion: The ELAN trial found that the timing of initiating DOACs in patients with acute ischemic stroke and AF did not significantly impact the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days. The results indicated a range of the primary outcome estimate that was 2.8 percentage points lower to 0.5 percentage points higher for early initiation compared to later initiation of DOACs, based on the 95% confidence interval. These findings suggest that both early and later initiation of DOACs may be reasonable approaches in this patient population, with no significant differences observed between the two groups.
Introduction: The DIGAMI 2 trial aimed to evaluate the effect of insulin-based glucose control in type 2 diabetic patients following myocardial infarction compared to conventional management at similar levels of glucose control. The study investigated three treatment strategies: group 1 received acute insulin-glucose infusion followed by insulin-based long-term glucose control, group 2 received insulin-glucose infusion followed by standard glucose control, and group 3 received routine metabolic management according to local practice.
Methods: The trial enrolled 1253 patients with type 2 diabetes and suspected acute myocardial infarction. Key features of the study design included:
Treatment Groups: Participants were randomly assigned to one of the three treatment groups: group 1 (n=474), group 2 (n=473), or group 3 (n=306).
Primary Endpoint: The primary endpoint was all-cause mortality between groups 1 and 2.
Secondary Objective: The secondary objective was to compare total mortality between groups 2 and 3.
Tertiary Objectives: Tertiary objectives included evaluating morbidity differences among the three treatment groups.
Results: The median study duration was 2.1 years. At randomization, HbA1c levels were similar in all three groups (around 7.2-7.3%), and blood glucose levels were around 12.5-12.9 mmol/L. Blood glucose levels were significantly reduced after 24 hours in all groups, with greater reductions observed in groups 1 and 2 receiving insulin-glucose infusion compared to group 3. Long-term glucose-lowering treatment differed between groups, with group 1 having a higher proportion of patients receiving multidose insulin.
By the end of the follow-up period, HbA1c levels did not differ significantly among the three groups (approximately 6.8%). Target fasting blood glucose levels were not reached in group 1. The overall study mortality (combined for groups 1-3) was 18.4%. However, there were no significant differences in mortality between groups 1 and 2 or between groups 2 and 3. Additionally, there were no significant differences in non-fatal reinfarctions and strokes among the three groups.
Conclusion: The DIGAMI 2 trial did not find evidence to support the notion that acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction compared to conventional management at similar levels of glucose control. The trial also did not demonstrate a reduction in non-fatal myocardial reinfarctions and strokes with insulin-based treatment. However, the study confirmed that glucose levels are a strong independent predictor of long-term mortality in this patient population, underscoring the importance of glucose control in their management.
Introduction: The KEYNOTE 671 trial aimed to investigate the efficacy of perioperative pembrolizumab, an immune checkpoint inhibitor, in patients with resectable early-stage non–small-cell lung cancer (NSCLC). This randomized, double-blind, phase 3 trial assessed the benefits of neoadjuvant and adjuvant pembrolizumab in combination with chemotherapy compared to chemotherapy alone.
Methods: The trial enrolled participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC. Key features of the study design included:
Treatment Groups: Participants were randomly assigned in a 1:1 ratio to receive either neoadjuvant pembrolizumab (200 mg) or placebo every 3 weeks, along with cisplatin-based chemotherapy for 4 cycles. This was followed by surgery and adjuvant pembrolizumab or placebo every 3 weeks for up to 13 cycles.
Primary Endpoints: The trial’s primary endpoints were event-free survival (time from randomization to local progression, unresectable tumor, progression/recurrence, or death) and overall survival.
Secondary Endpoints: Major pathological response, pathological complete response, and safety were among the secondary endpoints assessed.
Inclusion Criteria: To be eligible for the trial, participants had to meet the following criteria:
Previously untreated and pathologically confirmed resectable Stage II, IIIA, or IIIB (N2) NSCLC.
Compliance with contraceptive measures or abstinence for males, and for females, compliance with contraception and agreement not to donate eggs or freeze/store them for reproduction purposes during the treatment period and elimination time of each study intervention.
Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue sample blocks or unstained slides for central programmed death-ligand 1 (PD-L1) testing.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Adequate organ function.
Exclusion Criteria: Participants were excluded from the trial if they met any of the following criteria:
Tumor involvement of the superior sulcus, large cell neuro-endocrine cancer (LCNEC), or sarcomatoid tumor.
History of pneumonitis/interstitial lung disease requiring steroids or current pneumonitis/interstitial lung disease requiring steroids.
Active infection requiring systemic therapy.
History of allogenic tissue/solid organ transplant.
Severe hypersensitivity to pembrolizumab or any study chemotherapy agents.
Active autoimmune disease requiring systemic treatment in the past 2 years.
History of human immunodeficiency virus (HIV) infection, Hepatitis B, Hepatitis C, or active tuberculosis.
Any condition, therapy, or abnormality that could confound trial results or interfere with participation.
Psychiatric or substance abuse disorders hindering trial cooperation.
Prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2 agents or agents targeting co-inhibitory T-cell receptors.
Prior systemic anti-cancer therapy or investigational agents for the current malignancy before randomization.
Prior radiotherapy within 2 weeks of trial treatment initiation.
Recent live vaccine administration or participation in another investigational trial or use of investigational devices within 4 weeks prior to trial treatment.
Results: The KEYNOTE 671 trial analyzed 397 participants in the pembrolizumab group and 400 in the placebo group. Key results from the trial include:
Event-Free Survival: At 24 months, event-free survival was 62.4% in the pembroliz
umab group compared to 40.6% in the placebo group (hazard ratio 0.58, 95% CI 0.46 to 0.72, P<0.001).
Overall Survival: The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P=0.02, not meeting significance criterion).
Pathological Responses: A major pathological response occurred in 30.2% of the pembrolizumab group compared to 11.0% in the placebo group (P<0.0001). Pathological complete response rates were 18.1% and 4.0% respectively (P<0.0001).
Safety: Grade 3 or higher treatment-related adverse events occurred in 44.9% of the pembrolizumab group and 37.3% of the placebo group.
Conclusions: Neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response compared to neoadjuvant chemotherapy alone followed by surgery in resectable, early-stage NSCLC. The overall survival difference did not reach statistical significance in this analysis. The KEYNOTE 671 trial findings provide valuable insights into the potential benefits of perioperative immune checkpoint inhibition in the management of early-stage NSCLC.
ELEKT-D Trial: Ketamine vs. ECT for Treatment-Resistant Major Depression
Introduction: The groundbreaking ELEKT-D Trial sought to compare the efficacy of electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine for the treatment of patients with treatment-resistant major depression. This study aimed to determine whether ketamine was noninferior to ECT in producing a treatment response and explored secondary outcomes such as memory function and patient-reported quality of life.
Methods: The trial employed an open-label, randomized, noninferiority design, enrolling 403 patients diagnosed with treatment-resistant major depression without psychosis. Participants were assigned in a 1:1 ratio to receive either ketamine or ECT. Key features of the study methodology included:
Initial Treatment Phase: Patients received ECT three times per week or ketamine (0.5 mg/kg over 40 minutes) twice per week over a period of three weeks.
Primary Outcome Measure: Treatment response, defined as a ≥50% reduction in the score on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report.
Secondary Outcomes: Assessment of memory function through memory tests and evaluation of patient-reported quality of life.
Follow-up Period: Patients who responded to treatment were followed for six months.
Results: The trial outcomes revealed compelling findings, demonstrating the comparative effectiveness of ketamine and ECT in the treatment of major depression:
Treatment Response: A significant response was observed in 55.4% of the ketamine group compared to 41.2% of the ECT group (difference of 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001), indicating that ketamine was noninferior to ECT.
Memory Function: ECT treatment appeared to cause transient memory recall impairment during the initial phase, which showed gradual recovery during follow-up. In contrast, the ketamine group did not exhibit significant memory-related side effects.
Patient-Reported Quality of Life: Both ketamine and ECT showed comparable improvements in patient-reported quality of life, indicating that both treatments had a positive impact on overall well-being.
Adverse Effects: ECT was associated with musculoskeletal adverse effects, whereas ketamine was primarily associated with dissociative effects.
Conclusion: The ELEKT-D Trial conclusively demonstrated that ketamine is noninferior to ECT for the treatment of treatment-resistant major depression without psychosis. These findings offer clinicians and patients an alternative therapeutic option for individuals who have not responded favorably to traditional treatments. The trial contributes valuable evidence to guide clinical decision-making in the management of treatment-resistant major depression, expanding treatment possibilities and potentially enhancing patient outcomes.
Inclusion and Exclusion Criteria: To be eligible for the trial, participants had to meet the following criteria:
Inclusion Criteria:
Written informed consent prior to study-related procedures
Inpatients or outpatients referred for ECT treatment, meeting eligibility criteria
Males/females aged 21 to 75 years
Diagnosis of Major Depressive Episode according to DSM-5 criteria, confirmed through clinician’s diagnostic evaluation and the MINI International Neuropsychiatric Interview
Current depressive episode lasting a minimum of four weeks
Specific scores on symptom rating scales at screening: Montgomery Asberg Depression Rating Scale (MADRS) >20, Young Mania Rating Scale (YMRS) ≤5, Montreal Cognitive Assessment (MoCA) ≥18
At least two adequate trials of antidepressants or augmentation strategies in their lifetime
Patient’s willingness and ability to comply with scheduled visits, treatment plan, and trial procedures for the study’s duration
Exclusion Criteria:
Diagnosis of bipolar disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, mental retardation, or pervasive developmental disorder according to DSM-5 criteria
Meeting any exclusion criteria for ECT or ketamine treatment as described in clinical guidelines or determined by the investigator
Pregnancy or breastfeeding
Severe medical illness or severe neurological disorder
Known ketamine allergy or concomitant use of medications that may interact with ketamine
Diagnosis of major depressive disorder with psychotic features during the current depressive episode
Inability to provide informed consent
Prior enrollment or randomization in the trial
In summary, the ELEKT-D Trial provides compelling evidence that ketamine is noninferior to ECT in treating treatment-resistant major depression without psychosis. These findings offer an innovative therapeutic option for individuals who have not responded adequately to traditional treatments, expanding the range of possibilities for managing this challenging condition.
The VITAL trial aimed to investigate whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease. It was a nationwide, randomized, placebo-controlled trial conducted with a two-by-two factorial design, including vitamin D3 (cholecalciferol) at a dose of 2000 IU per day and marine n−3 (omega-3) fatty acids at a dose of 1 g per day. The trial focused on men aged 50 years or older and women aged 55 years or older in the United States.
The primary endpoints were invasive cancer of any type and major cardiovascular events, which included myocardial infarction, stroke, or death from cardiovascular causes. Secondary endpoints included site-specific cancers, death from cancer, and additional cardiovascular events. This report specifically presents the results of the comparison between vitamin D and placebo.
A total of 25,871 participants, including 5,106 black participants, were randomized and underwent the study. The findings showed that supplementation with vitamin D was not associated with a lower risk of either of the primary endpoints. During a median follow-up of 5.3 years, the incidence of cancer was similar between the vitamin D group and the placebo group, with 793 cases in the vitamin D group and 824 cases in the placebo group (hazard ratio, 0.96; 95% CI, 0.88 to 1.06; P=0.47). Likewise, the occurrence of major cardiovascular events was comparable between the two groups, with 396 events in the vitamin D group and 409 events in the placebo group (hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69).
The analysis of secondary endpoints, including specific cancer types and additional cardiovascular events, also did not show significant differences between the vitamin D and placebo groups. The hazard ratios for death from cancer, breast cancer, prostate cancer, colorectal cancer, major cardiovascular events plus coronary revascularization, myocardial infarction, stroke, and death from cardiovascular causes were not statistically significant.
The analysis of death from any cause also did not demonstrate a significant difference between the two groups. No excess risks of hypercalcemia or other adverse events associated with vitamin D supplementation were identified.
In conclusion, the VITAL trial found that supplementation with vitamin D at a dose of 2000 IU per day did not lead to a lower incidence of invasive cancer or major cardiovascular events compared to placebo. The results suggest that vitamin D supplementation does not provide substantial benefits in terms of reducing the risk of cancer or cardiovascular disease.
The VITAL trial aimed to investigate whether supplementation with vitamin D reduces the risk of cancer or cardiovascular disease. It was a nationwide, randomized, placebo-controlled trial conducted with a two-by-two factorial design, including vitamin D3 (cholecalciferol) at a dose of 2000 IU per day and marine n−3 (omega-3) fatty acids at a dose of 1 g per day. The trial focused on men aged 50 years or older and women aged 55 years or older in the United States.
The primary endpoints were invasive cancer of any type and major cardiovascular events, which included myocardial infarction, stroke, or death from cardiovascular causes. Secondary endpoints included site-specific cancers, death from cancer, and additional cardiovascular events. This report specifically presents the results of the comparison between vitamin D and placebo.
A total of 25,871 participants, including 5,106 black participants, were randomized and underwent the study. The findings showed that supplementation with vitamin D was not associated with a lower risk of either of the primary endpoints. During a median follow-up of 5.3 years, the incidence of cancer was similar between the vitamin D group and the placebo group, with 793 cases in the vitamin D group and 824 cases in the placebo group (hazard ratio, 0.96; 95% CI, 0.88 to 1.06; P=0.47). Likewise, the occurrence of major cardiovascular events was comparable between the two groups, with 396 events in the vitamin D group and 409 events in the placebo group (hazard ratio, 0.97; 95% CI, 0.85 to 1.12; P=0.69).
The analysis of secondary endpoints, including specific cancer types and additional cardiovascular events, also did not show significant differences between the vitamin D and placebo groups. The hazard ratios for death from cancer, breast cancer, prostate cancer, colorectal cancer, major cardiovascular events plus coronary revascularization, myocardial infarction, stroke, and death from cardiovascular causes were not statistically significant.
The analysis of death from any cause also did not demonstrate a significant difference between the two groups. No excess risks of hypercalcemia or other adverse events associated with vitamin D supplementation were identified.
In conclusion, the VITAL trial found that supplementation with vitamin D at a dose of 2000 IU per day did not lead to a lower incidence of invasive cancer or major cardiovascular events compared to placebo. The results suggest that vitamin D supplementation does not provide substantial benefits in terms of reducing the risk of cancer or cardiovascular disease
The VITAMINS trial aimed to determine whether the combination of vitamin C, hydrocortisone, and thiamine is more effective than hydrocortisone alone in expediting the resolution of septic shock. The trial included 216 patients with septic shock and compared the duration of time alive and free of vasopressor administration over 7 days between the two treatment groups.
Patients were randomly assigned to either the intervention group (n=109) receiving intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or the control group (n=107) receiving intravenous hydrocortisone alone until shock resolution or up to 10 days.
The primary outcome measured was the duration of time alive and free of vasopressor administration up to day 7. Secondary outcomes, including 90-day mortality, were also assessed. Among the randomized patients who completed the primary outcome measurement, no statistically significant difference was observed in the duration of time alive and vasopressor free up to day 7 between the two groups. The median difference was -0.6 hours (95% CI, -8.3 to 7.2 hours; P=0.83). Additionally, most of the prespecified secondary outcomes did not show a statistically significant difference.
Ninety-day mortality rates were similar between the intervention group (28.6%) and the control group (24.5%), with no significant difference observed (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported during the trial.
In conclusion, the VITAMINS trial found that treatment with intravenous vitamin C, hydrocortisone, and thiamine did not result in a more rapid resolution of septic shock compared to treatment with intravenous hydrocortisone alone. The combination therapy did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. These findings suggest that the addition of vitamin C and thiamine to hydrocortisone does not provide substantial benefits in the management of septic shock compared to hydrocortisone alone.
The VOYAGER PAD trial aimed to assess the efficacy and safety of rivaroxaban, a factor Xa inhibitor, in patients with peripheral artery disease (PAD) who had undergone lower-extremity revascularization. Patients with PAD who have undergone revascularization are at a high risk of major adverse limb and cardiovascular events, but the role of rivaroxaban in this context was uncertain.
In this double-blind trial, patients with PAD and a history of revascularization were randomly assigned to receive either rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The main safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification, with major bleeding defined by the International Society on Thrombosis and Haemostasis (ISTH) as a secondary safety outcome.
A total of 6,564 patients underwent randomization, with 3,286 assigned to the rivaroxaban group and 3,278 assigned to the placebo group. The primary efficacy outcome occurred in 508 patients in the rivaroxaban group and 584 in the placebo group. The estimated incidence at 3 years, according to Kaplan-Meier analysis, was 17.3% in the rivaroxaban group and 19.9% in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.76 to 0.96; P=0.009). TIMI major bleeding occurred in 62 patients in the rivaroxaban group and 44 patients in the placebo group (2.65% and 1.87%, respectively; hazard ratio, 1.43; 95% CI, 0.97 to 2.10; P=0.07). ISTH major bleeding occurred in 140 patients in the rivaroxaban group and 100 patients in the placebo group (5.94% and 4.06%, respectively; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P=0.007).
In conclusion, among patients with peripheral artery disease who had undergone lower-extremity revascularization, the addition of rivaroxaban (2.5 mg twice daily) to aspirin was associated with a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes compared to aspirin alone. The incidence of TIMI major bleeding did not differ significantly between the rivaroxaban and placebo groups. However, the incidence of ISTH major bleeding was significantly higher with rivaroxaban and aspirin than with aspirin alone. These findings suggest that the combination of rivaroxaban and aspirin may be beneficial in reducing cardiovascular events in this patient population, but the potential risk of major bleeding should be considered when making treatment decisions.
