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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Premature withdrawal and alternative therapies to dual oral antiplatelet therapy

Jean-Philippe Collet^* and Gilles Montalescot

Institut de Cardiologie Hôpital Pitié-Salpêtrière, 47 bvd de l'Hôpital, 75013 Paris, France

^* Corresponding author. Tel: +33 01 42 16 30 13; fax: +33 01 42 16 29 31. E-mail address: Jean-philippe.collet{at}psl.ap-hop-paris.fr

	Abstract

Top Abstract Introduction What are the recommendations... Is oral antiplatelet therapy... Interruption of a single... Interruption of dual oral... What are the perspectives? What can we recommend... Conclusions References

 
Premature interruption of dual oral antiplatelet therapy is an issue of increasing importance, and is particularly critical for at least three major reasons. First, patients eligible for temporary dual oral antiplatelet therapy are at high risk of acute recurrent thrombosis because they underwent a recent drug-eluting stent implantation or they experienced a recent acute coronary syndrome. Secondly, the proportion of these patients is now increasing and definite guidelines on how to manage interruption do not exist. Lastly, there is now evidence that premature interruption of oral antiplatelet therapy can lead to recurrence of events, with a significant impact on outcome in these high-risk patients. A perceived risk of increased bleeding events often leads to the interruption of oral antiplatelet therapy, but in many instances, the interruption is unjustified. Whether premature interruption of oral antiplatelet therapy is appropriate, and whether alternative therapies should be substituted are two important questions that, to date, remain unresolved. It is unlikely that the issue of premature withdrawal of dual oral antiplatelet therapy in high bleeding risk situations will ever be solved by randomized studies. Indeed, there is an urgent need to define an evidence-based strategy for the management of oral antiplatelet therapy in the peri-operative period. The risks of bleeding and ischaemic events, and the need to interrupt oral antiplatelet therapy, need to be evaluated for common situations such as dental care, or fibroscopic examination of the digestive tract.

Key Words: Antiplatelet agent • Aspirin • Acute coronary syndrome • Stroke • Atherothrombosis • Thrombosis

	Introduction

Top Abstract Introduction What are the recommendations... Is oral antiplatelet therapy... Interruption of a single... Interruption of dual oral... What are the perspectives? What can we recommend... Conclusions References

 
Evidence-based medicine has become the standard for guiding antithrombotic therapy use in the setting of acute coronary syndromes (ACS), but also to prevent recurrent ischaemic events in the chronic evolution of atherothrombosis. Interruption of oral antithrombotic therapy is a critical issue, given the great variety of situations and the potential risk of rebound thrombotic events that may occur in otherwise stable patients. Interruption is mainly driven by the potential risk of bleeding complications in the context of planned surgery. It may also concern stable patients treated with chronic oral antiplatelet therapy, who did not experience any recurrent vascular event or revascularization procedure, and who require surgery, or any other intervention that incurs an addition bleeding risk.

This real life issue clearly lacks prospective and scientific evaluation, and physicians are often unsure how to approach this dilemma. The present review aims to identify the potential risks of interrupting oral antiplatelet therapy, and how this situation can be handled in practical terms. The statement of the French scientist François Jacob that ‘It is not knowledge, but ignorance that is dangerous’ perfectly summarizes this review.

	What are the recommendations regarding oral antiplatelet therapy?

Top Abstract Introduction What are the recommendations... Is oral antiplatelet therapy... Interruption of a single... Interruption of dual oral... What are the perspectives? What can we recommend... Conclusions References

 
Current recommendations, particularly the guidelines of the American College of Chest Physicians stipulate that low-dose aspirin remains the cornerstone of oral antiplatelet therapy to prevent acute vascular events in stable patients with an established atherothrombotic disease.^1,2 Current recommendations for this situation are:

1. For all patients with chronic stable coronary artery disease (CAD), aspirin should be given (75–162 mg/J) (Grade 1A) and be continued indefinitely (Grade 2C).
   
2. For all patients with stable CAD with a risk profile indicating a high likelihood of developing acute myocardial infarction (AMI), long-term clopidogrel in addition to aspirin is given (Grade 2C)
   

Dual oral antiplatelet therapy was introduced relatively recently after evidence accrued that clopidogrel, which inhibits the ADP-induced activation of platelets, on top of aspirin, provides an additional 20% reduction in the relative risk of MI, or stroke as compared with aspirin alone in patients with ACS, but also in the setting of coronary stent placement.^3–5 Specific recommendations have been issued regarding drug-eluting stents (DES) given the potential risk of late-stent thrombosis:

1. For all patients with NST-ACS, aspirin (75–162 mg/day) should be continued lifelong (Grade 1A) and clopidogrel (75 mg/day) should be maintained for 9–12 months (Grade 1A or Grade 1B).
   
2. In stable patients who underwent stent placement, clopidogrel (75 mg) should be continued:
   • For 3–4 weeks after bare-metal stent (BMS) (Grade 1A)
     
   • For 6–12 months after DES (Grade 1C).
     
   
   

The specific issue of oral antiplatelet therapy interruption was not addressed in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines update for perioperative cardiovascular evaluation for non-cardiac surgery.⁶

	Is oral antiplatelet therapy interruption a real clinical issue?

Top Abstract Introduction What are the recommendations... Is oral antiplatelet therapy... Interruption of a single... Interruption of dual oral... What are the perspectives? What can we recommend... Conclusions References

 
Three questions summarize the issue of premature interruption of oral antiplatelet therapy.

1. Is interruption associated with a rebound of thrombotic events? Interruption of oral antiplatelet therapy is associated with a progressive recovery of platelet function and therefore with a potential rebound of thrombotic arterial events. However, there is a great variability in platelet function recovery. In addition, whether platelet recovery will end up with more reactive new platelets and/or an acute thrombotic event in a patient initially stable is unknown and impossible to predict.
   
2. When is premature interruption of oral antiplatelet therapy necessary? The question of premature interruption of oral antiplatelet therapy arises when there is a need for planned surgery that carries a high risk of bleeding. However, there is limited clinical evidence, and no clear recommendations exist for the management of oral antiplatelet therapy in this setting.
   
3. Should alternative therapies be recommended when withdrawing oral antiplatelet therapy? This is a critical question, especially for patients with high risk features for recurrent thrombotic events facing situations with a high risk of bleeding.
   

	Interruption of a single oral antiplatelet agent

Top Abstract Introduction What are the recommendations... Is oral antiplatelet therapy... Interruption of a single... Interruption of dual oral... What are the perspectives? What can we recommend... Conclusions References

 
Five key points summarize this specific point.

1. The average time delay between single oral antiplatelet therapy interruption and rebound of thrombotic events is 11 days. Because this time delay corresponds to platelet half-life and therefore to platelet functional recovery after interruption, it is assumed that there is a causal relationship between interruption and acute vascular events.^7–10 Interestingly, this time delay may vary according to the size of the arterial bed considered, ranging from 8 days on average for events related to CAD, up to 20 days for event related to PAD (Figure 1).¹¹
   
2. Single oral antiplatelet therapy interruption may account for 5% of ACS^9,10 and for 10% of all vascular events whatever be the arterial bed.¹¹ Interruption of aspirin has been shown to account for up to 15% of recurrent ACS in stable patients with an established CAD.¹⁰ Late-stent thrombosis in BMS was also described in this particular setting.
   
3. Single oral antiplatelet therapy interruption in the setting of ACS is particularly detrimental leading to a two-fold increase in the rate of short-term mortality (OR, 2.02; 95% CI, 1.33–6.90; P=0.003) (Figure 2). In addition, it was found to be an independent correlate for bleeding events (OR, 2.6; CI, 1.26–5.30; P<0.01).⁹
   
4. The reason for interrupting single oral antiplatelet therapy was not appropriate and was medically motivated in the vast majority of the cases. Indeed, spontaneous discontinuation was infrequent (Figure 3).⁹
   
5. A recent meta-analysis evaluated the cardiovascular risks after perioperative withdrawal of low-dose aspirin as compared with the bleeding risks associated with maintenance of aspirin. Although aspirin increased the rate of bleeding complications by a factor of 1.5, it did not lead to increased severity of bleeding complications, except for intracranial surgery and prostatectomy.¹¹
   

View larger version (19K): [in this window] [in a new window]   Figure 1 Temporal relationship between oral antiplatelet agent interruption and recurrent vascular event.11

 

View larger version (16K): [in this window] [in a new window]   Figure 2 Short-term clinical outcome of ACS patients according to the pattern of oral antiplatelet therapy use. Interruption of oral antiplatelet agents was associated with a significant two-fold increase in both death and bleeding complications (e-PARIS Registry).9 *Indicates a significant difference between non-users and recent withdrawers (2 with Bonferroni correction, P<0.017).

 

View larger version (27K): [in this window] [in a new window]   Figure 3 Reasons for aspirin interruption among patients admitted with ACS.9,10 In the vast majority of cases, interruption was inappropriate (in red) and could have been avoided.

 

	Interruption of dual oral antiplatelet therapy

Top Abstract Introduction What are the recommendations... Is oral antiplatelet therapy... Interruption of a single... Interruption of dual oral... What are the perspectives? What can we recommend... Conclusions References

 
Three different situations should be considered separately in this particular setting.

1. Interruption of oral antiplatelet therapy within the first month after BMS placement in high-risk patients. A catastrophic rate of events has been reported in this situation, with reports of death rate from 25 to 50%. In this situation, an excess of both bleeding and ischaemic complications has been observed because oral antiplatelet therapy was interrupted shortly before surgery (48 h). Patients experienced a high rate of major bleeding complications. As a consequence, re-introduction of oral antiplatelet therapy was delayed,^12,13 and a high rate of ischaemic events was observed. It is interesting to note that a time delay of <14 days between placement of a BMS and interruption of oral antiplatelet therapy was the most powerful predictive factor of acute-stent thrombosis (AST).
   
2. Oral antiplatelet therapy in the context of DES implantation. DES has been shown to be very effective to prevent in-stent restenosis and to be associated with a similar rate of AST as compared with BMS. Prolonged dual oral antiplatelet therapy has been recommended after DES implantation because late-stent thrombosis has been described as a consequence of delayed endothelialization. A substantially higher rate of AST was reported in registries including all patients submitted to DES implantation, as compared with clinical randomized trials. Premature interruption of oral antiplatelet therapy seems to be the strongest correlate for delayed AST (Figure 4).^13–16 Some reports have suggested that if more than 50% of PCI patients receive DES, then an increment of one death per 1000 PCI with DES can be anticipated. New evidence suggests that patients with AST have an abnormally high rate of high platelet reactivity.^17,18
   
3. Stable CAD patients with recent ACS. This situation is frequent. In addition, there are convincing data showing that interruption of clopidogrel in the context of dual oral antiplatelet therapy in diabetic patients was associated with a rebound of prothrombotic effects.¹⁹ However, whether interruption of clopidogrel after 9–12 months following ACS is associated with a rebound of acute thrombotic events remains to be established (Figure 5). The CURE and CREDO trials showed a sustained benefit of dual oral antiplatelet therapy as compared with aspirin alone with a good safety.^3,4 The recent CHARISMA trial²⁰ led to the conclusion that patients with established and symptomatic atherothrombosis benefit from long-term dual oral antiplatelet therapy (OR, 0.88; 95% CI, 0.77–0.99; P=0.046) without any significant increase in the rate of major bleeding (OR, 1.25; 95% CI, 0.97–1.61, P=0.09). Interestingly, in 20% of the CHARISMA population, oral antiplatelet therapy was interrupted during follow-up, even though patients were treated and followed long-term into the CHARISMA study (median treatment=25 months, median follow-up into the study=28 months). This subgroup of patients should provide new evidence about the risk of interrupting oral antiplatelet therapy in situations at high risk of ischaemic events.
   

View larger version (41K): [in this window] [in a new window]   Figure 4 Independent predictors of DES thrombosis. Premature discontinuation was found to be the most powerful factor independently associated with both subacute and late-stent thrombosis. Adapted from Iakovou et al.16

 

View larger version (13K): [in this window] [in a new window]   Figure 5 Potential rebound of vascular events following clopidogrel discontinuation in patients with non-ST-elevation ACS within the past year and treated with chronic dual oral antiplatelet therapy. Adapted from the CURE trial.4

 

	What are the perspectives?

Top Abstract Introduction What are the recommendations... Is oral antiplatelet therapy... Interruption of a single... Interruption of dual oral... What are the perspectives? What can we recommend... Conclusions References

 
Oral antiplatelet agent compliance and premature interruption has become a great concern for cardiologists and for all practitioners in charge of patients with atherothrombosis, given the expanding use of DES and the recent data about the long-term benefit of dual oral antiplatelet therapy. The following key points should be taken into consideration.

There is an urgent need to determine a strategy for managing antiplatelet therapy in the peri-operative period. To date, only scarce data exist, so it is difficult to issue firm recommendations. The ASPIRIN (Antiplatelet Strategies in the Perioperative period In patients at Risk of Ischemic eveNts) trial is ongoing. This is an investigator-driven French nationwide, multicenter, randomized, double-blind, placebo-controlled trial comparing low-dose aspirin therapy vs. placebo during the perioperative period in patients with documented symptomatic stable atherothrombotic disease, taking antiplatelet therapy, and undergoing extracardiac surgery. In addition, registries to assess routine practice of oral antiplatelet therapy interruption are also needed for educational purposes.

Recommendations from professional organizations in the field of cardiology are needed. The management of specific situations should be defined, and recommendations issued. Some scientific societies have issued specific recommendations in other fields, such as for gastro-enterology, anaesthesiology, and dentistry. These recommendations are available on the websites of these organizations.^21–23 It is clearly specified that oral antiplatelet therapy interruption is not necessary before oral surgical procedures²³ or during fibroscopic examination of the digestive tract, which carries an exceptional risk of bleeding, although it can be controlled by endoscopy (oral gastroscopy, rectosigmoidoscopy, colonoscopy without polypectomy). In addition, these recommendations state that carrying out biopsies during these procedures does not significantly increase the risk of bleeding.²⁴ Recommendations are lacking in the field of cardiovascular disease.

Risk profile assessment is a key step to prevent inappropriate management. Although ischaemic risk profile is easy to assess in stable patients, evaluation of the bleeding risk sometimes remains difficult depending on the type of surgery. In addition, there are confounding factors that are associated with both bleeding and ischaemic events, and these are usually exclusion criteria for randomized studies (Figure 6). Obviously management of patients with high ischaemic and high bleeding risks requires a multidisciplinary approach.

View larger version (31K): [in this window] [in a new window]   Figure 6 Assessment of the risk of ischaemic events and bleeding events to guide management of oral antiplatelet therapy interruption.

 
Education of patients treated with long-term oral antiplatelet therapy may prevent inappropriate or premature oral antiplatelet therapy interruption. An identification card highlighting patient status and oral antiplatelet therapy is an example of an educational program that is now being implemented in France.

There are no alternative therapies to oral antiplatelet therapy. NSAIDs and low-molecular weight heparin are very often used as substitute therapies when discontinuing oral antiplatelet therapy, although there is no good scientific evaluation for their efficacy in this context.

1. A variety of non-selective NSAIDS can inhibit TXA2-dependent platelet activation through competitive reversible inhibition of Cox1 activity by 70–90%. Sulfinpyrazone, flurbiprofen, indobufen, and triflusal have been evaluated in the context of CAD.²⁵ In France, flurbiprofen (50 mg bid) has been approved as an alternative therapy to aspirin in case of interruption for surgery in coronary patients.
   
2. There is no evidence for the efficacy of LMWH at curative dosage regimen as an alternative therapy to oral antiplatelet therapy. In addition, LMWH are ineffective to prevent AST. Furthermore, preoperative use of LMWH has been shown to significantly increase post-operative bleeding and re-exploration in cardiac surgery.²⁶ However, the ease of use and rapid reversibility of this strategy have led to its use as an alternative to oral antiplatelet therapy in case of temporary cessation.
   

In addition, using alternative therapies may increase the time window without effective oral antiplatelet therapy before planned surgery and may delay immediate reintroduction of oral antiplatelet therapy.

	What can we recommend in routine practice?

Top Abstract Introduction What are the recommendations... Is oral antiplatelet therapy... Interruption of a single... Interruption of dual oral... What are the perspectives? What can we recommend... Conclusions References

 
There are three plausible scenarios regarding the temporary interruption of dual oral antiplatelet therapy for planned surgery according to the bleeding risk of certain acts of surgery (Figure 7).

1. Low bleeding risk: Interruption of oral antiplatelet therapy is not necessary, irrespective of the ischaemic risk profile.
   
2. Intermediate bleeding risk: Interruption of oral antiplatelet therapy should be decided after assessing the ischaemic risk. In low ischaemic risk patients, the interruption of clopidogrel 5 days before surgery with reintroduction as soon as possible is an option. In high ischaemic risk patients, planned surgery should be postponed. If surgery cannot be postponed, then the interruption of clopidogrel 5 days before surgery with reintroduction as soon as possible is an option with or without alternative therapies.
   
3. High bleeding risk: The first option is to postpone planned surgery if possible. Otherwise, it should be possible either to stop aspirin and clopidogrel 5 days before planned surgery, without alternative therapies or stop aspirin and clopidogrel 10 days before planned surgery with alternative therapies. These recommendations are not based on evidence, but rather emanate from a consensus document on the management of this particular situation published by three professional organizations in France. Their statement was published on the respective websites of the societies [French Society of Anesthesia and Intensive Care (www.sfar.org), French Society of Cardiology (www.sfcardio.org), and the Groupe d'Etude sur l'Hémostase et la Thrombose (GEHT)] www.geht.org/fr.
   

View larger version (34K): [in this window] [in a new window]   Figure 7 Recommendations of the SFAR (Société Française d'Anesthésie Réanimation) regarding management of oral antiplatelet therapy in patients with DES.

 

	Conclusions

Top Abstract Introduction What are the recommendations... Is oral antiplatelet therapy... Interruption of a single... Interruption of dual oral... What are the perspectives? What can we recommend... Conclusions References

 
The interruption of oral antiplatelet therapy, especially if premature, should be carefully handled given the risk of acute recurrent thrombotic event as a consequence of progressive platelet function recovery. Ignorance of the risks incurred by interrupting oral antiplatelet therapy is the clinician's worst enemy. Insufficient scientific evidence in this field makes it impossible to issue clear guidelines. The first question that should always be asked is whether interruption is really appropriate, and whether it can be avoided. Then, evaluation of the bleeding-associated risk is a key step in the decision-making of interruption. Difficult situations arise when high-risk features for both ischaemic and bleeding events are present simultaneously. Fortunately, this is a rare scenario. There is an urgent need for dedicated studies to assess the real magnitude of the problem, which could lead to firm recommendations from scientific societies.

Conflict of interest: none declared.

	References

Top Abstract Introduction What are the recommendations... Is oral antiplatelet therapy... Interruption of a single... Interruption of dual oral... What are the perspectives? What can we recommend... Conclusions References

 

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