Restrictive access to clopidogrel and mortality following coronary stent implantation

Craig S McLachlan PhD MPH, University of Technology Sydney

Sheehy and associates (1) examined the association between 12 month mortality outcomes in coronary stented patients and the delay in filling a clopidogrel prescription at the time of hospital discharge. Importantly, if the prescription delay was 1 day this equated to a 34% increase in mortality during a 12 month follow-up period.

Importantly, the study findings by Sheery et al. (1), likely did not encompass stent “late loss” contributing toward overall mortality. For example, identified rates of 18-month cardiac death/MI due to acute thrombosis are not different between patients with bare metal (BMS) or drug eluting (DES) stents. However, after the discontinuation of clopidogrel (between 7 and 18 months), thrombus events have been previously reported to occur in 4.9% after DES versus 1.3% after BMS implantation (2).

From the Sheehy et al (1) study the following questions emerge; firstly, whether acute thrombosis would have been associated with transient clopidogrel stoppage due to prescription delay? Secondly whether acute thrombosis contributed to the overall 12 month mortality increase observed by Sheehy et al (1)? Indeed, a clustering of adverse events in the initial 90 days after stopping clopidogrel among both medically treated and PCI-treated patients with acute coronary syndromes (ACS) has recently been reported upon, supporting the possibility of a clopidogrel rebound effect. (3).

Interestingly Sheehy et al. (1) selected patients based on whether they had filled at least 1 prescription for acetylsalicylic acid, warfarin, oral antidiabetic, antihypertensive or lipid-modifying drug. The selection of a diabetic group is relevant because it has been previously demonstrated that in diabetics that clopidogrel withdrawal is associated with acute pro-aggregatory and pro-inflammatory outcomes at 30 days post withdrawal (4).

In conclusion, whether a 1 day transient stoppage in the use of clopidogrel would be responsible for an acute clopidogrel re-bound effect contributing to mortality across all stent subpopulations remains unanswered. Certainly further clinical investigation on transient interruptions to clopidogrel therapy in ACS are required. The findings of such studies will be important to establish whether the existence of very early and rapid re-bound effects has an adverse effect on ACS clinical outcomes.

References

1) Sheehy O, LeLorier J, Rinfret S. Restrictive access to clopidogrel and mortality following coronary stent implantation. CMAJ. 2008 Feb 12;178(4):413-20

2) M. Pfisterer, H. Brunner-La Rocca, P. Buser, P. Rickenbacher, P. Hunziker, C. Mueller, R. Jeger, F. Bader, S. Osswald, C. Kaiser Late Clinical Events After Clopidogrel Discontinuation May Limit the Benefit of Drug-Eluting StentsAn Observational Study of Drug-Eluting Versus Bare- Metal Stents. JACC, Volume 48, Issue 12,2584-2591

3) Ho PM, Peterson ED, Wang L, Magid DJ, Fihn SD, Larsen GC, Jesse RA, Rumsfeld JS Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA. 2008 6;299(5):532-9.

4) Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramírez C, Sabaté M, Jimenez-Quevedo P, Hernández R, Moreno R, Escaned J, Alfonso F, Bañuelos C, Costa MA, Bass TA, Macaya C. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes. 2006 Mar;55(3):780-4.

Conflict of Interest:

None declared