Clopidogrel

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					Disease in any vascular bed increases the lifetime risk of
            multiple atherothrombotic events

History                     Increased risk of MI                   Increased
                                                                 risk of stroke
MI                                  5-7 X                            3-4 X
                                  greater risk                    greater risk
                               (includes death)                  (includes TIA)
Ischemic Stroke                     2-3 X                              9X
                                 greater risk                     greater risk
                            (includes angina and
                                sudden death)
PAD                                   4X                             2-3 X
                                greater risk                      greater risk
                      (includes only fatal MI and other          (includes TIA)
                       coronary heart disease death)



                  Circulation 1994; 89: 1333-1363; J Cardiovasc Risk 1994; 1:333-339;
                               Arch Neurol 1992; 42:857-863; NEJM 1992; 326: 381-386
CAPRIE trial: Risk reduction in specific subgroups


                                           Stroke subgroup   PAD subgroup         MI subgroup
                                      0
  Risk reduction in event rate (%)




                                      -5

                                     -10        -7.3                                  -7.4

                                     -15

                                     -20

                                     -25                        -23.3
                                                                            Lancet 1996; 348: 1329-1339
                                      CURE study: Results

                           0.14
                                                                                  20%
                           0.12
CV death, nonfatal MI or


                                             Placebo
                           0.10
      stroke (%)



                                                               Clopidogrel
                           0.08

                           0.06

                           0.04                        P<0.001

                           0.02

                           0.00
                                  0      3           6           9           12
                                             Months of follow-up

                                                                       NEJM 2001; 345:495-502
                                CURE Trial: Results (Contd.)


                                               At 24 hours
                          2.5                                           34%
                                       2.1%
CV death, nonfatal MI,
stroke or refractory or




                           2
   severe ischemia




                                                              1.5%
                          1.5

                           1

                          0.5

                           0
                                  Placebo + aspirin    Clopidogrel + aspirin
                                                              NEJM 2001; 345:495-502
                                 Risk reduction (%)




                          -35
                                -30
                                      -25
                                            -20
                                                    -15
                                                          -10
                                                                -5
                                                                     0
                                                                          CV death,
                                                                         nonfatal MI,
                                                                          stroke or




                                                  -14
                                                                          refractory
                                                                          ischemia



                                                                         MI




                                      -23
                                                                            Refractory
                                                                         ischemia during




                          -32
                                                                              initial
                                                                          hospitalisation



                                                                         Revascularisation
                                                          -8




                                                                            procedure




                                                                         Stroke
                                                  -14
                                                                                             CURE trial: Results (Contd.)




                                                                         Heart failure
                                            -18




NEJM 2001; 345: 494-502
                                     CURE Trial: Results (Contd.)


                                                                                                                     18%
                       2.5
                                                43%                               8        7.2%
                                2%                                                7
thrombolytic therapy




                                                         % patients requiring
% patients requiring




                                                         GP IIb/IIIa inhibitors
                        2                                                                                     5.9%
                                                                                  6
                       1.5                                                        5
                                            1.1%                                  4
                        1                                                         3
                                                                                  2
                       0.5
                                                                                  1
                        0                                                         0
                             Placebo +   Clopidogrel +                                Placebo + aspirin   Clopidogrel +
                               aspirin      aspirin                                                          aspirin


                                                                                         NEJM 2001; 345:495-502
              PCI-CURE study: Results


Primary outcome (cardiovascular death, myocardial infarction,
             urgent revascularisation) events

Number of days      Placebo      Clopidogrel           Risk
  after PCI         (n=1345)      (n=1313)           Reduction
      <2              3.0%           2.4%                20%
      <7              4.4%           3.0%                31%
      < 14            5.4%           3.7%                33%
      < 30            6.4%           4.5%                30%

                                            Lancet 2001; 358: 527-533
                                 PCI-CURE study: Results

                 0.15                             Placebo
                                                                         31%
CV death or MI




                 0.10
                                                        Clopidogrel         A= median time from
                                                                            randomisation to
                                                                            percutaneous
                 0.05                                                       coronary intervention.
                                                   p=0.002
                                                                            B = 30 days after
                                                                            median time of PCI.

                 0.00
                        010 40    100         200         300         400
                                        Days of follow-up
                         A B
                                                                      Lancet 2001; 358: 527-533
                                       Clopidogrel v/s Ticlopidine in
                                            Coronary Stenting

                                               Ticlopidine (n=827)       Clopidogrel (n=500)

                          1.8         Dose: Aspirin >325mg + Clopidogrel 300 mg (loading), 75mg (14 days)
                                                                     OR                                     1.6
Event rate, 30 days (%)




                          1.6
                                          Aspirin + Ticlopidine 500 mg (loading), 250 mg bd (14 days)
                          1.4
                          1.2   1.1
                            1                                                                                     0.8
                          0.8                                          0.7
                          0.6                      0.5                                     0.5
                                      0.4                                                        0.4
                          0.4                                                0.2
                          0.2                             0
                            0
                                 Death            Myocardial             Stent         Repeat PTCA or       Any event
                                                  infarction          thrombosis           CABG
                                                  (nonfatal)
                                                                                                 JACC 1999; 34:1891-1894
                                  CLASSICS: Results
Occurrence of composite of major peripheral or bleeding complications, neutropenia, thrombocytopenia or
         early discontinuation due to noncardiac event (skin disorder, GI disorder, allergy, etc)
                                                    P=0.005

                                                P=0.001
   10                       P=0.194
    9
                  9.1
    8
                                                   P=0.043
    7
    6                                     6.3
  %
    5
    4                                                                                     4.6
    3
                                                                  2.9
    2
                N=31/340                N=11/335
    1                                                          N=10/345                N=31/680
    0
          Ticlopidine 250 mg      Clopidogrel 75 mg       Clopidogrel 300/75      Clopidogrel Total
                  bid                    od                     mg od
                                                                          Circulation 2000; 102:624-629
Clopidogrel in patients with prior bypass surgery
               (CAPRIE substudy)
             A
                        10                               9.7%
                         9                                             43%
                         8                               8.1%
   Vascular death (%)

                         7
                         6
                         5
                         4       Aspirin
                         3
                         2                 Clopidogrel
                         1                        p = 0.03
                         0
                             0    6 12 18 24 30 36
N=1480                             Months of Follow-up
                                                         Circulation 2001; 103: 363-368
Clopidogrel in patients with prior bypass surgery
               (CAPRIE substudy)
                                                  B   50
                                                                                                                    46.1%
                                                      45

         rehospitalisation for ischemia or bleeding
                                                                                                                            31%
                                                      40
              Vascular death, MI, stroke or

                                                                                                                    36.7%
                                                      35

                                                      30

                                                      25
                                                               Aspirin
                                                      20

                                                      15                        Clopidogrel

                                                      10
                                                                                                   p = 0.001
                                                       5

                                                       0
                                                           0      6        12      18         24     30        36
                                                                         Months of Follow-up
N=1480                                                                                                    Circulation 2001; 103:363-368
                  Clopidogrel vs. Aspirin
   More effective in ADP-mediated platelet aggregation (stenosed
    arteries or sites of endothelial injury)
   Greater reduction in vascular events, as shown by CAPRIE trial
   Lesser hospitalisations for ischemic events
   10-45% patients may be “aspirin-resistant”
   Many patients may not tolerate aspirin (allergy - aspirin triad, GI
    intolerance, peptic ulcers)
   Lesser drug interactions (none seen with acetazolamide,
    anticonvulsants, beta blockers, diuretics, methotrexate, oral
    hypoglycemics and uricosuric agents)
   Lesser incidence of GI hemorrhage
   No interactions with ACE inhibitors
   No interaction with alcohol, unlike aspirin
               Clopidogrel vs Ticlopidine
   Six times more potent
   Faster onset of action (within 24 hours as compared to 3 days)
   Better tolerability profile
    - Lesser incidence of severe neutropenia (0.04% vs 2.5%) and
    TTP (4 cases per million patients vs. one case per 2000 to 4000
    patients)
    - Routine hematologic monitoring not essential
    - Does not cause increase in cholesterol levels
   Once daily regimen
   Lesser drug interactions (none seen with antipyrine, antacids,
    cimetidine, digoxin or theophylline)
   More economical
      Clopidogrel: Indications & Dosage

 Prevention of vascular events in patients with
  atherosclerosis documented by recent stroke, recent
  MI or established PAD
  75 mg once daily
 Acute coronary syndrome
  300 mg (loading dose) followed by 75 mg once daily
 PTCA (with or without stenting)
  300 mg (loading dose) followed by 75 mg once daily
 Prior bypass surgery
  75 mg once daily

				
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