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P Clot Trial

Introduction

Venous thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary embolism (PE), and splanchnic vein thrombosis, is a frequent complication of cancer.1 The development of cancer-associated VTE is associated with reduced quality of life and places a significant economic burden on both the patient and the health care system.2 VTE is the second-leading cause of death in cancer outpatients receiving chemotherapy and has been shown to be an independent predictor of mortality in the population of patients with cancer.3,4 The management of cancer-associated VTE treatment can be challenging because the risks of recurrent VTE and anticoagulant-related bleeding are high despite appropriate management.5 In addition, drug interactions and cancer-related comorbidities, such as renal and/or hepatic dysfunction, decreased oral intake, chemotherapy-induced nausea and vomiting, and thrombocytopenia also add to treatment complexity by limiting the choice of anticoagulant agent.

Clinical Trials Evaluating Low Molecular Weight Heparin for the Treatment of Cancer-Associated VTE

In STAR, women in the raloxifene group had 28 percent fewer deep-vein thromboses (blood clots in a major vein) and 20 percent fewer pulmonary embolisms (blood clots in the lung) than women on tamoxifen: 118 of 9,736 women in the tamoxifen group had a deep-vein thrombosis compared to 86 of 9,754 women in the raloxifene group. Kellner pointed to the more detailed results presented by the trial’s surgical co-chair Issam Awad, MD (University of Chicago, IL), showing that there is a significant relationship between a lesser amount of residual clot and a greater likelihood of achieving a good functional outcome.

  1. Patients with residual flow and a shorter clot length (≤15 mm) were most likely to reperfuse (70.6%). Patients with clots in the M1 MCA without residual flow reperfused more if clots were distal and had a clot interface ratio in Hounsfield units of clots without residual flow reperfused 8% of the time.
  2. In STAR, women in the raloxifene group had 28 percent fewer deep-vein thromboses (blood clots in a major vein) and 20 percent fewer pulmonary embolisms (blood clots in the lung) than women on tamoxifen: 118 of 9,736 women in the tamoxifen group had a deep-vein thrombosis compared to 86 of 9,754 women in the raloxifene group.

The long-term use of low molecular weight heparin (LMWH) for the treatment of VTE in patients with active cancer is recommended as first-line therapy based on the results of multiple open-label randomized controlled trials (RCTs).6,7 The two largest studies published to date, the CLOT (Comparison of Low-molecular-weight heparin versus Oral anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer) and CATCH (Comparison of Acute Treatments in Cancer Haemostasis) trials, compared a LMWH to vitamin K antagonist therapy in patients with active cancer and acute symptomatic proximal DVT or PE. See Table 1 for baseline characteristics and Table 2 for study results.8,9 Both trials used an open-label study design, the same target international normalized ratio (INR) in the vitamin K antagonist control arm, the same active cancer definition, and the same duration of treatment and had comparable patient eligibility criteria.

P Clot Trial Test

Table 1: Study Design and Baseline Characteristics of the CATCH and CLOT Trials

Table 2: Outcomes in the CLOT and CATCH Trials

The CLOT trial, published in 2003, randomized 676 patients to receive dalteparin (200 IU/kg daily for 1 month followed by 150 IU/kg daily for 5 months) or vitamin K antagonist (warfarin or acenocoumarol with target INR 2.5 for a total of 6 months with an initial 5-7 days overlap with dalteparin 200 IU/kg).8 Symptomatic recurrent DVT or PE, including death related to PE, was observed in 27 patients (7.0%) randomized to dalteparin and in 53 patients (15%) randomized to vitamin K antagonist (hazard ratio [HR] 0.48; 95% confidence interval [CI], 0.30-0.77; p = 0.002). No difference in the rates of major bleeding (6 vs. 4%; p = 0.27), any bleeding (15 vs. 19%; p = 0.09), or death (39 vs. 41%; p = 0.53) were observed between the 2 groups.

In the CATCH trial, published over 10 years later in 2015, 900 patients were randomized to tinzaparin (175 IU/kg daily without dose reduction) or warfarin (target INR 2.0-3.0 with initial tinzaparin 175 IU/kg overlap for 5-10 days) for a total of 6 months.9 The primary composite endpoint of recurrent VTE including incidental proximal DVT and PE occurred in 31 patients (6.9%) in the tinzaparin arm and 45 patients (10%) in the warfarin arm (HR 0.65; 95% CI, 0.41-1.03; p = 0.07). Symptomatic DVT occurred in significantly fewer patients treated with tinzaparin (2.7 vs. 5.3%; HR 0.48; 95% CI, 0.24-0.96; p = 0.04). Although major bleeding rates were similar in both arms, a significant reduction in clinically relevant, non-major bleeding was observed with tinzaparin (10.9 vs. 15.3%; HR 0.58; 95% CI, 0.40-0.84; p = 0.004). Mortality was similar in both groups, with approximately one-third of patients dying during the study period (33.4 vs. 30.6%; p = 0.54). Although tinzaparin did not significantly reduce the primary composite endpoint of recurrent VTE, the CATCH study results do support the use of long-term LMWH as the preferred treatment for cancer-associated VTE due to a lower risk of clinically relevant major bleeding and a significant reduction in recurrent DVT.

The failure of the CATCH trial to meet statistical significance for the primary endpoint may be due to the lower-than-expected recurrent VTE rate observed in the warfarin arm. One possible explanation for this observation could be an improvement in warfarin management in the CATCH trial. However, similar levels of INR control in both studies argue against this (time in therapeutic range was 46% in CLOT vs. 47% in CATCH; time above the therapeutic range was 24% in CLOT vs. 27% in CATCH). A more likely explanation is a bias in the selection of 'less sick' patients for enrollment in the CATCH trial. Although the CATCH and CLOT studies used similar inclusion and exclusion criteria, key differences in baseline characteristics exist between the two patient populations, particularly with respect to thrombotic and prognostic risk factors. A higher proportion of patients in the CLOT trial were receiving active cancer treatment (72% CLOT vs. 53% CATCH), had a history of prior VTE (11% CLOT vs. 6% CATCH), had evidence of metastatic disease (67% CLOT vs. 55% CATCH), and had a poorer performance status (Eastern Cooperative Oncology Group score of 2 in 36% CLOT vs. 23% CATCH). In addition, mortality during the 6-month treatment period was also higher in the CLOT population (39% CLOT vs. 32% CATCH). Thus, the CATCH patient population likely had a lower inherent risk of recurrent VTE compared with CLOT study patients. It is highly probable that investigators did not enroll patients into CATCH if they felt LMWH would be more beneficial than warfarin, resulting in the selective enrollment of patients who were less likely to develop recurrent VTE.

Trials Evaluating Direct Oral Anticoagulants in Cancer-Associated VTE

Patient selection bias is even more evident in the recent randomized trials evaluating the efficacy and safety of direct oral anticoagulants (DOACs) for treatment of acute VTE.10 These oral anticoagulants have been extensively studied over the last decade in atrial fibrillation, VTE treatment, and VTE prevention. In the landmark phase III clinical trials for acute VTE treatment, it was consistently demonstrated that DOACs are non-inferior to warfarin (pooled relative risk [RR] 0.90; 95% CI, 0.77-1.06) in preventing recurrent VTE, and they have a similar or reduced risk of major bleeding (pooled RR 0.40; 95% CI, 0.45-0.83).11 Among those patients who were classified as having 'cancer' or 'active cancer' in these studies, DOACs also seem to perform similarly to warfarin.12 But a more in-depth examination of these post-hoc data reveals important patient-selection bias and questions the generalizability of the DOAC trial results to 'real life' patients with cancer with VTE. In addition to the heterogeneous definitions of 'active cancer' used in these trials that differed from the CLOT and CATCH trials, important determinants of recurrent VTE and bleeding were also very different in the DOAC patients with cancer from the LMWH cancer-specific trials (Table 3). These include presence of metastatic disease and concomitant use of anticancer therapy. The vast differences in mortality during the study period also argue that very different groups of patients with 'cancer' were included in the DOAC versus LMWH trials. Furthermore, unlike LMWH, which is associated with a significant reduction in risk of recurrent VTE compared with vitamin K antagonists (RR 0.52; 95% CI, 0.36-0.74), DOACs did not significantly reduce this risk in a meta-analysis of 1,132 patients with cancer enrolled in the EINSTEIN clinical trial program, HOKUSAI-VTE (Edoxaban Versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism), RECOVER (Efficacy and Safety of Dabigatran Compared to Warfarin for 6-Month Treatment of Acute Symptomatic Venous Thromboembolism), and AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) RCTs (RR 0.66; 95% CI, 0.39-1.11).10 All these considerations should caution the unselected use of DOACs in patients with active cancer and acute, symptomatic VTE.13

Table 3: Study Design and Baseline Characteristics of the Subgroups of Patients With Cancer From the Phase III DOAC Trials

Conclusions

All major evidence-based consensus guidelines recommend LMWH for the initial and long-term treatment of cancer-associated VTE.6,7,13 This recommendation is based on the observation that LMWH not only is more effective than warfarin for the prevention of recurrent VTE, but also offers additional advantages over oral agents including stable anticoagulation in patients with poor oral intake, a lack of drug interactions, and clinical experience in the management of anticoagulation surrounding invasive procedures and thrombocytopenia. Although DOACs are not currently recommended for VTE treatment in patients with cancer, RCTs comparing rivaroxaban and edoxaban to LMWH are currently ongoing and will help to clarify their role in cancer-associated VTE.6,13

References

  1. Khorana AA, Dalal M, Lin J, Connolly GC. Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer 2013;119:648-55.
  2. Kourlaba G, Relakis J, Mylonas C, et al. The humanistic and economic burden of venous thromboembolism in cancer patients: a systematic review. Blood Coagul Fibrinolysis 2015;26:13-31.
  3. Kuderer NM, Ortel TL, Francis CW. Impact of venous thromboembolism and anticoagulation on cancer and cancer survival. J Clin Oncol 2009;27:4902-11.
  4. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5:632-4.
  5. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-8.
  6. Lyman GH, Bohlke K, Khorana AA, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update 2014. J Clin Oncol 2015;33:654-6.
  7. Streiff MB, Holmstrom B, Ashrani A, et al. Cancer-Associated Venous Thromboembolic Disease, Version 1.2015. J Natl Compr Canc Netw 2015;13:1079-95.
  8. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-53.
  9. Lee AY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients With Active Cancer: A Randomized Clinical Trial. JAMA 2015;314:677-86.
  10. Carrier M, Cameron C, Delluc A, Castellucci L, Khorana AA, Lee AY. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res 2014;134:1214-9.
  11. van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014;124:1968-75.
  12. Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest 2015;147:475-83.
  13. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-52.
  14. Agnelli G, Büller HR, Cohen A, et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost 2015;13:2187-91.
  15. Prins MH, Lensing AW, Brighton TA, et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014;1:e37-46.
  16. Raskob GE, van Es N, Segers A, et al. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol 2016;3:e379-87.
  17. Schulman S, Goldhaber SZ, Kearon C, et al. Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. Thromb Haemost 2015;114:150-7.

Clinical Topics:Anticoagulation Management, Arrhythmias and Clinical EP, Cardio-Oncology, Pulmonary Hypertension and Venous Thromboembolism, Anticoagulation Management and Atrial Fibrillation, Anticoagulation Management and Venothromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias

Clot

Keywords:Cardiotoxins, Cardiotoxicity, Heparin, Low-Molecular-Weight, Warfarin, Anticoagulants, International Normalized Ratio, Acenocoumarol, Dalteparin, Antithrombins, Venous Thromboembolism, Risk Factors, Atrial Fibrillation, Outpatients, Research Personnel, Quality of Life, Pyridones, Pyrazoles, Pyridines, Thiazoles, Venous Thrombosis, Pulmonary Embolism, Thrombosis, Thrombocytopenia, Comorbidity, Hemostasis, Neoplasms


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blog homePersonal Injury Signs That You May Have a Blood Clot

Blood clots are one of the leading causes for death in the United Sates. According to the Centers for Disease Control and Prevention (CDC), one American dies of a blood clot every six minutes. Shockingly, many medical professionals overlook the signs of blood clots, and fail to catch the issue in time to administer proper care. Knowing the signs yourself can help you determine when you need emergency treatment.

The Danger of Blood Clots

A blood clot is a small lump of blood cells that have fused together in a hardened state. Everyone develops blood clots at some point in their lives, as these clots help people from continuing to bleed after suffering a cut. They are, essentially, scabs. However, when clots detach from the inside of a blood vessel and begin to travel through the bloodstream, they can become very dangerous.

A blood clot can float freely until it reaches a vessel too tight to pass through. At that point, it will become stuck, blocking blood to the vessel’s end destination. This may happen in an arm or leg, or it could happen in the heart, brain, or lungs. Wherever blood travels, so can a blood clot, meaning a clot can become lodged almost anywhere in the body.

Blood clots become particularly dangerous when they reach the heart, brain, and lungs. There, they can cause extreme damage, such as a stroke or heart attack, or organ death due to lack of oxygen. If these clots are not treated swiftly, they will likely become fatal. That is why medical professionals need to suspect blood clots first when a patient has symptoms or is in a high-risk group.

How to Spot a Blood Clot

Not everyone who has developed a blood clot shows symptoms, which can make it difficult to detect. In fact, late diagnosis is one of the leading causes of blood clot fatalities. However, even when symptoms do become apparent, they are often chalked up to other disorders, leading to an incorrect diagnosis. Knowing the signs can help you identify when you may have a blood clot, and allow you to get emergency care as soon as possible.

If you have a blood clot in your arm or leg, known as deep vein thrombosis (DVT), then you may experience:

  • Swelling in the impacted limb
  • Pain or tenderness in the impacted limb
  • Abnormally warm skin in the impacted limb
  • Discoloration of the skin on the impacted limb, usually red or blue

However, if you have a blood clot in the lungs (pulmonary embolism) or heart (cardiac embolism), then your symptoms can include:

  • Difficulty breathing
  • Coughing up blood
  • Shortness of breath
  • Intense chest pain
  • Irregular or fast heartbeat

If you have a blood clot in one of the arteries leading to your brain, you may have an ischemic stroke. However, strokes, especially in low-risk patients such as people below the age of 60, can be overlooked by medical professionals. Symptoms of an ischemic stroke include:

  • Difficulty speaking
  • Difficulty understanding others
  • Paralysis of the face
  • Difficulty seeing out of one or both eyes
  • Intense headaches
  • Difficulties maintaining balance and walking

Always keep in mind that blood clots are life-threatening. If you are unsure as to whether you are suffering from a blood clot, get checked out anyway. This is especially important these days because COVID-19 places people at a higher risk for developing blood clots — if you have been treated for COVID recently, you are a high-risk blood clot patient.

How Hospital Stays Can Harm

It is possible that your blood clot came about as the result of medical malpractice, especially if you developed it after a surgery or a lengthy stay in the hospital. Being confined to a hospital bed, or being unconscious for several hours during a surgery, can increase your chances of developing a deadly blood clot. Doctors and surgeons can minimize the formations of a blood clot in these cases, but often neglect to do so.

For example, during surgery, a serial compression device could be used on your limbs to promote proper blood floor. Or doctors could administer a blood-thinning, anti-coagulant drug to prevent your blood from clotting. Despite having these tools, medical professionals often overlook the risk of blood clots, which leads to patients becoming ill or even dying.

Seek Medical Help

If you are showing signs of a blood clot, then you need to seek medical help as soon as you can. DVT is not immediately life-threatening, which means you can call you general practitioner and set up an appointment. However, if you have the symptoms of a heart, lung, or brain-related clot, visit the emergency room immediately.

P Clot Trial Definition

If you believe that you suffered a blood clot due to the actions of a medical professional, then you should file a lawsuit. Getting compensation, however, will require the help of a top medical malpractice attorney. Thankfully, you can find plenty of them at our firm, Leventhal Puga Braley P.C. Call us at (303) 759-9945 or toll-free at (877) 433-3906 to schedule a no-cost consultation.

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