Clinical trial NCT03229941: Transfusion Trigger After Operations in High Cardiac Risk Patients
Official title: CSP #599 - Transfusion Trigger After Operations in High Cardiac Risk Patients (TOP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Myocardial Infarction
Coronary Revascularization
Acute Renal Failure
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2017-07-26
Enrollment: 3012
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The goal of the proposed study is to determine whether a liberal transfusion strategy (transfusion trigger at Hb \< 10 gm/dl) in Veterans at high cardiac risk who undergo major open vascular and general surgery operations is associated with decreased risk of adverse postoperative outcomes compared to a restrictive transfusion strategy (transfusion trigger at Hb \< 7 gm/dl).

Detailed description: Background: Despite the need for clinically appropriate use of blood products in the postoperative setting, blood transfusion practices are empiric and variable. In the absence of a physiologic test that can effectively guide transfusion-related decisions after an operative intervention, hemoglobin-based transfusion triggers have been suggested as clinical tools. Traditionally, clinicians have transfused patients to maintain hemoglobin (Hb) above a minimum (typically 10 gm/dl) level, in order to prevent adverse cardiac events and death. Recent randomized trials, however, have shown that restrictive transfusion policies (transfusion when Hb falls below 8 gm/dl or even lower) are well tolerated by specific patient populations. Furthermore, these trials have demonstrated that in some patient subsets reduced transfusion is associated with reduction in postoperative complications and death. Thus, guidelines have been developed emphasizing the need for a restrictive transfusion strategy in most stable hospitalized patients.

Despite the emerging enthusiasm with respect to the safety of restrictive transfusion strategies, high quality evidence on the value of such an approach in patients at high risk for postoperative adverse cardiac events remains scarce. This is a serious limitation of the current literature, as ischemic heart disease (IHD) is highly prevalent and represents the leading cause of mortality in this country, accounting for the death of one American every minute. Furthermore, there is evidence from small trials and secondary analyses that in this subset of patients withholding transfusion when Hb falls below 10 gm/dl increases the risk of death or myocardial infarction, suggesting that widespread use of restrictive transfusion policies may actually result in patient harm. This uncertainty on transfusion thresholds in high cardiac risk patients has created a knowledge gap that requires urgent attention. IHD is highly prevalent in patients with peripheral arterial disease (PAD), and myocardial infarction represents the leading cause of postoperative mortality in patients undergoing PAD-related surgical interventions. Furthermore, a substantial proportion of patients undergoing Vascular and General Surgery operations have history of prior IHD, making this patient population an ideal high cardiac risk group in which to analyze the effect of transfusion strategies. In order to address the knowledge gap of postoperative transfusion thresholds in patients at high risk for postoperative adverse cardiac events, the investigators propose the current study under the hypothesis that transfusion strategy will affect important postoperative outcomes after major surgical interventions in high cardiac risk patients.

Objectives: The goal of the proposed study is to determine whether a liberal postoperative transfusion strategy (transfusion trigger at Hb\<10gm/dl) in patients at high risk for postoperative adverse cardiac events will reduce the risk of adverse postoperative outcomes after major vascular and general surgery operative interventions. The primary end point is the composite rate of all-cause mortality, acute myocardial infarction (MI), coronary revascularization, stroke, or acute renal failure within 90 days from the time of randomization. The secondary end points are rates of postoperative infectious complications (wound infections, pneumonia, and sepsis), and postoperative cardiac complications (new cardiac arrhythmias, congestive heart failure exacerbation, and cardiac arrest) at 90 days post-randomization; the composite rate of all-cause mortality, MI, coronary revascularization, stroke, or acute renal failure, within 30 days from the time of randomization; the length of hospital stay; and all-cause mortality up to one year after randomization.

Design: CSP #599 - TOP study is a randomized, intent-to-treat, two-arm, parallel design, single blind, multicenter trial. Vascular and General Surgery programs at Veterans Affairs Medical Centers with expertise in performing the operations of interest will be invited to participate and participants will be screened for enrollment using established inclusion/exclusion criteria. Enrolled participants will be randomized to one of the two arms; liberal (transfusion trigger at Hb \< 10gm/dl) or restrictive (transfusion trigger at Hb \< 7gm/dl). Consent for the study will be obtained prior to the index surgical intervention. Randomization will be performed postoperatively after the patient has a confirmed Hb \< 10gm/dl. Assessments will be collected pre/post-operatively and at discharge, or at 30 days after randomization if the patient is still hospitalized. Follow up forms will be filled out during a clinic visit after the 30th and 90th post-randomization day. Patients who cannot present to the clinic will have a phone call for follow up. One year post-randomization mortality will be ascertained using electronic medical records, phone follow-up, and search of the national death index.

Sample Size and Study Duration: This study will randomize 1520 participants undergoing major vascular and general operations at 15 VA medical centers with expertise in Vascular and General surgical procedures. Assuming a recruitment rate of 3 participants per site per month, total recruitment will take approximately four years to complete. The duration of the study will be five years with four year recruitment, three months active follow up, and nine months passive follow up which will be performed by the Chairman's office in order to collect 1-year post-randomization data on all-cause mortality.

Study Population: The study will include a) patients who undergo open (non-endovascular) PAD - related operations, and b) patients who undergo selected major Vascular and General Surgery operations and have prior history of PAD or IHD. Vascular Surgery operations examined will include, but not be limited to, PAD-related: aortobifemoral or aortobiiliac bypass, open abdominal aortic aneurysm repair with simultaneous repair of aortoiliac occlusive disease, visceral bypass, iliofemoral bypass, femoral bypass or endarterectomy, infrainguinal bypass, supra-aortic trunk bypass or endarterectomy, carotid endarterectomy, and major lower extremity amputations (transfemoral, through the knee, or transtibial); Other vascular surgeries: open aneurysm repair (including but not limited to carotid, subclavian, abdominal aortic, iliac, femoral, or popliteal aneurysms); and complex endovascular aneurysm repair (defined as fenestrated endograft, or endograft with need for iliac conduit, or endovascular aneurysm repair with simultaneous femoral artery reconstruction or bypass). General Surgery operations examined will include open cholecystectomy or other complex biliary reconstruction (such as open common bile duct exploration for stones, reconstruction as part of oncologic operations such as palliative pancreatic cancer procedures) , small bowel resection, pancreatectomy, colon resection, rectal resection, splenectomy, transhiatal esophagectomy, liver resection, and open ventral hernia repair. Patients will be included in the study if their postoperative Hb falls below 10gm/dl within 15 days after surgery. Intervention: Liberal transfusion strategy is the conventional transfusion method for the surgical procedures the investigators will include in the study, and is defined as transfusion when the postoperative Hb drops below 10gm/dl, with a goal to maintain Hb above 10 gm/dl. Restrictive transfusion strategy will be defined as transfusion when the postoperative Hb drops below 7gm/dl with goal to maintain Hb above 7 gm/dl.

Significance: The proposed CSP# 599 study is uniquely positioned to address the knowledge gap of postoperative transfusion thresholds in high cardiac risk patients undergoing major surgical interventions, who are currently transfused based on data from patient populations with different risk profile. The study will include patients with high IHD burden, a population that should be the most likely to benefit from a liberal transfusion strategy and CSP#599 will examine this hypothesis directly. Conversely, if the proposed trial demonstrates that this high cardiac risk patient population can tolerate restrictive transfusion well, then the results will be easy to generalize to other patient populations and the question of transfusion thresholds will be definitively addressed. Thus, the investigators believe that regardless of outcome this trial will have significant clinical and policy implications, and will substantially impact the VA and national transfusion-related guidelines.

Eligibility criteria: Inclusion Criteria:

* Males and females older than 18 years of age who have postoperative Hb \< 10gm/dl within 15 days after the index operation
* Patients who undergo an operation in either one of the three following categories:

  * Veterans who undergo PAD - related operations including but not limited to the following:

    * aortobifemoral or aortobiiliac bypass
    * open abdominal aortic aneurysm repair with simultaneous repair of aortoiliac occlusive disease
    * visceral bypass
    * iliofemoral bypass
    * femoral bypass or endarterectomy
    * infrainguinal bypass
    * thromboembolectomy
    * supra-aortic trunk bypass or endarterectomy
    * carotid endarterectomy
    * major lower extremity amputations (transfemoral, through the knee, or transtibial)
  * Veterans with past medical history of ischemic stroke or IHD or PAD who undergo the following general surgery procedures, defined as:

    * known prior MI
    * ECG findings consistent with prior MI
    * prior percutaneous coronary intervention
    * prior coronary artery bypass surgery
    * history of angina for which the patient is currently receiving treatment
    * stress test indicating myocardial ischemia
    * who undergo the following General Surgery operations:

      * Open cholecystectomy or other complex biliary reconstruction
      * such as open common bile duct exploration for stones
      * reconstruction as part of oncologic operations such as palliative pancreatic cancer procedures)
    * small bowel resection
    * pancreatectomy
    * colon resection
    * rectal resection
    * splenectomy
    * transhiatal esophagectomy
    * liver resection
    * gastric resection
    * open ventral hernia repair
    * Colostomies (reversals and takedowns)
    * Intestinal anastomosis takedowns and revisions
    * Gastric bypass
    * Adrenalectomies
    * Major diaphragmatic hiatal hernia repairs
  * Veterans with past medical history of ischemic stroke or IHD or PAD who undergo the following Vascular Surgery operations:

    * Open aneurysm repair, including but not limited to:

      * carotid
      * subclavian
      * abdominal aortic
      * iliac
      * femoral
      * popliteal aneurysms
    * and complex endovascular aneurysm repair, defined as:

      * fenestrated endograft
      * or endograft with need for iliac conduit
      * or endovascular aneurysm repair with simultaneous femoral artery reconstruction or bypass
    * Subclavian/vertebral bypasses and transpositions
* Patients undergoing the above procedures will be included in the study regardless of their preoperative Hb level, and regardless of preoperative or intraoperative transfusion they might have received.

Exclusion Criteria:

* Veteran unable to consent
* Veteran unwilling to follow protocol (such as Jehovah's witnesses)
* Veteran with known history of hereditary anemias such as Thalassemia or Sickle cell disease
* Veteran with known history of hereditary bleeding disorders, such as factor VIII or factor IX deficiency
* Veteran with prior history of adverse reaction to blood administration, such as fever, rash, or hemolysis
* Veteran does not speak or understand English
* Veteran hemodynamically unstable or in cardiogenic shock for \>48 hours after the index procedure
* Veteran participating in another interventional trial whose objective is to evaluate the effect of transfusion on outcomes
* Pregnancy in female Veterans
* Veteran is a prisoner or in custody of law enforcement
* Prior randomization in the CSP#599
* Patients who are known to have tested positive for COVID-19 and have not recovered prior to consent will not be consented. Any participant who is known to have a positive COVID-19 test during the screening process and has not recovered will be excluded prior to randomization.

Primary outcomes:
measure: A composite endpoint of all-cause post-randomization mortality, myocardial infarction (MI), coronary revascularization, acute renal failure, or post-randomization ischemic stroke up to 90 days after randomization.
timeFrame: 90 days after randomization
Secondary outcomes:
measure: A composite endpoint of postoperative infectious complications at 90 days post-randomization: Infectious complications will include wound infections, pneumonia, and sepsis.
timeFrame: 90 days after randomization
measure: A composite endpoint of cardiac complications (other than MI) at 90 days post-randomization: Cardiac complications will include new cardiac arrhythmias that necessitate new treatment, new or worsening congestive heart failure (CHF), and cardiac arrest no
timeFrame: 90 days after randomization
measure: All-cause mortality at 1 year after randomization.
timeFrame: 12 months after randomization
measure: A composite endpoint of all-cause mortality,
timeFrame: 30 days after randomization
measure: Length of hospital stay.
timeFrame: At hospital discharge, up to 1 year
Other outcomes:
measure: The investigators will examine individual rates of the outcomes that consist of individual components of the primary endpoint.
timeFrame: 90 days after randomization
Locations:
city: Little Rock
country: United States
facility: Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR
state: Arkansas
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System, Loma Linda, CA
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System, Long Beach, CA
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
city: San Francisco
country: United States
facility: San Francisco VA Medical Center, San Francisco, CA
state: California
city: Gainesville
country: United States
facility: North Florida/South Georgia Veterans Health System, Gainesville, FL
state: Florida
city: Tampa
country: United States
facility: James A. Haley Veterans' Hospital, Tampa, FL
state: Florida
city: Minneapolis
country: United States
facility: Minneapolis VA Health Care System, Minneapolis, MN
state: Minnesota
city: Buffalo
country: United States
facility: VA Western New York Healthcare System, Buffalo, NY
state: New York
city: Asheville
country: United States
facility: Asheville VA Medical Center, Asheville, NC
state: North Carolina
city: Cleveland
country: United States
facility: Louis Stokes VA Medical Center, Cleveland, OH
state: Ohio
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
state: Pennsylvania
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System Seattle Division, Seattle, WA
state: Washington
Study officials:
affiliation: Brooklyn Campus of the VA NY Harbor Healthcare System, Brooklyn, NY
name: Panagiotis Kougias, MD MSc
role: STUDY_CHAIR
References:
citation: Carson JL, Stanworth SJ, Dennis JA, Trivella M, Roubinian N, Fergusson DA, Triulzi D, Doree C, Hebert PC. Transfusion thresholds for guiding red blood cell transfusion. Cochrane Database Syst Rev. 2021 Dec 21;12(12):CD002042. doi: 10.1002/14651858.CD002042.pub5.