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J Am Coll Cardiol Intv, 2008; 1:62-64, doi:10.1016/j.jcin.2007.11.005
© 2008 by the American College of Cardiology Foundation
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Editorial Comment

Dual Antiplatelet and Oral Anticoagulant Therapy

Increasing Use and Precautions for a Hazardous Combination*

Elaine M. Hylek, MD, MPH{dagger},2,*, David E. Solarz, MD{ddagger}

{dagger} Clinical Epidemiology Unit and Research Unit–Section of General Internal Medicine, Boston University School of Medicine, Boston, Massachusetts
{ddagger} Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.

The prevalence of atrial fibrillation (AF) in the U.S. is projected to reach nearly 8 million individuals by 2020 (1). Stroke prevention in AF is the most common indication for warfarin. Approximately one-third of these individuals will also have coronary artery disease. Overall, the number of warfarin prescriptions has increased from 21 million in 1998 to nearly 31 million in 2004 (2). This surge in warfarin use has paralleled an increase in aspirin use for primary and secondary prevention of cardiovascular disease. The increased incidence of major hemorrhage, particularly among the older patient population, is at least in part attributable to the increased use of combination antithrombotic therapy (3). This risk was also recently highlighted in the Warfarin Antiplatelet Vascular Evaluation trial that randomized patients with peripheral arterial disease to antiplatelet or combination therapy (4).

In this issue of JACC: Cardiovascular Interventions, Rogacka et al. (5) report their findings from 127 consecutive patients discharged on aspirin, a thienopyridine (clopidogrel or ticlopidine), and warfarin after coronary stent implantation. Atrial fibrillation was the indication for warfarin in 59% of patients. The mean exposure to combination therapy was 5.6 ± 4.6 months. Of the 127 patients, 6 experienced a major hemorrhage, 4 of which were intracranial hemorrhages (ICH), and 3 were fatal. Most events occurred within the first month.

This study importantly adds to the growing body of evidence documenting the hemorrhagic risk of combined dual antiplatelet and warfarin therapy. The hazards of triple therapy after percutaneous coronary intervention were first highlighted in a retrospective analysis of 65 patients discharged after coronary stenting on aspirin, clopidogrel, and warfarin. Six patients (9.2%; 95% confidence interval [CI] 3.5 to 19.0) experienced a bleeding complication; 2 met criteria for major hemorrhage (6). Khurram et al. (7) subsequently published a retrospective study of 107 patients. Major bleeding occurred in 7 patients (6.6%); the hazard ratio of triple therapy was 5.4 compared with dual antiplatelet therapy alone. Similar findings were reported from Finland. Among 185 patients treated for a mean of 4 months, 18 (8.2%) sustained a major hemorrhage, including 3 ICH (2 related to trauma) (8).

Limitations of these studies include small sample size, retrospective design, lack of international normalized ratio (INR) data, and small number of events that prohibits meaningful assessment of risk. In the study by Rogacka et al. (5), the distribution of hemorrhage raises additional concern. Four of the 6 major bleeds were ICH. Information on blood pressure was not provided. The disproportionate number of ICH suggests incomplete ascertainment of major extracranial hemorrhage and a subsequent under-estimate of the aggregate bleeding rate. It is also important to note that although the authors attempt to assess differences in hemorrhage with different types of stents, in the absence of randomized data, this is problematic because of confounding by indication (i.e., patients at higher risk of hemorrhage might have preferentially received bare-metal stents to minimize exposure to triple therapy).

The risk of upper gastrointestinal bleeding or perforated peptic ulcer with aspirin use increases exponentially with age (9). Aspirin in combination with clopidogrel increases this risk more than 3-fold (adjusted rate ratio [RR] 3.9, 95% CI 2.8 to 5.5), and aspirin plus warfarin increases this risk more than 6-fold (adjusted RR 6.5, 95% CI 4.3 to 9.9) (10). The number needed to harm with antiplatelet therapy is 33 among high-risk female patients with a history of complicated ulcer who are ≥80 years of age and 17 for the comparable risk stratum in men. Nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with aspirin greatly magnify this risk (9).


   Potential Strategies to Minimize Hemorrhagic Complications
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Consistent risk factors for major hemorrhage on warfarin include older age, anticoagulation intensity, early course of therapy, prior bleed, and concomitant antiplatelet therapy (11,12). Additional risk factors for ICH include prior stroke and hypertension. The clinical challenge is how best to navigate optimal prevention of thrombosis while minimizing serious bleeding consequences. Combination antiplatelet therapy is less effective than warfarin for stroke prevention in AF (13). Improved risk stratification in AF is a logical first step. Current AF guidelines recommend warfarin for CHADS2 scores of ≥2 (Congestive heart failure = 1 point; Hypertension = 1 point; Age ≥75 years = 1 point; Diabetes mellitus = 1 point; prior Stroke/transient ischemic attack = 2 points) and aspirin or warfarin for a CHADS2 score of 1 point (14). This point is emphasized by the current study in which 2 of the patients with ICH had CHADS2 scores = 0 and 1.

It is unclear to what degree hemorrhage on triple therapy is attributable to suboptimal control of warfarin. Proven strategies to minimize anticoagulant-related bleeding should be aggressively implemented, and interventions to ameliorate the hazards of antiplatelet therapy should be instituted (Table 1) (15). Prophylactic treatment with the proton-pump inhibitor (PPI) lansoprazole coupled with eradication of H. pylori infection was shown to significantly reduce the risk of recurrence of ulcer complications associated with aspirin (16,17). Patients were treated with 100 mg aspirin and lansoprazole 30 mg daily after confirmed H. pylori eradication. The risk of recurrence was 1.6% in the PPI group (95% CI 0% to 9%) and 14.8% in the placebo group (95% CI 7% to 26%); adjusted hazard ratio 9.6 (95% CI 1.2 to 76.1). The number needed to treat was only 7.6 to prevent 1 bleeding complication.


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  		Table 1 Potential Strategies to Minimize Major Hemorrhage Among Patients on Triple Therapy After Coronary Stent Implantation
 

   Future Directions
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It is possible that newer anticoagulant drugs with shorter half-lives and a wider therapeutic window might be safer to use in combination with antiplatelet therapy. The balance between antithrombotic potency and safety will demand improved risk stratification particularly among individuals ≥75 years of age as highlighted by the recent trial that compared clopidogrel with prasugrel for the prevention of in-stent thrombosis (18). The mean age of trial participants was 61 years, and 13% were ≥75 years of age. Insights into the mechanisms of enhanced gastrointestinal susceptibility to antithrombotic therapy particularly in the elderly patient population warrant further study (19). Further data, preferentially from randomized trials, are needed to better assess the effects of staggered therapy, single versus dual antiplatelet therapy and warfarin, and optimal duration of antiplatelet therapy among different risk subgroups (20).


   Footnotes
 
* Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology. Back

2 Dr. Hylek has received research funding from AstraZeneca and Bristol-Myers Squibb and has served in an advisory capacity to Bristol-Myers Squibb. Back

* Reprint requests and correspondence: Dr. Elaine M. Hylek, Boston University School of Medicine, Clinical Epidemiology Unit and Research Unit–Section of General Internal Medicine, 91 East Concord Street, Suite 200, Boston, Massachusetts 02118. (Email: ehylek{at}bu.edu).


   REFERENCES
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 Potential Strategies to Minimize...
 Future Directions
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  1. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmstead County, Minnesota, 1980–2000, and implications on the projections for future prevalence Circulation 2006;114:119-125.[Abstract/Free Full Text]
  2. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use Arch Intern Med 2007;167:1414-1419.[Abstract/Free Full Text]
  3. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation Circulation 2007;115:2689-2696.[Abstract/Free Full Text]
  4. The Warfarin Antiplatelet Vascular Evaluation Trial Investigators Oral anticoagulant and antiplatelet therapy and peripheral arterial disease N Engl J Med 2007;357:217-227.[Abstract/Free Full Text]
  5. Rogacka R, Chieffo A, Michev I, et al. Dual antiplatelet therapy after percutaneous coronary intervention with stent implantation in patients taking chronic oral anticoagulation J Am Coll Cardiol Intv 2008;1:56-61.[Abstract/Free Full Text]
  6. Orford JL, Fasseas P, Melby S, et al. Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation Am Heart J 2004;147:463-467.[CrossRef][Web of Science][Medline]
  7. Khurram Z, Chou E, Minutello R, et al. Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding J Invasive Cardiol 2006;18:162-164.[Medline]
  8. Karjalainen PP, Porela P, Ylitalo A, et al. Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting Eur Heart J 2007;28:726-732.[Abstract/Free Full Text]
  9. Hernández-Díaz S, García Rodríguez LA. Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications BMC Med 2006;4:22.[CrossRef][Medline]
  10. Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug-drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding CMAJ 2007;177:347-351.[Abstract/Free Full Text]
  11. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek EM. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004;126:204S-233S.[CrossRef][Web of Science][Medline]
  12. Levine MN, Raskob G, Beyth RJ, Kearon C, Schulman S. Hemorrhagic complications of anticoagulant treatment Chest 2004;126:287S-310S.[CrossRef][Web of Science][Medline]
  13. The ACTIVE Writing Group on Behalf of the ACTIVE Investigators Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with Irbesartan for prevention of Vascular Events (ACTIVE W) Lancet 2006;367:1903-1912.[CrossRef][Web of Science][Medline]
  14. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee on Practice Guidelines J Am Coll Cardiol 2006;48:854-906.[Free Full Text]
  15. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: Recent data and ideas Stroke 2005;36:1588-1593.[Abstract/Free Full Text]
  16. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use N Engl J Med 2002;346:2033-2038.[Abstract/Free Full Text]
  17. Chey WD, Wong BC, Practice Parameters Committee of the American College of Gastroenterology American College of Gastroenterology guideline on the management of Helicobacter pylori infection Am J Gastroenterol 2007;102:1808-1825.[CrossRef][Web of Science][Medline]
  18. Wiviott SD, Braunwald E, McCabe CH, et al. TRITON–TIMI 38 Investigators Prasugrel versus clopidogrel in patients with acute coronary syndromes N Engl J Med 2007;357:2001-2015.[Abstract/Free Full Text]
  19. Lanas A, Garcia-Rodriquez LA, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants Am J Gastroenterol 2007;102:507-515.[CrossRef][Web of Science][Medline]
  20. Nguyen MC, Lim YL, Walton A, et al. GRACE Investigators Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events: is it safe and effective to use just one antiplatelet agent? Eur Heart J 2007;28:1717-1722.[Abstract/Free Full Text]

Related articles in JACC Interventions:

Dual Antiplatelet Therapy After Percutaneous Coronary Intervention With Stent Implantation in Patients Taking Chronic Oral Anticoagulation
Renata Rogacka, Alaide Chieffo, Iassen Michev, Flavio Airoldi, Azeem Latib, John Cosgrave, Matteo Montorfano, Mauro Carlino, Giuseppe M. Sangiorgi, Alfredo Castelli, Cosmo Godino, Valeria Magni, Tiziana C. Aranzulla, Enrico Romagnoli, and Antonio Colombo
JACC Interventions 2008 1: 56-61. [Abstract] [Full Text]  



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Journal Watch Cardiology, June 4, 2008; 2008(604): 3 - 3.
[Full Text]

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