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Clinical Scenario

Clinical Scenario.

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Clinical Scenario

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  1. Clinical Scenario Pt is a 36 year old woman who is admitted with acute onset shortness of breath and pleuritic chest pain. Pulse oximetry is 88% on room air. CXR is unremarkable. Pt undergoes spiral CT which reveals acute PE in the right branch of pulmonary artery. Lower extremity dopplers reveal acute DVT in the right popliteal vein. Pt has no significant PMHx, is on no medications, and is a non-smoker.

  2. Clinical Questions • What recommendations should be made for this patient? • What should be the Goal INR? • What should be the duration of anticoagulation?

  3. Long-Term, Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism New England Journal of Medicine Volume 348(15): 1425-1434 April 10, 2003

  4. Introduction • Standard therapy to prevent recurrent venous thromboembolism includes 3 to 12 months of treatment with full dose warfarin with a target INR of 2.0-3.0. • After cessation of anticoagulation therapy, recurrent venous thromboembolism is a major clinical problem, estimated rate of 6-9% annually. • For long-term management however, no therapeutic agent has shown an acceptable benefit to risk ratio

  5. Introduction • Extended use of full-dose warfarin is associated with reduced rates of recurrent venous thromboembolism, but also associated with rates of major bleeding episodes ranging from 5-9% annually. • In contrast, low-intensity warfarin carries low risk of bleeding when used on a long-term basis and may require less frequent monitoring.

  6. Introduction • The PREVENT trial was initiated to test the hypothesis that long-term, low-intensity warfarin therapy (INR 1.5-2.0) might provide a safe and effective method of reducing the risk of recurrent venous thromboembolism among patients who have had a previous idiopathic venous thromboembolism

  7. MethodsStudy Patients • Men and women 30 years of age or older with documented idiopathic venous thromboembolism eligible: • Completed >3 uninterrupted months of full dose warfarin • Documented venous thromboembolism by objective criteria including Dopplers or MRI in case of DVT and by V/Q, CT, or angiography in case of PE • Event did not occur within 90 days of surgery or trauma

  8. MethodsStudy Patients • Exclusion criteria: • h/o metastatic cancer • Major GI bleeding • Hemorrhagic CVA • Life expectancy of less than 3 years • On dipyridamole, ticlopidine, plavix, heparin, >325mg ASA, or drugs that affect PT • Known lupus anticoagulant Abs and anti-Phospholipid Abs

  9. MethodsStudy Design • Run-In Phase • 28-day open label phase • Patients started on steady dose of warfarin, not exceeding 10mg/day to achieve INR of 1.5-2.0 • Used to exclude patients with level of compliance of <85% • Randomization Phase • Patients randomized to low-intensity warfarin or placebo groups • Patients followed once every 2 months, including blinded evaluations of INR with dose adjustment

  10. MethodsFollow-up and Study Endpoints • No surveillance for asymptomatic thrombosis undertaken • Endpoint of recurrent DVT confirmed by either positive venographic Doppler or MRI • Endpoint of PE confirmed with either positive angiogram, V/Q with at least 2 segmental defects without ventilation defects, or CT/MRI with clear evidence of thrombosis. • Major hemorrhage defined as any bleeding episode that led to hospitalization or transfusion

  11. MethodsStatistical Analysis • Wilcoxon rank-sum test used for comparisons between treatment groups in the distribution of continuous variables • Chi-square used for comparison of categorical variables • Primary analysis was intention to treat comparison, with a 2-sided log-rank of 2 treatment groups in terms of time to the first confirmed recurrent VTE after randomization • Kaplan-Meier method used to estimate the probability of recurrence over time in each treatment group • Proportional hazard model used to estimate relative hazard of recurrent events associated with low-intensity warfarin treatment and obtained CIs from this model

  12. Table 1. Baseline Characteristics of the Study Participants

  13. ResultsPatients, Therapy, and Evaluations of INR • 578 patients entered the 28-day run-in phase between 7/98-12/02 • Trial was terminated early as adequate data had been obtained • 508 patients had undergone randomization: 253 placebo, 255 low-intensity • Mean duration of follow-up after randomization was 2.1 years, with maximal duration of treatment of 4.3 years • Median INR in placebo group was 1.0 (range 1.0-1.1), in warfarin group 1.7 (range 1.4-2.0) • Median dose of warfarin was 4mg (3-6mg)

  14. Table 2. Major Study End Points According to Treatment Group

  15. ResultsRecurrent Venous Thromboembolism • 51 confirmed recurrences of venous thrombosis after randomization • 39 involved DVT only • 12 involved PE • 86% idiopathic • 14% associated with new diagnosis of cancer, recent surgery, or trauma • Placebo group (253 patients) • 37 with confirmed recurrent venous thromboembolism (7.2 per 100 person years) • Warfarin group (25 patients) • 14 with confirmed recurrent venous thromboembolism (2.6 per 100 person years); risk reduction of 64%, p<0.001

  16. Figure 2. Cumulative Risk of the Primary Study Endpoint…

  17. ResultsRecurrent Venous Thromboembolism • Cumulative risk of recurrent venous thromboembolism shown in Figure 2 • Low intensity warfarin had similar efficacy in prevention of early and late recurrent events • On basis of these rates 10 patients would need to be treated for 3 years to prevent one recurrent event • No significant interactions between the magnitude of the reduction in risk and categories of age, time since randomization, time since cessation of full dose warfarin therapy, or number of previous venous thromboembolic events

  18. ResultsBleeding Episodes • Placebo group • 2 patients with bleeding necessitating hospitalization (0.4 per 100 person years) • 34 patients with minor bleeding/bruising • Warfarin group • 5 patients with bleeding necessitating hospitalization (0.9 per 100 person years) • 3 involved GI bleeds • 1 hematoma in the leg • 1 hematuria associated with removal of kidney stone • 60 patients with minor bleeding/bruising • Difference between placebo and warfarin groups was non-significant p=0.25

  19. ResultsDeath, Stroke, and Other Endpoints • Placebo group • 8 deaths; 3 fatalities- 2 fatal PEs, 1 fatal hemorrhagic CVA • 2 confirmed CVAs • 9 with new diagnosis of cancer • Warfarin group • 4 deaths (p=0.26) • 1 confirmed CVA • 4 with new diagnosis of cancer (p=0.18) • Rate of composite end point (recurrent venous thromboembolism, major hemorrhage, or death from any cause) was reduced by 48% in warfarin group (p=0.01)

  20. Discussion • This randomized, double-blind, placebo-controlled trial demonstrates that long-term, low-intensity warfarin therapy given with a target INR of 1.5-2.0 results in a large and significant reduction in the risk of venous thromboembolism, with little evidence of any increase in the risk of major hemorrhage or stroke, despite infrequent monitoring of anticoagulation therapy • It is concluded in this study that long-term low-intensity warfarin therapy is a highly effective method of preventing recurrent VTE compared to placebo.

  21. Discussion • Previous studies demonstrated short term use of full dose warfarin is highly effective after a first episode of venous thromboembolism • On the basis of evidence from randomized trials, usual care typically includes full dose warfarin therapy for up to 12 months • Use of full dose warfarin for longer than 1 year continues to provide efficacy in preventing recurrent events (compared to placebo)

  22. Discussion • Full dose warfarin preliminarily shown to provide greater reduction in the rate of recurrent venous thromboembolism compared to low dose warfarin • However, rates of major bleeding episodes were high during extended therapy with full dose warfarin • This raises the question regarding the net clinical benefit for long term warfarin therapy with target INR of 2.0-3.0

  23. Comparison of Low-Intensity Warfarin Therapy with Conventional Intensity Warfarin for Long-term Prevention of Recurrent Venous Thromboembolism New England Journal of Medicine Volume 349(7): 631-639 August 14, 2003

  24. Introduction • Unprovoked venous thromboembolism is associated with a higher risk of recurrent thrombosis after the discontinuation of anticoagulant therapy than is thrombosis that is associated with a transient risk factor • It had been previously shown that in patients who had an episode of unprovoked venous thrombosis it was better to continue warfarin therapy for an additional 2 years than to discontinue treatment after 3 months • In that study and another trial of anticoagulant therapy in patients who had had 2 episodes of venous thrombosis, no patient had recurrent thrombosis while receiving extended warfarin therapy adjusted to achieve an INR of 2.0-3.0.

  25. Introduction • This suggests that anticoagulant therapy that achieves an INR of 2.0 may be of greater intensity than is necessary for effective long-term prevention of recurrent venous thromboembolism • In both earlier studies, risk of bleeding was a limitation of extended warfarin therapy

  26. MethodsStudy Patients • Consecutive patients with one or more episodes of unprovoked venous thromboembolism were eligible if they had completed 3 or more months of oral anticoagulation at conventional intensity • Unprovoked venous thromboembolism defined as objectively confirmed, symptomatic, proximal DVT or PE that occurred in absence of a major risk factor for thrombosis • Risk factors included: • Fracture or plaster casting of leg • Hospitalization with confinement to bed for 3 consecutive days • Surgery with general anesthesia lasting longer than 30 minutes • Cancer that had been active within the previous 2 years

  27. MethodsStudy Patients • Patients were ineligible if they had: • Other indications for warfarin therapy • Contraindication to long-term warfarin therapy (including high risk of bleeding) • Antiphospholipid antibodies (patients with other hypercoagulable states were eligible) • Allergy to contrast medium • Life expectancy of less than 2 years

  28. MethodsRandomization and Treatment • Randomization of patients with stratification according to clinical center and according to whether the patient had completed 3-4 months or >4 months of initial anticoagulant therapy • Computer algorithm generated lists in which patients were assigned to either • long-term, low-intensity warfarin therapy (INR 1.5-1.9) or • conventional-intensity warfarin therapy (INR 2.0-3.0)

  29. MethodsRandomization and Treatment • After enrollment, all subsequent measures of INR forwarded to the center-specific anticoagulation monitor who was not involved in the patients’ care • For patients in conventional-intensity therapy this monitor relayed the true INR results • For patients in low-intensity therapy, the monitor converted the INR results to a higher value with the use of a predefined table, then this higher value was relayed to research personnel at each center, who then provided instructions to patients about adjusting dose of warfarin • This procedure maintained the double-blind design of the study • The frequency of INR monitoring was left to the discretion of the clinical center

  30. MethodsFollow-up and Outcome Measures • Patients were assessed every 6 months and were told to report to the center immediately if symptoms developed that were suggestive of venous thromboembolism or if they had bleeding • Suspected recurrent venous thromboembolism was evaluated by objective diagnostic testing • No surveillance was performed to detect asymptomatic venous thromboembolism • Bleeding was defined as major if it was: • Clinically overt • Associated with a decrease in hemoglobin level of at least 2g • Need for transfusion of two or more units of RBCs • Bleeding at a critical site (retroperitoneal or intracranial)

  31. MethodsLaboratory Assays • Assays for Factor V Leiden and the G20210A mutation in the prothrombin gene were performed in a central laboratory • Results not made available to clinical centers during the study

  32. MethodsStatistical Analysis • Trial designed to establish whether low-intensity warfarin therapy would cause less bleeding than conventional-intensity therapy and would be similarly effective at preventing recurrent thrombosis • Expected rate of major bleeding episodes in conventional therapy group: 3.0 per 100 patient years and in low-intensity therapy group: 1.0 per 100 patient years • Average of 2.5 years of follow-up per patient • Loss to follow-up of <5% of total patient years • With these assumptions, 357 patients needed in each group to be able to detect a reduction in the incidence of major bleeding with a power of 90%, with a 5% chance of an incorrect conclusion that low-intensity therapy caused less bleeding • Kaplan-Meier methods were used to analyze each type of outcome event • Hazard ratios and log-rank tests used to compared treatment groups • Cox proportional-hazards model and likelihood ratio test used to assess the influence of variables on the relation between treatment-group assignment and outcome and to determine whether there was any evidence of interactions between treatment and covariates • All reported p values are 2-sided

  33. ResultsStudy Patients • Patients recruited at 16 clinical centers from 12/98 to 5/01 and follow up stopped in 6/02. • Total of 1455 patients met criteria for inclusion, 366 of which met criteria for exclusion • Four most common reasons for exclusion were: • Another indication for warfarin (101) • Life expectancy of less than 2 years (98) • Contraindication to long term warfarin therapy (45) • Antiphospholipid Antibody (31)

  34. Table 1. Baseline Characteristics of the Patients

  35. ResultsStudy Patients • Of the 1089 eligible patients, 738 (68%) provided written consent and were randomly assigned to continue conventional intensity therapy (369 patients) or to receive low-intensity therapy (369 patients). Table 1

  36. ResultsTreatment and INR Evaluations • Mean duration of follow-up was 2.4 years in both groups • Mean period patients received double-blind treatment was 2.1 years in low-intensity therapy group and 2.2 years in the conventional therapy group • Double blind treatment was permanently discontinued in 84 patients assigned to low-intensity therapy and in 58 patients assigned to the conventional therapy

  37. ResultsTreatment and INR Evaluations • Mean INR was 1.8 among patients assigned to low-intensity therapy and 2.4 among those assigned to conventional intensity therapy • Low-intensity group had an INR of • 1.5-1.9 during 63% of the time • Below 1.5 18% of the time • Above 1.9 19% of the time • Average time between INR checks 24 days • Conventional intensity group had an INR of • 2.0-3.0 during 69% of the time • Below 2.0 20% of the time • Above 3.0 11% of the time • Average time between INR checks 26 days

  38. Table 2. Main Outcomes According to Treatment Group

  39. ResultsBleeding Complications • Low-intensity group • 9 major bleeding episodes (1.1 per 100 person years) • 39 major and minor bleeding episodes (4.9 per 100 person years) • 7/9 INR values recorded: 1.7, 1.7, 2.9, 4.9, 5.3, 7.2, 11.3 • None with intracranial bleed or were fatal • 5 treated with transfusion, 5 resulted in hospital admission • Conventional-intensity group • 8 major bleeding episodes (0.9 per 100 person years) • 31 major and minor bleeding episodes (3.7 per 100 person years) • 8/8 INR values recorded: 1.9, 2.7, 2.9, 2.9, 3.1, 3.7, 3.8, 7.7 • None were intracranial bleed or fatal; 2 subdural hematomas caused by falls, 1 spinal hematoma • 4 treated with transfusion, 7 resulted in hospital admission • No interaction with baseline variables and hazard of bleeding with low-intensity compared to conventional-intensity therapy

  40. ResultsBleeding Complications • Higher rate of bleeding episodes among patients 65 years or older • Rate increased with the number of predefined risk factors for bleeding: • Age>65 • Previous stroke • Previous PUD • Previous GI bleed • Renal impairment • Anemia • Thrombocytopenia • Liver disease • DM • Use of anti-platelet therapy

  41. ResultsRecurrent Venous Thromboembolism • Low-intensity group had 16 episodes of recurrent thromboembolism • 1 fatal PE, 2 non-fatal PEs, 13 DVTs (1.9 events per 100 person years) • 5/16 occurred after warfarin therapy discontinued • 11/16 during therapy • INRs: 1.4, 1.5, 1.5, 1.8, 1.8, 1.9, 2.1, 2.1, 3.1 • Rate of reoccurrence 1.4 events per 100 person years • Conventional-intensity group had 6 episodes • 2 fatal PEs, 4 DVTs (0.7 events per 100 person years) • 3/6 occurred after warfarin therapy was discontinued • 3/6 during therapy • INRs: 1.7, 1.9 • Rate of reoccurrence 0.4 events per 100 person years • Cumulative probability of recurrent venous thromboembolism shown in Figure 2; the difference was statistically significant (p=0.03)

  42. Figure 2. Cumulative Probability of Recurrent Venous Thromboembolism

  43. ResultsRecurrent Venous Thromboembolism • Rates of recurrent venous thromboembolism did not differ according to whether patients had presented with DVT or PE (p=0.51), whether they had abnormal results on compression US at enrollment (p=0.82), or whether they had Factor V Leiden or G20210A mutation (p=0.21)

  44. ResultsDeaths • 16 deaths in the Low-intensity therapy group • 1 PE, 7 cancer, 8 other causes • Conventional-intensity therapy group • 2 PEs, 1 cancer, 5 other causes

  45. Discussion • Conventional-intensity warfarin therapy is more effective than lo-intensity warfarin at preventing recurrent thrombosis in patients who have had unprovoked venous thromboembolism, reducing their risk by two-thirds. • Low-intensity regimen did not reduce the frequency of bleeding, which was low with treatment of either intensity • These findings were consistent among various subgroups

  46. Discussion • Findings consistent with PREVENT study a placebo-controlled trial which evaluated warfarin therapy with a target INR of 1.5 to 2.0 for extended treatment of patients who had unprovoked venous thromboembolism. • In the PREVENT study rate of major bleeding was 0.9 per 100 person-years, and the rate of recurrent venous thromboembolism was 2.6 per 100 person years • Rates were similar to this study’s low-intensity therapy group (1.1 and 1.9 events per 100 person years) • Results of this study along with 3 other trials indicate that low-intensity anticoagulant therapy reduces the risk of recurrent thrombosis by about 75%, whereas conventional-intensity therapy reduces this risk by over 90%

  47. Conclusion • The intensity of anticoagulant therapy for patients who have an unprovoked venous thromboembolism should not be reduced after the first three months of treatment • Such a reduction increases the risk of recurrent thrombosis and there is no evidence that it reduces the risk of bleeding • Long-term conventional-intensity warfarin therapy is very effective at preventing recurrent thrombosis and is associated with a low frequency of bleeding.

  48. Validity • In both of these studies • Random assignment to treatment groups • Use of double blind design with an intention to treat • Objective diagnosis of recurrent venous thromboembolism • Adequate follow-up • Lacked mention of power of study

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