<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03229941</url>
  </required_header>
  <id_info>
    <org_study_id>599</org_study_id>
    <nct_id>NCT03229941</nct_id>
  </id_info>
  <brief_title>Transfusion Trigger After Operations in High Cardiac Risk Patients</brief_title>
  <acronym>TOP</acronym>
  <official_title>CSP #599 - Transfusion Trigger After Operations in High Cardiac Risk Patients (TOP)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The goal of the proposed study is to determine whether a liberal transfusion strategy&#xD;
      (transfusion trigger at Hb &lt; 10 gm/dl) in Veterans at high cardiac risk who undergo major&#xD;
      open vascular and general surgery operations is associated with decreased risk of adverse&#xD;
      postoperative outcomes compared to a restrictive transfusion strategy (transfusion trigger at&#xD;
      Hb &lt; 7 gm/dl).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Despite the need for clinically appropriate use of blood products in the&#xD;
      postoperative setting, blood transfusion practices are empiric and variable. In the absence&#xD;
      of a physiologic test that can effectively guide transfusion-related decisions after an&#xD;
      operative intervention, hemoglobin-based transfusion triggers have been suggested as clinical&#xD;
      tools. Traditionally, clinicians have transfused patients to maintain hemoglobin (Hb) above a&#xD;
      minimum (typically 10 gm/dl) level, in order to prevent adverse cardiac events and death.&#xD;
      Recent randomized trials, however, have shown that restrictive transfusion policies&#xD;
      (transfusion when Hb falls below 8 gm/dl or even lower) are well tolerated by specific&#xD;
      patient populations. Furthermore, these trials have demonstrated that in some patient subsets&#xD;
      reduced transfusion is associated with reduction in postoperative complications and death.&#xD;
      Thus, guidelines have been developed emphasizing the need for a restrictive transfusion&#xD;
      strategy in most stable hospitalized patients.&#xD;
&#xD;
      Despite the emerging enthusiasm with respect to the safety of restrictive transfusion&#xD;
      strategies, high quality evidence on the value of such an approach in patients at high risk&#xD;
      for postoperative adverse cardiac events remains scarce. This is a serious limitation of the&#xD;
      current literature, as ischemic heart disease (IHD) is highly prevalent and represents the&#xD;
      leading cause of mortality in this country, accounting for the death of one American every&#xD;
      minute. Furthermore, there is evidence from small trials and secondary analyses that in this&#xD;
      subset of patients withholding transfusion when Hb falls below 10 gm/dl increases the risk of&#xD;
      death or myocardial infarction, suggesting that widespread use of restrictive transfusion&#xD;
      policies may actually result in patient harm. This uncertainty on transfusion thresholds in&#xD;
      high cardiac risk patients has created a knowledge gap that requires urgent attention. IHD is&#xD;
      highly prevalent in patients with peripheral arterial disease (PAD), and myocardial&#xD;
      infarction represents the leading cause of postoperative mortality in patients undergoing&#xD;
      PAD-related surgical interventions. Furthermore, a substantial proportion of patients&#xD;
      undergoing Vascular and General Surgery operations have history of prior IHD, making this&#xD;
      patient population an ideal high cardiac risk group in which to analyze the effect of&#xD;
      transfusion strategies. In order to address the knowledge gap of postoperative transfusion&#xD;
      thresholds in patients at high risk for postoperative adverse cardiac events, the&#xD;
      investigators propose the current study under the hypothesis that transfusion strategy will&#xD;
      affect important postoperative outcomes after major surgical interventions in high cardiac&#xD;
      risk patients.&#xD;
&#xD;
      Objectives: The goal of the proposed study is to determine whether a liberal postoperative&#xD;
      transfusion strategy (transfusion trigger at Hb&lt;10gm/dl) in patients at high risk for&#xD;
      postoperative adverse cardiac events will reduce the risk of adverse postoperative outcomes&#xD;
      after major vascular and general surgery operative interventions. The primary end point is&#xD;
      the composite rate of all-cause mortality, acute myocardial infarction (MI), coronary&#xD;
      revascularization, stroke, or acute renal failure within 90 days from the time of&#xD;
      randomization. The secondary end points are rates of postoperative infectious complications&#xD;
      (wound infections, pneumonia, and sepsis), and postoperative cardiac complications (new&#xD;
      cardiac arrhythmias, congestive heart failure exacerbation, and cardiac arrest) at 90 days&#xD;
      post-randomization; the composite rate of all-cause mortality, MI, coronary&#xD;
      revascularization, stroke, or acute renal failure, within 30 days from the time of&#xD;
      randomization; the length of hospital stay; and all-cause mortality up to one year after&#xD;
      randomization.&#xD;
&#xD;
      Design: CSP #599 - TOP study is a randomized, intent-to-treat, two-arm, parallel design,&#xD;
      single blind, multicenter trial. Vascular and General Surgery programs at Veterans Affairs&#xD;
      Medical Centers with expertise in performing the operations of interest will be invited to&#xD;
      participate and participants will be screened for enrollment using established&#xD;
      inclusion/exclusion criteria. Enrolled participants will be randomized to one of the two&#xD;
      arms; liberal (transfusion trigger at Hb &lt; 10gm/dl) or restrictive (transfusion trigger at Hb&#xD;
      &lt; 7gm/dl). Consent for the study will be obtained prior to the index surgical intervention.&#xD;
      Randomization will be performed postoperatively after the patient has a confirmed Hb &lt;&#xD;
      10gm/dl. Assessments will be collected pre/post-operatively and at discharge, or at 30 days&#xD;
      after randomization if the patient is still hospitalized. Follow up forms will be filled out&#xD;
      during a clinic visit after the 30th and 90th post-randomization day. Patients who cannot&#xD;
      present to the clinic will have a phone call for follow up. One year post-randomization&#xD;
      mortality will be ascertained using electronic medical records, phone follow-up, and search&#xD;
      of the national death index.&#xD;
&#xD;
      Sample Size and Study Duration: This study will randomize 1520 participants undergoing major&#xD;
      vascular and general operations at 15 VA medical centers with expertise in Vascular and&#xD;
      General surgical procedures. Assuming a recruitment rate of 3 participants per site per&#xD;
      month, total recruitment will take approximately four years to complete. The duration of the&#xD;
      study will be five years with four year recruitment, three months active follow up, and nine&#xD;
      months passive follow up which will be performed by the Chairman's office in order to collect&#xD;
      1-year post-randomization data on all-cause mortality.&#xD;
&#xD;
      Study Population: The study will include a) patients who undergo open (non-endovascular) PAD&#xD;
      - related operations, and b) patients who undergo selected major Vascular and General Surgery&#xD;
      operations and have prior history of PAD or IHD. Vascular Surgery operations examined will&#xD;
      include, but not be limited to, PAD-related: aortobifemoral or aortobiiliac bypass, open&#xD;
      abdominal aortic aneurysm repair with simultaneous repair of aortoiliac occlusive disease,&#xD;
      visceral bypass, iliofemoral bypass, femoral bypass or endarterectomy, infrainguinal bypass,&#xD;
      supra-aortic trunk bypass or endarterectomy, carotid endarterectomy, and major lower&#xD;
      extremity amputations (transfemoral, through the knee, or transtibial); Other vascular&#xD;
      surgeries: open aneurysm repair (including but not limited to carotid, subclavian, abdominal&#xD;
      aortic, iliac, femoral, or popliteal aneurysms); and complex endovascular aneurysm repair&#xD;
      (defined as fenestrated endograft, or endograft with need for iliac conduit, or endovascular&#xD;
      aneurysm repair with simultaneous femoral artery reconstruction or bypass). General Surgery&#xD;
      operations examined will include open cholecystectomy or other complex biliary reconstruction&#xD;
      (such as open common bile duct exploration for stones, reconstruction as part of oncologic&#xD;
      operations such as palliative pancreatic cancer procedures) , small bowel resection,&#xD;
      pancreatectomy, colon resection, rectal resection, splenectomy, transhiatal esophagectomy,&#xD;
      liver resection, and open ventral hernia repair. Patients will be included in the study if&#xD;
      their postoperative Hb falls below 10gm/dl within 15 days after surgery. Intervention:&#xD;
      Liberal transfusion strategy is the conventional transfusion method for the surgical&#xD;
      procedures the investigators will include in the study, and is defined as transfusion when&#xD;
      the postoperative Hb drops below 10gm/dl, with a goal to maintain Hb above 10 gm/dl.&#xD;
      Restrictive transfusion strategy will be defined as transfusion when the postoperative Hb&#xD;
      drops below 7gm/dl with goal to maintain Hb above 7 gm/dl.&#xD;
&#xD;
      Significance: The proposed CSP# 599 study is uniquely positioned to address the knowledge gap&#xD;
      of postoperative transfusion thresholds in high cardiac risk patients undergoing major&#xD;
      surgical interventions, who are currently transfused based on data from patient populations&#xD;
      with different risk profile. The study will include patients with high IHD burden, a&#xD;
      population that should be the most likely to benefit from a liberal transfusion strategy and&#xD;
      CSP#599 will examine this hypothesis directly. Conversely, if the proposed trial demonstrates&#xD;
      that this high cardiac risk patient population can tolerate restrictive transfusion well,&#xD;
      then the results will be easy to generalize to other patient populations and the question of&#xD;
      transfusion thresholds will be definitively addressed. Thus, the investigators believe that&#xD;
      regardless of outcome this trial will have significant clinical and policy implications, and&#xD;
      will substantially impact the VA and national transfusion-related guidelines.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 5, 2018</start_date>
  <completion_date type="Anticipated">February 29, 2024</completion_date>
  <primary_completion_date type="Actual">June 30, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <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.</measure>
    <time_frame>90 days after randomization</time_frame>
    <description>MI will be defined using the Third Universal Definition of Myocardial Infarction. Acute renal failure will be defined as Acute Kidney Injury stage III according to RIFLE criteria. Baseline creatinine will be considered the creatinine upon admission prior to the index operation. The above urine output criteria will be only used for patients who are in the ICU and have precise monitoring of their urinary output. For patients on the surgical floor only serum creatinine changes will be used for assessment of this endpoint. Coronary revascularization will be defined as a coronary artery bypass graft, or percutaneous coronary intervention (either angioplasty or stenting). Stroke will be defined as new unilateral neurological deficit that lasts for more than 24 hours, and is confirmed by a brain imaging modality (computed tomography or magnetic resonance imaging study) demonstrating new brain infarct.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>A composite endpoint of postoperative infectious complications at 90 days post-randomization: Infectious complications will include wound infections, pneumonia, and sepsis.</measure>
    <time_frame>90 days after randomization</time_frame>
    <description>Wound infection will be defined according to the Centers for Disease Control and Prevention (CDC) guidelines as a) positive wound culture, or b) drainage of pus from a wound, or c) suspicion of wound infection that was drained operatively.&#xD;
Pneumonia will be defined according to the CDC definition as chest radiograph with new or progressive infiltrate, consolidation, cavitation, or pleural effusion and any of the following: new onset of purulent sputum or change in character of sputum, or organism isolated from blood culture, trans-tracheal aspirate, bronchial brushings, or biopsy.&#xD;
Sepsis will be defined as a combination of two of the following systemic inflammatory response syndrome (SIRS) criteria, plus suspected or present source of infection. SIRS criteria will include the following: temperature greater than 38C, heart rate greater than 90 beats/min, WBC &gt; 12,000 or &lt; 4,000, or &gt; 10% bands.</description>
  </secondary_outcome>
  <secondary_outcome>
    <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</measure>
    <time_frame>90 days after randomization</time_frame>
    <description>The diagnosis of cardiac arrhythmias will be based on EKG findings. Only arrhythmias that result in initiation of new treatment regimen (to include medications, implantable devices, or surgical intervention) during hospitalization will be recorded.&#xD;
CHF will require at least one of the following symptoms or signs new or worsening: dyspnea at rest, orthopnea, or paroxysmal nocturnal dyspnea and radiological evidence of heart failure or worsening heart failure and increase/initiation of established treatment.&#xD;
Cardiac arrest will be defined as the cessation of cardiac pump function activity that results in loss of consciousness and absence of circulating blood flow as evidenced by absent carotid pulse. Only episodes of cardiac arrest that are reversed will be collected under this endpoint. If they are not reversed the event will be categorized as death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality at 1 year after randomization.</measure>
    <time_frame>12 months after randomization</time_frame>
    <description>The investigators will determine vital status by telephoning participants after hospital discharge, by searching the electronic medical record and the National Death Index.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>A composite endpoint of all-cause mortality,</measure>
    <time_frame>30 days after randomization</time_frame>
    <description>MI, coronary revascularization, acute renal failure, or postoperative ischemic stroke.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of hospital stay.</measure>
    <time_frame>At hospital discharge, up to 1 year</time_frame>
    <description>Length of hospital stay</description>
  </secondary_outcome>
  <other_outcome>
    <measure>The investigators will examine individual rates of the outcomes that consist of individual components of the primary endpoint.</measure>
    <time_frame>90 days after randomization</time_frame>
    <description>All cause postoperative mortality, Postoperative MI, Postoperative coronary revascularization, Postoperative stroke,Postoperative acute renal failure</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">3012</enrollment>
  <condition>Myocardial Infarction</condition>
  <condition>Coronary Revascularization</condition>
  <condition>Acute Renal Failure</condition>
  <arm_group>
    <arm_group_label>Restrictive</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Transfusion trigger: Hb&lt;7gm/dl</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Liberal</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Transfusion trigger: Hb&lt;10gm/dl</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Blood Transfusion</intervention_name>
    <description>Blood Transfusion</description>
    <arm_group_label>Liberal</arm_group_label>
    <arm_group_label>Restrictive</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males and females older than 18 years of age who have postoperative Hb &lt; 10gm/dl&#xD;
             within 15 days after the index operation&#xD;
&#xD;
          -  Patients who undergo an operation in either one of the three following categories:&#xD;
&#xD;
               -  Veterans who undergo PAD - related operations including but not limited to the&#xD;
                  following:&#xD;
&#xD;
                    -  aortobifemoral or aortobiiliac bypass&#xD;
&#xD;
                    -  open abdominal aortic aneurysm repair with simultaneous repair of aortoiliac&#xD;
                       occlusive disease&#xD;
&#xD;
                    -  visceral bypass&#xD;
&#xD;
                    -  iliofemoral bypass&#xD;
&#xD;
                    -  femoral bypass or endarterectomy&#xD;
&#xD;
                    -  infrainguinal bypass&#xD;
&#xD;
                    -  thromboembolectomy&#xD;
&#xD;
                    -  supra-aortic trunk bypass or endarterectomy&#xD;
&#xD;
                    -  carotid endarterectomy&#xD;
&#xD;
                    -  major lower extremity amputations (transfemoral, through the knee, or&#xD;
                       transtibial)&#xD;
&#xD;
               -  Veterans with past medical history of ischemic stroke or IHD or PAD who undergo&#xD;
                  the following general surgery procedures, defined as:&#xD;
&#xD;
                    -  known prior MI&#xD;
&#xD;
                    -  ECG findings consistent with prior MI&#xD;
&#xD;
                    -  prior percutaneous coronary intervention&#xD;
&#xD;
                    -  prior coronary artery bypass surgery&#xD;
&#xD;
                    -  history of angina for which the patient is currently receiving treatment&#xD;
&#xD;
                    -  stress test indicating myocardial ischemia&#xD;
&#xD;
                    -  who undergo the following General Surgery operations:&#xD;
&#xD;
                         -  Open cholecystectomy or other complex biliary reconstruction&#xD;
&#xD;
                         -  such as open common bile duct exploration for stones&#xD;
&#xD;
                         -  reconstruction as part of oncologic operations such as palliative&#xD;
                            pancreatic cancer procedures)&#xD;
&#xD;
                    -  small bowel resection&#xD;
&#xD;
                    -  pancreatectomy&#xD;
&#xD;
                    -  colon resection&#xD;
&#xD;
                    -  rectal resection&#xD;
&#xD;
                    -  splenectomy&#xD;
&#xD;
                    -  transhiatal esophagectomy&#xD;
&#xD;
                    -  liver resection&#xD;
&#xD;
                    -  gastric resection&#xD;
&#xD;
                    -  open ventral hernia repair&#xD;
&#xD;
                    -  Colostomies (reversals and takedowns)&#xD;
&#xD;
                    -  Intestinal anastomosis takedowns and revisions&#xD;
&#xD;
                    -  Gastric bypass&#xD;
&#xD;
                    -  Adrenalectomies&#xD;
&#xD;
                    -  Major diaphragmatic hiatal hernia repairs&#xD;
&#xD;
               -  Veterans with past medical history of ischemic stroke or IHD or PAD who undergo&#xD;
                  the following Vascular Surgery operations:&#xD;
&#xD;
                    -  Open aneurysm repair, including but not limited to:&#xD;
&#xD;
                         -  carotid&#xD;
&#xD;
                         -  subclavian&#xD;
&#xD;
                         -  abdominal aortic&#xD;
&#xD;
                         -  iliac&#xD;
&#xD;
                         -  femoral&#xD;
&#xD;
                         -  popliteal aneurysms&#xD;
&#xD;
                    -  and complex endovascular aneurysm repair, defined as:&#xD;
&#xD;
                         -  fenestrated endograft&#xD;
&#xD;
                         -  or endograft with need for iliac conduit&#xD;
&#xD;
                         -  or endovascular aneurysm repair with simultaneous femoral artery&#xD;
                            reconstruction or bypass&#xD;
&#xD;
                    -  Subclavian/vertebral bypasses and transpositions&#xD;
&#xD;
          -  Patients undergoing the above procedures will be included in the study regardless of&#xD;
             their preoperative Hb level, and regardless of preoperative or intraoperative&#xD;
             transfusion they might have received.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Veteran unable to consent&#xD;
&#xD;
          -  Veteran unwilling to follow protocol (such as Jehovah's witnesses)&#xD;
&#xD;
          -  Veteran with known history of hereditary anemias such as Thalassemia or Sickle cell&#xD;
             disease&#xD;
&#xD;
          -  Veteran with known history of hereditary bleeding disorders, such as factor VIII or&#xD;
             factor IX deficiency&#xD;
&#xD;
          -  Veteran with prior history of adverse reaction to blood administration, such as fever,&#xD;
             rash, or hemolysis&#xD;
&#xD;
          -  Veteran does not speak or understand English&#xD;
&#xD;
          -  Veteran hemodynamically unstable or in cardiogenic shock for &gt;48 hours after the index&#xD;
             procedure&#xD;
&#xD;
          -  Veteran participating in another interventional trial whose objective is to evaluate&#xD;
             the effect of transfusion on outcomes&#xD;
&#xD;
          -  Pregnancy in female Veterans&#xD;
&#xD;
          -  Veteran is a prisoner or in custody of law enforcement&#xD;
&#xD;
          -  Prior randomization in the CSP#599&#xD;
&#xD;
          -  Patients who are known to have tested positive for COVID-19 and have not recovered&#xD;
             prior to consent will not be consented. Any participant who is known to have a&#xD;
             positive COVID-19 test during the screening process and has not recovered will be&#xD;
             excluded prior to randomization.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Panagiotis Kougias, MD MSc</last_name>
    <role>Study Chair</role>
    <affiliation>Michael E. DeBakey VA Medical Center, Houston, TX</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Central Arkansas VHS John L. McClellan Memorial Veterans Hospital, Little Rock, AR</name>
      <address>
        <city>Little Rock</city>
        <state>Arkansas</state>
        <zip>72205-5484</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Loma Linda Healthcare System, Loma Linda, CA</name>
      <address>
        <city>Loma Linda</city>
        <state>California</state>
        <zip>92357</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Long Beach Healthcare System, Long Beach, CA</name>
      <address>
        <city>Long Beach</city>
        <state>California</state>
        <zip>90822</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Palo Alto Health Care System, Palo Alto, CA</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94304-1290</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>San Francisco VA Medical Center, San Francisco, CA</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94121</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>North Florida/South Georgia Veterans Health System, Gainesville, FL</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32608</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>James A. Haley Veterans' Hospital, Tampa, FL</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Minneapolis VA Health Care System, Minneapolis, MN</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55417</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Western New York Healthcare System, Buffalo, NY</name>
      <address>
        <city>Buffalo</city>
        <state>New York</state>
        <zip>14215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Asheville VA Medical Center, Asheville, NC</name>
      <address>
        <city>Asheville</city>
        <state>North Carolina</state>
        <zip>28805</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Louis Stokes VA Medical Center, Cleveland, OH</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Portland Health Care System, Portland, OR</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15240</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75216</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Michael E. DeBakey VA Medical Center, Houston, TX</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030-4211</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VA Puget Sound Health Care System Seattle Division, Seattle, WA</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Kougias P, Mi Z, Zhan M, Carson JL, Dosluoglu H, Nelson P, Sarosi GA Jr, Arya S, Norman LE, Sharath S, Scrymgeour A, Ollison J, Calais LA, Biswas K. Transfusion trigger after operations in high cardiac risk patients (TOP) trial protocol. Protocol for a multicenter randomized controlled transfusion strategy trial. Contemp Clin Trials. 2023 Mar;126:107095. doi: 10.1016/j.cct.2023.107095. Epub 2023 Jan 20.</citation>
    <PMID>36690072</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>July 7, 2017</study_first_submitted>
  <study_first_submitted_qc>July 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 26, 2017</study_first_posted>
  <last_update_submitted>August 11, 2023</last_update_submitted>
  <last_update_submitted_qc>August 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acute Kidney Injury</mesh_term>
    <mesh_term>Myocardial Infarction</mesh_term>
    <mesh_term>Infarction</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03229941
org study id: 599
nct id: NCT03229941
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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).
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: Single (Participant)
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.
time frame: 90 days after randomization
description: MI will be defined using the Third Universal Definition of Myocardial Infarction. Acute renal failure will be defined as Acute Kidney Injury stage III according to RIFLE criteria. Baseline creatinine will be considered the creatinine upon admission prior to the index operation. The above urine output criteria will be only used for patients who are in the ICU and have precise monitoring of their urinary output. For patients on the surgical floor only serum creatinine changes will be used for assessment of this endpoint. Coronary revascularization will be defined as a coronary artery bypass graft, or percutaneous coronary intervention (either angioplasty or stenting). Stroke will be defined as new unilateral neurological deficit that lasts for more than 24 hours, and is confirmed by a brain imaging modality (computed tomography or magnetic resonance imaging study) demonstrating new brain infarct.
measure: A composite endpoint of postoperative infectious complications at 90 days post-randomization: Infectious complications will include wound infections, pneumonia, and sepsis.
time frame: 90 days after randomization
description: Wound infection will be defined according to the Centers for Disease Control and Prevention (CDC) guidelines as a) positive wound culture, or b) drainage of pus from a wound, or c) suspicion of wound infection that was drained operatively.
Pneumonia will be defined according to the CDC definition as chest radiograph with new or progressive infiltrate, consolidation, cavitation, or pleural effusion and any of the following: new onset of purulent sputum or change in character of sputum, or organism isolated from blood culture, trans-tracheal aspirate, bronchial brushings, or biopsy.
Sepsis will be defined as a combination of two of the following systemic inflammatory response syndrome (SIRS) criteria, plus suspected or present source of infection. SIRS criteria will include the following: temperature greater than 38C, heart rate greater than 90 beats/min, WBC > 12,000 or < 4,000, or > 10% bands.
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
time frame: 90 days after randomization
description: The diagnosis of cardiac arrhythmias will be based on EKG findings. Only arrhythmias that result in initiation of new treatment regimen (to include medications, implantable devices, or surgical intervention) during hospitalization will be recorded.
CHF will require at least one of the following symptoms or signs new or worsening: dyspnea at rest, orthopnea, or paroxysmal nocturnal dyspnea and radiological evidence of heart failure or worsening heart failure and increase/initiation of established treatment.
Cardiac arrest will be defined as the cessation of cardiac pump function activity that results in loss of consciousness and absence of circulating blood flow as evidenced by absent carotid pulse. Only episodes of cardiac arrest that are reversed will be collected under this endpoint. If they are not reversed the event will be categorized as death.
measure: All-cause mortality at 1 year after randomization.
time frame: 12 months after randomization
description: The investigators will determine vital status by telephoning participants after hospital discharge, by searching the electronic medical record and the National Death Index.
measure: A composite endpoint of all-cause mortality,
time frame: 30 days after randomization
description: MI, coronary revascularization, acute renal failure, or postoperative ischemic stroke.
measure: Length of hospital stay.
time frame: At hospital discharge, up to 1 year
description: Length of hospital stay
measure: The investigators will examine individual rates of the outcomes that consist of individual components of the primary endpoint.
time frame: 90 days after randomization
description: All cause postoperative mortality, Postoperative MI, Postoperative coronary revascularization, Postoperative stroke,Postoperative acute renal failure
arm group label: Restrictive
arm group type: Experimental
description: Transfusion trigger: Hb<7gm/dl
arm group label: Liberal
arm group type: Experimental
description: Transfusion trigger: Hb<10gm/dl
intervention type: Procedure
intervention name: Blood Transfusion
description: Blood Transfusion
arm group label: Liberal
arm group label: Restrictive
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Panagiotis Kougias, MD MSc
role: Study Chair
affiliation: Michael E. DeBakey VA Medical Center, Houston, TX
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country: United States
citation: Kougias P, Mi Z, Zhan M, Carson JL, Dosluoglu H, Nelson P, Sarosi GA Jr, Arya S, Norman LE, Sharath S, Scrymgeour A, Ollison J, Calais LA, Biswas K. Transfusion trigger after operations in high cardiac risk patients (TOP) trial protocol. Protocol for a multicenter randomized controlled transfusion strategy trial. Contemp Clin Trials. 2023 Mar;126:107095. doi: 10.1016/j.cct.2023.107095. Epub 2023 Jan 20.
PMID: 36690072
responsible party type: Sponsor
mesh term: Acute Kidney Injury
mesh term: Myocardial Infarction
mesh term: Infarction
sharing ipd: No