Platelet inhibition and bleeding complications in cardiac surgery: A review

Abstract

Dual antiplatelet therapy (DAPT) with acetylsalicylic acid and a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) reduces thrombotic events in patients with acute coronary syndrome (ACS), but it is also associated with an increased risk of bleeding complications. Excessive bleeding in cardiac surgery patients is associated with increased morbidity and mortality and high costs. In this review, different aspects of platelet inhibition in cardiac surgery patients will be discussed, including direct effects on bleeding and transfusion requirements, discontinuation and reinstitution of antiplatelet drugs before and after surgery, and the use of perioperative platelet function testing.

Keywords:

• Platelets
• platelet inhibition
• bleeding
• cardiac surgery

Introduction

Bleeding remains a significant problem in cardiac surgery. Excessive bleeding is associated with increased morbidity and mortality and high costs. The bleeding may be caused by surgical factors or an impaired hemostasis or a combination thereof. One important factor resulting in impaired hemostasis is preoperative use of antithrombotic medication such as platelet inhibitors and anticoagulation. In this review, different aspects of platelet inhibition in cardiac surgery patients will be discussed, including direct effects on bleeding and transfusion requirements, discontinuation, and reinstitution of antiplatelet drugs before and after surgery, and the use of perioperative platelet function testing.

Bleeding complications in cardiac surgery

Cardiac surgery patients normally bleed approximately 400–700 ml after the procedure. However, excessive bleeding is common and occurs in approximately 5–15% of the patients. The large variation in different studies is mainly depending on the definition of excessive bleeding. Bleeding after cardiac surgery is often multifactorial and may depend both on patient and procedural factors, the surgical trauma, and on an impaired hemostasis during and after the operation. Patient- and procedure-related factors persistently associated with increased bleeding in cardiac surgery in different studies are advanced age, low body mass index, low plasma concentration of fibrinogen, impaired renal function, previous sternotomy, large surgical procedure, and acute operations. The impaired hemostasis also depends on different factors including hemodilution, exposure to non-endothelialized surfaces in the extracorporeal circulation circuit, preoperative use of antithrombotic drugs, and increased fibrinolysis.[1] Independently of the cause, excessive bleeding presents an important clinical issue as bleeding complications are strongly associated with poor outcome after cardiac surgery.[2,3] Major bleeding in the setting of adult cardiac surgery was in a recent study associated with an eight-fold increase in mortality after adjustment for other factors influencing mortality, Figure 1.[2] It is not understood in detail why bleeding complications present such a threat to cardiac surgery patients, but the blood loss in itself, the iterated surgical trauma during re-exploration for bleeding, as well as transfusions seem to play a role in the increased morbidity.[4–6]

Figure 1. Bleeding complications and operative mortality. Reprinted from Dyke, et al. [2] with permission from Elsevier.

Re-exploration for bleeding occurs in 2–8% of procedures, and is also strongly associated with increased morbidity and mortality.[5–9] Transfusion of blood products, especially red cell transfusion, has also been linked to increased short- and long-term morbidity and mortality in retrospective observational studies,[4] even if the patient is transfused with as little as one or two units of blood.[10] It should, however, be pointed out that retrospective studies of transfusion are severely hampered by selection bias. Differences between transfused and non-transfused cohorts are virtually impossible to control for, even with advanced statistical methods. Interestingly, in a recent large randomized study, a restrictive transfusion regimen after cardiac surgery was associated with increased mortality.[11]

Antiplatelet drugs

Acetylsalicylic acid

Secondary prevention with ASA reduces mortality, myocardial infarction, and stroke in patients with different cardiovascular diseases but increases the risk for bleeding complications.[12,13] Today, the majority of coronary artery bypass grafting (CABG) patients, independently if they are acute, urgent or elective, are treated with ASA before the operation. ASA inhibits production of prostaglandin and thromboxane A₂ platelet activation by binding irreversibly to cyclooxygenase (COX)-1.[14] Complete inhibition of COX-1 occurs already at low doses of ASA, whereas the dosage most commonly used in patients with coronary artery disease in Europe (75–100 mg daily), only partially inactivates COX-2. The effect of ASA is irreversible, i.e. the effect remains throughout the lifespan of the platelet (8–9 d).[14]

A recent meta-analysis compared preoperative ASA administration with no treatment in CABG patients.[15] In the analysis, treatment with ASA reduced the risk of perioperative myocardial infarction (OR 0.56 (0.33–0.96)) but not the mortality risk (OR 1.16 (0.42–3.22)) while postoperative bleeding, red cell transfusions, and surgical re-explorations increased with ongoing ASA-treatment.

P2Y₁₂-inhibitors

The first P2Y₁₂-receptor antagonists ticlopidine and clopidogrel were introduced in the late 1990s,[16,17] starting the era of dual antiplatelet therapy (DAPT). Clopidogrel rapidly became the primary platelet inhibitor in acute coronary syndrome (ACS) patients, due to severe side effects with ticlopidine. Clopidogrel is a thienopyridine that requires metabolism in the liver via cytochrome P450 enzymes. The active metabolites bind irreversibly to the P2Y₁₂-receptor, blocking ADP-mediated platelet aggregation. Maximum platelet inhibition by clopidogrel is achieved 3 h after administration of the loading dose.[18]

Due to the non-optimal pharmacological properties of clopidogrel, development of platelet inhibitors continued, with prasugrel [19] and ticagrelor [20] being introduced in 2009 and 2010, respectively. Prasugrel is a thienopyridine and a prodrug, like clopidogrel. The metabolism of prasugrel is less variable than with clopidogrel and prasugrel has a more rapid onset of effect, approximately 30 min after administration.[18] Prasugrel also binds irreversibly to the P2Y₁₂-receptor. Prasugrel gives a higher degree of platelet inhibition than clopidogrel and increases the risk of major bleeding complications.[19] In spite of markedly more perioperative bleeding, there was still improved survival with prasugrel compared with clopidogrel in CABG patients in the TRITON CABG substudy.[21]

Ticagrelor is a triazolopyrimidine, a slightly different class of ADP-receptor antagonist. Ticagrelor is direct-acting, and binds reversibly to the P2Y₁₂-receptor.[18] The onset of effect is more rapid, and it gives a more potent inhibition of platelet aggregation compared with clopidogrel. Maximum plasma concentration and platelet inhibition are achieved after 1–3 h. Off-set of the inhibitory effect is also faster with ticagrelor compared with clopidogrel.[22] There is currently no clinically available direct antidote, although experimental data have been presented.[23] In the PLATO trial in ACS patients, ticagrelor reduced cardiovascular events and mortality compared with clopidogrel but increased the risk for non-procedure-related bleeding complications.[20,24] In the PLATO-CABG substudy, ticagrelor improved survival, with a relative reduction of nearly 50% in both cardiovascular and all-cause mortality.[25] On one hand, there was no overall difference in CABG-related major bleeding between the ticagrelor and the clopidogrel in that study. In current guidelines, ticagrelor and prasugrel are recommended over clopidogrel in most subgroups of ACS patients.[12,13] In a recent comparison, ticagrelor was overall associated with less CABG-related bleeding complications than clopidogrel, both in unadjusted and adjusted analyses.[26] The effect was most likely caused by the faster off-set of the antiplatelet effect with ticagrelor. On the other hand, there was an increased incidence of bleeding complications with ticagrelor when the P2Y₁₂-inhibitor was stopped <24 h before CABG.

Discontinuation of antiplatelet drugs before surgery

Acetylsalicylic acid

Current guidelines do not recommend discontinuation of ASA in cardiac surgery patients.[27] On one hand, the recommendations are based on studies showing that ongoing treatment reduces the risk for perioperative myocardial infarction.[15] However, a recent large randomized controlled trial (RCT), not included in the meta-analyses, showed no significant effect of ASA-treatment on thrombotic events.[28] On the other hand, ASA treatment did not increase the incidence of perioperative bleeding. It should be noted that the study did not directly compare discontinuation with no discontinuation, since patients were included in the study only if they had stopped ASA at least 5 d before surgery, or were not using ASA preoperatively. Further RCT’s and observational studies support that ongoing treatment with ASA in cardiac surgery patients is associated with a lower rate of major cardiovascular events but an increased or similar rate of postoperative bleeding complications.[29,30] Interestingly, recent data suggest that the inhibiting effect of ASA on platelet aggregability can be completely restored by platelet transfusion.[31–33] The possibility to counteract the effect of ASA argues for continuation of ASA. The increased risk of bleeding complications if ASA and other antithrombotic drugs are continued must also be weighed against the potentially increased risk of thrombotic complications during the preoperative cessation period. In patients with high bleeding risk and in patients who do not accept blood transfusion, discontinuation of ASA may be considered.

P2Y₁₂-inhibitors

Since the risk of bleeding complications is increased if the P2Y₁₂-inhibitor is maintained until surgery, it is currently recommended that clopidogrel and ticagrelor are discontinued 5 d and prasugrel 7 d prior to elective or subacute major surgical procedures,[12,13,27] Table 1. Recommendations regarding timing of discontinuation are based on pharmacological data of the different platelet inhibitors and data from clinical studies. For clopidogrel, it was shown in the CABG substudy of the CURE-trial that discontinuation 5 d of more before CABG did not increase the risk for bleeding complications.[34] For prasugrel, a longer time interval is recommended due to the longer off-set time compared with clopidogrel [18] and the high incidence of CABG-related bleeding complications reported in the CABG substudy of the TRITON-TIMI 38 trial.[23] For ticagrelor, 5 d discontinuation time is recommended. Given the differences in pharmacological properties of ticagrelor and clopidogrel with a significantly shorter offset-time with ticagrelor, a shorter discontinuation period may be considered for ticagrelor. This hypothesis was recently tested in a large retrospective study which showed that there was no significant difference in the incidence of major bleeding complications when ticagrelor was stopped 72–120 h before surgery compared with >120 h (OR 0.93 (95% CI 0.53–1.64), p = .80).[26] The findings, which indicate that it is possible to recommend a discontinuation time of 72 h for ticagrelor, were recently also supported by a study from a Dutch registry.[35] A reduction of the waiting time from 5 to 3 d would reduce the risk for thrombotic events while waiting for surgery, and save hospital resources, as it would shorten hospital length-of-stay.

Table 1. An overview of oral P2Y12-inhibitors.

	Clopidogrel	Prasugrel	Ticagrelor
Class	Thienopyridine	Thienopyridine	Triazolopyrimidine
Metabolism to active form	Hepatic	Hepatic and intestinal	Not required
Non-responders	Up to 30%	Uncommon	No
Binding	Irreversible	Irreversible	Reversible
Onset	2–4 h	30 min	30 min
Effect duration	3–10 d	5–10 d	3–4 d
Discontinuation prior to surgery	5 d	7 d	5 d

Even though discontinuation of platelet inhibition is favorable in terms of reducing bleeding risk, it may also increase risk of thrombosis,[36] and it is, therefore, important to optimize timing of surgery after discontinuation. The timing of discontinuation of P2Y₁₂-inhibitors is in clinical reality influenced by a number of factors, including institutional guidelines, the patient’s condition, logistical reasons and the individual surgeon’s decision.[37] It is, therefore, not surprising that the reported variability in discontinuation time is high. In Hansson et al.’s recent study, approximately 40% of the CABG patients were operated after a shorter discontinuation than recommended in guidelines.[26] However, the current European revascularization guidelines do open up for case-by-case decisions regarding discontinuation when patients are at risk from both bleeding and thrombosis, e.g. in ACS patients.[27]

Reinstitution of antiplatelet drugs after surgery

ASA

If ASA, against current guidelines, is discontinued before the operation, the question of restarting the treatment arises. In a large prospective observational trial, patients who restarted ASA within 48 h after CABG had a lower mortality rate than those who did not receive ASA during this period (1.3% versus 4.0%, p < .001).[38] In this study, early reinstitution of ASA was also associated with marked reductions in myocardial infarction (−48%), stroke (−50%), and renal failure (−74%). However, as mentioned above, selection bias may contribute to the differences in non-randomized studies.

P2Y₁₂-inhibitors

Two meta-analyses have compared DAPT with ASA only after CABG.[39,40] In Verma et al.’s analysis, based on RCTs only, there were no differences in all-cause mortality between the DAPT and ASA only.[39] Conversely, all-cause mortality was significantly lower in ASA + ticagrelor and ASA + prasugrel versus ASA + clopidogrel RCTs. In Deo et al.’s meta-analysis based on both RCT’s and observational studies, only DAPT patients treated with clopidogrel were included.[40] In this study, early mortality (in-hospital or 30-d mortality) was lower with ASA + clopidogrel compared with ASA alone while the risk of angina or perioperative myocardial infarction was comparable. Long-term mortality was not reported. Patients treated with ASA + clopidogrel after CABG had a trend towards higher incidence of major bleeding episodes, compared with ASA alone. Both meta-analyses are weakened by a large variation in the included studies regarding study drug, study design, patient inclusion criteria, study quality, and length of follow-up. The positive effect on survival appears to be more pronounced in ACS patients and in patients treated with the second-generation P2Y₁₂-inhibitors ticagrelor and prasugrel. However, reinstitution of DAPT after CABG may also slightly increase the risk for bleeding complications. Current guidelines recommended that DAPT is restarted in patients with ACS as soon as considered safe after CABG. The optimal timing of the restart remains unclear, but 24–72 h after the operation appears reasonable.

Platelet function testing

Besides the variances in platelet inhibitory effect between different P2Y₁₂-inhibitors, there is also a large individual variation in the magnitude and duration of the antiplatelet effect.[22,37,41] Because platelets play such an important role in hemostasis and are at risk of dysfunction in cardiac surgery patients, the prospect of determining perioperative platelet function is appealing. The gold standard for platelet function tests is light transmission aggregometry,[42] which is time consuming and requires a special laboratory. In addition, this in vitro test is performed under non-physiological conditions (platelet rich plasma, low calcium concentration, and high pH). Hence, many different point-of-care whole blood methods for testing of platelet function have been developed.[43] Several studies have shown that the results of preoperative platelet function testing can predict bleeding complications in cardiac surgery.[37,44–46] Previous studies have investigated the use of impedance aggregometry to assess bleeding risk after CABG in patients with clopidogrel or a mix of different P2Y₁₂-inhibitors, and identified cut-off levels of ADP-initiated platelet aggregation which predicted major bleeding complications.[45,46] Malm et al. recently showed that the same levels may also be applicable to ticagrelor-treated patients.[37] Because of the individual variation in response to platelet inhibitors, the use of platelet function tests may also aid in optimizing timing of surgical procedures. Platelet function tests have been used to facilitate timing of CABG after discontinuation of DAPT with clopidogrel, resulting in shorter waiting time.[47] Furthermore, platelet function tests could be of value to establish the grade of platelet inhibition in patients in whom time since discontinuation is unclear, e.g. in unconscious or confused patients, and in patients with uncertain compliance to the treatment. However, it should be pointed out that no RCT or observational study has compared the incidence of perioperative bleeding complications between time since discontinuation-based and platelet function test-based timing of surgery. Additionally, cut off levels for severe bleeding have only been identified for some of the available platelet function testing devices.

Conclusions and future perspectives

More potent platelet inhibition is associated with a higher rate of bleeding in cardiac surgery patients, especially if the treatment is continued until time of surgery. It is, therefore, important to carefully consider the indication for treatment and timing of surgery, weighing the risk of bleeding against the risk of thrombosis. Nevertheless, it is important to note that treatment with DAPT, and especially the new more potent platelet inhibitors, is beneficial for the ACS patient, with lower morbidity and mortality compared with ASA alone, also in the cardiac surgery setting.[21,25,34]

As bleeding complications most likely will remain an important issue in cardiac surgery in spite of future technical developments, the pursuit of understanding and preventing bleeding will be continuous. As an increasing number of patients are subject to treatment with potent platelet inhibitors, and with longer duration of treatment,[48] more patients may need major surgery – cardiac and non-cardiac – despite ongoing platelet inhibition, with the associated higher risk of bleeding.

New antiplatelet drugs will also most likely have an impact on bleeding complications and management of patients. Today, the intravenous short-acting platelet inhibitor cangrelor has been licensed for use in ACS patients.[49] It is yet too early to define the role of cangrelor in CABG patients but one apparent field of application is to bridge high risk ACS patients to CABG.

Due to the large variability in recovery of platelet function after discontinuation, platelet function testing may prove to be a valuable tool in timing of surgery, especially in patients with high risk of bleeding and thrombosis. Individualizing treatment and timing of surgery will require a greater amount of flexibility from hospitals and care providers, but will likely improve outcome for patients and thereby be cost-effective.

Disclosure statement

E. C. H. has received speaker’s honoraria from AstraZeneca. A. J. has received speaker’s honoraria from AstraZeneca and Roche Diagnostics, honorarium for advisory boards from Roche Diagnostics, The Medicines Company and AstraZeneca, and support from AstraZeneca for investigator-initiated studies.