WAKE-UP Trial: MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset

wake up trial stroke

WAKE-UP Trial Summary

The WAKE-UP trial aimed to investigate the potential benefits of intravenous alteplase, a thrombolytic agent, in treating acute stroke patients with an unknown time of onset. Current guidelines recommend intravenous thrombolysis only if the time since symptom onset is less than 4.5 hours. However, the trial sought to determine whether patients with stroke who exhibited features of recent cerebral infarction on magnetic resonance imaging (MRI) but had an unknown time of onset could still benefit from thrombolysis.

In this multicenter trial, patients with stroke of unknown onset time were randomly assigned to receive either intravenous alteplase or placebo. All patients had an ischemic lesion visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), indicating that the stroke likely occurred within the previous 4.5 hours. Patients scheduled for thrombectomy were excluded from the study. The primary outcome measure was a favorable outcome defined as a score of 0 or 1 on the modified Rankin scale, which assesses neurologic disability, at 90 days. A secondary outcome measure was the likelihood of alteplase leading to lower ordinal scores on the modified Rankin scale compared to placebo (shift analysis).

The trial was halted prematurely due to funding discontinuation after enrolling 503 patients out of the planned 800. Among the enrolled patients, 254 were randomly assigned to the alteplase group, while 249 received placebo. At 90 days, a favorable outcome was observed in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). The alteplase group experienced 10 deaths (4.1%), whereas the placebo group had 3 deaths (1.2%) (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15).

In conclusion, the WAKE-UP trial demonstrated that in patients with acute stroke and an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the ischemic region resulted in significantly improved functional outcomes at 90 days compared to placebo. However, it should be noted that there were slightly more instances of intracranial hemorrhage in the alteplase group. These findings suggest that alteplase may be beneficial in this patient population, but careful consideration of the risk-benefit profile is warranted when deciding on thrombolytic therapy.


WARFASA Trial: Aspirin for Preventing the Recurrence of VTE

warfasa trial

WARFASA Trial Summary

The WARFASA trial aimed to evaluate the effectiveness of aspirin in preventing recurrent venous thromboembolism (VTE) in patients who had previously experienced an unprovoked VTE event. Approximately 20% of patients with unprovoked VTE experience a recurrence within two years after discontinuing oral anticoagulant therapy. While extended anticoagulation can prevent recurrences, it is also associated with an increased risk of bleeding. The role of aspirin in preventing recurrent VTE remains uncertain.

In this double-blind, multicenter, investigator-initiated study, patients with a first-ever unprovoked VTE who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to receive either aspirin (100 mg daily) or placebo for two years, with the option of extending the study treatment. The primary efficacy outcome was the recurrence of VTE, while major bleeding served as the primary safety outcome.

Among the 205 patients who received aspirin, 28 experienced a recurrence of VTE, whereas 43 of the 197 patients who received placebo had a recurrence. The annualized rates of recurrence were 6.6% in the aspirin group and 11.2% in the placebo group, resulting in a hazard ratio of 0.58 (95% confidence interval [CI], 0.36 to 0.93) over a median study period of 24.6 months. During a median treatment period of 23.9 months, 23 patients in the aspirin group and 39 patients in the placebo group experienced a recurrence, with annualized rates of 5.9% and 11.0% respectively, yielding a hazard ratio of 0.55 (95% CI, 0.33 to 0.92). Notably, one patient in each treatment group experienced a major bleeding episode, and adverse events were comparable between the two groups.

In conclusion, the WARFASA trial demonstrated that aspirin reduced the risk of recurrent VTE in patients with unprovoked VTE who had discontinued anticoagulant treatment, without a discernible increase in the risk of major bleeding. These findings suggest that aspirin can be a beneficial treatment option for preventing VTE recurrence in this patient population.


WASID Trial Summary: Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis

wasid trial arterial stenosis

WASID Trial Summary

The WASID trial sought to compare the effectiveness of warfarin and aspirin in the treatment of atherosclerotic intracranial arterial stenosis, a significant cause of stroke. While warfarin is often preferred over aspirin for this condition, the two therapies had not been previously compared in a randomized trial.

In this double-blind, multicenter clinical trial, patients with transient ischemic attack or stroke caused by angiographically verified 50 to 99 percent stenosis of a major intracranial artery were randomly assigned to receive either warfarin (target international normalized ratio, 2.0 to 3.0) or aspirin (1300 mg per day). The primary endpoint was a composite of ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke.

After 569 patients were randomized, enrollment was stopped due to concerns about patient safety in the warfarin group. Over a mean follow-up period of 1.8 years, adverse events were observed in both groups. The aspirin group had a lower rate of death (4.3 percent) compared to the warfarin group (9.7 percent), with a hazard ratio of 0.46 (95 percent confidence interval, 0.23 to 0.90; P=0.02). Major hemorrhage occurred in 3.2 percent of the aspirin group and 8.3 percent of the warfarin group, with a hazard ratio of 0.39 (95 percent confidence interval, 0.18 to 0.84; P=0.01). The rates of myocardial infarction or sudden death were 2.9 percent in the aspirin group and 7.3 percent in the warfarin group, with a hazard ratio of 0.40 (95 percent confidence interval, 0.18 to 0.91; P=0.02). The rate of death from vascular causes was 3.2 percent in the aspirin group and 5.9 percent in the warfarin group (P=0.16), while the rate of death from nonvascular causes was 1.1 percent and 3.8 percent, respectively (P=0.05). The primary endpoint occurred in 22.1 percent of the patients in the aspirin group and 21.8 percent in the warfarin group, with a hazard ratio of 1.04 (95 percent confidence interval, 0.73 to 1.48; P=0.83).

In conclusion, the WASID trial demonstrated that warfarin was associated with higher rates of adverse events and provided no additional benefit over aspirin for patients with intracranial arterial stenosis. Therefore, aspirin should be the preferred treatment option for these patients.


WATERFALL Trial Summary: Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis

waterfall trial pancreatitis

WATERFALL Trial Summary

The WATERFALL trial aimed to evaluate the effectiveness and safety of early aggressive hydration in the management of acute pancreatitis. While early aggressive hydration is a commonly recommended approach, limited evidence exists to support this practice.

Conducted at 18 centers, the trial randomly assigned patients presenting with acute pancreatitis to receive either goal-directed aggressive resuscitation or moderate resuscitation with lactated Ringer’s solution. The aggressive fluid resuscitation group received a bolus of 20 ml per kilogram of body weight, followed by 3 ml per kilogram per hour. In contrast, the moderate fluid resuscitation group received a bolus of 10 ml per kilogram in patients with hypovolemia or no bolus in patients with normovolemia, followed by 1.5 ml per kilogram per hour in all patients in this group. Fluid resuscitation was adjusted based on the patient’s clinical status at 12, 24, 48, and 72 hours.

The primary outcome of the trial was the development of moderately severe or severe pancreatitis during the hospitalization. The main safety outcome was fluid overload. The study initially planned to include 744 patients, with a planned interim analysis after enrolling 248 patients.

However, the trial was halted prematurely due to significant between-group differences in safety outcomes, without a notable difference in the incidence of moderately severe or severe pancreatitis. In the aggressive-resuscitation group, 22.1% of patients developed fluid overload, compared to 6.3% in the moderate-resuscitation group. This translated to an adjusted relative risk of 2.85 (95% confidence interval [CI], 1.36 to 5.94, P=0.004). Conversely, the incidence of moderately severe or severe pancreatitis was 17.3% in the moderate-resuscitation group and 22.1% in the aggressive-resuscitation group, with an adjusted relative risk of 1.30 (95% CI, 0.78 to 2.18, P=0.32).

The median duration of hospitalization was similar between the groups, with 6 days (interquartile range, 4 to 8) for the aggressive-resuscitation group and 5 days (interquartile range, 3 to 7) for the moderate-resuscitation group.

In conclusion, the WATERFALL trial demonstrated that early aggressive fluid resuscitation in patients with acute pancreatitis led to a higher incidence of fluid overload without any improvement in clinical outcomes. These findings challenge the common practice of aggressive hydration and highlight the importance of carefully considering the balance between fluid administration and potential complications in the management of acute pancreatitis. Further research is needed to guide optimal fluid resuscitation strategies in this patient population.


WHiTE 5 Trial Summary: Cemented or Uncemented Hemiarthroplasty for Hip Fracture

white 5 trial

WHiTE 5 Trial Summary

The WHiTE5 trial, a multicenter, randomized, controlled trial, has provided valuable insights into the use of bone cement in hip fractures treated with hemiarthroplasty. The trial aimed to compare the health-related quality of life and outcomes of patients undergoing cemented versus uncemented hemiarthroplasty for intracapsular hip fractures in individuals aged 60 years or older.

Traditionally, the use of bone cement in hemiarthroplasty has been a topic of debate, with limited data available on the long-term quality of life outcomes. In this study, 610 patients were assigned to undergo cemented hemiarthroplasty, while 615 patients were assigned to undergo modern uncemented hemiarthroplasty. Follow-up data at 4 months were available for 71.6% of the patients.

The primary outcome measure was health-related quality of life, assessed using utility scores from the EuroQol Group 5-Dimension (EQ-5D) questionnaire at 4 months after randomization. The EQ-5D utility score ranges from -0.594 to 1, with higher scores indicating better quality of life. The minimal clinically important difference ranges from 0.050 to 0.075.

The results of the trial demonstrated a significant difference in health-related quality of life between the two groups. The mean EQ-5D utility score was 0.371 in the cemented group and 0.315 in the uncemented group, with an adjusted difference of 0.055 (95% confidence interval [CI], 0.009 to 0.101; P=0.02). This indicates that patients undergoing cemented hemiarthroplasty had a modestly better quality of life compared to those undergoing uncemented hemiarthroplasty.

The between-group difference observed at 1 month was consistent with the 4-month results. However, the difference in quality of life between the two groups at 12 months was smaller than at 4 months. Additionally, the trial evaluated mortality rates at 12 months, which were 23.9% in the cemented group and 27.8% in the uncemented group. The odds ratio for death was 0.80 (95% CI, 0.62 to 1.05), indicating a slightly lower mortality risk in the cemented group, although the difference was not statistically significant.

Furthermore, the trial assessed the occurrence of periprosthetic fractures, a potential complication of hemiarthroplasty. The incidence of periprosthetic fractures was 0.5% in the cemented group and 2.1% in the uncemented group, with an odds ratio of 4.37 (95% CI, 1.19 to 24.00), indicating a significantly lower risk of periprosthetic fractures in the cemented group.

In conclusion, the WHiTE5 trial has provided important evidence regarding the use of bone cement in hemiarthroplasty for intracapsular hip fractures. Among patients aged 60 years or older, cemented hemiarthroplasty was associated with a modest but significant improvement in health-related quality of life compared to uncemented hemiarthroplasty. Additionally, the use of cemented hemiarthroplasty was associated with a lower risk of periprosthetic fractures. These findings have implications for the selection of surgical techniques and the optimization of outcomes in patients undergoing hemiarthroplasty for intracapsular hip fractures.


WOEST Trial Summary: Clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing PCI

WOEST Trial Summary

The WOEST trial, a groundbreaking study published in The Lancet, has shed light on a significant issue faced by patients undergoing percutaneous coronary intervention (PCI) while taking oral anticoagulants. Traditionally, triple therapy involving aspirin and clopidogrel has been recommended, but it comes with an increased risk of severe bleeding. The trial aimed to compare the safety and efficacy of clopidogrel alone (double therapy) versus clopidogrel plus aspirin (triple therapy).

Conducted from November 2008 to November 2011, this open-label, multicenter, randomized, controlled trial enrolled 573 adult patients receiving oral anticoagulants and undergoing PCI across 15 centers in Belgium and the Netherlands. The primary outcome assessed was any bleeding episode within one year of PCI, using an intention-to-treat approach. Out of the total patients, 279 (98.2%) were assigned double therapy, and 284 (98.3%) were assigned triple therapy.

The results were striking. In the double-therapy group, only 19.4% of patients experienced bleeding episodes, compared to 44.4% in the triple-therapy group. This marked reduction in bleeding complications was highly significant (hazard ratio [HR] 0.36, 95% CI 0.26-0.50, p<0.0001). Furthermore, the double-therapy group showed fewer instances of multiple bleeding events (2.2% vs. 12.0%) and a lower need for blood transfusions (3.9% vs. 9.5%) compared to the triple-therapy group (odds ratio from Kaplan-Meier curve 0.39, 95% CI 0.17-0.84, p=0.011).

The trial’s findings provide valuable insights. The use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications, with no observed increase in thrombotic events. This outcome suggests that clopidogrel alone is a safer alternative for patients on oral anticoagulants undergoing PCI, as it effectively minimizes the risk of bleeding without compromising thrombotic protection.

The authors of the study highlight the clear advantage of clopidogrel monotherapy over triple therapy. They emphasize that administering clopidogrel alone to patients taking oral anticoagulants requiring PCI results in a significantly lower rate of bleeding complications at the one-year mark compared to the use of clopidogrel plus aspirin. Additionally, the trial did not identify any evidence of an increased risk of thrombotic events associated with withholding aspirin.

Although the trial’s sample size was relatively small, the implications of its findings are noteworthy. The results challenge the conventional approach of triple therapy and provide clinicians with evidence-based guidance to improve patient outcomes. By adopting double therapy with clopidogrel alone in this specific patient population, healthcare professionals can effectively manage the delicate balance between bleeding and thrombotic risks associated with PCI and oral anticoagulant use.

In conclusion, the WOEST trial has contributed valuable insights into the management of patients undergoing PCI while taking oral anticoagulants. The study’s results highlight the superiority of clopidogrel monotherapy over triple therapy, demonstrating a substantial reduction in bleeding complications without an increased risk of thrombotic events. These findings have the potential to transform clinical practice and improve the safety and efficacy of PCI in this patient population.


WOMAN Trial Summary: Early tranexamic acid in women with post-partum haemorrhage

woman trial tranexamic acid

WOMAN Trial: The Use of Tranexamic Acid in Reducing Death Due to Post-Partum Haemorrhage

Post-partum haemorrhage (PPH) is a leading cause of maternal mortality worldwide. The administration of tranexamic acid has been shown to decrease bleeding-related deaths in trauma patients. A recent trial aimed to assess the impact of early tranexamic acid administration on death, hysterectomy, and other relevant outcomes in women experiencing PPH.

This randomized, double-blind, placebo-controlled trial (WOMAN trial) included women aged 16 years and older who had been clinically diagnosed with PPH after vaginal birth or cesarean section. Women were randomly assigned to receive either 1g intravenous tranexamic acid or a matching placebo, along with standard care. A second dose could be administered if bleeding persisted after 30 minutes or resumed within 24 hours of the first dose.

The study, which initially aimed to enroll 15,000 women, increased its sample size to 20,060 women to more accurately estimate the effect of tranexamic acid on the risk of death from PPH. The study participants, caregivers, and outcome assessors were all masked to the allocation.

The results showed a significant reduction in death due to bleeding in women who received tranexamic acid (1.5%) compared to those who received a placebo (1.9%). This reduction was particularly evident in women who received treatment within 3 hours of giving birth. However, tranexamic acid did not significantly reduce the rate of hysterectomy nor the composite primary endpoint of death from all causes or hysterectomy. Moreover, adverse events, including thromboembolic events, did not significantly differ between the tranexamic acid and placebo groups.

In conclusion, this study revealed that tranexamic acid can reduce death due to bleeding in women experiencing PPH, without any adverse effects. The findings suggest that tranexamic acid should be administered as early as possible after the onset of bleeding during the post-partum period.


WOSCOPS Trial: Pravastatin’s Role in Reducing the Incidence of MI and Death

woscops trial

WOSCOPS Trial Summary

“The WOSCOPS Trial: Pravastatin’s Role in Reducing the Incidence of Myocardial Infarction and Death from Cardiovascular Causes”

The West of Scotland Coronary Prevention Study (WOSCOPS) has significantly contributed to our understanding of the role of pravastatin in managing hypercholesterolemia and reducing the risk of coronary heart disease. This landmark double-blind study focused on men with hypercholesterolemia, aged 45 to 64, who had no history of myocardial infarction. The main goal was to ascertain whether the administration of pravastatin could reduce the combined incidence of nonfatal myocardial infarction and death from coronary heart disease.

In this trial, 6595 participants were randomly assigned to receive either pravastatin (40 mg each evening) or a placebo. The study had an average follow-up period of 4.9 years. Clinical end points were determined using medical records, electrocardiographic recordings, and the national death registry.

Results from the WOSCOPS trial were notable. Pravastatin effectively lowered plasma cholesterol levels by 20% and low-density lipoprotein cholesterol levels by 26%. In contrast, no significant changes were observed in the placebo group. The study reported 248 definite coronary events in the placebo group, compared to 174 in the pravastatin group. This indicated a relative reduction in risk with pravastatin of 31%, with a 95% confidence interval of 17% to 43%.

The WOSCOPS trial showed that pravastatin provided similar reductions in the risk of definite nonfatal myocardial infarctions and death from coronary heart disease. Specifically, a 31% reduction was reported for nonfatal myocardial infarctions, a 28% reduction for definite cases of death from coronary heart disease, and a 32% reduction for death from all cardiovascular causes. Importantly, there was no increase in deaths from noncardiovascular causes in the pravastatin group.

Overall, the results of the WOSCOPS trial demonstrated that treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes. These findings highlighted the potential benefits of pravastatin for men with moderate hypercholesterolemia and no history of myocardial infarction, thus marking a significant advance in our understanding of primary prevention strategies for cardiovascular disease.


WRAP-IT Trial: Utilizing Antibiotic-Eluting Envelopes to Reduce Infections After Cardiac Device Implantation

wrap it trial antibacterial envelope

WRAP-IT Trial Summary

Infections following the placement of cardiac implantable electronic devices (CIEDs) can lead to significant morbidity and mortality. Although preoperative antibiotics are a standard prophylactic strategy, evidence for other preventive approaches is limited. The WRAP-IT trial sought to examine the efficacy and safety of an absorbable, antibiotic-eluting envelope in reducing CIED-associated infections.

The WRAP-IT trial was a randomized, controlled clinical study involving patients undergoing CIED pocket revision, generator replacement, system upgrade, or initial implantation of a cardiac resynchronization therapy defibrillator. Patients were randomly assigned in a 1:1 ratio to either receive the antibiotic-eluting envelope or not. Standard-of-care strategies for infection prevention were utilized in all patients. The primary endpoint was the occurrence of infection necessitating system extraction or revision, long-term antibiotic therapy with infection recurrence, or death, within 12 months after the CIED implantation procedure. The secondary endpoint was procedure-related or system-related complications within 12 months.

A total of 6983 patients were randomized, with 3495 assigned to the envelope group and 3488 to the control group. The primary endpoint occurred in 25 patients in the envelope group and 42 patients in the control group. The 12-month Kaplan-Meier estimated event rate was 0.7% in the envelope group and 1.2% in the control group (hazard ratio, 0.60; 95% confidence interval [CI], 0.36 to 0.98; P=0.04). The safety endpoint occurred in 201 patients in the envelope group and 236 patients in the control group, with a 12-month Kaplan-Meier estimated event rate of 6.0% and 6.9% respectively (hazard ratio, 0.87; 95% CI, 0.72 to 1.06; P<0.001 for noninferiority).

The mean duration of follow-up was 20.7±8.5 months. Major CIED-related infections throughout the entire follow-up period occurred in 32 patients in the envelope group and 51 patients in the control group (hazard ratio, 0.63; 95% CI, 0.40 to 0.98).

In conclusion, the findings from the WRAP-IT trial demonstrate that the adjunctive use of an antibacterial envelope significantly reduces the incidence of major CIED infections compared to standard-of-care infection-prevention strategies alone. Furthermore, this approach does not increase the incidence of complications. These results offer valuable insights into new strategies for preventing CIED-associated infections, and they signal a potential advancement in patient care in the field of cardiac device implantation.


ZUMA 7 Trial: Axi-Cel Therapy- A New Hope for Patients with Early Relapsed or Refractory Large B-Cell Lymphoma

zuma 7 trial axicabtagene ciloleucel

ZUMA 7 Trial Summary

Patients with early relapsed or refractory large B-cell lymphoma often face poor prognoses after receiving first-line chemoimmunotherapy. However, a recent international, phase 3 trial has demonstrated promising results with the use of axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy.

In this trial, patients with large B-cell lymphoma, which had either become refractory to or relapsed within 12 months after the first-line chemoimmunotherapy, were randomized in a 1:1 ratio. One group was assigned to receive axi-cel therapy, while the other received standard care involving two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients responsive to the chemoimmunotherapy. The study aimed to measure event-free survival, response, overall survival, and safety.

With a total of 180 patients assigned to the axi-cel group and 179 to the standard care group, results showed a significant superiority of axi-cel therapy over standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group, over four times longer than the 2.0 months in the standard care group. The 24-month event-free survival was also considerably higher in the axi-cel group at 41%, compared to 16% in the standard care group (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001).

Moreover, a response was observed in 83% of patients in the axi-cel group and in only 50% of the standard-care group, with a complete response in 65% and 32% of patients, respectively. In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group.

Adverse events of grade 3 or higher were observed in 91% of the patients who received axi-cel and 83% of those who received standard care. Among the axi-cel group, 6% experienced grade 3 or higher cytokine release syndrome and 21% experienced grade 3 or higher neurologic events. However, no deaths related to these adverse events were reported.

In conclusion, axi-cel therapy demonstrated significant improvements in event-free survival and response compared to standard care, despite the expected level of high-grade toxic effects. These results provide new hope for patients with early relapsed or refractory large B-cell lymphoma, and they signal a potentially pivotal development in the treatment of this disease. Further research is required to confirm these findings and refine the use of axi-cel therapy. Source