Week 48 – Sepsis-3

“The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)”

JAMA. 2016 Feb 23;315(8):801-10. [free full text]

In practice, we recognize sepsis as a potentially life-threatening condition that arises secondary to infection. Because the SIRS criteria were of limited sensitivity and specificity in identifying sepsis and because our understanding of the pathophysiology of sepsis had purportedly advanced significantly during the interval since the last sepsis definition, an international task force of 19 experts was convened to define and prognosticate sepsis more effectively. The resulting 2016 Sepsis-3 definition was the subject of immediate and sustained controversy.

In the words of Sepsis-3, sepsis simply “is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.” The paper further defines organ dysfunction in terms of a threshold change in the SOFA score by 2+ points. However, the authors state that “the SOFA score is not intended to be used as a tool for patient management but as a means to clinically characterize a septic patient.” The authors note that qSOFA, an easier tool introduced in this paper, can identify promptly at the bedside patients “with suspected infection who are likely to have a prolonged ICU stay or die in the hospital.” A positive screen on qSOFA is identified as 2+ of the following: AMS, SBP ≤ 100, or respiratory rate ≥ 22. At the time of this endorsement of qSOFA, the tool had not been validated prospectively. Finally, septic shock was defined as sepsis with persistent hypotension requiring vasopressors to maintain MAP ≥ 65 and with a serum lactate > 2 despite adequate volume resuscitation.

As noted contemporaneously in the excellent PulmCrit blog post “Top ten problems with the new sepsis definition,” Sepsis-3 was not endorsed by the American College of Chest Physicians, the IDSA, any emergency medicine society, or any hospital medicine society. On behalf of the American College of Chest Physicians, Dr. Simpson published a scathing rejection of Sepsis-3 in Chest in May 2016. He noted “there is still no known precise pathophysiological feature that defines sepsis.” He went on to state “it is not clear to us that readjusting the sepsis criteria to be more specific for mortality is an exercise that benefits patients,” and said “to abandon one system of recognizing sepsis [SIRS] because it is imperfect and not yet in universal use for another system that is used even less seems unwise without prospective validation of that new system’s utility.”

In fact, the later validation of qSOFA demonstrated that the SIRS criteria had superior sensitivity for predicting in-hospital mortality while qSOFA had higher specificity. See the following posts at PulmCrit for further discussion: [https://emcrit.org/isepsis/isepsis-sepsis-3-0-much-nothing/] [https://emcrit.org/isepsis/isepsis-sepsis-3-0-flogging-dead-horse/].

At UpToDate, authors note that “data of the value of qSOFA is conflicting,” and because of this, “we believe that further studies that demonstrate improved clinically meaningful outcomes due to the use of qSOFA compared to clinical judgement are warranted before it can be routinely used to predict those at risk of death from sepsis.”

Additional Reading:
1. PulmCCM, “Simple qSOFA score predicts sepsis as well as anything else”
2. 2 Minute Medicine

Summary by Duncan F. Moore, MD

Image Credit: Mark Oniffrey, CC BY-SA 4.0, via Wikimedia Commons

Week 47 – Transfusion Strategies for Upper GI Bleeding

“Transfusion Strategies for Acute Upper Gastrointestinal Bleeding”

N Engl J Med. 2013 Jan 3;368(1):11-21. [free full text]

A restrictive transfusion strategy of 7 gm/dL was established following the previously discussed 1999 TRICC trial. Notably, both TRICC and its derivative study TRISS excluded patients who had an active bleed. In 2013, Villanueva et al. performed a study to establish whether there was benefit to a restrictive transfusion strategy in patients with acute upper GI bleeding.

The study enrolled consecutive adults presenting to a single center in Spain with hematemesis (or bloody nasogastric aspirate), melena, or both. Notable exclusion criteria included: a clinical Rockall score* of 0 with a hemoglobin level higher than 12g/dL, massive exsanguinating bleeding, lower GIB, patient refusal of blood transfusion, ACS, stroke/TIA, transfusion within 90 days, recent trauma or surgery

*The Rockall score is a system to assess risk for further bleeding or death on a scale from 0-11. Higher scores (3-11) indicate higher risk. Of the 648 patients excluded, the most common reason for exclusion (n = 329) was low risk of bleeding.

Intervention: restrictive transfusion strategy (transfusion threshold Hgb = 7.0 gm/dL) [n = 444]

Comparison: liberal transfusion strategy (transfusion threshold Hgb = 9.0 gm/dL) [n = 445]

During randomization, patients were stratified by presence or absence of cirrhosis.

As part of the study design, all patients underwent emergent EGD within 6 hours and received relevant hemostatic intervention depending on the cause of bleeding.

Primary outcome: 45-day mortality

Secondary outcomes, selected:

      • Incidence of further bleeding associated with hemodynamic instability or hemoglobin drop > 2 gm/dL in 6 hours
      • Incidence and number of RBC transfusions
      • Other products and fluids transfused
      • Hgb level at nadir, discharge, and 45 days

Subgroup analyses: Patients were stratified by presence of cirrhosis and corresponding Child-Pugh class, variceal bleeding, and peptic ulcer bleeding. An additional subgroup analysis was performed to evaluate changes in hepatic venous pressure gradient between the two strategies.

The primary outcome of 45-day mortality was lower in the restrictive strategy (5% vs. 9%; HR 0.55, 95% CI 0.33-0.92; p = 0.02; NNT = 24.8). In subgroup analysis, this finding remained consistent for patients who had Child-Pugh class A or B but was not statistically significant among patients who had Class C. Further stratification for variceal bleeding and peptic ulcer disease did not make a difference in mortality.

Secondary outcomes:
Rates of further bleeding events and RBC transfusion, as well as number of products transfused, were lower in the restrictive strategy. Subgroup analysis demonstrated that rates of re-bleeding were lower in Child-Pugh class A and B but not in C. As expected, the restrictive strategy also resulted in the lowest hemoglobin levels at 24 hours. Hemoglobin levels among patients in the restrictive strategy were lower at discharge but were not significantly different from the liberal strategy at 45 days. There was no group difference in amount of non-RBC blood products or colloid/crystalloid transfused. Patients in the restrictive strategy experienced fewer adverse events, particularly transfusion reactions such as transfusion-associated circulatory overload and cardiac complications. Patients in the liberal-transfusion group had significant post-transfusion increases in mean hepatic venous pressure gradient following transfusion. Such increases were not seen in the restrictive-strategy patients.

In patients with acute upper GI bleeds, a restrictive strategy with a transfusion threshold 7 gm/dL reduces 45-day mortality, the rate and frequency of transfusions, and the rate of adverse reactions, relative to a liberal strategy with a transfusion threshold of 9 gm/dL.

In their discussion, the authors hypothesize that the “harmful effects of transfusion may be related to an impairment of hemostasis. Transfusion may counteract the splanchnic vasoconstrictive response caused by hypovolemia, inducing an increase in splanchnic blood flow and pressure that may impair the formation of clots. Transfusion may also induce abnormalities in coagulation properties.”

Subgroup analysis suggests that the benefit of the restrictive strategy is less pronounced in patients with more severe hepatic dysfunction. These findings align with prior studies in transfusion thresholds for critically ill patients. However, the authors note that the results conflict with studies in other clinical circumstances, specifically in the pediatric ICU and in hip surgery for high-risk patients.

There are several limitations to this study. First, its exclusion criteria limit its generalizability. Excluding patients with massive exsanguination is understandable given lack of clinical equipoise; however, this choice allows too much discretion with respect to the definition of a massive bleed. (Note that those excluded due to exsanguination comprised only 39 of 648.) Lack of blinding was a second limitation. Potential bias was mitigated by well-defined transfusion protocols. Additionally, there a higher incidence of transfusion-protocol violations in the restrictive group, which probably biased results toward the null. Overall, deviations from the protocol occurred in fewer than 10% of cases.

Further Reading/References
1. Transfusion Strategies for Acute Upper GI Bleeding @ Wiki Journal Club
2. 2 Minute Medicine
3. TRISS @ Wiki Journal Club

Summary by Gordon Pelegrin, MD

Image Credit: Jeremias, CC BY-SA 3.0, via Wikimedia Commons

Week 46 – COURAGE


“Optimal Medical Therapy with or without PCI for Stable Coronary Disease”

by the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Research Group

N Engl J Med. 2007 Apr 12;356(15):1503-16 [free full text]

The optimal medical management of stable coronary artery disease has been well-described. However, prior to the 2007 COURAGE trial, the role of percutaneous coronary intervention (PCI) in the initial management of stable coronary artery disease was unclear. It was known that PCI improved angina symptoms and short-term exercise performance in stable disease, but its mortality benefit and reduction of future myocardial infarction and ACS were unknown.

The trial recruited patients with stable coronary artery disease. (See paper for inclusion/exclusion criteria. Disease had to be sufficiently and objectively severe, but not too severe, and symptoms could not be sustained at the highest CCS grade.) Patients were randomized to either optimal medical management (including antiplatelet, anti-anginal, ACEi/ARB, and cholesterol-lowering therapy) and PCI or to optimal medical management alone. The primary outcome was a composite of all-cause mortality and non-fatal MI.

2287 patients were randomized. Both groups had similar baseline characteristics with the exception of a higher prevalence of proximal LAD disease in the medical-therapy group. Median duration of follow-up was 4.6 years in both groups. Death or non-fatal MI occurred in 18.4% of the PCI group and in 17.8% of the medical-therapy group (p = 0.62). Death, non-fatal MI, or stroke occurred in 20.0% of the PCI group and 19.5% of the medical-therapy group (p = 0.62). Hospitalization for ACS occurred in 12.4% of the PCI group and 11.8% of the medical-therapy group (p = 0.56). Revascularization during follow-up was performed in 21.1% of the PCI group but in 32.6% of the medical-therapy group (HR 0.60, 95% CI 0.51–0.71, p < 0.001). Finally, 66% of PCI patients were free of angina at 1 year follow-up compared with 58% of medical-therapy patients (p < 0.001); rates were 72% and 67% at 3 years (p=0.02) and 72% and 74% at five years (not significant).

Thus, in the initial management of stable coronary artery disease, PCI in addition to optimal medical management provided no mortality benefit over optimal medical management alone. However, initial management with PCI did provide a time-limited improvement in angina symptoms.

As the authors of COURAGE nicely summarize on page 1512, the atherosclerotic plaques of ACS and stable CAD are different. Vulnerable, ACS-prone plaques have thin caps and spread outward along the wall of the coronary artery, as opposed to the plaques of stable CAD which have thick fibrous caps and are associated with inward-directed remodeling that narrows the artery lumen (and thus cause reliable angina symptoms and luminal narrowing on coronary angiography).

Notable limitations of this study: 1) the population was largely male, white, and 42% came from VA hospitals, thus limiting generalizability of the study; 2) drug-eluting stents were not clinically available until the last 6 months of the study, so most stents placed were bare metal.

Later meta-analyses were weakly suggestive of an association of PCI with improved all-cause mortality. It is thought that there may be a subset of patients with stable CAD who achieve a mortality benefit from PCI.

The 2017 ORBITA trial made headlines and engendered sustained controversy when it demonstrated in a randomized trial that, in the context of optimal medical therapy, PCI did not increase exercise time more than did a sham-PCI. Take note of the relatively savage author’s reply to commentary regarding the trial. See blog discussion here. The ORBITA-2 trial is currently underway.

Last month, the ISCHEMIA trial was published in NEJM. It demonstrated that among patients with stable CAD and moderate to severe ischemia, an initial invasive strategy did not reduce the risk of ischemic cardiovascular events or death from any cause at a median of 3.2 years follow-up.

It is important to note that all of the above discussions assume that the patient does not have specific coronary artery anatomy in which initial CABG would provide a mortality benefit (e.g. left main disease, multi-vessel disease with decreased LVEF). Finally, PCI should be considered in patients whose physical activity is limited by angina symptoms despite optimal medical therapy.

Further Reading:
1. COURAGE @ Wiki Journal Club
2. COURAGE @ 2 Minute Medicine
3. Canadian Cardiovascular Society grading of angina pectoris
4. ORBITA-2 @ ClinicalTrials.gov
5. ISCHEMIA @ ClinicalTrials.gov
6. Discussion re: ISCHEMIA trial changes @ CardioBrief
7. ISCHEMIA full text @ NEJM

Summary by Duncan F. Moore, MD

Image Credit: National Institutes of Health, US Public Domain, via Wikimedia Commons

Week 45 – FREEDOM

“Strategies for Multivessel Revascularization in Patients with Diabetes”

by the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) Trial investigators

N Engl J Med. 2012 Dec 20;367(25):2375-84. [free full text]

Previous studies, such as the 1996 BARI trial, have demonstrated that patients who have multivessel coronary artery disease (CAD) and diabetes mellitus (DM) and who received coronary artery bypass grafting (CABG) surgery lived longer than patients undergoing balloon angioplasty. However, since that publication, percutaneous coronary intervention (PCI) technology advanced significantly. Prior to the publication of FREEDOM in 2012, there had only been small, underpowered studies comparing PCI with drug-eluting stent (DES) to CABG. FREEDOM was powered appropriately to discover superiority of revascularization strategy (PCI with DES vs. CABG) in patients with DM and multivessel CAD.


Inclusion criteria:

      • 18 years or older
      • Diabetes mellitus – defined by American Diabetes Association
      • Multivessel Coronary Artery Disease
        • > 70% stenosis (angiographically confirmed)
        • 2 or more epicardial vessels
        • 2 or more coronary-artery territories

Selected exclusion criteria:

      • NYHA Class III-IV heart failure
      • Prior CABG, valve surgery, or PCI (< 6 months)
      • Prior significant bleed (< 6 months)
      • Left main stenosis ≥ 50%

Patients meeting criteria were assigned 1:1 into PCI with first-generation paclitaxel-eluting stent (51%) or sirolimus-eluting stent (43%) versus CABG. The PCI group was placed on aspirin and clopidogrel for dual antiplatelet therapy (DAPT) for at least 12 months. For the CABG group, arterial revascularization was encouraged. The mean SYNTAX score (tool used to score complexity of CAD) was 26.2 and did not significantly differ between groups. Guideline-driven targets for lowering medical risk factors were used: LDL <70, BP <130/80, HgbA1c <7. Minimum follow-up was 2 years. 

Primary: Composite of death from any cause, non-fatal myocardial infarction (MI), and non-fatal stroke


      1. Rate of major adverse cardiovascular and cerebrovascular events at 30 days and 12 months
      2. Repeat revascularization
      3. Annual all-cause mortality
      4. Annual cardiovascular mortality

953 patients and 947 patients were randomized into the PCI and CABG groups, respectively. At 5 years, the primary outcome (combined death, MI, or stroke) occurred in 200 of the PCI group and 146 of the CABG group (26.6% vs 18.7%, p = 0.005). The curves started diverging at 2 years. All-cause mortality was higher in the PCI group versus the CABG group (16.3% vs 10.9%, p = 0.049). Regarding secondary outcomes, 13.9% of patients in the PCI group had a repeat MI versus 6.0% in the CABG group (p < 0.001). There were fewer strokes in the PCI group than in the CABG group (2.4% vs 5.2%, p = 0.03). There was no statistically significant difference between study groups regarding cardiovascular death (10.9% vs 6.8%, p = 0.12).

At 5 years, the analysis of outcomes according to category of SYNTAX score (≤ 22, 23 to 32, ≥ 33) showed no significant subgroup interaction (p = 0.58).

Regarding safety, major bleeding between the two groups at 30 days was 0.02% for PCI vs 0.04% for CABG (p = 0.13). The incidence of acute renal failure requiring hemodialysis was observed in one patient in the PCI group and eight patients in the CABG group (p = 0.02)

The BARI Trial (1996) was the first trial to show that patients with DM and multivessel CAD derive mortality benefit from bypass grafting over PCI with balloon angioplasty. Furthermore, the BARI 2D (2009) trial demonstrated this benefit of bypass grafting over PCI with bare metal stents (BMS). At the time of the FREEDOM Trial, there had not been a randomized comparison of CABG versus PCI with newer technology and first-generation paclitaxel/sirolimus DES. In this study, CABG showed a 5.3% absolute reduction in all-cause mortality over PCI as well decreased rates of MI and repeat revascularization. CABG was associated with a mild absolute increase in stroke (2.8%). However, this mild increased stroke risk is consistent with most other comparative trials of the two treatment strategies. There was no statistical difference in major bleeding between the two groups.

CABG is likely better than PCI for various reasons. For one, diabetic arteries are affected diffusely and tend to have more extensive atherosclerotic disease compared to those without diabetes, so the likelihood of successful PCI alone is low. Many suspected that with advancement in PCI (i.e. DES) that the BARI data would become irrelevant. However, CABG continued to show benefit despite the technological advancements of drug-eluting stents and PCI. Improvement in surgical technique as well as the use of arterial revascularization (i.e. internal mammary artery) helped maintain superior outcomes with CABG compared to PCI.

The study was limited by the fact that due to low numbers, the subgroup analysis (i.e. SYNTAX scores) was not appropriately powered for statistical significance. Further, the study was not blinded, and patients may have been treated differently on the basis of their surgical procedure. Also, there was variability of STYNAX scores between the study groups, but this circumstance was thought to reflect real world heterogeneity.

Bottom Line:
CABG was superior to PCI with DES in patients with DM and multivessel CAD in that it significantly reduced rates of death and MI despite a small increased risk of stroke.

Further Reading/References:
1. BARI Trial
2. BARI 2D Trial
3. ACCF/AHA 2011 Guideline for Coronary Artery Bypass Graft Surgery
4. FREEDOM @ Wiki Journal Club
5. FREEDOM @ 2 Minute Medicine
5. FREEDOM @ Visualmed

Summary by Patrick Miller, MD.

Image Credit: Jerry Hecht, Public Domain, via Wikimedia Commons


“A Controlled Trial of Renal Denervation for Resistant Hypertension”

N Engl J Med. 2014 Apr 10;370(15):1393-401. [free full text]

Approximately 10% of patients with hypertension have resistant hypertension (SBP > 140 despite adherence to three maximally tolerated doses of antihypertensives, including a diuretic). Evidence suggests that the sympathetic nervous system plays a large role in such cases, so catheter-based radiofrequency ablation of the renal arteries (renal denervation therapy) was developed as a potential treatment for resistant HTN. The 2010 SYMPLICITY HTN-2 trial was a small (n = 106), non-blinded, randomized trial of renal denervation vs. continued care with oral antihypertensives that demonstrated a remarkable 30-mmHg greater decrease in SBP with renal denervation. Thus the 2014 SYMPLICITY HTN-3 trial was designed to evaluate the efficacy of renal denervation in a single-blinded trial with a sham-procedure control group.

The trial enrolled adults with resistant HTN with SBP ≥ 160 despite adherence to 3+ maximized antihypertensive drug classes, including a diuretic. (Pertinent exclusion criteria included secondary hypertension, renal artery stenosis > 50%, prior renal artery intervention.) Patients were randomized to either renal denervation with the Symplicity (Medtronic) radioablation catheter or to renal angiography only (sham procedure). The primary outcome was the mean change in office systolic BP from baseline at 6 months. (The examiner was blinded to intervention.) The secondary outcome was the change in mean 24-hour ambulatory SBP at 6 months. The primary safety endpoint was a composite of death, ESRD, embolic event with end-organ damage, renal artery or other vascular complication, hypertensive crisis within 30 days, or new renal artery stenosis of > 70%.

535 patients were randomized. On average, patients were receiving five antihypertensive medications. There was no significant difference in reduction of SBP between the two groups at 6 months. ∆SBP was -14.13 ± 23.93 mmHg in the denervation group vs. -11.74 ± 25.94 mmHg in the sham-procedure group for a between-group difference of -2.39 mmHg (95% CI -6.89 to 2.12, p = 0.26 with a superiority margin of 5 mmHg). The change in 24-hour ambulatory SBP at 6 months was -6.75 ± 15.11 mmHg in the denervation group vs. -4.79 ± 17.25 mmHg in the sham-procedure group for a between-group difference of -1.96 mmHg (95% CI -4.97 to 1.06, p = 0.98 with a superiority margin of 2 mmHg). There was no significant difference in the prevalence of the composite safety endpoint at 6 months with 4.0% of the denervation group and 5.8% of the sham-procedure group reaching the endpoint (percentage-point difference of -1.9, 95% CI -6.0 to 2.2).

In patients with resistant hypertension, renal denervation therapy provided no reduction in SBP at 6-month follow-up relative to a sham procedure.

This trial was an astounding failure for Medtronic and its Symplicity renal denervation radioablation catheter. The magnitude of the difference in results between the non-blinded, no-sham-procedure SYMPLICITY HTN-2 trial and this patient-blinded, sham-procedure-controlled trial is likely a product of 1) a marked placebo effect of procedural intervention, 2) Hawthorne effect in the non-blinded trial, and 3) regression toward the mean (patients were enrolled based on unusually high BP readings that over the course of the trial declined to reflect a lower true baseline).

Currently, there is no role for renal denervation therapy in the treatment of resistant HTN. However, despite the results of SYMPLICITY HTN-3, additional trials have since been conducted that assess the utility of renal denervation in patients with HTN not classified as resistant. SPYRAL HTN-ON MED demonstrated a benefit of renal denervation beyond that of a sham procedure (7.4 mmHg lower relative difference of SBP on 24hr ambulatory monitoring) in the continued presence of baseline antihypertensives. RADIANCE HTN-SOLO demonstrated a 6.3 mmHg greater reduction in daytime ambulatory SBP among ablated patients than that of sham-treatment patients notably after a 4-week discontinuation of up to two home antihypertensives. However, despite these two recent trials, the standard of care for the treatment of non-resistant HTN remains our affordable and safe default of multiple pharmacologic agents as well as lifestyle interventions.

Further Reading/References:
2. UpToDate, “Treatment of resistant hypertension,” heading “Renal nerve denervation”

Summary by Duncan F. Moore, MD