Prevention and Treatment of Venous Thromboembolism by stephan2

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									Prevention and Treatment of
 Venous Thromboembolism
       Franklin A. Michota, M.D.
        Assistant Professor of Medicine
    Director, Hospital Medicine Fellowship
Associate Director, Internal Medicine Residency
      Head, Section of Hospital Medicine
        The Cleveland Clinic Foundation
                                                  1
                          VTE Mortality
      • PE accounts for 10% of in-hospital
        mortality
         – 1-week survival following PE is only 71%
      • 25% of all PE cases present as sudden
        death
         – Pre fatal PE is not recognized
         – Death from PE occurs before our
           treatments are effective
      • 50% of PE deaths are preventable
Heit JA et al. Arch Int Med. 1999                     2
 30% of VTE survivors
  will develop serious
venous stasis syndrome
       in 10 years
                             Mohr et al. Mayo Clin Proc. 2000
                                                            3
                         Prandoni et al. Ann Intern Med. 1996
                Venous Thrombosis
                   Estimated Annual Incidence

                                   DVT
                                  2 Million



             Post-
                                       PE     Silent PE
          Thrombotic              600,000     1 Million
           Syndrome
            800,000
                                               Pulmonary
                                 Death        Hypertension
                                  100,000       30,000

         Estimated Cost of VTE Care $1.5 Billion/year
Goldhaber. Lancet 1999;353:1386-1389
       Incidence of VTE Verified by
         Necropsy Over 30 Years
                            % of Necropsy Finding
     Year            VTE            PE      Fatal PE
     1957            34.3%          21.0%   8.9%
     1964            31.3%          22.4%   8.3%
     1975            35.1%          24.4%   5.9%
     1987            34.75          26.1%   9.4%

Lindblad et al. BMJ 1991; 302:709                      5
                                  Adjusted Incidence Per
                                 100,000 of all VTE by Year
  Adj. Incidence per 100,000




                               160
                               140
                               120
                               100                                             DVT
                               80                                              PE+DVT
                               60                                              All VTE
                               40
                               20
                                0
                                     1966   1970   1975   1980   1985   1990
                                                      Year

Silverstein, et al. Arch Intern Med 1998; 158:585                                    6
          Virchow’s Triad

           HYPERCOAGULABILITY




VENOUS INJURY               STASIS
                                     7
                      Who is at risk?
                      Venous Stasis
     •   Age > 40                      • Hyperviscosity
     •   Immobilization                  syndromes
     •   Varicose veins                • Polycythemia
     •   MI                              vera
     •   CHF                           • Severe COPD
     •   Stroke                        • Anesthesia
     •   Paralysis                     • Repair or ligation
                                         of major venous
     •   Spinal cord injury              injury
Thrift Consensus Group. BMJ: 1992
Heit JA et al. Arch Intern Med. 2000                          8
                  Who is at risk?
                Endothelial Damage
     • Surgery
         – Orthopedic
         – Pelvic
         – Neurologic
         – Abdominal
     • Prior DVT
     • Central venous access
     • Trauma
Thrift Consensus Group. BMJ: 1992
Heit JA et al. Arch Intern Med. 2000   9
                   Who is at risk?
                  Hypercoaguability
     • Cancer                          • Thrombophilia
     • High estrogen states               – Activated protein C
        – Obesity, HRT, OCP,                resistance
          pregnancy,                      – ATIII deficiency
          postpartum                      – Protein C or S
     • Family history                       deficiency
     • Inflammatory bowel                 – Homocystinuria
       disease                            – Antiphospholipid Ab
     • Nephrotic syndrome                 – Lupus anticoagulant
     • Sepsis                             – Heparin-induced
     • Blood transfusions                   thrombocytopenia
Thrift Consensus Group. BMJ: 1992         – Prothrombin mutation
Heit JA et al. Arch Intern Med. 2000                               10
                           Who is at Risk?
        Prevalence of VTE risk in a typical hospital population:
        percentage of patients with at least 3 VTE risk factors




    All hospitalized                                  19% of hospitalized
  All major surgery
                                                      patients have at
                                                      least three risk
Abdominal surgery                                     factors
  Vascular surgery

     Neurosurgery
                                                                Up to 70%
           Urology
                                                                in some wards
   Cardiac surgery

                       0    10   20   30   40   50   60   70   80
                   Patients with at least three risk factors (%)
Anderson FA, et al. Arch Intern Med. 1992;152:1660-1664.                        11
VTE Risk in Surgical Patients

• Post-op DVT         • Fatal PE w/o
  – Gen Surg    20%     prophylaxis
  – Prostate    11%      – Gen Surg       1%
  – Gyn Surg    19%      – Trauma         2%
  – Neurosurg   29%      – Elective Hip   3%
  – Hip Surg    50%      – Knee Surg      3%
  – Knee Surg   65%      – Fract Hip      5%


                                               12
       VTE Prevention: Categories of Risk Are
          Defined in Surgical Populations


                      Calf DVT Proximal   Clinical   Fatal PE
                                 DVT         PE
           Low          2%      0.4%      0.2%       .002%

        Moderate      10-20%    2-4%      1-2%       .1-.4%

           High       20-40%    4-8%      2-4%       .4-1%

        Very High     40-80% 10-20%       4-10%       1-5%


Clagett et al. Chest: 2001
                                                                13
        VTE Risk in Medical Patients

                                           Gen med1,2 10-26%
    • Categories of
                                           Stroke3    11- 75%
      risk in medical
                                           MI3        17-34%
      patients have
      not been as                          SCI3       6 -100%
      well studied                         CHF4       20- 40%
                                           ICU1,5,6   25- 42%
1. Cade. Crit Care Med. 1982;10:448-450
2. Belch et al. Scott Med J. 1981;26:115-7
3. Nicolaides et al. Int Angiol. 1997;16:3-38
4. Anderson et al. Am Heart J. 1950;39:697-702
5. Dekker et al. Thromb Haemost. 1991;65:1348
6. Hirsh et al. JAMA. 1995;274:335-7                            14
         MEDENOX Trial
• Randomized,        • Cohort (Age = 72)
  double-blinded,      –   CHF = 33%
  placebo              –   Resp failure = 53%
  controlled trial     –   ID = 53%
• Enoxaparin           –   Cancer = 15%
• N=1102               –   Obesity = 20%
                       –   Previous VTE = 10%
• Outcome measure
                       –   Varicosities = 25%
  was all VTE
                       –   ERT = 2%
                     • >2 RF = 66%
                                                15
                                Results
                            Day 1-110

                                Placebo   20mg   40mg

                     20
                     18
                     16
                            Proximal DVT
     Incidence (%)




                     14
                     12
                     10
                             rate without
                      8     prophylaxis is
                      6
                      4         6-7%
                      2
                      0
                          VTE                     Prox DVT


Samama et al. N Eng J Med: 1999
                                                             16
      VTE Prevention: Categories of Risk Are
         Defined in Medical Populations


                     Calf DVT Proximal   Clinical   Fatal PE
                                DVT         PE
          Low          2%      0.4%      0.2%       .002%

       Moderate      10-20%    2-4%      1-2%       .1-.4%

          High       20-40%    4-8%      2-4%       .4-1%

       Very High     40-80% 10-20%       4-10%       1-5%



Clagett et al. Chest: 2001
                                                               17
      Adjusted Population Attributable
                   Risk
                                       CHF
                    Trauma                   CNS/paresis
    Cancer                                                 Varicosities



                              All VTE

 Hospitalization       First lifetime definite VTE Surgery
                   Olmstead County, MN (1976-1990)

Heit JA et al. Arch Intern Med. 2002                                  18
  Adjusted Population Attributable
               Risk



                         Hospitalization
                             60%




Hospitalization or nursing home residence accounted
       for 60% of the VTE in this community
                                                      19
        VTE Prevention

• Ambulation
• Elastic
  Stockings
• Arteriovenous
  Foot Pumps
• Sequential
  Compression
  Devices
                         20
              VTE Prevention
•   Aspirin
•   Warfarin
•   Heparin (UFH)
•   LMWH
• Experimental
    – Pentasaccharide*
      Thienopyridines,
      Direct Thrombin
      inhibitors (DTI),
      IIB/IIIA agents          21
             Heparin
• Discovered in 1916
• Used as an anticoagulant for over
  50 years
• Purified from animal tissues
• Polysaccharide with varying chain
  lengths
• Binds and activates antithrombin
  (ATIII)
                                      22
 Heparin is Heterogeneous

UFH



                   CLEAVAGE
                   PROCESS

LMWH

                              23
  Chemical And Enzymatic Methods
     For Preparation Of LMWH
                                                                                                                                                                      Dalteparin
                                               -                                                                                                   CO2-
                         CH2OX
                                            CO2               OSO -
                                                            CH2 3                                                              CH2
                                                                                                                                 OX                                    OSO3
                                                                                                                                                                     CH2   -
                 O           O                     O           O                                               O                   O                      O
                                                                                                      CO2 -                                                               O
        CO2-                 OX             OH                  OH              OH                     OH                      OX                  OH
         OH                                                                                                                                                          OH
      HO                                                   O                                        HO                     O                   O                 O
                         O              O
                     -                             OX                      -                                       OSO3-                                    OX               OH
                                                                                                                                                                           CH2
                 OSO3             NHY                                 NHSO3                                                          NHY
                                                          m                                                                                                      m


        Oxidation                                                                                                                                    Deaminative
                                              CH2 3-
                                                OSO                 CO2-               OX
                                                                                     CH2                                         OSO3
                                                                                                                               CH2   -               Degradation
                                                                           O             O                         O               O
                                                 O
                                                                                         OX                 CO2-                OH         OH
                                              OH                    OH                                      OH
                                        HO                                                              O                  O
                                                                O                    O
                                                            -              OX                 NHY                  OSO3-              NHSO3-
                                                       NHSO3
                                                                                                    n

     Chemical                                                                                                                                       Enzymatic
     ß-elimination                                                                                                                                  ß-elimination
     -OOC                                   CO2-              CH2 3-
                                                                OSO                             -OOC                                           CO2-                    -
                               OX
                             CH2                                                                                             OX
                                                                                                                           CH2                                     OSO3
                                                                                                                                                                 CH2
                 O               O                 O             O                                             O               O                        O            O
                             OH                                 OH              OH                                             OH                                    OH        OH
            OH                              OH                                                          OH                                     OH
                         O              O                  O                                                               O               O                     O
                 OX               NHY              OX                 NHSO3-                                   OSO3-                 NHY                OX                NHSO3-


                                                          m                                                                                                      m
Enoxaparin                                                                                                                                                           Tinzaparin
                                                                                                                                                                                    24
Characterization of LMWH
   Fareed J, SemThromb Hemost 1996; 22: 77-91



             Gradient (12-22%) Polyacrylamide Gel
                      Electrophoresis for
                   Oligosaccharide Mapping
             a - Porcine intestinal heparin
             b - LMWH by GPC fractionation
             c - Nadroparin sodium
             d - Dalteparin sodium
             e - Panaparin sodium
             f - Ardeparin sodium
             g - Enoxaparin sodium
             h - Tinzaparin sodium
                                                25
          Characteristics of UFH and
               LMWH Chains
                      5,400




                     5,000        10,000        15,000   20,000
                         Molecular weight (daltons)




Hirsh J, Levine MN. Blood. 1992; 79: 1-17
                                                                  26
      Differential Effects of UFH and
     LMWH on Factor Xa and Thrombin




Hirsh J, Levine MN. Blood. 1992; 79: 1-17    2
                                            27
             Anti-Xa:Anti-IIa Ratios for
                      LMWHs
                            Anti-Xa              Anti-IIa
                          (IU/mg dry           (IU/mg dry
                          substance)            substance)   Ratio
     Enoxaparin1              102.8                   24.9     4.1
     Nadroparin1              103.6                   29.9     3.5
     Reviparin2                127                    36       3.5
     Dalteparin1              167.2                   64.2     2.4
     Tinzaparin1              99.6                    53.7     1.9
     Certoparin1              106.4                   44.7     2.4
     UFH3                      193                    193      1.0
1.   European Pharmacopeia Commission (March 1994).
2.   Knoll Pharma
3.   Hirsh J, et al. Chest 1998;114:489S-510S.
4.   Bergqvist D, et al. Br J Surg 1995;82:496-501.                  28
          Prophylaxis Guidelines in
              Surgical Patients
  • Low Risk                 Aggressive
                             mobilization
  • Moderate risk            ES, IPC, LDUH, or
                             LMWH
  • High risk                LDUH Q8, LMWH,
                             -/+ IPC
  • Very High risk           LMWH, warfarin,
                             combination strategies
Geerts, et al. Chest 2001.                            29
         Adherence to Guidelines
   • 1995 ACCP Guidelines
   • Any prophylaxis
       – Orthopedic:                        94%
       – High-risk abdominal:               75%
   • “Grade A” prophylaxis
       – Hip replacement:                   84%
       – Knee replacement                   76%
       – Hip fracture repair                45%
       – High-risk abdominal                50%

Stratton MA et al. Arch Intern Med. 2000;
160:334-340                                       30
Investigation of the Epidemiology of Patients
         With Deep Vein Thrombosis



                                                31
         DVT FREE Study
• The largest ever epidemiological
  study of DVT
• Ultrasound-confirmed DVT/PE
   – >5,000 patients enrolled in four
     months
   – >150 urban, suburban, and rural
     hospitals throughout the U.S.
      • Hospital size up to 1368 beds
                                        32
          DVT FREE Study
• Patient status at the time of diagnosis*
  (4151)
           Only
   – OUTPATIENT 42% (N=835) (50%)
                                2061
           of inpatients were
   – INPATIENT                  2090 (50%)
              receiving some
• Inpatient status at diagnosis (2090)
           form of prophylaxis (78%)
   – NON-ICU                    1635
   – ICU                        445 (21%)
   – Mechanical ventilation     332 (16%)

                                             33
         DVT FREE Study
• Pharmacologic and mechanical
  prophylaxis within 30 days of
  diagnosis (N=835)
  – Pharmacologic        494 (56%)
  – Mechanical           181 (21%)
  – Both                 197 (22%)




                                     34
         DVT FREE Study
• Pharmacologic prophylaxis
  modalities in the last 30 days prior
  to diagnosis (N=524)
  – IV UFH                  63 (12%)
  – SC UFH                  254 (48%)
  – LMWH                    130 (25%)
  – Warfarin                174 (33%)
  – Aspirin                 205 (40%)
  – Other                   27 (5%)
                                         35
           ACCP Recommendations

• ACCP grade 1A treatment options for
  DVT prophylaxis in general medical
  patients with clinical risk factors for
  VTE (including cancer, bed rest,
  heart failure, and severe lung
  disease
    – Low-molecular-weight heparin
    – Low-dose UFH (q12 or q8)



Geerts WH, et al. CHEST 2001;119:132S-175S.   36
Enoxaparin vs UFH in the Prevention of
 Thrombosis in Non-Surgical Patients
35      Rate of thrombo-
        embolic events (%)                                          Enoxaparin
30                                 High risk                         40 mg qd
25                                                                  Heparin
                                                                    5000 IU t.i.d.
20                    Increased risk
15                                                                  Enoxaparin
                                                                    20 mg qd
10       Moderate risk
                                                                    Heparin
5                                                                   5000 IU b.i.d.
0
     Bergmann      PRIME    PRINCE 1     PRINCE 2     STROKE
        Study    (medical (respiratory    (heart    Study (PK555)
      (geriatric patients) disease)      failure)   (ischaemic
      patients)                                        stroke)
           Prophylaxis Failure?
  • Case series
  • N = 384
  • Assess whether
    patients who
    developed in-             52%
    house VTE
    received
    prophylaxis
                         ACCP Grade 1A
                          Prophylaxis
Goldhaber. Chest. 2000       Given       38
     Prophylaxis Failure?

N = 184

                                       63%




    UFH        UFH+SCD   SCD    Warfarin
    AC Combo   ES        LMWH   ES+SCD
                                             39
            VTE According to Service
                   (n=384)
                                                                 44%
            Medical
                                       16%
      Gen. surgical
                                   10%
     Med. oncology                                                   Total VTE
                                9%                                   PE
       Orthopedics                                                   DVT
                                8%
   Thoracic surgery
                                     14%
              Other

                      0   25    50     75    100   125   150   175
                                      Events (n)
Goldhaber, et al. Chest 2000;118:1680-4.                                         40
        LDUH Versus LMWH:
          Major Bleeding
4.00%                                            *P<.05
3.50%
3.00%
2.50%
                                                 LDUH
2.00%
                                                 LMWH
1.50%
1.00%
0.50%
0.00%
        Bergman       PRIME*       PRINCE*


   Bergman; 1996. Lechler; 1996. Kleber; 1998.
                                                          41
     Less Bleeding with LMWH
                    Meta-Analysis: N=4,669

                    LMWH         STD HEP     P
 Major Bleeds         0.4%         1.2%    0.05


 Overall,  52% risk reduction



Mismetti. Thromb Haemost. 2000
                                                  42
          Prophylaxis Guidelines in
              Medical Patients

 • Low Risk                         Aggressive
                                    mobilization   ?
 • Moderate risk                    LDUH or LMWH

 • High risk                        LDUH TID or LMWH

 • Very High risk                   LMWH
Michota. Clin Chest Med. 2003 (in press)               43
                                     MEDENOX
                           Survival estimates at Day 110
                                     Kaplan-Meier estimate: Logrank test, P = 0.31, Hazard ratio: 0.90. CI [0.7 to
                                     1.1]
                          1.00
Probability of survival




                                                                                                       Placebo
                          0.95                                  Enoxaparin 40 mg                        Enoxaparin 20 mg

                                                                                                        Enoxaparin 40 mg
                          0.90
                                                                             Placebo
                                                                                                       NS
                          0.85
                                                                                  Enoxaparin 20 mg


                          0.80 (1073)     (1022)        (983)        (965)        (943)        (231)
                                 0   10    20      30    40     50   60      70    80     90   100     Days

                                                                                                                       44
    A Double-blind, Placebo-controlled, Parallel,
          Multicenter Study On Extended
   VTE Prophylaxis In Acutely Ill Medical Patients
          With Prolonged Immobilization

                              Treatment period            Follow-up
                           Enoxaparin, sc qd 40mg
            Enoxaparin,
            sc qd 40mg

 -2 days    10±4 days                 28±4 days          up tp 180±10 d
                           Placebo

Screening   Initial open           Double-blind            Follow-up
             treatment              treatment




     Enrollment    Randomization                  End Treatment

								
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