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Therapeutics Letter, issue 37, September / October 2000

Antiplatelet Chemoprevention of Occlusive Vascular Events and Death 


Antiplatelet drugs are taken to prevent future adverse cardiovascular events. In this review, we summarize the benefit and harm from taking  four common antiplatelet drugs: acetylsalicylic acid, (Aspirin®, etc.), ticlopidine (Ticlid®), clopidogrel (Plavix®) and dipyridamole (Aggrenox®). The Antiplatelet Trialists Collaboration (ATC) systematic review published in 19941 provides the basic evidence. 

What are the clinical implications of the ATC systematic review?1

SECONDARY PREVENTION:

Patients with proven vascular occlusive disease (increased risk for subsequent event).

 

PRIMARY PREVENTION:

Patients without proven occlusive vascular disease (decreased risk for adverse cardiovascular event).

What is the role for other antiplatelet drugs?

The CAPRIE Trial

CAPRIE compared 75 mg of clopidogrel with 325 mg of ASA daily in 3 subgroups of patients: prior MI, prior TIA or stroke, and peripheral vascular disease.6  The primary outcome, a cluster of ischemic stroke, myocardial infarction, or vascular death as first events, was lower in the clopidogrel group,  9.8%, than in the ASA group, 10.7% (RR = 0.92, ARR = 0.9%, NNT = 115 for 1.9 yrs). The only subgroup showing a clinically significant  benefit were patients with peripheral vascular disease at entry (90% current or ex-smokers).

A Cochrane review7 which included the CAPRIE Trial findings presented data as single, as opposed to a cluster of clinical outcomes. The results are shown in Table 1. The small absolute benefit of a reduction in total MI, 0.7%, and GI hemorrhage, 0.4% for clopidogrel is partially offset by an increased incidence of rash, leading to withdrawal, ARI = 0.5%.

Table 1. Results of the CAPRIE trial7

Outcome Clopidogrel Events % ASA 
Events %
RR
(95% CI)
ARR / ARI
%
NNT / NNH
Total death 5.8 6.0 NS    
Total MI 2.9 3.6 0.8 (0.7, 0.9) 0.7 143
Total stroke 4.8 5.3 NS    
Any hemorrhage* 8.9 8.8 NS    
GI hemorrhage# 0.5 0.9 0.6 (0.4, 0.8) 0.4 250
Neutropenia^   0.05   0.04 NS    
Thrombocytopenia^ 0.2 0.1 NS    
Rash# 0.9 0.4 2.2 (1.5, 3.2) 0.5 200
Diarrhoea# 0.4 0.3 NS    

* excluding intracranial hemorrhage

# adverse effect leading to withdrawal

^ severe < 0.45 x 109 / L  for N, and < 80 x 109 / L   for P

The TASS Trial

TASS compared 500 mg of ticlopidine with 1300 mg of ASA, for patients with TIA, reversible ischemic neurological deficit (RIND) or mild stroke within the previous 3 months8. The primary outcome, stroke or death, was not significantly different, 20.0% for ticlopidine and 22.7% for ASA (RR = 0.88 [0.77,1.01]). Other results taken from a Cochrane review are shown in Table 2.7  The  benefit of ticlopidine seen as a reduced incidence of  stroke, 2.6%, and GI hemorrhage, 0.9%, are offset by increased harm leading to withdrawal: severe neutropenia, 0.9%, rash, 2%, and diarrhea, 4%.

 

Table 2. Results of the TASS trial7

Outcome Ticlopidine Events % ASA 
Events %
RR
(95% CI)
ARR / ARI
%
NNT / NNH
Total death 11.4 12.7 NS    
Total MI   6.8   5.8 NS    
Total stroke 11.2 13.8 0.8 (0.7, 0.99)    2.6  39
Any hemorrhage*   8.5   9.4 NS    
GI hemorrhage#   0.5   1.4 0.3 (0.1, 0.8)    0.9 111
Neutropenia^   0.9 0 7.5 (2.5, 22.3)    0.9 111
Rash# 3 1 3.1 (1.7, 5.5) 2  50
Diarrhoea# 6 2 2.8 (2.0, 4.1) 4  25

* excluding intracranial hemorrhage

# adverse effect leading to withdrawal

^ severe < 0.45 x 109 / L  for N, and < 80 x 109 / L   for P

Adding other antiplatelet drugs to ASA?

The ESPS-2 Trial

The ESPS-2 trial compared placebo to 3 active treatment groups: an extended release form of dipyridamole (DP), 400 mg/day, ASA, 50 mg/day and ASA-DP.9 This trial reported a reduction in non-fatal stroke as a first event in all 3 active treatment groups. The results are consistent with an additive benefit of ASA-DP on first event non-fatal stroke, 8.3% as compared to ASA alone, 11.3% (RR  = 0.7 [0.6,0.9], ARR = 3%, NNT = 33 for 2 yrs). However, the proper analysis of the data using the factorial design separates the ASA effect and the DP effect. This is shown in Table 3.

Any benefit of the combination of DP and ASA has to be weighed against a 7.4% increase in withdrawals due to adverse events with DP (primarily headache and GI events). There was no increase in these adverse events associated with ASA. It is also of concern that, while ASA as expected from the ATC analysis shows a trend towards a reduction in fatal stroke, RR = 0.78 [0.6, 1.04], DP shows the opposite, a trend towards an increased incidence of fatal stroke, RR = 1.14 [0.9, 1.5] (see Table 3).

  

Table 3. Results of the ESPS-2 trial9

  Dipyridamole effect ASA effect
DP no-DP   ASA no-ASA  
Outcome Event
%
Event
%
RR
(95% CI)
ARR ARI
%
NNT
NNH
Event
%
Event
%
RR
(95% CI)
ARR ARI
%
NNT
NNH
Total death 11.3 11.6 NS     11.1 11.8 NS    
Total MI   4.0   4.3 NS       3.8   4.5 NS    
Fatal stroke   2.8   2.5 NS       2.3   3.0 NS    
Non-fatal stroke   9.7 12.6 0.77(0.7,0.9) 2.9 34   9.8 12.4 0.79(0.7,0.9) 2.6  38
Withdrawals due to adverse effects 15.5   8.1 2.0(1.7,2.4) 7.4 14 12.2 11.4 NS    
Withdrawals due to GI hemorrhage   0.7   0.8 NS       1.2   0.2 3.9(2.2,6.8) 1.0 100

Do all antiplatelet drugs act by the same mechanism of action?

No. The mechanism of action and kinetics of platelet-active drugs has been recently reviewed.10 ASA uniquely acts to acetylate (PG)H-synthase and to irreversibly inhibit the cyclooxgenase activity in platelets and vascular endothelium. This action occurs with doses of ASA as low as 50 mg.

Ticlopidine and clopidogrel are thienopyridines which act by selectively inhibiting adenosine phosphate induced platelet aggregation. Platelet function only recovers slowly upon drug withdrawal. Dipyridamole inhibits platelet cyclic nucleotide phosphodiesterase and uptake of adenosine. Which of these actions leads to the antiplatelet effect  is unknown.

How are these drugs handled by the body?

ASA has a very short half life (15-20 min). However, because its effect on platelets is irreversible, the duration is dependent on the life span of the platelet. This results in a pharmacologic half-life of about 6 days. Ticlopidine and clopidogrel are extensively metabolized by the liver. Ticlopidine has a 4 day half-life with chronic dosing. Clopidogrel has an 8 hour elimination half-life, but the pharmacologic half-life is relatively long and it takes 4 to 7 days of administration to reach a steady state effect on platelets. Dipyridamole is metabolized in the liver and has a terminal half-life of 10 hours. The recommended dose and the cost of these drugs are shown in Table 4. 

 

Table 4. Dose and cost of antiplatelet drugs

Chemical name Trade Name Daily dose Daily cost
ASA Aspirin®, etc. 80-325 mg $0.01 - $0.16
Clopidogrel Plavix® 75 mg $2.56
Ticlopidine Ticlid®, generic 250 mg BID $1.56
Dipyridamole/ASA Aggrenox® 200/25 mg BID $1.69

Conclusions

SECONDARY PREVENTION:

  1. ASA, 80 -325 mg/day, is proven effective for the prevention of vascular occlusive events for patients with established disease. There is little evidence of benefit beyond a maximum dose of ASA of 325 mg/day.

  2. Other antiplatelet drugs should be used for patients allergic to or intolerant of ASA. 

  3. Patient characteristics, benefits, harm and cost should be considered when selecting an agent other than ASA. 

  4. Combination of ASA with other antiplatelet agents requires further study.

 

PRIMARY PREVENTION:

Benefit of platelet prevention has not been shown to exceed harm in patients without proven vascular occlusive disease.

 


Abbreviations used in tables:

 RR=Relative Risk

 CI=Confidence Interval

 NS=Not Statistically Significant

 ARR=Absolute Risk Reduction

 NNT=Number Needed to Treat to prevent one event

 ARI=Absolute Risk Increase

 NNH=Number Needed to cause one Harmful event

This Therapeutics Letter contains an assessment and synthesis of published (and whenever possible peer-reviewed) publications up to October 1, 2000. We attempt to maintain the accuracy of the information contained in the Therapeutics Letter by extensive literature searches and verification by both the authors and the editorial board. In addition this Therapeutics Letter was submitted for review to 81 experts and primary care physicians in order to correct any identified shortcomings or inaccuracies and to ensure that the information is concise and relevant to clinicians.


References

  1. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy – I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106.

  2. Gubitz G, Sandercock P, Counsell C. Antiplatelet therapy for acute ischaemic stroke (Cochrane Review). The Cochrane Library, Issue 4, 2000.  Oxford: Update Software.

  3. Taylor DW, Barnett HJM, Haynes RB, et al. Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. Lancet 1999;353:2179-84.

  4. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-62.

  5. Hart RG, Halperin JL, McBride R, et al. Aspirin for the primary prevention of stroke and other major vascular events; Meta-analysis and hypotheses. Arch Neurol 2000;57:326-332.

  6. CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.

  7. Hankey GJ, Sudlow CLM, Dunbabin DW. Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients (Cochrane Review). The Cochrane Library, Issue 4, 2000.  Oxford: Update Software.

  8. Hass WK, Easton JD, Adams HP Jr. et al.  A randomised trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. Ticlopidine Aspirin Stroke Study Group. N Engl J Med 1989;321:501-7.

  9. Diener HC, Forbes C, Riekkinen PJ, et al. European stroke prevention study 2; Efficacy and safety data. J Neurol Sci 1997;151:S1-S77.

  10. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: The relationships among dose, effectiveness, and side effects. Chest 1998;114:470S-488S.


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