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March 2009
Managing Patients After PCI
Combined dual-antiplatelet and anticoagulant therapy after PCI in patients with an indication for warfarin.
Each year, more than 1 million percutaneous coronary interventions (PCI) are performed in the US. At the same time, it is estimated that more than 2 million people are currently being treated with warfarin for various indications. Given the size of these two patient populations, overlap of these populations is inevitable and management of patients with an indication for warfarin after PCI has become a common clinical scenario.
In the 1990s, in the early days of coronary stenting, patients were administered potent combinations of antiplatelet and antithrombotic drugs, largely without clear evidence of benefit, in an effort to prevent stent thrombosis. In the late 1990s, a series of trials confirmed the superiority of dual-antiplatelet therapy over other regimens—including combination aspirin and warfarin—in preventing stent thrombosis.1-4 These studies led to the widespread adoption of the current aspirin and thienopyridine regimen after stent deployment.
Conversely, warfarin has proven to be a superior treatment for a number of medical conditions. Randomized controlled trials have firmly established warfarin anticoagulation as the preferred management strategy in several commonly encountered prothrombotic conditions, including hypercoagulable states, venous thromboembolism, and atrial fibrillation. It also remains the standard of care for patients with mechanical valve prostheses.
The benefit of warfarin to avoid systemic thrombosis is in contrast to its ineffectiveness in preventing stent thrombosis. Conversely, dual-antiplatelet therapy is much more effective in preventing coronary stent thrombosis but is much less effective than warfarin for other thrombotic conditions. Balancing the risks of thrombosis and bleeding in a patient after PCI with a coincidental indication for anticoagulation, the cardiologist is faced with the question of whether to combine both anticoagulant and antiplatelet strategies (ie, "triple therapy") or adopt a hybrid of two of the three drugs. In this article, we review the existing data and guideline recommendations to assist in decision making and highlight current areas of uncertainty.
PATIENTS WITH MECHANICAL HEART VALVES
The annual risk of thromboemboli in patients with a mechanical valve prosthesis is 1% to 3% (in the aortic position) and 3% to 6% (in the mitral position). These mechanical valves require the long-term use of full-dose anticoagulation.5 Patients with mechanical valves who also have certain high-risk features for thromboembolism (eg, atrial fibrillation, left ventricular dysfunction, a hypercoagulable state, or previous thromboembolism) are often advised to take a low-dose aspirin, in addition to warfarin.6 Although a role for dual-antiplatelet agents without warfarin has been suggested for mechanical valves in the aortic position (eg, in the ongoing PROACT trial), the need for maintaining full-dose anticoagulation after mechanical valve implantation is generally considered mandatory.
Given the relatively lackluster results of combination aspirin and warfarin therapy in preventing stent thrombosis compared with aspirin and thienopyridine therapy, strong consideration should be given to triple therapy in the mechanical valve population after PCI. Current American College of Cardiology/American Heart Association (ACC/AHA) PCI Guidelines continue to highlight the need for triple therapy with warfarin, aspirin, and a thienopyridine after stent placement in patients with indications for warfarin.7 The risks of bleeding are certainly higher with this combination (although there are no studies specifically addressing these risks among patients with prosthetic heart valves), so these guidelines recommend maintaining an international normalized ratio (INR) at the lower end of the therapeutic range for the duration of triple therapy.
PATIENTS WITH VENOUS THROMBOEMBOLISM
Patients with venous thromboembolism, in general, represent a heterogeneous group with a spectrum of underlying clinical disorders. In most cases of venous thromboembolism, it is warranted to continue warfarin therapy along with dual-antiplatelet therapy, although this decision will invariably need to be individualized based on the patient's propensity to have a recurrent thrombotic event and his risk of bleeding.
PATIENTS WITH ATRIAL FIBRILLATION
Most practice variation appears to be in patients with atrial fibrillation. This variation reflects the physician's assessment of the patient's probability of thromboembolism and stroke, which is known to vary widely depending on additional stroke risk factors. This probability of systemic embolic events is weighed against the risk of bleeding associated with aggressive anticoagulation. Often, patients at the highest risk for thromboembolism are also those at greatest perceived risk for bleeding, making the risk-benefit ratio of triple therapy difficult to estimate. Less commonly, patients may present with paroxysmal atrial fibrillation in the setting of an acute coronary syndrome. This may be self-limiting, and the physician may not feel compelled to anticoagulate this type of patient.
There are no good data to guide the provider in this regard. Several series and case-control studies have been published8-10 but all suffer from the severe methodological limitations inherent to retrospective datasets. There are currently no data from randomized studies available.
The largest series of patients with atrial fibrillation undergoing PCI come from Spain.11,12 In these studies, the reported 12- to 18-month rates of major adverse cardiovascular events were 26% to 27% in patients receiving triple therapy compared with 21% to 39% among patients treated with dual-antiplatelet therapy alone. Not surprisingly, the rates of major bleeding in these series were higher among combined warfarin users (15%–22%) than those on aspirin/thienopyridine alone (4%–9%). This is in keeping with other studies, which have suggested an approximately fivefold excess risk of bleeding with triple therapy.8,13,14 Although withholding warfarin anticoagulation after PCI has been suggested to be associated with adverse outcomes in multivariate modeling,12 glaring study limitations (including a case-control design, absence of propensity modeling, and lack of adjustment for contraindications to anticoagulation) preclude the blanket recommendation that all patients with atrial fibrillation be treated with triple therapy.
Not surprisingly, current guidelines are somewhat ambiguous on this subject. Both the 2007 ACC/AHA PCI and ST-segment elevation myocardial infarction guidelines suggest the combination of low-dose aspirin, clopidogrel, and warfarin, with a goal INR of 2.0 to 2.5 in patients receiving coronary stents "requiring warfarin" (a class I, grade C indication). Which patients with atrial fibrillation require warfarin during the period of dual-antiplatelet therapy is not stipulated, however. The 2006 ACC/AHA Guidelines for the Management of Atrial Fibrillation recommend a regimen of clopidogrel 75 mg daily along with warfarin anticoagulation to a target INR of 2.0 to 3.0 after PCI (a class IIb, grade C recommendation).15 There are, however, no clear data to support that combination after stent placement.
It seems reasonable to individualize therapy based on the patient's risk for thromboembolism weighed against the risk of bleeding. The CHADS2 (congestive heart failure, hypertension, age >75, diabetes, prior stroke or TIA) score is a validated tool of predicting annualized risk of stroke from atrial fibrillation (Tables 1 and 2).16 Patients with a low CHADS2 score appear to be at low risk for embolism during the period of clopidogrel use and are likely to be more at risk for bleeding complications. Conversely, patients with a number of risk factors for stroke, particularly a previous history of cerebrovascular disease, probably require the combination of dual-antiplatelet therapy and warfarin anticoagulation (preferably at the lower end of the therapeutic range).
ROLE OF STENT CHOICES
The choice of stent type, either drug eluting or bare metal, is a key question in patients who require long-term anticoagulation. Current guidelines recommend treatment with clopidogrel for at least 1 month after bare-metal stent placement and for at least 1 year after drug-eluting stent implantation, even when on triple therapy.7,17 Because multiple studies have shown that bleeding events continue to accrue over time with antiplatelet and anticoagulant therapy,18 it seems reasonable to consider bare-metal stent implantation as the preferred coronary stent implant in most patients with a need for long-term warfarin anticoagulation. Again, however, the ultimate choice of stent type will need to take into account individual patient and coronary lesion characteristics (eg, diabetes, in-stent restenosis, lesion length, vessel diameter, etc).
MONITORING ANTICOAGULATION IN PATIENTS ON TRIPLE THERAPY
Once the patient has been committed to combined dual-antiplatelet and warfarin therapy, the risks of bleeding complications are significantly elevated. Published series have estimated the risk of bleeding to be three- to sevenfold higher on combination therapy versus dual-antiplatelet therapy alone.8,13,14 This estimation may, in fact, be somewhat of an underestimation, given the significant treatment biases that preclude prescription of warfarin to patients who clinicians believe are at high risk for bleeding and who otherwise would not appear in such case series. Current ACC/AHA PCI and ST-segment elevation myocardial infarction guidelines highlight this increased risk for bleeding and recommend close monitoring of prothrombin times (class I, grade B recommendation).7,17 Additionally, these guidelines recommend managing patients at the lower end of their target INR (ie, 2.0–2.5). Although this approach is logical, there are limited data to support this (hence, it is class 1, grade C), and it is important to note that more than 70% of patients with a hemorrhagic complication on combination therapy had an INR <3.0 at the time of their bleeding event.8
CONCLUSIONS
Increasingly, interventional cardiologists and clinicians are finding themselves managing patients in the post-PCI setting who have an indication for concomitant warfarin. The decision to prescribe triple therapy is neither straightforward, nor based on extensive randomized evidence. Currently, these decisions must be individualized, based on the patient's risk for thrombosis (ie, stent thrombosis or systemic thromboembolism) compared with the excess risk for bleeding complications associated with triple therapy. Unfortunately, the data to guide the decision-making process are only observational. In the meantime, physicians must continue to carefully weigh stent choices, patient characteristics, indications for anticoagulation, and perceived thrombosis and bleeding risks to best care for these patients.
Aslan T. Turer, MD, is from the Division of Cardiovascular Medicine, Duke University Medical Center, Durham, North Carolina. Dr. Turer may be reached at (919) 684-8111; turer001@mc.duke.edu.
J. Kevin Harrison, MD, is from the Division of Cardiovascular Medicine, Duke University Medical Center, Durham, North Carolina. Dr. Harrison may be reached at (919) 681-3763; harri015@mc.duke.edu.
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