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Fatal bleeding rare with extended dual antiplatelet therapy

London, UK – 31 Aug 2015: Fatal bleeding is rare with extended dual antiplatelet therapy, according to a secondary analysis of the DAPT Study presented for the first time today at ESC Congress.1 Bleeding-related mortality accounted for a minority of deaths in patients treated with dual antiplatelet therapy beyond one year.

Vascular Diseases
Microcirculation, Angiogenesis, Arteriogenesis

EMBARGO : 31 August 2015 at 14:45 BST

“Given the lack of adequate randomised trial data, there is considerable uncertainty in the medical community regarding the duration of dual antiplatelet therapy after percutaneous coronary intervention (PCI),” said principal investigator Dr Laura Mauri, a cardiologist at Harvard Medical School, and the Brigham and Women’s Hospital in Boston, US. “The Dual Antiplatelet Therapy (DAPT) Study compared the benefits and risks of 30 versus 12 months of dual antiplatelet therapy in preventing stent thrombosis or major adverse cardiovascular and cerebrovascular events in patients treated with a coronary stent.”

After coronary stent placement with drug-eluting (DES) or bare-metal (BMS) stents, patients were given open-label aspirin plus thienopyridine (clopidogrel or prasugrel). After 12 months, patients who were treatment-compliant and event-free (myocardial infarction, stroke, moderate or severe bleeding) were randomised to continued thienopyridine or placebo, each in addition to aspirin, for an additional 18 months. At month 30, patients discontinued randomised treatment but remained on aspirin for three months.2 Results in the 9 961 patients treated with DES showed a reduction in ischaemic cardiovascular events but an unexpectedly higher mortality rate with 30 months of dual antiplatelet therapy compared to 12 months.3

This new and much-awaited analysis examined causes of death in all 11 648 randomised patients treated with either DES or BMS. All deaths were carefully reviewed and adjudicated by an independent committee of cardiologists and oncologists who were blinded to the randomised treatment groups. Any death that was possibly, probably or definitely related to any prior clinically-evident bleeding event was adjudicated as “bleeding-related”, and any death that was possibly, probably, or definitely related to a malignancy or to complications from treatments specifically administered for the malignancy was adjudicated as “cancer-related”. Fatal bleeding was defined using the Bleeding Academic Research Consortium (BARC) definition.

The investigators found mortality rates during the randomised treatment period of 1.9% in the group of patients taking 30 months and 1.5% in the group taking 12 months of dual antiplatelet therapy (p=0.07). While there was no difference between the two randomised groups during that same period in the rates of cardiovascular mortality (1.0% vs 1.0%, respectively, p=0.97), rates of non-cardiovascular mortality were significantly different (0.9% vs. 0.5%, respectively, p=0.01) (Figure 1).

Over the 21 month follow-up period (18 months of randomised treatment plus 3 months of aspirin monotherapy), there were no differences between randomised groups in rates of fatal bleeding or death related to any prior bleeding. In an exploration of cancer-related deaths during this same time period, whereas there was no significant difference in the incidence of cancer between randomised groups, cancer-related deaths occurred in 0.6% of the group taking 30 months of dual antiplatelet therapy vs. 0.3% in those taking 12 months (p=0.02). However, after excluding the cancer-related deaths that occurred in patients whose cancer was diagnosed before enrolling in the DAPT Study, the difference in cancer-related death became non-significant (0.4% vs. 0.3%, respectively, p=0.16), and these cancer-related deaths were rarely related to bleeding (0.1% vs. 0, respectively, p=0.25).

“This analysis of the DAPT Study provides valuable insight to suggest that fatal bleeding is rare with extended dual antiplatelet therapy and may be avoided with careful patient selection,” said Dr Mauri. “While cancer-related death was higher in the group treated with 30 months of dual antiplatelet therapy, this finding was no longer significant when patients with a pre-existing diagnosis of cancer were removed from the analysis.”

She concluded: “Given the clear benefits of dual antiplatelet therapy in reducing myocardial infarction, these medications remain essential for patients with acute coronary syndromes or coronary stents. The relationship with cancer requires further investigation.”

Figure 1: Causes of mortality in all randomised patients

Notes: Adjudicated causes of mortality by randomised treatment arm from 12-33 months (combined randomised and aspirin only periods) are shown. All deaths were adjudicated for each category and may be represented in more than one category. Non-cardiovascular causes were identified in more than half of deaths overall




1Dr Mauri will present the abstract ‘Mortality related to bleeding is uncommon with continued thienopyridine use beyond one year’ at 14:45 during:
•    Clinical Trial Update II – Antiplatelet therapy on Monday 31 August at 14:00 in Hyde Park (The Hub)
2The co-primary efficacy endpoints were the cumulative incidence of definite or probable stent thrombosis according to Academic Research Consortium (ARC) criteria and of major adverse cardiovascular and cerebrovascular events defined as the composite of death, myocardial infarction, or stroke. The primary safety endpoint was the incidence of moderate or severe bleeding during this same period according to the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries [GUSTO] criteria.
3Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. New England Journal of Medicine. 2014;371:2155-2166.

Notes to editor

SOURCES OF FUNDING: The research was a unique public and private collaboration, funded by Abbott, Boston Scientific, Cordis, Medtronic, Bristol-Myers Squibb–Sanofi Pharmaceuticals Partnership, Eli Lilly, and Daiichi Sankyo, and by a grant (1RO1FD003870-01) from the United States Department of Health and Human Services.
DISCLOSURES: Grants to institution – Abbott, Boeringher Ingleheim, Boston Scientific, Cordis, Medtronic Vascular, Eli Lilly, Daiichi Sankyo, Bristol Myers Squibb, Sanofi Aventis, Biotronik (all significant); Consulting – Medtronic Vascular, Biotronik, Boeringher Ingleheim, St. Jude Medical, Eli Lilly, Recor, Biotronik (all modest); Honoraria - Sanofi-Aventis, modest.

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