THROMBOSIS

CARDIOLOGY

VTE Safety Zone 2023 Program Highlights

<p>Watch Prof. Ajay Kakkar Director of Thrombosis Research Institute, London, UK, Sheds the light on 2023 VTE Safety Zone Program and its importance which aims to provide a forum for discussion and exchange in the field of VTE.</p>

Pre vs post operative initiation of Thromboprophylaxis in Liver surgeries

<p>Watch Prof. Mario Serradilla HPB Surgeon at Miguel Servet University Hospital, Associate Professor at University of Zaragoza, FACS, shedding the light on how to reduce risk of VTE in Liver surgeries.</p>

<p><strong>Standard duration<sup>1</sup></strong></p>
<ul>
 <li>Up to 7-10 days 
  <ul>
   <li>VTE prophylaxis</li>
  </ul></li>
</ul>
<p><strong>Do you consider longer treatment duration for some patients?</strong></p>
<p><strong>Extended duration<sup>1</sup></strong></p>
<ul>
 <li>4 weeks 
  <ul>
   <li>VTE prophylaxis</li>
  </ul></li>
</ul>

<p><strong>Multiple guidelines recommend extended duration prophylaxis (up to 4 weeks) with LMWH such as Clexane<sup>®</sup>for patients with cancer undergoing abdominal or pelvic surgery<sup>2-6</sup></strong></p>

black

<h2>Benefit of Prophylaxis for your high-risk surgical patient</h2>
<p><strong>In high-risk surgical patients</strong></p>
<ul>
 <li>Without prophylaxis,&nbsp;<strong>40-80 %</strong></li>
 <li>Experienced a DVT event</li>
 <li>Among high-risk surgical patients with multiple risk factors<sup>7</sup>
  <ul>
   <li>With standard duration<sup>*8</sup>,&nbsp;<strong>9.4 %</strong></li>
   <li>Had a VTE event</li>
   <li>Among patients undergoing major colorectral surgery receiving standard duration prophylaxis(up to 7-10 days, 40 mg Clexane)<sup>8</sup></li>
  </ul></li>
</ul>
<p><strong>In high-risk surgical patients&nbsp;with cancer</strong></p>
<ul>
 <li>With standard duration<sup>*9</sup>,&nbsp;<strong>12 %</strong></li>
 <li>Experienced a VTE event</li>
 <li>Among surgical patients undergoing abdominal surgery<sup>9</sup>
  <ul>
   <li>With extended duration<sup>9</sup></li>
   <li>Clexane<sup>®</sup>:&nbsp;<strong>60 %</strong></li>
   <li>Fewer VTE events&nbsp;vs&nbsp;only standard duration<sup>9</sup></li>
  </ul></li>
</ul>
<h2>Which of your surgical patients is at an increased risk of VTE?</h2>
<p>Certain patient-specific risk factors increase the VTE risk of surgical patients (in addition to the type of surgery)<sup>2,10,11</sup></p>
<ul>
 <li>Cancer</li>
 <li>Previous VTE</li>
 <li>Older age</li>
 <li>Obesity</li>
</ul>
<p>*Standard duration 6-10 days with 40 mg Clexane<sup>®</sup>.<sup>8,9<br>
   †</sup>Standard duration 6-10 days + extended duration 21 days of 40 mg Clexane<sup>®</sup>.<sup>9<br>
   ‡</sup>In high-risk surgical patients with cancer after receiving 40 mg Clexane<sup>®</sup>&nbsp;standard duration Prophylaxis of 6-10 days vs 40 mg Clexane<sup>®</sup>&nbsp;extended duration prophylaxis for additional 21 days,<br>
  12% of patients had a VTE event vs 4.8% with extended duration.<sup>3</sup></p>

References

Benefit of Prophylaxis for High-Risk Surgical Patients

<h2>Key Takeaway</h2>
<ul>
 <li>The 2019 European Society of Cardiology (ESC) guidelines for the diagnosis and management of acute pulmonary embolism (PE) developed in collaboration with the European Respiratory Society features important updates on diagnosis, risk assessment, acute and chronic phase management, prevention of recurrence, management in patients with cancer and pregnant women and post-PE care.</li>
</ul>
<h2>Key Highlights</h2>
<h3>Updated recommendations</h3>
<ul>
 <li>The recommendation for rescue thrombolytic therapy in the setting of haemodynamic deterioration has been upgraded to class I.</li>
 <li>The recommendation for use of surgical embolectomy or catheter-directed as alternatives to rescue thrombolytic therapy has been upgraded to class IIa.</li>
 <li>Use of D-dimer and clinical prediction rules to rule out PE during pregnancy or post-partum is now an IIa recommendation.</li>
 <li>Further assessment of asymptomatic PE survivors at increased risk for chronic thromboembolic pulmonary hypertension (CTEPH) is now an IIb recommendation.</li>
</ul>
<h3>New recommendations</h3>
<p><strong>Diagnosis</strong></p>
<ul>
 <li>D-dimer cut-offs adjusted to age and clinical probability should be considered instead of fixed values (IIa).</li>
 <li>A positive proximal compression ultrasonography result calls for a risk assessment to guide the management of PE (IIa).</li>
 <li>Ventilation/perfusion (V/Q) single-photon emission computed tomography may be considered for the diagnosis of PE (IIb).</li>
</ul>
<p><strong>Risk assessment</strong></p>
<ul>
 <li>Assessment of the right ventricular function using imaging or laboratory biomarkers should be considered, even if the Pulmonary Embolism Severity Index is low or Simplified Pulmonary Embolism Severity Index is 0 (IIa).</li>
 <li>The severity of PE may be further stratified using validated scoring systems combining clinical, imaging and laboratory prognostic factors (IIb).</li>
</ul>
<p><strong>Acute treatment</strong></p>
<ul>
 <li>Non-vitamin K antagonist oral anticoagulants (NOACs) are recommended as the primary choice for anticoagulant treatment when oral anticoagulation is to be initiated in a patient with PE eligible for a NOAC (I).</li>
 <li>Multidisciplinary teams should be established for the management of high-risk and selected cases of intermediate-risk PE (IIa).</li>
 <li>Extracorporeal membrane oxygenation may be considered, in addition to surgical embolectomy or catheter-directed treatment for patients with refractory circulatory collapse or cardiac arrest (IIb).</li>
</ul>
<p><strong>Chronic treatment and preventing recurrence</strong></p>
<ul>
 <li>The guidelines no longer support terminology such as “provoked” vs “unprovoked” PE/venous thromboembolism.</li>
 <li>Patients with antiphospholipid antibody syndrome should receive indefinite treatment with a vitamin K antagonist (I).</li>
 <li>Extended anticoagulation should be considered for patients without any identifiable risk factor for the index PE event, those with a persistent risk factor apart from antiphospholipid antibody syndrome and those with a minor transient/reversible risk factor for the index PE event (IIa).</li>
 <li>A low dose of apixaban or rivaroxaban for extended anticoagulation should be considered after the first 6 months of treatment (IIa).</li>
</ul>
<p><strong>Post-PE care</strong></p>
<ul>
 <li>Routine assessment using an integrated model of care is recommended 3-6 months after acute PE and symptomatic patients with mismatched perfusion defects (on V/Q scan) &gt;3 months post-PE should be referred to an expert CTEPH centre (I).</li>
</ul>

Reference

The guidelines provide an update on the 2014 guidelines.

2019 ESC Guidelines for Acute Pulmonary Embolism

<h2>Key Takeaway</h2>
<p>Garfield-VTE study results showed that patients with VTE and concomitant anemia had a higher risk of adverse clinical outcomes vs those without anemia.</p>

<p>Baseline anemia is a prominent predictor of the risk of major bleeding and all-cause mortality but does not influence the risk of recurrent VTE.*</p>

<p>Patients with anemia were more likely to receive parenteral anticoagulants and VKAs and less likely to receive DOACs.<sup>†</sup></p>

<p>GARFIELD-VTE registry study analyzed real-world population of VTE patients, thus allowing an understanding of current outcomes and treatment protocols in a clinical setting.</p>

<p>This study demonstrated the need for appropriate therapeutic management strategies to reduce the risk of major bleeding and mortality for patients with VTE and concomitant anemia.</p>

<h2>Study Design</h2>
<p>&nbsp;</p>
<p>Garfield-VTE: Global, Prospective, Non-interventional Registry (10,685 Adult Patients With Vte [415 Sites Across 28 Countries Worldwide])</p>

<h3>Key Inclusion Criteria</h3>
<p>Objective diagnosis of VTE within ± 30 days of entry into the registry</p>

<h3>Key Exclusion Criteria</h3>
<p>Long-term follow-up was not planned; Hb values were not measured; or Hb values were measured outside the 30-day window of entry into the registry</p>

<p><strong>Primary clinical outcomes:</strong>&nbsp;All-cause mortality, recurrent VTE, and major bleeding<sup>‡</sup>&nbsp;in patients with and without anemia over 24-months from VTE diagnosis</p>
<p><strong>Secondary clinical outcomes:</strong>&nbsp;Non-major bleeding<sup>§</sup>, MI/ACS, non-hemorrhagic stroke/TIA, and cancer</p>

<h2>Key Results</h2>
<p><strong>72.1 %</strong>&nbsp;patients&nbsp;<strong>(7,698/10,679)</strong>&nbsp;diagnosed with VTE were eligible for analysis</p>
<ul>
 <li>Patients with Anemia: n =&nbsp;<strong>2,771</strong>
  <ul>
   <li>(median age = 62.6 years; DVT events = 61.1%; PE ± DVT events = 38.9%)</li>
  </ul></li>
 <li>Patients without Anemia: n =&nbsp;<strong>4,927</strong>
  <ul>
   <li>(median age = 58.9 years; DVT events = 55.9%; PE ± DVT events = 44.0%)</li>
  </ul></li>
</ul>

<h3>VTE Risk Factors (Patients with vs without Anemia):</h3>
<ul>
 <li>
  <p>Active cancer:<br><strong>20.1%</strong>&nbsp;vs&nbsp;<strong>5.6%</strong></p></li>
 <li>
  <p>History of cancer:<br><strong>22.4%</strong>&nbsp;vs&nbsp;<strong>9.2%</strong></p></li>
 <li>
  <p>CHF:&nbsp;<strong>4.2</strong>&nbsp;vs&nbsp;<strong>2.5%</strong></p></li>
 <li>
  <p>Chronic immobilization:<br><strong>8.2%</strong>&nbsp;vs&nbsp;<strong>4.0%</strong></p></li>
 <li>
  <p>Renal insufficiency:<br><strong>6.6%</strong>&nbsp;vs&nbsp;<strong>2.4%</strong></p></li>
 <li>
  <p>Hospitalization:<br><strong>22.0%</strong>&nbsp;vs&nbsp;<strong>6.8%</strong></p></li>
 <li>
  <p>Surgery:&nbsp;<strong>19.2%</strong>&nbsp;vs&nbsp;<strong>8.2%</strong></p></li>
 <li>
  <p>Previous VTE:<br><strong>10.0%</strong>&nbsp;vs&nbsp;<strong>17.9%</strong></p></li>
</ul>

<h3>Primary Clinical Outcomes (Patients with vs without Anemia)<sup>¶</sup>:</h3>
<ul>
 <li>
  <p>All-cause mortality: HR =&nbsp;<strong>1.84</strong><br>
    (95% CI: 1.56–2.18; P &lt;0.0001)</p></li>
 <li>
  <p>Major bleeding: HR =&nbsp;<strong>2.83</strong><br>
    (95% CI: 2.14–3.75; P &lt;0.0001)</p></li>
 <li>
  <p>Recurrent VTE: HR =&nbsp;<strong>0.96</strong><br>
    (95% CI: 0.79–1.16; P = 0.6440)</p></li>
</ul>

<h3>Secondary Clinical Outcomes (Patients with vs without Anemia)<sup>¶</sup>:</h3>
<ul>
 <li>
  <p>Any bleeds: HR =&nbsp;<strong>1.41</strong><br>
    (95% CI: 1.23–1.62; P &lt;0.0001)</p></li>
 <li>
  <p>MI/ACS: HR =&nbsp;<strong>2.01</strong><br>
    (95% CI: 1.21–3.34; P &lt;0.0092)</p></li>
 <li>
  <p>Stroke/TIA: HR =&nbsp;<strong>1.56</strong><br>
    (95% CI: 1.01–2.41; P = 0.0489)</p></li>
 <li>
  <p>Cancer: HR =&nbsp;<strong>1.07</strong><br>
    (95% CI: 0.83–1.38; P = 0.6150)</p></li>
</ul>

<p>Patients who remained on anticoagulant treatment at 24-months (with vs without anemia):&nbsp;<strong>40.0%</strong>&nbsp;vs&nbsp;<strong>51.2%</strong></p>

<h2>Key Limitations</h2>
<ul>
 <li>Data collection was non-randomized</li>
 <li>Intention-to-treat concept was used; however, this approach did not consider treatment duration/discontinuation or fluctuating Hb values after initial assessment at baseline</li>
 <li>Hb values were only available for 7,698/10,679 patients</li>
</ul>
<p>* Patients with severe anemia vs those with mild/moderate anemia had higher risk of all-cause mortality (HR = 1.42 [95% CI: 1.17–1.72]; P = 0.0004) and major bleeding (HR = 1.84 [95% CI: 1.33–2.55]; P = 0.0003).<br><sup>†</sup>&nbsp;Patients with vs without anemia (at baseline): Parenteral therapy alone = 26.6% vs 11.7%; VKA alone = 5.7% vs 5.0%; VKA + parenteral therapy = 25.6% vs 28.1%; DOACs alone = 24.5% vs 32.8%; DOAC + parenteral therapy = 14.0% vs 20.7%.<br><sup>‡</sup>Clinically overt bleeding associated with a critical site, a fall in Hb of 2 g/dL, transfusion of 2 or more units of red blood cells, hemorrhagic stroke, or fatal outcome.<br><sup>§</sup>Any bleeding that did not meet the major bleeding criteria.<br><sup>¶</sup>At 24 months, after adjustment for cancer status, age, ethnicity, and BMI (adjusted HR for mortality with 95% CIs for 24-month outcomes after VTE diagnosis between patients with anemia and or with no-anemia [reference group]).</p>

Abbreviations

Impact of anemia on long-term clinical outcomes in venous thromboembolism: Findings from Garfield-VTE registry

<h2>Compression stockings in addition to low-molecular-weight heparin to prevent venous thromboembolism in elective surgical inpatients in need of pharmacological thromboprophylaxis: the Gaps trial</h2>
<p>In the Gaps non-inferiority randomized controlled trial (RCT) in elective surgical inpatients at moderate or high risk of venous thromboembolism (VTE), administration of pharmacological thromboprophylaxis alone was non-inferior to a combination of pharmacological thromboprophylaxis plus graduated compression stockings (GCS).</p>
<ul>
</ul>

<h2>Main Takeaway</h2>
<ul>
 <li>In elective surgical inpatients with moderate or high risk of VTE requiring pharmacological thromboprophylaxis; low-molecular-weight heparin (LMWH)-alone was non-inferior to LMWH + GCS in the overall population. 
  <ul>
   <li>Non-inferiority of LMWH was sustained in the subgroup analyses based on age (&lt;65 or ≥65 years) and baseline VTE risk (moderate or high risk).</li>
   <li>Primary outcome event (VTE) occurred in 1.7% vs 1.4% of the patients in LMWH group vs LMWH + GCS group (risk difference = 0.3% [95% confidence interval {CI}: –0.65% to 1.26%]; P &lt; 0.001).</li>
   <li>For the overall trial population, there was no evidence of a difference in the secondary outcomes (quality of life or adverse events) between the two treatment groups (LMWH group vs LMWH + GCS group).</li>
   <li>Based on the study findings GCS may be unnecessary for most elective surgical patients.</li>
  </ul></li>
</ul>

<h2>Why This Matters</h2>
<ul>
 <li>Surgical patients are at an increased risk of VTE. Although, the guidelines recommended both pharmacological thromboprophylaxis and mechanical thromboprophylaxis in surgical patients with moderate or high risk of VTE, use of GCS was found to be associated with undesirable effects in the real-world.</li>
</ul>

<h2>Study Design</h2>
<ul>
 <li>The GAPS trial was a pragmatic, prospective, non-inferiority RCT (randomization [1:1]: LMWH [intervention] or LMWH + GCS [standard care]; trial period: May 2016 to January 31, 2019; N =1,905; sites: seven NHS hospitals in England).</li>
 <li>Key inclusion criteria: Elective surgical inpatients aged ≥18 years with moderate or high risk of VTE</li>
 <li>Key exclusion criteria: Contraindications to LMWH; contraindications to GCS; thrombophilia or thrombogenic disorder; need for therapeutic anticoagulation; previous VTE; and pregnancy</li>
 <li>Primary endpoint: Symptomatic or asymptomatic VTE up to 90 days after surgery</li>
 <li>Secondary endpoints: Quality of life over 90 days; compliance with LMWH and GCS; and overall mortality</li>
</ul>

<h2>Key Results</h2>
<ul>
 <li>Of the 1,905 patients randomized, 17 were excluded post randomization (overall population: N = 1,888 [LMWH {N = 948} group vs LMWH + GCS group {N = 940}: mean age = 59.3 vs 58.1 years; females = 63.4% vs 63.2%]). 
  <ul>
   <li>Overall, 1,858 patients had surgery (LMWH group vs LMWH + GCS group: 937 vs 921 patients) 
    <ul>
     <li>Treatment received (LMWH group vs LMWH + GCS group): (1) LMWH + GCS = 37 vs 750 patients; (2) LMWH alone = 758 vs 21 patients; (3) GCS alone = 18 vs 142 patients; and (4) Neither LMWH nor GCS = 124 vs 8 patients</li>
    </ul></li>
  </ul></li>
 <li>Primary outcome (intention-to-treat analysis): VTE event occurred in 1.7% (16/937) vs 1.4% (13/921) of the patients in LMWH group vs LMWH + GCS group (risk difference = 0.3% [95% CI: –0.65% to 1.26%]; P &lt; 0.001 [non-inferiority of LMWH-alone was shown]) 
  <ul>
   <li>Non-inferiority of LMWH was sustained in the subgroup analyses based on age (&lt;65 or ≥65 years) and baseline VTE risk (moderate or high risk).</li>
  </ul></li>
 <li>Secondary outcomes (overall population [LMWH group {N = 948} vs LMWH + GCS group {N = 940}]): 
  <ul>
   <li>EuroQol-5 Dimensions, five-level version, n; mean: 774; 0.856 vs 743; 0.843 (mean difference = 0.011 [95% CI: –0.009 to 0.031; P = 0.272])</li>
   <li>EuroQol-visual analogue scale, n; mean: 773; 80.2 vs 743; 80.7 (mean difference = –0.29 [95% CI: –1.94 to 1.37; P = 0.732])</li>
   <li>Compliance with GCS (stockings worn for 75% of the total re-admission time), n (%): 37 (4.0) vs 750 (81.4)</li>
   <li>Compliance with LMWH (received all prescribed LMWH doses), n (%): 768 (82.0) vs 755 (82.0)</li>
  </ul></li>
 <li>Complications, overall mortality, and serious adverse events (SAEs) (overall population [LMWH {N = 779} vs LMWH + GCS {N = 787} vs GCS {N = 160}vs neither {N = 132}]): 
  <ul>
   <li>GCS-related complications, n (%): 2 (0.3) vs 50 (6.4) vs 5 (3.1) vs 1 (0.8 [wore stockings for &lt;1 hour, classified as not wearing stockings])</li>
   <li>Adverse reactions to LMWH, n (%): 6 (0.8) vs 2 (0.3) vs 0 (0) vs 0 (0) 
    <ul>
     <li>Overall mortality, n (%): 2 (0.3) vs 0 (0) vs 0 (0) vs 1 (0.8)</li>
    </ul></li>
   <li>Number of patients with a SAE: 92 (11.8) vs 103 (13.1) vs 5 (3.1) vs 10 (7.6) 
    <ul>
     <li>Total number of SAEs: 110 vs 112 vs 5 vs 12</li>
    </ul></li>
  </ul></li>
</ul>

<h2>Limitations</h2>
<ul>
 <li>Few patients (15%) missed the duplex ultrasound scan, which could have helped detect further asymptomatic DVT.</li>
 <li>The event rate might have been potentially overestimated.</li>
 <li>Patients aged ≥65 years with moderate risk of VTE were underrepresented.</li>
</ul>

GAPS trial: Low-dose LMWH and GCS in in elective surgical inpatients at moderate or high risk VTE

<h2>Enoxaparin monotherapy more effective and economical than unfractionated heparin monotherapy among inpatients with NSTEMI</h2>
<p>Findings from analysis of real-world data from more than 1 million patients from 859 US hospitals.</p>
<h2>Main Takeaway</h2>
<ul>
 <li>Enoxaparin was associated with a significantly lower risk for ischaemic complications and death than unfractionated heparin (UFH) among inpatients with myocardial infarction (MI) with no ST-segment elevation (NSTEMI) but not in patients with unstable angina (UA) and STEMI.</li>
 <li>Enoxaparin vs UFH was associated with significantly lower odds of major bleeding and costs among all 3 acute coronary syndrome (ACS) cohorts.</li>
</ul>
<h2>Why This Matters</h2>
<ul>
 <li>Despite proven effectiveness, enoxaparin monotherapy is much less used than UFH monotherapy across all spectrums of ACS.</li>
 <li>Additional research is needed to better understand the methods for improving the upstream selection of anticoagulants to optimise clinical outcomes.</li>
</ul>
<h2>Study Design</h2>
<ul>
 <li>Study evaluated 1,048,053 patients (age, ≥18 years) with an inpatient admission for initial episode of ACS between 2010 and 2016 across 859 US hospitals.</li>
 <li>Outcomes evaluated: all-cause in-hospital mortality, non-fatal MI, recurrent angina and composite ischaemic complications during any hospital visit within 30 days post-index discharge.</li>
 <li>Secondary outcomes: prevalence of anticoagulant use, enoxaparinand UFH-related treatment costs, total length of stay and risk for 30-day readmission.</li>
 <li>Funding: Sanofi Inc.</li>
</ul>
<h2>Key Results</h2>
<ul>
 <li>Overall, 20.9%, 55.6% and 23.5% patients were diagnosed with UA, NSTEMI and STEMI, respectively.</li>
 <li>Among the overall population, 11.4% and 47.4% received enoxaparin and UFH monotherapy, respectively.</li>
 <li>Among patients with NSTEMI, enoxaparin vs UFH was associated with lower odds of: 
  <ul>
   <li>MI: adjusted OR (aOR), 0.95 (95% CI, 0.92-0.99);</li>
   <li>recurrent angina: aOR, 0.88 (95% CI, 0.78-0.98);</li>
   <li>in-hospital mortality: aOR, 0.88 (95% CI, 0.81-0.95); and</li>
   <li>composite ischaemic complications: aOR, 0.95 (95% CI, 0.92-0.98)</li>
  </ul></li>
 <li>Among patients with UA, odds of having composite ischaemic complications (aOR, 1.09; 95% CI, 1.00-1.19) and recurrent angina (aOR, 1.15; 95% CI, 1.03-1.28) were slightly higher in enoxaparin vs UFH group, whereas MI and all-cause in-hospital mortality were comparable.</li>
 <li>Among patients with STEMI, odds of all mentioned outcomes were lower in enoxaparin group; however, results were not statistically significant.</li>
 <li>Enoxaparin was associated with lower odds of major bleeding in all 3 cohorts: 
  <ul>
   <li>UA: aOR, 0.77 (95% CI, 0.66-0.91);</li>
   <li>NSTEMI: aOR, 0.68 (95% CI, 0.64-0.72); and</li>
   <li>STEMI: aOR, 0.72 (95% CI, 0.63-0.83)</li>
  </ul></li>
 <li>The estimated overall cost savings during index admission until 30 days post-index discharge for enoxaparin over UFH cohort were $2972/patient, $2475/patient and $3050/patient for UA, NSTEMI and STEMI cohorts, respectively.</li>
 <li>30-day all-cause readmission was lower in enoxaparin vs UFH group for NSTEMI (adjusted mean [aM], 0.95; 95% CI, 0.92-0.98) and STEMI cohorts (aM, 0.92; 95% CI, 0.86-0.98) but higher for UA cohort (aM, 1.12; 95% CI, 1.03-1.22).</li>
 <li>The total length of hospital stay during the 30-day follow-up was not statistically different in any of the 3 cohorts.</li>
</ul>
<h2>Limitations</h2>
<ul>
 <li>Limitations of typical retrospective analysis using a hospital administrative database should be considered.</li>
 <li>Key outcome variables might have been underestimated.</li>
 <li>Factors that could influence anticoagulant selection were not captured.</li>
</ul>

Enoxaparin monotherapy vs UFH monotherapy among inpatients with NSTEMI

<h2>Enoxaparin in VTE Prophylaxis in Cancer Surgery</h2>
<p>Landmark trials of enoxaparin in cancer surgery</p>
<h2>Enoxacan Study Group (Enoxaparin and cancer)</h2>
<p>European, multicenter, double-blind, parallel group study¹</p>
<h2>Study Design¹</h2>

<h2>Treatment Groups¹</h2>
<ul>
 <li><strong>Enoxaparin</strong>, administered&nbsp;<strong>40 mg subcutaneously</strong>&nbsp;[SC] (either in the lateral abdominal wall or in the thigh)&nbsp;<strong>qd</strong>&nbsp;with the first dose given 2 hours prior to surgery and continuing for&nbsp;<strong>10±2 days&nbsp;</strong>in&nbsp;<strong>555 patients.</strong>&nbsp;was compared to</li>
 <li><strong>UFH 5,000 IU SC every 8 hours (q8h) in 560 patients.</strong></li>
</ul>
<h2>Primary Endpoint¹</h2>
<ul>
 <li>The primary endpoint was VTE determined by bilateral ascending venography within 24 hours after the last injection of drug.</li>
 <li>Efficacy was determined in all-treated patients as well as in evaluable patients, who met the protocol entry criteria.</li>
 <li>Of the 1,115 all-treated patients,&nbsp;<strong>631 (56.6%) were evaluable (UFH; n=319, enoxaparin; n=312).</strong></li>
</ul>
<h2>Results: Efficacy¹</h2>
<p>The total incidence of DVT and PE in the evaluable patients</p>

<p>* In the evaluable-patients, PE was diagnosed in 2 patients in the UFHtreated group versus none in the enoxaparin treated group</p>
<h2>Results: Safety¹</h2>
<ul>
 <li>Two deaths occurred in the enoxaparin-treated group due to thromboembolic origin.</li>
 <li>Major bleeding* was seen in&nbsp;4.1%&nbsp;(23/555) of the enoxaparin-treated patients and in&nbsp;2.9%&nbsp;(16/560) of the UFH-treated patients.</li>
</ul>
<p>* Defined as hemorrhage caused by a significant clinical event or a drop in hemoglobin of ≥2.0 g/dL or a transfusion of ≥2 units of packed red cells.</p>

<p>The authors concluded that enoxaparin 40 mg SC qd was as effective and safe as UFH SC q8h in preventing thromboembolism after surgery for abdominal and pelvic malignancy.¹</p>
<h2>Enoxacan II Study</h2>
<p>Multicenter, prospective, double-blind, placebo-controlled, parallel-group, randomized study²</p>
<h2>Objective²</h2>
<p>Evaluate the efficacy and safety of prolonged thromboprophylaxis with enoxaparin for prevention of VTE after elective, curative surgery for abdominal malignancy. A standard thromboprophylaxis regimen of enoxaparin, given for 1 week, was compared with a prolonged regimen of enoxaparin given for 4 weeks.</p>
<h2>Study Design²</h2>
<p>In the open phase of the study</p>

<p><strong>Primary efficacy endpoint:</strong>&nbsp;The incidence of VTE between days 25-31.<sup>2</sup></p>
<p><strong>Secondary efficacy endpoint:</strong>&nbsp;The incidence of death from thromboembolic disease before 3 months.<sup>2</sup></p>
<p><strong>Primary safety endpoint:</strong>&nbsp;The incidence of hemorrhage during the double-blind treatment period.<sup>2</sup></p>
<h2>Results: Efficacy²</h2>
<ul>
 <li>Of the 613 patients recruited, 501 underwent randomization and 332 (165 and 167 for enoxaparin and placebo, respectively) had evaluable venograms.</li>
 <li>The mean duration of treatment was 19.3 days in the enoxaparin arm and 19.5 days in the placebo arm.</li>
 <li>Gastrointestinal surgery followed by genitourinary tract, female reproductive organs, palliative, and other surgeries were the most common procedures.</li>
</ul>

<h2>Results: Safety²</h2>
<ul>
 <li>There were no significant differences in major or minor hemorrhage or other serious adverse events (AEs) during the double-blind period or during the 2-month follow-up period.</li>
 <li>None of the showed thrombocytopenia during either period and there were no deaths during the double-blind period.</li>
 <li>During the 2-month follow-up period, 6 patients (3.6%) died in the placebo group and 3 (1.8%) died in the enoxaparin group.</li>
</ul>
<p>&nbsp;</p>
<p>The authors concluded that prophylaxis with enoxaparin for 4 weeks following abdominal or pelvic cancer surgery was safe and significantly reduced the incidence of venographically demonstrated thrombosis compared with enoxaparin prophylaxis for 1 week.²</p>
<h2>Enoxacan II Follow-up Study³</h2>
<h2>Objective³</h2>
<p>compared long term, all-cause mortality in the enoxaparin group versus the placebo</p>
<h2>Primary Efficacy Endpoint³</h2>
<p>Survival at 1 year was the primary efficacy endpoint, however every site had collected survival data beyond 1 year (up to 44 months) and therefore a post hoc analysis utilizing all available data was conducted.</p>
<h2>Study Design³</h2>
<p>A cox regression model was used to measure prognostic factors, which for the primary analysis, were defined as whether surgery was palliative or curative, and treatment assignment.</p>
<h2>Population³</h2>
<p>Both treatment groups had similar baseline characteristics, including disease site and risk factors.</p>
<h2>Results³</h2>
<p>At 1 year there were 243 enoxaparin-treated patients (96%) and 229 placebo-treated patients (92%) with available follow-up data group.</p>
<p><strong>1-year survival rate</strong>:<sup>3</sup>&nbsp;90.2% for the enoxaparin group and 91.9% for the placebo groups</p>
<p><strong>Palliative surgery:<sup>3</sup></strong>&nbsp;The percentage of patients that underwent palliative surgery was significantly greater in the enoxaparin group compared with the placebo group (10.3% vs. 4.0%; P &lt;0.05).</p>
<p><strong>Curative surgery:<sup>3</sup>&nbsp;</strong>Curative surgery was a more significant prognostic factor compared with palliative surgery (hazard ratio [HR]=0.099; P=0.0001).</p>
<ul>
 <li>Neither the interaction between type of surgery and treatment nor the treatment effect were significant.<sup>3</sup></li>
 <li>At the longest follow-up time periods (43.3 months for the enoxaparin group and 43.5 months for the placebo group), increased survival was greater in the enoxaparin group (HR=0.47, P=0.078).<sup>3</sup></li>
 <li>The mortality rate was significantly greater (P &lt;0.0001) in patients who underwent palliative surgery compared with curative surgery.<sup>3</sup></li>
 <li>After adjustment for the type of surgery, there was a tendency towards decreased mortality among patients undergoing palliative surgery in the enoxaparin group (HR=0.598; P=0.3565) which increased after the 1-year follow-up period (HR=0.469; P=0.078).<sup>3</sup></li>
</ul>
<p>The authors concluded that further studies are needed to evaluate the effect of prolonged prophylaxis with enoxaparin in cancer patients undergoing palliative surgery on long-term survival.<sup>3</sup></p>

VTE Prophylaxis in Surgical Patients

<h2><strong>Duration of thromboprophylaxis following major abdominopelvic cancer-related surgery – an aid to informed clinical decisionmaking</strong></h2>
<h2>Key Takeaway</h2>
<p>Decision on use of extended duration thromboprophylaxis following major abdominopelvic cancer surgery should be made on individual patient basis.* Post-abdominopelvic cancer surgery:</p>
<h3>Extended duration LMWH thromboprophylaxis vs standard duration:</h3>
<p>Significantly reduces 30-day incidence of clinical VTE. No significant increase in 30-day post-operative incidences of clinically relevant bleeding</p>
<h3>Risk prediction:</h3>
<p>In the post-operative period, risk prediction scores like the&nbsp;<u>Caprini score</u>&nbsp;are not used regularly in clinical practice to decide the duration of thromboprophylaxis.</p>
<h2>Why This Matters</h2>
<p>Risk of post-operative VTE is 2-fold higher and risk of fatal PE is 3-fold higher in patients with cancer vs those undergoing similar surgical procedures for benign disease:</p>
<p>In patients with cancer undergoing abdominopelvic surgery, VTE was noted as the greatest cause of 30-day post-operative mortality</p>
<h3>This systematic review and meta-analysis:</h3>
<p>Provides clinicians with event rates of symptomatic VTE and clinically relevant bleeding for shared decisionmaking on the duration of thromboprophylaxis in surgical cancer patients</p>
<h2>Key Highlights</h2>
<p>Systematic Review and Meta-Analysis:</p>
<p>68 Studies (9 RCTS and 59 Observational Studies): 1,631,118 Adult Patients Who Underwent Cancer-Related Abdominopelvic Surgery</p>

<table align="center" border="0" cellpadding="10" cellspacing="1">
 <tbody>
  <tr>
   <td colspan="4" style="background-color: rgb(244, 242, 246); border-color: rgb(244, 242, 246);">
    <p><strong>30-Day post-operative incidences†<br>
       of clinical VTE</strong></p></td>
  </tr>
  <tr>
   <td rowspan="2">Overall rate</td>
   <td rowspan="2">With extended<br>
     duration<br>
     Thromboprophylaxis<br>
     vs without</td>
   <td colspan="2">Extended duration<br>
     Thromboprophylaxis vs standard</td>
  </tr>
  <tr>
   <td>RCTs</td>
   <td>Observational<br>
     studies</td>
  </tr>
  <tr>
   <td><b>1.7%</b><br>
     (95% CI: 1.5–1.9)</td>
   <td><b>0.5% vs 1.8%</b><br>
     (95% CI: 0.2–0.9) vs<br>
     (95% CI: 1.3–2.4)</td>
   <td><b>Non significant<br>
      reduction<br>
      0.3% vs 1.4%</b><br>
     (RR: 0.33)</td>
   <td><b>Statistically significant<br>
      reduction<br>
      1.0% vs 2.1%</b><br>
     (RR: 0.48)</td>
  </tr>
 </tbody>
</table>
<table align="center" border="0" cellpadding="10" cellspacing="1">
 <tbody>
  <tr>
   <td colspan="4" style="background-color: rgb(244, 242, 246); border-color: rgb(244, 242, 246);"><strong>30-Day post-operative incidences†<br>
      of clinically-relevant bleeding complications</strong></td>
  </tr>
  <tr>
   <td rowspan="2">Overall rate</td>
   <td rowspan="2">With extended<br>
     duration<br>
     Thromboprophylaxis<br>
     vs without</td>
   <td colspan="2">Extended duration<br>
     Thromboprophylaxis vs standard</td>
  </tr>
  <tr>
   <td>RCTs</td>
   <td>Observational<br>
     studies</td>
  </tr>
  <tr>
   <td><b>3.5%</b><br>
     (95% CI: 1.6–6.1)</td>
   <td><b>2.4% vs 3.5%</b><br>
     (95% CI: 0.9–4.7) vs<br>
     (95% CI: 2.0–5.4)</td>
   <td><b>Non significant<br>
      reduction<br>
      2.4% vs 2.0%</b><br>
     (RR: 1.2)</td>
   <td><b>Statistically significant<br>
      reduction<br>
      4.0% vs 4.9%</b><br>
     (RR: 1.0)</td>
  </tr>
 </tbody>
</table>

<p>Including observational studies in this systematic review, may be more representative of current clinical practice and better capture the real-world effectiveness of LMWH prophylaxis by including a much broader patient population.</p>
<p>30-day event rates remain important information to establish risk-benefit ratio on the duration of thromboprophylaxis for adult patients who underwent abdominopelvic cancer surgery.</p>
<h2>Study findings suggest:</h2>
<ul>
 <li>Although, extended duration thromboprophylaxis reduces VTE risk, the absolute clinical benefit of reduction in symptomatic VTE events is relatively low</li>
</ul>
<h2>Limitations</h2>
<p>Possibility of bias<sup>‡</sup>&nbsp;due to inclusion of observational studies and RCTs together with studies reporting of asymptomatic events</p>
<p>High levels of statistical heterogenecity<sup>§</sup>&nbsp;in the pooled analysis</p>
<p>Absence of detailed description of patient population or procedures performed in most studies</p>
<p>The rates of fatal pulmonary embolism were not consistently reported and could not be assessed with the meta-analysis.</p>
<p data-font="legal">* Based on underlying risk of bleeding, costs and patient's values and preferences.<br>
  † Subgroup analysis of VTE incidence data from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) have not been provided as they did not report on thromboprophylaxis.<br>
  ‡ Selection bias, confounding and misdiagnosis bias.<br>
  § With respect to different cancer types, modes of surgical intervention and type/dose/duration of thromboprophylaxis.</p>

Duration of thromboprophylaxis following major abdominopelvic cancer-related surgery

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