WOEST - Optimal Antiplatelet Treatment in Patient Already taking Anticoagulants

Dual antiplatelet therapy (aspirin and clopidogrel or another P2Y12 inhibitor) is almost always prescribed (and is beneficial in preventing future adverse cardiovascular events) to patients with coronary artery disease who undergo coronary intervention and have stents placed (although it is associated with increased risk of bleeding). For most patients with atrial fibrillation or mechanical heart valves, anticoagulation therapy is a the standard of care (although it is associated with increased bleeding risk).

Question remains as to what to do with patients who are on anticoagulation but then develop coronary artery disease, undergo percutaneous coronary intervention (PCI) and stent placement. Use of dual antiplatelet therapy along with anticoagulation increases the overall risk of bleeding considerably and whether such a high risk of bleeding overshadows the benefit associated with dual antiplatelet therapy remains unknown.

In an ideal situation, one would randomize patients who are taking anticoagulants and who have undergone PCI with stent placement in one of the three arms: dual antiplatelet therapy, aspirin alone, or clopidogrel (or another P2Y12 agent) alone. Of course, all the three groups should continue taking their anticoagulation treatment. While, we don’t have such an ideal study, we do have results of a study (reported today in the ESC Congress 2012) in which patients taking anticoagulants were randomized to dual antiplatelet agents or clopidogrel alone. The results are interesting; not only that dual antiplatelet therapy in addition to anticoagulation was associated with increased risk of bleeding, it was also associated with higher risk of all-cause mortality (6.4% vs. 2.5%; p = 0.027).

One thing is certain from this study and that is that dual antiplatelet therapy, in addition to anticoagulation, is not optimal treatment and a single antiplatelet agent is likely to do a better job in reducing not only bleeding but also in decreasing all-cause mortality. However, whether this single antiplatelet agent has to be aspirin or clopidogrel, that remains unclear. In fact, it is quite possible that aspirin may have larger benefit than clopidogrel when used in such population. Perhaps future studies may be better able to point us relative benefits of antiplatelet agents in patients with PCI and stents who are also taking anticoagulants.

Clopidogrel vs. Prasugrel in Medically Managed ACS

Clopidogrel (famous by its brand name Plavix) is now generic and while prices vary from one pharmacy to another, it is very likely that very soon its price will come down. On the other hand, Prasugrel (which works the same way as clopidogrel) has a long way to go before it becomes generic and thus is likely to remain costly for next several years.

Prasugrel has one advantage over clopidogrel; its metabolism is not dependent on CYP2C19 (a member of cytochrome P450 system). A mutation within the gene of this particular enzyme decreases its function and decreases the conversion of the pro-drug, clopidogrel, into its active metabolite. The metabolism is shunted towards inactive metabolites and hence individuals with certain mutations in this gene are associated with increased platelet reactivity while on clopidogrel. This was shown conclusively in a GWAS by Alan Shuldiner and his team.

Prasugrel does seem to be superior to clopidogrel in individuals who undergo percutaneous coronary intervention (PCI) however, it was not clear if prasugrel is also superior to clopidogrel in individuals who are managed conservatively.

The results of the TRILOGY-ACS trial (double blind, randomized, double-dummy, active control, event-driven), announced today at the ESC Congress 2012 suggest that there is no difference. In this study, investigators randomized >9,000 patients with acute coronary syndromes (ACS) to either clopidogrel+acetyl salicylic acid (ASA or aspirin) or prasugrel+ASA. The primary end point of the trial was cardiovascular death, myocardial infarction, or stroke. The study did not find a benefit of prasugrel over clopidogrel for either the primary outcome or individual components of the primary outcome (p = 0.21). Post-hoc analysis suggests some interesting hypothesis that may be worth looking into in future studies.

Ticagrelor, another anti-platelet agent that also works by inhibiting the same ADP receptors (P2Y12), on the other hand, was shown to be superior to clopidogrel in a similar type of medically managed population in the PLATO trial. It will be interesting to see how they do in their head-to-head comparison (if ever done).

GWAS of Correlated Traits

Korte et al has written an interesting paper which extends the analysis of correlated traits to genome-wide association studies (GWAS). (Korte A, Vilhjálmsson BJ, Segura V, Platt A, Long Q,Nordborg M. A mixed-model approach for genome-wide association studies of correlated traits in structured populations. Nat Genet. 2012 Aug 19. doi: 10.1038/ng.2376. [Epub ahead of print] PubMed PMID: 22902788.)

GWA studies have commonly employed a simple statistical model in which a single locus is tested for association with a single phenotype (usually in an additive model). There have been few attempts so far, if any to utilize correlated phenotypes and perhaps improve power of the studies. 

In the 2011 meeting of American Society of Human Genetics at Montreal, Canada, I have used one, relatively simple, method to combine results from two correlated traits with resulting increase in power of GWAS. (Qayyum R et al. Correlated meta-analysis of genome-wide association studies of agonist-mediated native platelet aggregation in African Americans). What we did was to conduct two separate GWAS studies of correlated platelet aggregation phenotypes and then combined the results using meta-analysis. However, the resulting p-values were adjusted for correlation between the two phenotypes using tetrachoric correlation. We further conformed our findings using the simulations from correlated distributions, confirming our findings. 

Korte et al, use linear mixed model approach to not only adjust for population stratification but also for correlation between phenotypes. They use ASReml and R for this analysis and provide R scripts on their website. Using their techniques, Korte et al unveil additional SNPs in a GWAS of LDL and triglycerides.

 

Some Interesting Articles to Read

This one claims that odds are against men because of natural selection

Extreme phenotypes are helpful in identifying genetic loci and this study provides such an example

Here is introduction to Personal Genome Project, an interesting resource.