The ACCF/ACG/AHA Clinical Expert Consensus Document on GI Risks and Antiplatelet Therapies: A Groundbreaking Collaboration with Broad Implications
Pub Date: Monday, October 6, 2008
Author: Glenn N. Levine, MD, FAHA, FACC
The clinical expert consensus document on reducing the gastrointestinal (GI) risks of antiplatelet therapy and nonsteroidal antiinflammatory drug (NSAID) use represents a groundbreaking collaboration between medical specialists. The recognition of the integral role of platelet activation and aggregation in arterial thrombosis over the last several decades has led to the emergence and now universal acceptance of antiplatelet therapy in coronary artery disease, beginning with agents such as aspirin, and more recently evolving, in many cases, into dual antiplatelet therapy with aspirin plus clopidogrel.[2-5] The goal of oral antiplatelet therapy is the prevention of platelet activation through inhibition of the cyclooxygenase (COX)-1 receptor (aspirin) and/or the adenosine 5'-diphosphate P2Y12 receptor (thienopyridines such as clopidogrel). As is now well established, such receptor inhibition prevents platelet aggregation and other detrimental processes. The trade-off of the antithrombotic medications is a small but real increase in bleeding complications, including and specifically GI bleeding. Thus, the goals of cardiovascular therapy, namely the prevention of arterial thrombosis, can intersect with the goals of the gastroenterologist, which include the prevention of GI-related bleeding. Whereas this sets up a potential conflict between the goals of the two specialties, specialists from the American College of Cardiology Foundation, the American College of Gastroenterology, and the American Heart Association have, instead, chosen to collaborate on a series of recommendations that focus on the patient as a whole, weighing the relative risks and benefits of antiplatelet therapies and suggesting interventions to minimize bleeding risks.
In this thoughtful and detailed expert consensus document, numerous recommendations are given. The specific recommendations from the writing group can be summarized as follows:
- Gastroprotective therapy should be prescribed for at-risk patients treated with a combination of any NSAID (including COX-2 selective agents) and cardiac-dose aspirin.
- Gastroprotective therapy should be prescribed in patients at risk of adverse events who are treated with aspirin. Since the risk of upper GI events increases with aspirin dose, 81 mg of aspirin should be prescribed in the chronic phases of therapy.
- Proton pump inhibitor (PPI) therapy should be used in patients treated with aspirin and anticoagulant therapy. Patients treated with aspirin, clopidogrel, and warfarin should have a target international normalized ratio (INR) of 2.0-2.5.
- Substitution of clopidogrel for aspirin is not recommended to reduce the risk of recurrent ulcer bleeding and is inferior to a strategy of treating the patient with aspirin and a PPI.
- PPIs are the preferred agents for the treatment and prophylaxis of NSAID- and acetylsalicylic acid-associated GI injury.
- Testing for and eradication of H. pylori infections in patients with a history of ulcer disease are recommended before starting chronic antiplatelet therapy.
- Discontinuation of aspirin therapy in the setting of acute ulcer bleeding must be made on an individual basis, weighing the cardiac and GI risks.
- Endoscopic therapy may be performed in high-risk cardiovascular patients on dual antiplatelet therapy; the timing of any cessation of antiplatelet therapy should weigh the cardiac and bleeding risks.
- Most of these recommendations are straightforward and require no further discussion, although several pose some uncertainty for the clinician or have such broad implications that they merit comment.
The first above recommendation specifies that gastroprotective therapy should be prescribed for at-risk patients treated with a combination of any NSAID (including COX-2 selective agents) and cardiac-dose aspirin. The document does not specifically state in the text what is defined as an "at-risk" patient, although Figure 1 implies such risk factors include (1) age ≥60 years, (2) corticosteroid use, and (3) dyspepsia or gastroesophageal reflux disease (GERD) symptoms.
The second above recommendation, which specifies that gastroprotective therapy should be prescribed in patients "at risk of adverse events" who are treated with aspirin, also does not specify in the text which patients have enough risk to merit preventive therapy, only that a history of peptic ulcer, particularly associated with bleeding, is the most important risk factor, and that age ≥60 years is also a risk factor. Given that up to 50 million persons may be taking aspirin for its cardiovascular protective effects , this recommendation has major medico-economic implications on the number of patients who may be recommended for PPI therapy.
"Triple therapy," involving aspirin, clopidogrel, and warfarin, is becoming increasingly prescribed to patients with acute coronary syndromes, those treated with coronary stents, and those with indications for anticoagulation, such as atrial fibrillation or mechanical heart valves. Few would quibble with the logic of prescribing PPIs in patients treated with both antiplatelet therapy and anticoagulant therapy, as stated in the third above recommendation. While the recommendation of a target INR of 2.0-2.5 in patients treated with "triple therapy," made previously by King et al. in the ACC/AHA 2007 PCI guidelines update, seems reasonable , there are few actual data to support this recommendation, and one must assume it does not apply to certain situations such as older mechanical valves (e.g., caged-ball valves), for which higher degrees of anticoagulation are recommended.
A strong rationale is given for the recommendation for testing for and eradication of H. pylori infections in patients with a history of ulcer disease before starting chronic antiplatelet therapy. We are, however, left with the logistic implications of this recommendation. Patients admitted with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergo cath and percutaneous intervention within 24-48 hours of admission  and are discharged shortly afterward, usually on indefinite aspirin and at least 1 year of clopidogrel. When, during this brief admission, should patients be tested and treatment initiated? Incorporating this recommendation into day-to-day practice will be a challenge to clinicians.
While the document text leaves open certain questions about who is "at risk" and should be treated with PPI, Figure 1 of the document casts a clear and broad net over those who should be treated. In essence, for all patients requiring antiplatelet therapy:
- all those with a history of ulcer complication and a history of ulcer disease (even nonbleeding ulcer) should be tested for H. pylori and treated if infected.
- all those with a history of GI bleeding, and all those who are to receive dual antiplatelet therapy and/or concomitant anticoagulant therapy, should be treated with a PPI.
- all those with more than one risk factor of (1) age ≥60 years, (2) corticosteroid use, and (3) dyspepsia or GERD symptoms should be treated with a PPI.
The above recommendations imply that likely several million patients (at least) should now be screened and, if indicated, treated for H. pylori infection and/or treated with a PPI. Although ACC/AHA guidelines recommend 1 year of dual antiplatelet treatment for patients with ACS and dual antiplatelet treatment for at least 1 year for those treated with drug-eluting stents [10,11], many such patients are treated indefinitely. In addition, millions of patients are prescribed indefinite aspirin therapy for primary and secondary prevention. We are left to ponder whether such patients should be treated indefinitely (for life?) with a PPI and what the economic and perhaps medical consequences of such treatment will be.
An important final statement of the document is that endoscopic therapy may be performed in high-risk cardiovascular patients on dual antiplatelet therapy. Many cases of stent thrombosis are due to the physician-instructed cessation of antiplatelet therapy after stent implantation. Such cessation of therapy in the first weeks after bare metal stent implantation and in the months after drug-eluting stent implantation has clearly been associated with a marked increased risk of stent thrombosis. There are actually very few data supporting the need to discontinue antiplatelet therapy (at least aspirin) before invasive procedures and surgeries, except in such cases as neurosurgical procedures and perhaps some prostatic procedures. While aspirin continuation may modestly increase the rate of bleeding complications, it generally does not increase the severity of bleeding complications.[12,13] While there is clear evidence that the combination of aspirin and clopidogrel increases bleeding complications in patients undergoing the major procedure of cardiac surgery [14,15], there are few data on its effects on less invasive procedures and more minor surgeries. The American Heart Association has recommended that elective procedures requiring antiplatelet therapy cessation should be postponed until at least 1 month after bare metal stent implantation and at least 1 year after drug-eluting stent implantation. Unfortunately, there is no proven strategy of "bridging" patients who have undergone stent implantation when it is felt that antiplatelet therapy must be withheld.[11,16]
The document represents a truly collaborative approach to care of the patient, not just of the coronary artery or upper GI tract, and for this, the writing group members should be commended. What we as practitioners are now faced with is interpreting these recommendations and applying them to day-to-day clinical practice. We may find that while we have become familiar with such terms as dual antiplatelet therapy and triple therapy, we may now have to become familiar with quadruple therapy: aspirin, clopidogrel, warfarin, and a PPI.
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-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association