Open vs endovascular revascularization for ALI: a review of major trials

One discussion this week involved open surgical versus endovascular revascularization for acute limb ischemia (ALI).

Reference: Wang JC, Kim AH, Kashyap VS. Open surgical or endovascular revascularization for acute limb ischemia. Journal of Vascular Surgery. 2016 Jan;63(1):270-278. doi:10/1016/j.jvs.2015.09.055.

Summary: Peripheral arterial disease affects approximately 10 million Americans. It can lead to lower extremity ischemic rest pain or tissue loss (Rutherford classification 4 to 6, or Fontaine classification III and IV). Acute limb ischemia (ALI) is defined as the presence of symptoms within 2 weeks of onset. ALI pathogenesis includes vascular stenoses with subsequent in situ thrombosis or thromboembolism from a cardiac or aortoiliac source. Stenotic lesions may indicate untreated comorbidities (eg, hypertension, hypercholesterolemia, diabetes, or tobacco use), whereas thromboembolisms implicate undiagnosed cardiac arrhythmias, myocardial infarction (MI), or mural thrombus. Limb loss risk due to ALI can be as high as 40% with an attendant mortality rate of 15% to 20% (p.270).

Limb salvage (LS) revascularization is traditionally achieved with emergent surgical thromboembolectomy or bypass. Catheter-based technologic advancements have afforded a wide array of endovascular therapy (ET) amenable for treating ALI, including catheter-directed thrombolysis (CDT), pharmacomechanical thrombolysis (PMT), angioplasty, and stenting.

For this review, a systematic literature review using MEDLINE (1990-
2014) was performed with querying keywords acute limb ischemia, acute occlusion, peripheral arteries, thrombectomy, thrombolysis, and complications. Clinical trials, registry reports, open vs endovascular arterial revascularization, and review articles were included. Attention was given to revascularization techniques, short- and long-term patency, LS rates, amputation-free survival (AFS), overall survival (OS), and complications. Four RCTs and 5 other study types were analyzed.

RCTs1

 

RCTs2

 

CONCLUSION: ALI remains a morbid condition with high risk for limb loss and death. Based on the current evidence, ET is effective for LS and safer in the short term than urgent open revascularization in the studied patients. Still, individual patient factors need to be carefully considered for further generalization. ET and surgery are complementary rather than competing strategies for treating ALI. Further good-quality clinical trial data are required to define longer term outcomes.

Balanced crystalloids vs saline in adult non-ICU patients

One discussion this week included the question of balanced crystalloids vs saline in ICU and non-ICU patients.

Reference: Self WH, et al. Balanced crystalloids versus saline in noncritically ill adults. NEJM. 2018 Mar 1; 378:819-828. doi:10.1056/NEJMoa1711586

(Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SALT-ED ClinicalTrials.gov number, NCT02614040.)

Summary: METHODS: This was a single-center, pragmatic, multiple-crossover trial comparing balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) with saline among adults who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU. The type of crystalloid that was administered in the emergency department was assigned to each patient on the basis of calendar month, with the entire emergency department crossing over between balanced crystalloids and salinemonthly during the 16-month trial. The primary outcome was hospital-free days (days alive after discharge before day 28). Secondary outcomes included major adverse kidney events within 30 days – a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) – all censored at hospital discharge or 30 days, whichever occurred first.

RESULTS: A total of 13,347 patients were enrolled, with a median crystalloid volume administered in the emergency department of 1079 ml and 88.3% of the patients exclusively receiving the assigned crystalloid. The number of hospital-free days did not differ between the balanced-crystalloids and saline groups (median, 25 days in each group; adjusted odds ratio with balanced crystalloids, 0.98; 95% confidence interval [CI], 0.92 to 1.04; P=0.41). Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01).

The authors note that a strength of this trial was high adherence to the assigned crystalloid group. Use of an unblinded, pragmatic design in a learning health care system facilitated incorporation of the trial into routine practice, allowing the assigned crystalloid to be systematically used for early fluid resuscitation immediately after arrival in the emergency department.

CONCLUSION: Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids and treatment with saline.

Balanced crystalloids vs saline in adult ICU patients

One discussion this week included the question of balanced crystalloids vs saline in ICU and non-ICU patients.


Reference: Semler MW, et al. Balanced crystalloids versus saline in critically ill adults. NEJM. 2018 Mar 1;378:829-839. doi:10.1056/NEJMoa1711584

Summary: Although both saline and balanced crystalloids have been administered to patients in clinical practice for decades, few trials have addressed the effects of crystalloid composition on clinical outcomes.

The authors conducted an unblinded, cluster-randomized, multiple-crossover trial in which the use of balanced crystalloids was compared with saline for intravenous fluid administration among critically ill adults admitted to five ICUs at Vanderbilt University Medical Center between June 1, 2015, and April 30, 2017. A total of 15,802 patients were enrolled. The median age was 58, and 57.6% of patients were men.

The primary outcome was the proportion of patients who met one or more criteria for a major adverse kidney event within 30 days — the composite of death, new receipt of renal-replacement therapy, or persistent renal dysfunction (defined as a final inpatient creatinine value ≥200% of the baseline value) — all censored at hospital discharge or 30 days after enrollment, whichever came first.

Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04). In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60).

In this trial of critically ill adults, the intravenous administration of balanced crystalloids rather than saline had a favorable effect on the composite outcome of death, new renal-replacement therapy, or persistent renal dysfunction.

Additional Reading: Hammond DA, et al. Balanced crystalloids versus saline in critically ill adults: a systematic review and meta-analysis. Annals of Pharmacotherapy. 2019 Jul 31:1060028019866420. doi: 10.1177/1060028019866420.

Step-up vs open necrosectomy for pancreatitis: the PANTER trial’s 2019 followup

One discussion this week included the question of step-up approach versus open necrosectomy for pancreatitis.


Summary: 

BACKGROUND: The 2010 randomized PANTER trial in (infected) necrotizing pancreatitis found a minimally invasive step-up approach to be superior to primary open necrosectomy for the primary combined endpoint of mortality and major complications, but long-term results are unknown.

NEW FINDINGS: With extended follow-up, in the step-up group, patients had fewer incisional hernias, less exocrine insufficiency and a trend towards less endocrine insufficiency. No differences between groups were seen for recurrent or chronic pancreatitis, pancreatic endoscopic or surgical interventions, quality of life or costs.

IMPACT: Considering both short and long-term results, the step-up approach is superior to open necrosectomy for the treatment of infected necrotizing pancreatitis.

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D1 vs D2 resection for gastric cancer

One discussion this week included a trial out of Denmark comparing D1 and D2 lymph-node dissection for gastric cancer.

Reference: Bonenkamp JJ, et al. Extended lymph-node dissection for gastric cancer. NEJM. 1999 Mar 25;340(12):908-914.

Summary: Curative resection is the treatment of choice for gastric cancer, but it is unclear whether this operation should include an extended (D2) lymph-node dissection or a limited (D1) dissection. The authors conducted a randomized trial in 80 Dutch hospitals in which they compared D1 with D2 lymph-node dissection for gastric cancer in terms of morbidity, postoperative mortality, long-term survival, and cumulative risk of relapse after surgery.

Between August 1989 and July 1993, 996 patients were enrolled. Of these, 711 underwent randomly assigned treatment (D1 = 380, D2 = 331) and 285 received palliative treatment.

General findings:

  • Complications: 43% in D2, 25% in D1
  • Postoperative deaths: 10% in D2, 4% in D1
  • Length of stay: 16 median days in D2, 14 days in D1
  • 5-year survival rates: 47% in D2, 45% in D1

 

d1 v d2

One of the arguments for D2 dissection is its ability to reduce rates of local recurrence, thereby increasing the quality of life. The distressing finding of local recurrence, usually in a terminal phase of the disease, often leads to second operations to restore gastrointestinal continuity. In this trial, there was a tendency toward a reduced cumulative risk of relapse after D2 dissection, but the rate of relapse remained high and the difference from D1 dissection was not significant. A subgroup analysis indicated a significant or marginally significant difference for patients with disease in UICC stages II and IIIA, but this difference was attributable largely to stage migration.

The MAGIC Trial: Does perioperative ECF improve outcomes for gastric cancer patients?

One discussion this week included the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial. [Current Controlled Trials number: ISRCTN93793971.]

Reference: Cunningham D, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. NEJM. 2006 Jul 6;355(1):11-20.

Summary: A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. The MAGIC Trial assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer.

METHODS: We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative  chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival.

CONCLUSIONS: In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival.

MAGIC

(p.16)

Additional Reading: Cunningham D, et al. Perio-operative chemoterhapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial. Lancet Oncology. 2017 Mar;18(3):357-370.  doi: 10.1016/S1470-2045(17)30043-8.

[ClinicalTrials.gov, number NCT00450203.]

The timing and accuracy of SLNB for nodal management after NAC

One discussion this week included nodal management after neoadjuvant chemotherapy (NAC).


Reference: Pilewskie M and Morrow M. Axillary nodal management following neoadjuvant chemotherapy. JAMA Oncology. 2017 Apr 1;3(4):549-555.

Summary: The increasing use of NAC has raised questions about the optimal approach to the axilla, including accuracy and timing of sentinel lymph node biopsy (SLNB) in patients who are clinically node negative (cN0) at presentation, use of NAC to avoid axillary lymph node dissection (ALND) in patients presenting with node-positive disease, and the relative importance of pre-and post-NAC stage in predicting the risk of locoregional recurrence (LRR).

The decrease in nodal metastases in cN0 patients undergoing post-NAC axillary staging and the increasing rates of pCR in the breast in patients treated with current chemotherapy regimens led to the study of SLNB among patients presenting with cN+ disease. Table 3 (below) summarizes data from three prospective, multi-institutional trials assessing the accuracy of SLNB after NAC among node-positive patients.

SLNB

The authors conclude: NAC reduces the need for ALND, and SLNB is an accurate
method of determining nodal status post NAC. The demonstration that SLNB accurately stages the axilla after NAC regardless of the presenting nodal stage (cN0, cN1) provides an important rationale for the use of NAC for axillary downstaging in patients who are candidates for breast-conserving surgery at presentation or who desire mastectomy. SLN identification rates and FNRs in those who are cN0 are similar to those seen with initial SLN surgery, and nodal recurrence after a negative SLNB is uncommon.

 

Additional Reading: Boughey JC, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013 Oct 9;310(14):1455-1461. doi:10.1001/jama.2013.278932.

Restrictive vs liberal red-cell transfusion strategy: the Transfusions Requirements in Critical Care (TRICC) trial

One discussion this week included the TRICC trial.

Reference: Herbert PC, et al…the Transfusion Requirements in Critical Care Investigators for the Canadian Critical Care Trials Group. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. NEJM. 1999 Feb 11;340(6):409-417.

Summary:  The aim of the study was to determine whether a restrictive strategy of red-cell transfusion and a liberal strategy produced equivalent results in critically ill patients, we compared the rates of death from all causes at 30 days and the severity of organ dysfunction.

Methods: Between 1994 and 1997, the trial enrolled 838 critically ill patients with euvolemia after initial treatment who had hemoglobin concentrations of less than 9.0 g per deciliter within 72 hours after admission to the intensive care unit and randomly assigned 418 patients to a restrictive strategy of transfusion, in which red cells were transfused if the hemoglobin concentration dropped below 7.0 g per deciliter and hemoglobin concentrations were maintained at 7.0 to 9.0 g per deciliter, and 420 patients to a liberal strategy, in which transfusions were given when the hemoglobin concentration fell below 10.0 g per deciliter and hemoglobin concentrations were maintained at 10.0 to 12.0 g per deciliter.

Results: The use of a threshold for red-cell transfusion as low as 7.0 g of hemoglobin per deciliter, combined with maintenance of hemoglobin concentrations in the range of 7.0 to 9.0 g per deciliter, was at least as effective as and possibly superior to a liberal transfusion strategy (threshold, 10.0 g per deciliter; maintenance range, 10.0 to 12.0) in critically ill patients with normovolemia. There was a trend toward decreased 30-day mortality among patients who were treated according to the restrictive transfusion strategy. The significant differences in mortality rates during hospitalization, rates of cardiac complications, and rates of organ dysfunction all favored the restrictive strategy.

TRICC trial

Overall, 30-day mortality was similar in the two groups (18.7 percent vs. 23.3 percent, P= 0.11). However, the rates were significantly lower with the restrictive transfusion strategy among patients who were less acutely ill — those with an Acute Physiology and Chronic Health Evaluation II score of < or =20 (8.7 percent in the restrictive-strategy group and 16.1 percent in the liberal-strategy group; P=0.03) — and among patients who were less than 55 years of age (5.7 percent and 13.0 percent, respectively; P=0.02), but not among patients with clinically significant cardiac disease (20.5 percent and 22.9 percent, respectively; P=0.69). The mortality rate during hospitalization was significantly lower in the restrictive-strategy group (22.3 percent vs. 28.1 percent, P=0.05).

Conclusion:  On the basis of the trial’s results, the authors recommend that critically ill patients receive red-cell transfusions when their hemoglobin concentrations fall below 7.0 g per deciliter and that hemoglobin concentrations should be maintained between 7.0 and 9.0 g per deciliter. The diversity of the patients enrolled in this trial and the consistency of the results suggest that these conclusions may be generalized to most critically ill patients, with the possible exception of patients with active coronary ischemic syndromes.

 

The STITCH trial: a summary

One discussion this week mentioned the STITCH trial.

Reference: Deerenberg EB, et al. Small bites versus large bites for closure of abdominal midline incisions (STITCH): a double-blind, multicentre, randomised control trial. Lancet. 2015 Sep 26;386(10000):1254-1260. doi: 10.1016/S0140-6736(15)60459-7.

Summary: Incisional hernia is a frequent complication of abdominal operations with an incidence of 10–23%, which can increase to 38% in specific risk groups. It is associated with pain and discomfort, resulting in a decreased quality of life. Incarceration and strangulation of abdominal contents can take place, for which emergency surgery is indicated, with associated morbidity and mortality. The authors (2015) estimate about 348,000 operations for incisional hernia are done every year in the US with $3.2 billion in annual associated costs.

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Is TNT a viable treatment strategy for rectal cancer?

One discussion this week included total neoadjuvant therapy (TNT) for rectal cancer.

Reference: Cercek A, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncology. 2018 Jun 14;4(6):e180071. doi:10.1001/jamaoncol.2018.0071.

Summary: Treatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases.

OBJECTIVE: To compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvantchemotherapy with the more recent TNT approach for LARC.

METHODS: A retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified; 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT). Of the 628 patients, 373 (59%) were men, 255 (41%) were women, and the mean age was 56.7 years.

RESULTS: Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with plannned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort. TNT(Cerek et al, 2018)

CONCLUSIONS: Total neoadjuvant therapy was associated with improved delivery of systemic therapy and increased response to treatment, and it provides a promising platform for nonoperative watch-and-wait protocols. Long-term follow-up is necessary to determine if early systemic chemotherapy improves overall outcome

The authors conclude their findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer.