As it turns out, patients with ARDS should be belly sleepers.  The PROSEVA trial, freshly published in NEJM, examined the role of prone positioning in patients with early, severe acute respiratory distress syndrome (ARDS). Background Prior to PROSEVA, trials examining prone positioning in ARDS generally showed improvement in surrogate physiologic parameters (eg, oxygenation), but failed to show a benefit in patient outcomes.  This French study was designed to examine patients with severe ARDS focusing on early proning for prolonged periods of time. Study Design Multicenter, randomized trial in France and Spain Included patients with early, severe ARDS "Early" was defined as being included to the trial within 36 hours of meeting ARDS criteria "Severe" was defined as a PaO2:FiO2 ratio < 150 mm Hg (with FiO2 of at least 60%, PEEP 5 cm H20, and tidal volume of 6 mL/kg ideal weight) All patients meeting inclusion criteria underwent a 12-24 hour "stabilization" period to verify inclusion criteria prior to randomization Randomized patients to either prone or supine positioning daily for up to 28 days Importantly, the study received no commercial support and did not use any special equipment Intervention Prone positioning was conducted for at least 16 consecutive hours per day in standard ICU beds.  The patient's head was rotated (left or right) every two hours while prone For those more familiar with special proning beds, check out the NEJM video demonstrating the process on a standard ICU bed Proning was stopped once the patient met oxygenation requirements while supine for at least four hours (PaO2:FiO2 ≥ 150 mm Hg with PEEP ≤ 10 and FiO2 ≤ 60%) Adjustments to mechanical ventilation, weaning parameters, sedation, and paralytics were protocolized in a similar manner between groups Of note, all ICUs included in the trial had been using this prone positioning protocol for more than 5 years.  Given the complexity and resources required for proning, this is a potential issue for external validity. Results Randomized 466 patients (mean PaO2:FiO2 100 mm Hg) to supine or prone positioning.  Most patients had ARDS due to pneumonia (about 60%), and most received vasopressors (73-83%), neuromuscular blockers (82-91%), and many received glucocorticoids (40-45%) Prone positioning significantly reduced 28-day all-cause mortality compared to supine positioning (16% vs 32.8%, HR 0.39, NNT 6, p<0.001) Proning also reduced 90-day mortality (23.6% vs. 41%, HR 0.44, NNT 6, p<0.001) Although those randomized to supine positioning may have been slightly sicker at baseline (higher SOFA score), this mortality benefit was still significant after adjustments for baseline SOFA scores On average, prone patients received 4±4 prone sessions lasting for 17±3 hours.  These patients were proned for 73% of the time spent on a ventilator Discussion and Conclusions ARDS trials have been fraught with failed interventions (high-frequency oscillation, surfactants, inhaled prostacyclin or nitric oxide, β2 agonists, N-acetylcysteine, ketoconazole, antioxidants, omega-3 fatty acids, GM-CSF, statins, ibuprofen, liposomal prostaglandin E1, lisofylline, pentoxifylline -- just to name a few), which highlights the excitement of an ARDS trial showing more than a 50% mortality benefit The trial was powered for a 28-day mortality rate of 60% in the control group (was actually 32.8%); however, because the effect size was so great, PROSEVA had a post-hoc statistical power of 99% It is unclear why previous proning trials were not favorable.  Likely suspects for benefit in PROSEVA include early intervention (within 36 hours of ARDS), selecting the most appropriate patients (using a 12-24 hour stabilization period), and the significant proportion of time spent proning (73% versus closer to 30% in other trials) As discussed, the biggest limitation to the trial is that the nursing staff had years of experience in proning patients.  It is unclear whether less trained staff may experience more complications during the proning process Proning can be done without purchasing a new bed or special equipment, and based on this trial, can reduce mortality by more than half.  A reduction of 50% in mortality is absolutely unheard of in the ARDS literature.  While the results seem "too good to be true", it's difficult to ignore. Reference Guérin C, Reignier J, Richard JC, et al. Prone Positioning in Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2013. Photo by db Photography | Demi-Brooke

Voluven (hydroxyethyl starch 130/0.4) was heralded to the hospital community as a cheaper alternative to albumin, but safer than previous hydroxyethyl starch (HES) products that were shown to cause bleeding and renal failure. Although Voluven is likely "safer" than older HES products, it still is NOT safer than traditional volume repletion with normal saline or albumin.  It was a good run, Voluven, but it's time to pull the plug. Comparison to Older HES Products Voluven is safer than older HES products.  Specifically, Voluven's lower molecular weight and degree of substitution seems to confer a lower risk of coagulopathy and renal impairment.1  Because all HES products are NOT created equal, the medical community has been forced to wait for Voluven-specific trials to determine its role in volume repletion. Comparison to Albumin In theory, Voluven and other HES products are attractive compared to albumin because they are fully synthetic (not derived from human plasma) -- thus, they can be manufactured at lower costs and do not have the theoretical risk of disease transmission. Despite high-quality comparative data between albumin and Voluven, we do know that Voluven causes an apparent coagulopathy (eg, increased PTT or TEG findings) compared to albumin, but it isn't clear whether this translates into hard clinical endpoints.2 A History of Fraudulent Data Nothing can destroy a drug's reputation quicker than fraudulent trial data.  One major author of numerous Voluven (and other HES product) trials, Joachim Boldt, has had many of his articles retracted due to data falsification and lack of IRB approval.  You can read the full story in all of its glory here. Joachim Boldt's disgusting actions have had dramatic effects -- not only did it change public opinion regarding the "favorable" safety of Voluven, but many of his fraudulent trials were even included in a large meta-analysis.  The take-home point?  When examining the Voluven data, be very careful with the source of the data. The 6S Trial with Tetraspan (Perner 2012) The 6S trial was one of the first high-quality, large trials examining the use of a low molecular weight, low substitution HES product.3  Although 6S used Tetraspan (6% HES 130/0.42) and not Voluven (6% HES 130/0.4), the products are extremely similar. In this trial, patients with severe sepsis were given either lactated ringer's or Tetraspan (max 33 mL/kg/day).  At 90-days, Tetraspan patients had higher mortality (51% vs. 43%, p=0.03) and required more renal replacement therapy (22% vs. 16%, p=0.04).  The conclusion was clear: Tetraspan (a product that is very similar to Voluven) increased mortality and renal failure. The CHEST Trial with Voluven (Myburgh 2012) There was a big to-do when the 6S trial was published because of the confusion between HES 130/0.4 (Voluven) and 130/0.42 (Tetraspan).  Unfortunately for Voluven, its time in the spotlight was only months away in the same journal. The CHEST trial was a large, 7000-patient study modeled after the SAFE study.  CHEST was designed to compare normal saline to Voluven (130/0.4) in a heterogeneous ICU patient population.  Although 90-day mortality was not different between normal saline and Voluven (17% vs. 18%, p=0.26), Voluven was associated with a greater risk of renal replacement therapy (5.8% vs. 7%, p=0.04) and renal injury (34.6% vs. 38%, p=0.005). Is Voluven Really Cheaper than Albumin? The CHEST trial was modeled after the SAFE trial, which compared albumin to normal saline.  In both trials, the investigator was blinded to the treatment -- thus, it is possible to compare the clinical "potency" between the two agents based on how frequently patients needed additional doses. In the SAFE trial, albumin was about 40% more "potent" than normal saline, meaning that patients receiving albumin could receive 40% less volume but still obtain the same net hemodynamic benefit.  In the CHEST trial, Voluven was a paltry 15% more "potent" than normal saline. The biggest theoretical benefit of Voluven (cost) quickly comes into question when you consider that it may not be as potent as albumin on an mL-per-mL basis and the fact that hemodialysis is required more often with Voluven. Fresenius Kabi: It's Time to Pull The Plug At this point, is there any reason to consider using Voluven at all?  It definitely causes more renal injury (including a need for hemodialysis), is unlikely to be as potent as albumin, may cause coagulopathy, and is unlikely to have a true cost benefit.  Potentially most concerning, a very similar product (Tetraspan) was shown to INCREASE mortality among patients with septic shock. With all of that said: Fresenius Kabi -- it's time to pull the plug and voluntarily withdraw Voluven from the market. References Langeron O, Doelberg M, Ang ET, et al. Voluven, a lower substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5. Anesth Analg. 2001;92(4):855-62. PMID 11273914. Green RS, Hall RI. Con: starches are not preferable to albumin during cardiac surgery: a contrary opinion. J Cardiothorac Vasc Anesth. 2008;22(3):485-91. PMID 18503946. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012;367(2):124-34. PMID 22738085. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901-11. PMID 23075127. Photo by stefanx80

The ASPIRE trial, recently published in the NEJM, examined the role of aspirin after patients with VTE's had completed at least 6 weeks of full anticoagulation (although most completed 6+ months).  This is the sister trial to the WARFASA trial, which required 6-18 months of warfarin therapy. Important Inclusion/Exclusion Criteria Included patients with a first-ever, unprovoked VTE after completion of 6 weeks to 24 months of full anticoagulation therapy "Provoked" VTE's included confinement to bed, major surgery, pregnancy, and oral contraceptives/hormone replacement therapy Study Design Multicenter, randomized, double-blind study Randomized to aspirin 100 mg daily or placebo for 2-4 years Primary efficacy endpoint: symptomatic recurrent VTE (DVT or PE) Primary safety endpoint: major or clinically relevant non-major bleeding An Underpowered Study Originally, the trial was designed and powered for 3,000 patients; however, this number was reduced to a goal of 1,500 patients due to slow recruitment With the smaller enrollment goal, the trial was powered for a secondary endpoint of major vascular events (composite of VTE, MI, CVA, cardiovascular death) It was prospectively determined that the trial results would be combined with its sister trial, WARFASA, to be powered for the recurrent VTE In the end, the trial completed enrollment of only 822 patients, which severely limited its power Results Included 822 patients with most (73%) completing at least 6 months of full anticoagulation prior to enrollment.  Patients completed a median of about 27 months of study treatment. There was no difference in the primary endpoint (recurrent VTE) between aspirin and placebo (14% vs. 18%, HR 0.52 to 1.05, p=0.09) Recall that the study was severely underpowered to detect a difference The WARFASA trial had a 2-year recurrence rate of 6.6% (aspirin) and 11.2% (placebo) The "main" secondary endpoint (major vascular events) was improved with aspirin (5.2% per year vs. 8% per year, p=0.01, NNT 35) Bleeding events were rare and no different between treatment groups "In this context, aspirin, although substantially less effective than warfarin, provides an attractive alternative because it is simple and inexpensive and its safety profile is well documented." - ASPIRE author conclusion Pooled Data with WARFASA The ASPIRE and WARFASA trials were designed a priori to be combined in a single analysis.  The authors report the results of the pooled analysis within the ASPIRE manuscript: Recurrent VTE was improved with aspirin (HR 0.68, 95% CI 0.51 to 0.90) Major vascular events were improved with aspirin (HR 0.66, 95% CI 0.51 to 0.86) Clinically relevant bleeding was no different between aspirin and placebo (HR 1.47, 95% CI 0.70 to 3.08) Discussion and Conclusion Although ASPIRE was dramatically underpowered, it generally supports the same data (particularly in a pooled analysis) as WARFASA Pharmacologically, 81 mg should have the same antiplatelet effect as the higher aspirin dose used in both ASPIRE and WARFASA (100 mg) Given the extremely favorable side safety profile, aspirin therapy should be considered in patients with unprovoked VTE's after completing an appropriate duration of full anticoagulation Reference Brighton et al. Low-Dose Aspirin for Preventing Recurrent Venous Thromboembolism. N Engl J Med. 2012. DOI 10.1056/NEJMoa1210384.

The WARFASA trial, recently published in the NEJM, examined the role of aspirin after patients with VTE's had completed 6-18 months of warfarin therapy.  Given the safety of the treatment and the impressive reduction in VTE recurrence, it's very likely that the results of the  WARFASA trial will find their way into the next CHEST guideline updates. Update 11/5/2012: The results of the ASPIRE trial have now been published.  Read more about ASPIRE by clicking here. Important Inclusion/Exclusion Criteria First episode of unprovoked symptomatic VTE (including proximal DVT or PE) "Unprovoked" (idiopathic) meaning there was no known risk factor for the VTE event.   The trial, supplement, and protocol do not adequately describe what constitutes a risk factor worthy of exclusion from the trial.  The protocol does mention exclusion for active cancer and women taking estro-progestin therapy. Study Design Multicenter, double-blind study in Italy Randomized to aspirin 100 mg daily or placebo for 2 years Primary efficacy endpoint: symptomatic VTE recurrence Primary safety endpoint: major bleeding (bleed in critical location, Hgb drop > 2, or RBC transfusion of > 2 units)  Results Included 402 patients, nearly all were Caucasian, about 60% with an index case of DVT (40% PE), and most received warfarin for 6-12 months (about 10% with 18 months of therapy) Aspirin significantly reduced recurrent VTE (6.6% vs. 11.2%, p=0.02, HR 0.58, NNT 21) The risk of VTE recurrence was highest among male patients (HR 2.02, 95% CI 1.16 to 3.49) and those older than 65 years (HR 2.26, 95% CI 1.16 to 4.41) The duration of warfarin (>6 months vs. 6 months) was not shown to affect the risk of VTE recurrence (HR 1.21, 95% CI 0.73 to 1.99) There was no difference in major or minor bleeding (4 events in each arm) or mortality Discussion and Conclusion The study excluded patients with risk factors for VTE, but the study protocol only excluded active cancer and estro-progestin therapy.  There are a number of other risk factors (smoking, obesity, immobilization, trauma, surgery) that the trial protocol did not specify as exclusion criteria. The aspirin dose used (100 mg) is not readily available in the United States.  Pharmacologically, 81 mg should have the same antiplatelet effect as a higher dose. The results of a similar trial (ASPIRE) are due to be published in 2012 have now been published (see this blog post), which included patients with a shorter duration of warfarin therapy (3-6 months, not longer than 12). With an extremely favorable safety profile and an impressive reduction in VTE recurrence, aspirin therapy should strongly be considered in patients completing a 6-12 month warfarin regimen for an idiopathic VTE. Reference Becattini et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959-67.  PMID 22621626