Tag Archives: RCT


Clopidogrel and aspirin for TIA

A large Chinese trial compared aspirin alone with combination aspirin / clopidogrel in patients who had had a TIA in the previous 24 hours. 90-day stroke outcome was reduced in the combination therapy group without an apparent increase in haemorrhage.

Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack
N Engl J Med. 2013 Jul 4;369(1):11-19


Background Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone.

Methods In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis. Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random effect.

Results Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of hemorrhagic stroke was 0.3% in each group.

Conclusions Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage.

Family presence during resuscitation

CPR-iconFamilies allowed to be present during attempted cardiopulmonary resuscitation had improved psychological outcomes at ninety days.

Adult family members of adult patients were studied in this randomized study from France.

Resuscitation team member stress levels and effectiveness of resuscitation did not appear to be affected by family presence.

Family Presence during Cardiopulmonary Resuscitation
N Engl J Med. 2013 Mar 14;368(11):1008-18


BACKGROUND: The effect of family presence during cardiopulmonary resuscitation (CPR) on the family members themselves and the medical team remains controversial.

METHODS: We enrolled 570 relatives of patients who were in cardiac arrest and were given CPR by 15 prehospital emergency medical service units. The units were randomly assigned either to systematically offer the family member the opportunity to observe CPR (intervention group) or to follow standard practice regarding family presence (control group). The primary end point was the proportion of relatives with post-traumatic stress disorder (PTSD)-related symptoms on day 90. Secondary end points included the presence of anxiety and depression symptoms and the effect of family presence on medical efforts at resuscitation, the well-being of the health care team, and the occurrence of medicolegal claims.

RESULTS: In the intervention group, 211 of 266 relatives (79%) witnessed CPR, as compared with 131 of 304 relatives (43%) in the control group. In the intention-to-treat analysis, the frequency of PTSD-related symptoms was significantly higher in the control group than in the intervention group (adjusted odds ratio, 1.7; 95% confidence interval [CI], 1.2 to 2.5; P=0.004) and among family members who did not witness CPR than among those who did (adjusted odds ratio, 1.6; 95% CI, 1.1 to 2.5; P=0.02). Relatives who did not witness CPR had symptoms of anxiety and depression more frequently than those who did witness CPR. Family-witnessed CPR did not affect resuscitation characteristics, patient survival, or the level of emotional stress in the medical team and did not result in medicolegal claims.

CONCLUSIONS: Family presence during CPR was associated with positive results on psychological variables and did not interfere with medical efforts, increase stress in the health care team, or result in medicolegal conflicts.

Restricting transfusion in upper GI bleeding

Improved outcomes and reduced complications were associated with a restrictive transfusion strategy in patients with upper gastrointestinal bleeding. Note that patients with “massive exsanguinating bleeding” were excluded from the study so this shouldn’t be extrapolated to such presentations.

The benefit seemed to be most marked in patients with variceal haemorrhage, but not those with the most severe Child-Pugh class. In portal hypertensive-related bleeding, transfusion may increase portal pressure and exacerbate bleeding.

The patients were ‘scoped within 6 hours, and less than 10% received FFP or platelets. Both groups averaged over 5 litres of crystalloid in the first 72 hours.

Transfusion Strategies for Acute Upper Gastrointestinal Bleeding
N Engl J Med. 2013 Jan 3;368(1):11-21


BACKGROUND: The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy.

METHODS: We enrolled 921 patients with severe acute upper gastrointestinal bleeding and randomly assigned 461 of them to a restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Randomization was stratified according to the presence or absence of liver cirrhosis.

RESULTS: A total of 225 patients assigned to the restrictive strategy (51%), as compared with 61 assigned to the liberal strategy (14%), did not receive transfusions (P<0.001) [corrected].The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% vs. 91%; hazard ratio for death with restrictive strategy, 0.55; 95% confidence interval [CI], 0.33 to 0.92; P=0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group as compared with 16% of the patients in the liberal-strategy group (P=0.01), and adverse events occurred in 40% as compared with 48% (P=0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (hazard ratio, 0.70; 95% CI, 0.26 to 1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child-Pugh class A or B disease (hazard ratio, 0.30; 95% CI, 0.11 to 0.85), but not in those with cirrhosis and Child-Pugh class C disease (hazard ratio, 1.04; 95% CI, 0.45 to 2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P=0.03) but not in those assigned to the restrictive strategy.

CONCLUSIONS: As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding. (Funded by Fundació Investigació Sant Pau; ClinicalTrials.gov number, NCT00414713.).

Pleurodesis for spontaneous pneumothorax?

A Taiwanese study demonstrated a lower recurrence rate when primary spontaneous pneumothoraces requiring drainage received pleurodesis using minocycline(1). However, significantly more pleurodesed patients required opioid analgesia, and the success rates were less than are found with surgical methods, which are recommended in the West, where pleurodesis is reserved for patients unfit for surgery(2).

1. Simple aspiration and drainage and intrapleural minocycline pleurodesis versus simple aspiration and drainage for the initial treatment of primary spontaneous pneumothorax: an open-label, parallel-group, prospective, randomised, controlled trial
Lancet. 2013 Apr 13;381(9874):1277-82


BACKGROUND: Simple aspiration and drainage is a standard initial treatment for primary spontaneous pneumothorax, but the rate of pneumothorax recurrence is substantial. We investigated whether additional minocycline pleurodesis after simple aspiration and drainage reduces the rate of recurrence.

METHODS: In our open-label, parallel-group, prospective, randomised, controlled trial at two hospitals in Taiwan, patients were aged 15-40 years and had a first episode of primary spontaneous pneumothorax with a rim of air greater than 2 cm on chest radiographs, complete lung expansion without air leakage after pigtail catheter drainage, adequate haematological function, and normal renal and hepatic function. After simple aspiration and drainage via a pigtail catheter, patients were randomly assigned (1:1) to receive 300 mg of minocycline pleurodesis or no further treatment (control group). Randomisation was by computer-generated random numbers in sealed envelopes. Our primary endpoint was rate of pneumothorax recurrence at 1 year. This trial is registered with ClinicalTrials.gov (NCT00418392).

FINDINGS: Between Dec 31, 2006, and June 30, 2012, 214 patients were randomly assigned-106 to the minocycline group and 108 to the control group (intention-to-treat population). Treatment was unsuccessful within 7 days of randomisation in 14 patients in the minocycline group and 20 patients in the control group. At 1 year, pneumothoraces had recurred in 31 of 106 (29·2%) patients in the minocycline group compared with 53 of 108 (49·1%) in the control group (p=0·003). We noted no procedure-related complications in either group.

INTERPRETATION: Simple aspiration and drainage followed by minocycline pleurodesis is a safe and more effective treatment for primary spontaneous pneumothorax than is simple aspiration and drainage only. Minocycline pleurodesis should be an adjunct to standard treatment for primary spontaneous pneumothorax.

2. Primary spontaneous pneumothorax: to pleurodese or not?
Lancet. 2013 Apr 13;381(9874):1252-4

5 days of steroids for COPD exacerbation

A randomised trial showed 5 days of oral steroid therapy (40 mg prednisone) was non-inferior to 14 days’ duration in delaying the next exacerbation.

Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial
JAMA. 2013 Jun 5;309(21):2223-31


IMPORTANCE: International guidelines advocate a 7- to 14-day course of systemic glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease (COPD). However, the optimal dose and duration are unknown.

OBJECTIVE: To investigate whether a short-term (5 days) systemic glucocorticoid treatment in patients with COPD exacerbation is noninferior to conventional (14 days) treatment in clinical outcome and whether it decreases the exposure to steroids.

DESIGN, SETTING, AND PATIENTS: REDUCE: (Reduction in the Use of Corticosteroids in Exacerbated COPD), a randomized, noninferiority multicenter trial in 5 Swiss teaching hospitals, enrolling 314 patients presenting to the emergency department with acute COPD exacerbation, past or present smokers (≥20 pack-years) without a history of asthma, from March 2006 through February 2011.

INTERVENTIONS: Treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The predefined noninferiority criterion was an absolute increase in exacerbations of at most 15%, translating to a critical hazard ratio of 1.515 for a reference event rate of 50%.

MAIN OUTCOME AND MEASURE: Time to next exacerbation within 180 days.

RESULTS: Of 314 randomized patients, 289 (92%) of whom were admitted to the hospital, 311 were included in the intention-to-treat analysis and 296 in the per-protocol analysis. Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of -1.2% (95% CI, -12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently.

CONCLUSIONS AND RELEVANCE: In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD.

Potential new therapy for acute heart failure

Interesting new drug to know about: Serelaxin, recombinant human relaxin-2. It’s hard to assess the clinical significance of the statistically significant findings. Let’s see if a benefit is replicated in future studies. It’s hard to imagine a normotensive patient that can’t be fixed with existing therapies though.

Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.

Lancet. 2013 Jan 5;381(9860):29-39


BACKGROUND: Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.

METHODS: RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806.

FINDINGS: 1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120-775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13·0%]; serelaxin, 76 events [13·2%]; hazard ratio [HR] 1·02 [0·74-1·41], p=0·89] or days alive out of the hospital up to day 60 (placebo, 47·7 [SD 12·1] days; serelaxin, 48·3 [11·6]; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42-0·93; p=0·019).

INTERPRETATION: Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality

TracMan results

The TracMan trial – a multicentre randomised trial of early vs late tracheostomy in ICU patients – has been published, showing no difference in the primary outcome of mortality.

A review of the trial is posted on the excellent PulmCCM blog:

There was no proven difference between groups in 30-day mortality (30.8% early vs. 31.5% late, primary outcome), nor in any other outcome including 2-year mortality.

Patients getting early tracheostomies required fewer days of sedation, and there was a suggestion of a reduction of -1.7 ventilator days with early trach (mean 13.6 days vs 15.2 days, p=0.06). However, ICU stays were exactly equal at a median 13 days.

Also, 7% of patients had significant bleeding attributed to their tracheostomies (defined as needing IV fluids or another intervention); this amounted to 11 patients in the early group and 8 in the late group.

PulmCCM is an excellent free resource that will deliver critical care updates to your inbox. It has a number of other useful features, like free board review questions – highly recommended!

Effect of early vs late tracheostomy placement on survival in patients receiving mechanical ventilation: the TracMan randomized trial
JAMA. 2013 May 22;309(20):2121-9


IMPORTANCE: Tracheostomy is a widely used intervention in adult critical care units. There is little evidence to guide clinicians regarding the optimal timing for this procedure.

OBJECTIVE: To test whether early vs late tracheostomy would be associated with lower mortality in adult patients requiring mechanical ventilation in critical care units.

DESIGN AND SETTING: An open multicentered randomized clinical trial conducted between 2004 and 2011 involving 70 adult general and 2 cardiothoracic critical care units in 13 university and 59 nonuniversity hospitals in the United Kingdom.

PARTICIPANTS: Of 1032 eligible patients, 909 adult patients breathing with the aid of mechanical ventilation for less than 4 days and identified by the treating physician as likely to require at least 7 more days of mechanical ventilation.

INTERVENTIONS: Patients were randomized 1:1 to early tracheostomy (within 4 days) or late tracheostomy (after 10 days if still indicated).

MAIN OUTCOMES AND MEASURES: The primary outcome measure was 30-day mortality and the analysis was by intention to treat.

RESULTS: Of the 455 patients assigned to early tracheostomy, 91.9% (95% CI, 89.0%-94.1%) received a tracheostomy and of 454 assigned to late tracheostomy, 44.9% (95% CI, 40.4%-49.5%) received a tracheostomy. All-cause mortality 30 days after randomization was 30.8% (95% CI, 26.7%-35.2%) in the early and 31.5% (95% CI, 27.3%-35.9%) in the late group (absolute risk reduction for early vs late, 0.7%; 95% CI, -5.4% to 6.7%). Two-year mortality was 51.0% (95% CI, 46.4%-55.6%) in the early and 53.7% (95% CI, 49.1%-58.3%) in the late group (P = .74). Median critical care unit length of stay in survivors was 13.0 days in the early and 13.1 days in the late group (P = .74). Tracheostomy-related complications were reported for 6.3% (95% CI, 4.6%-8.5%) of patients (5.5% in the early group, 7.8% in the late group).

CONCLUSIONS AND RELEVANCE: For patients breathing with the aid of mechanical ventilation treated in adult critical care units in the United Kingdom, tracheostomy within 4 days of critical care admission was not associated with an improvement in 30-day mortality or other important secondary outcomes. The ability of clinicians to predict which patients required extended ventilatory support was limited.

Endovascular stroke treatment

Two randomised controlled trials have been published which compare endovascular stroke treatments with intravenous tPA. Both the American Interventional Management of Stroke (IMS) III trial (1) and the Italian SYNTHESIS Expansion trial (2) had Modified Rankin Scores as their primary endpoint. No significant differences in this outcome or in mortality or intracranial haemorrhage rates were found in either trial, and IMS III was terminated early due to futility.

A third trial, from North America, called MR RESCUE, randomised patients within 8 hours after the onset of large vessel, anterior-circulation strokes to undergo mechanical embolectomy or receive standard care(3). No clinical outcome differences were demonstrated.

An accompanying editorial (4) draws the following conclusion:


“The IMS III and SYNTHESIS Expansion studies show that intravenous thrombolysis should continue to be the first-line treatment for patients with acute ischemic stroke within 4.5 hours after stroke onset, even if imaging shows an occluded major intracranial artery. Beyond 4.5 hours, the MR RESCUE trial does not provide data supporting the use of endovascular treatment in patients with an ischemic penumbra of any size.”

Many might argue that showing endovascular treatment is equivalent to thrombolysis just means endovascular treatment doesn’t work, because a significant proportion of the emergency medicine community views this as the correct interpretation of a thorough analysis of the stroke thrombolysis literature.

1. Endovascular Therapy after Intravenous t-PA versus t-PA Alone for Stroke
NEJM Feb 8, 2013 Full Text Link

2. Endovascular Treatment for Acute Ischemic Stroke
NEJM Feb 8, 2013 Full Text Link

3. A Trial of Imaging Selection and Endovascular Treatment for Ischemic Stroke
NEJM Feb 8, 2013 Full Text Link

4.Endovascular Treatment for Acute Ischemic Stroke — Still Unproven
NEJM Feb 8, 2013 Full Text Link

Therapeutic hypothermia for newborns

More evidence that cooling the hypoxic neonatal brain improves outcomes….

OBJECTIVE Mild hypothermia after perinatal hypoxic-ischemic encephalopathy (HIE) reduces neurologic sequelae without significant adverse effects, but studies are needed to determine the most-efficacious methods.

METHODS In the neo.nEURO.network trial, term neonates with clinical and electrophysiological evidence of HIE were assigned randomly to either a control group, with a rectal temperature of 37°C (range: 36.5–37.5°C), or a hypothermia group, cooled and maintained at a rectal temperature of 33.5°C (range: 33–34°C) with a cooling blanket for 72 hours, followed by slow rewarming. All infants received morphine (0.1 mg/kg) every 4 hours or an equivalent dose of fentanyl. Neurodevelopmental outcomes were assessed at the age of 18 to 21 months. The primary outcome was death or severe disability.

RESULTS A total of 129 newborn infants were enrolled, and 111 infants were evaluated at 18 to 21 months (53 in the hypothermia group and 58 in the normothermia group). The rates of death or severe disability were 51% in the hypothermia group and 83% in the normothermia group (P = .001; odds ratio: 0.21 [95% confidence interval [CI]: 0.09–0.54]; number needed to treat: 4 [95% CI: 3–9]). Hypothermia also had a statistically significant protective effect in the group with severe HIE (n = 77; P = .005; odds ratio: 0.17 [95% CI: 0.05–0.57]). Rates of adverse events during the intervention were similar in the 2 groups except for fewer clinical seizures in the hypothermia group.

CONCLUSION Systemic hypothermia in the neo.nEURO.network trial showed a strong neuroprotective effect and was effective in the severe HIE group.

Systemic Hypothermia After Neonatal Encephalopathy: Outcomes of neo.nEURO.network RCT
Pediatrics. 2010 Oct;126(4):e771-8

Update Dec 2014:

An RCT to determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.

Longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. Small study.

Effect of depth and duration of cooling on deaths in the NICU among neonates with hypoxic ischemic encephalopathy: a randomized clinical trial
JAMA. 2014 Dec 24;312(24):2629-39