European Heart Journal Advance Access originally published online on August 2, 2007
European Heart Journal 2007 28(18):2183-2184; doi:10.1093/eurheartj/ehm326
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Aggressive antiplatelet strategies: time to reconsider?
HeartDrugTM Research Laboratories, Johns Hopkins University, Osler Medical Building, 7600 Osler Drive, Suite 307, Towson, MD 21204, USA
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This editorial refers to ‘An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial’ by T.H. Wang et al., on page 2200
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
The landmark second analysis of the CHARISMA trial strongly suggests that dual therapy with clopidogrel and aspirin in asymptomatic patients is associated with excess cardiovascular mortality when compared with those patients treated with aspirin alone.1 Indeed, based on the data from 3284 primary prevention patients, there was a highly significant (P = 0.001) increase of cardiovascular death from 2.2% in the aspirin only group up to 3.9% in patients treated with clopidogrel and aspirin combination. The importance of the message, and perfect timing of publication, is impossible to underestimate. Hopefully, these data will be a ‘cold shower’ to the advocates of the uniformed aggressive antiplatelet strategies which are obviously dominant today. Unjustified by the randomized data on doubled and even tripled clopidogrel loading regimens, attempts to increase the maintenance clopidogrel dose based on low platelet responsiveness or even hypothetical ‘resistance’ cause extra bleeding risks with no definite evidence whatsoever of better vascular outcomes. In fact, the postulate ‘the more-the better’, while being reasonable for cholesterol lowering with statins, also works well for the treatment of arterial hypertension, but is very questionable when applied to antiplatelet regimens and improved outcomes, especially considering hardcore randomized evidence. Table 1 outlines the general trends on how the degree of platelet inhibition caused by antiplatelet agent(s) transforms into the vascular outcome benefit.
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Despite the obvious limitations of such comparison, apparently the trend is that a higher degree of platelet inhibition is associated with worsened, not better, clinical outcomes. The more broadly we try to expand the indications for aggressive antiplatelet therapy, the more failures will occur. While there is no doubt that the concept of inhibiting platelets is vital for the treatment of vascular ischaemic disease, the optimal degree of such inhibition remains an unsolved mystery. Importantly, without routine individual laboratory assessment of platelet function, mild regimens will have an advantage of being more suitable for the majority of patients. On the other hand, if we can determine baseline platelet status and intelligently apply therapy based on platelet activity in each particular patient, clinical outcomes will be better. Avoiding excessive bleeding risks after aggressive strategies in patients with normal or already decreased platelet function, but targeting those who indeed exhibit activated platelets, may improve risk stratification and save lives.
The authors of the paper under discussion1 delicately avoided any speculations on the potential explanations for the excess mortality in the combination arm. However, there are at least two likely factors which may be responsible for such unanticipated adverse association. First, non-compliance is a major and the most logical practical reason for lack of antiplatelet benefit. Unfortunately, we do not routinely monitor for strict compliance in the randomized studies including the CHARISMA trial. Obviously pill counts and ‘soul-breaking’ conversations fall far too short to secure adherence to the prescribed therapy. This is especially true for more aggressive antiplatelet strategies when even minor bleeding complications while shaving or tooth brushing are enough of a deterrent to stop therapy, especially when the benefits of the drug are not readily apparent. This critical limitation of antiplatelet therapy stands in contrast to drugs that alleviate actual symptoms, rather than merely preventing future acute events. A recent elegant meta-analysis of 10 antiplatelet prevention studies suggests that the range of non-compliance was 12–52% in all patients, while only 3–21% of the patients discontinued the prescribed drug because of (real or perceived) drug-induced adverse events.14 This in turn may lead to rebound platelet activation and higher risks for the development of acute secondary vascular fatal events.15
Secondly, when the stimulus for the persistent activity is not consistent, as in the asymptomatic cohort, chronic antiplatelet therapy may cause platelets to switch to the alternative pathways of activation, as has been documented for the GPIIb/IIIa inhibitors such as tirofiban16 and roxifiban.17 This chain of events may cause excess vascular events and death, as previously reported for the oral GPIIb/IIIa inhibitors.18
Finally, the fate of future antiplatelet strategies is heavily dependent on the results of the nearly completed TRITON8 trial. Should much more aggressive strategies with prasugrel be superior to conventional clopidogrel regimens with regard to lower mortality and better vascular outcomes, only then will continuation of the other trials assessing aggressive antiplatelet therapy be well justified. However, should therapy with prasugrel not only cause more bleeding but also result in worsened vascular outcomes for the reasons outlined here, then future antiplatelet trials should be primarily focused on better safety (less bleeding) with a similar vascular protection profile.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehm274 
References
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Related articles in EHJ:
- An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial
- Thomas H. Wang, Deepak L. Bhatt, Keith A.A. Fox, Steven R. Steinhubl, Danielle M. Brennan, Werner Hacke, Koon-Hou Mak, Thomas A. Pearson, William E. Boden, P. Gabriel Steg, Marcus D. Flather, Gilles Montalescot, Eric J. Topol, and on behalf of the CHARISMA Investigators
EHJ 2007 28: 2200-2207.[Abstract] [FREE Full Text]
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