INTERNATIONAL JOURNAL OF CARDIOLOGY AND CARDIOVASCULAR MEDICINE (ISSN:2517-570X)

Background: Dual Antiplatelet Therapy requires the combination of Aspirin and a P2Y12inhibitor. It is the current standard practice in preventing cardiovascular thrombotic complications. Evidence in literature proves the efficacy of DAPT in preventing thromboses and MI events in acute coronary syndromes. However, patients who receive DAPT with subsequent cardiac surgery are at higher risk for bleeding complications. This article aims to highlight the benefits and disadvantages of DAPT in a cardiac surgery setting.

Materials and Methods: A search of major research websites, including Pubmed, Medline, and Update were starting November 2018.The systematic review was done on articles that included the impact of DAPT on cardiovascular surgery. Other articles that studied the effect of P2Y12inhibitors and Aspirin were also reviewed meticulously.

Results: DAPT therapyreduced the incidence of MI by 2.0% and reduced major adverse cardiac events by 1.6%. Roughly 1 on 10 patients on DAPT will need cardiac surgery, and although preoperative discontinuation of platelet inhibition minimizes the risk of postoperative bleeding, it predisposes to thrombotic events. When considering the timing of surgery, one must weigh the risk of an interval ischemic event during the period of “drug washout” against the risk of perioperative bleeding.

Conclusion: DAPT is the cornerstone treatment for preventing thrombotic complications in ACS, as it reduces overall mortality and morbidity. When faced with cardiac surgery, and the increased risk of bleeding, managing DAPT therapy in this setting is challenging. Knowledge of the evidence concerning this dilemma can help inform rational decisionmaking. 

CABG; Anti platelet therapy; Aspirin; Cardiac surgery; Bleeding; Bridging therapy 

Dual antiplatelet therapy (DAPT) is the current practice in preventing myocardial infarction, stroke, and stent thrombosis. It is a standard therapy for coronary artery disease (CAD) patients suffering from Acute Coronary Syndrome (ACS). The currently available recommendations set by the ACS guidelines involve the initiation of DAPT, comprising a P2Y12 inhibitor and aspirin, at the time of presentation of a patient with an acute ischemic event. The aim of the treatment is to reduce the incidence of recurrent ischemic events, a major complication accompanying ACS patients.According to the PEGASUS-TIMI 54 trial, patients with a previous MI (1-3 years) randomized to DAPT (Aspirin and Ticagrelor) vs Aspirin monotherapy benefited by a 1.2%-1.3% absolute reduction in cardiovascularrelated deaths, MI, and stroke, decreasing the incidence from 9.0% to approximately 7.8% [1]. In the extended dual antiplatelet therapy study, performed in patients with drug-eluting stents [2], patients who received DAPT for 12 months without having had a bleeding complication had DAPT or Aspirin monotherapy extended for an additional 18 month. The results illustrated that extended DAPT therapy (18-36 months after DES implantation) reduced the incidence of MI by 2.0% and reduced all major adverse cardiac events by 1.6%. However, those patients who undergo coronary bypass surgery on DAPT therapy experience significant increases in postoperative bleeding complications. This review aims to highlight the evidence informing the cardiac surgeon as to the benefits and drawbacks of dual antiplatelet therapy in the setting of anticipated cardiac surgery.

Perioperative bleeding is universal after cardiac surgery. On average, bleeding, as measured by chest tube output, is 6-800 cc for the first 24 hours. Routinely, bleeding is significant enough that close to 50% of postoperative coronary bypass patients receive a transfusion of packed red blood cells (pRBC), and roughly 25% of patients receive clotting factor as well as platelet transfusions. Two percent of patients bleed enough to warrant a re-exploration to rule out a surgically correctable problem [3]. Although there exist defined complications of cardiac surgery such as renal injury, prolonged ventilation, stroke and infections, a clear definition of when perioperative bleeding reaches the level of a “complication” has not yet been established. Attempts to remedy this have led to a proposed, universal definition of perioperative bleeding (UDPB), involving easily measurable clinical variables such as blood loss from chest tubes during the first 12 postoperative hours, blood product transfusions and surgical re-exploration [4]. Specifically, 9 perioperative variables makeup the definition, including postoperative chest tube output, any blood product transfusion, the administration of factor concentrates, the use of recombinant activated factor VII (rVIIa) and surgical reoperation. Based on these variables, the UDPB system defines 5 classes of bleeding: insignificant, mild, moderate, severe and massive (Table 1) [5]. Preoperative and intraoperative transfusions are not considered in the UDPB, as the indications for those transfusions relate more to preoperative anemia and intraoperative hemodilution than to bleeding. Similarly, pre and intraoperative transfusions of platelets, cryoprecipitate, and FFP are not figured into the definitions, just postop transfusions of these products.

Significant postoperative bleeding is a marker for poor outcomes. For example, severe/massive bleeding (>2L chest tube output in the first 12 postoperative hours) has been shown to have a mortality rate of up to 22% [4], and reoperations for bleeding increase mortality two-to-four-fold with an increase in postoperative complications as well [5]. It is understood that factors such as low BMI, non-elective surgery, redo-sternotomies, increasing age, smaller body surface area and longer cardiopulmonary bypass times, all of which increase postoperative bleeding, are not modifiable. However, given the morbidity and mortality associated with excessive postoperative blood loss [3,6,7], it behooves the practitioner to decrease any risk over which he does have control. It is within this context that we address the issue of antiplatelet therapy.

As explained above, DAPT mainly targets platelet aggregation (Table 2) via COX-inhibition (Aspirin) and the blocking of the platelet P2Y12 receptor (Clopidogrel, Ticlopidine, Ticagrelor, Prasgurel, Cangrelor). DAPT therapy is indicated in all patients who have been stented, as it drastically reduces the risk of in-stent thrombosis, especially in the first 3-6 months [8,9]. However, despite its benefits, the risks of dual antiplatelet therapy make its use in some situations less than straightforward. The anticipated open-heart surgery creates just such a dilemma.

Aspirin

Mechanism of action: The central mechanism of action of Aspirin is via inhibition of the Cyclooxygenase (COX) pathway (Figure 1). The 2 major COX pathways, COX 1 and COX 2, are expressed variably in most tissues. COX-1 is considered to be the “housekeeping” enzyme that controls normal cellular processes [10]. The COX-1 pathway generates Prostaglandin I2 and Prostaglandin E2, which play a role in protecting the gastric mucosa integrity and improving GFR (afferent arteriolar vasodilation) respectively. In addition, this pathway produces TXA2, which increases platelet activation and aggregation. COX-2, which is mainly expressed in the brain, kidney, and bone, (increases in other tissues during times of inflammation) leads to the production of inflammatory prostaglandins and proteases responsible for fever, pain, and inflammation. At low doses (75-81 mg/day), Aspirin will irreversibly inhibit COX-1, thus leading to decreased platelet release of TXA2, decreasing the ability of platelets to aggregate. However, as a consequence of the COX-1 inhibition, Aspirin can lead to gastric mucosal damage. The gastric mucosa depends on COX-1 to produce the protective prostaglandins (e.g. PGE2 reduces gastric acid secretion). At intermediate doses (650mg to 4gms/day), by inhibiting both COX-1 and COX-2, ASA will decrease TXA2, leading to an antithrombotic effect, as well as reduce the release of inflammatory prostaglandins (e.g. Prostaglandin E and Prostaglandin F2a) leading to analgesic and antipyretic effects [10].

Indications of aspirin use

Primary prevention

For many years, low dose Aspirin (75-100 mg PO once daily) has been administered for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Recent studies, including ASPREE [11], ASCEND [12], and ARRIVE [13], which studied over 47,000 patients, have concluded that aspirin should not be used in the routine primary prevention of ASCVD in the low-risk patient as a result of its GI effects. In the ASCEND study, which included a total of 15,480 participants, the results showed that although aspirin prevented vascular events in diabetic patients, it was also linked to major bleeding hazards. The increased bleeding tendency that accompanies aspirin counterbalanced the net benefit. According to the ASPREE study, including a total of 19,114 participants, it was observed that healthy patients who received aspirin daily had higher all-cause mortality in comparison to those who received a placebo. As a result, the new 2019 guideline established by the American College of Cardiology/American Heart Association (ACC/AHA) recommends that low dose aspirin should

A. Only be considered in individuals between 40-70 years of age at high ASCVD risk with no increased bleeding risk, b) not be routinely administered to adults over 70, and

B. Not be considered among adults with a bleeding diathesis (i.e. History of thrombocytopenia, coagulopathy, chronic kidney disease, peptic ulcer disease, or using drugs such as NSAIDs, steroids, or anticoagulants) [14].

Secondary prevention 

The benefits of aspirin in secondary prevention of ACS (ACS: STEMI, UA, NSTEMI) were studied by the Antithrombotic Trialists’ Collaborations meta-analyses [15]. With data from 195 different randomized clinical trials of Aspirin therapy, they showed that Aspirin reduced the risk of cardiovascular events by 22%, specifically bestowing protection in myocardial infarction, ischemic stroke, unstable/ stable angina, peripheral artery disease, and atrial fibrillation [15]. A further meta-analysis of recent secondary preventive trials done on 17,000 patients showed that the use of Aspirin in high-risk patients reduced the yearly risk of fatal events such as stroke (2.08% vs 2.54%, p=0.002) and decreased coronary artery disease (4.3% vs 5.3%, p<0.0001), without a significant increase in hemorrhagic events [16]. Therefore, the AHA/ACC guidelines recommend a daily Aspirin dose of 75-162 mg in all patients with coronary artery disease. The guidelines established by the European Society of Cardiology (ESC) support indefinite treatment with Aspirin for secondary prevention of thrombotic events in this population as well [17].

Aspirin effect on cardiac surgery outcome

Pharmacology and pharmacodynamics of P2Y12 inhibitors

Dual Antiplatelet Therapy (DAPT) is an intense antiplatelet therapy that involves the combination of aspirin and a P2Y12 inhibitor. The mechanism of action of aspirin as discussed above involves the irreversible inhibition of the cyclooxygenase (COX) enzyme, blocking TXA2 production. The second component of DAPT, thienopyridines, targets the platelet P2Y12 receptor. Platelet aggregation begins with the exposure of collagen to the von Willebrand factor (vWF), released by endothelial cells and platelet alpha granules, which binds the platelets via a GP1b platelet receptor at the site of the endothelial injury. The platelets then undergo a conformational change and release thromboxane A2 and adenosine diphosphate (ADP) from dense granules. ADP, through membrane-bound receptors, binds to P2Y1 and P2Y12 to induce GPIIb/IIIa expression at the platelet surface. GPIIb/IIIa increases the platelet’s affinity for fibrinogen and the coagulation cascade begins. By blocking P2Y12, (though not P2Y1) [27] thienopyridines, inhibits ADP induced formation of the GPIIb/IIIa complex, preventing platelet adherence to fibrinogen, and decreasing aggregation (Figure 2). Consequently, Aspirin and a thienopyridine, due to dual platelet inhibition blocking both TXA2 production and GPIIb/IIIa expression, are considered to be the cornerstone of management in patients with CAD [28].

Clopidogrel

Clopidogrel effect on cardiac surgery

The beneficial effect of DAPT has been well established in the treatment of acute coronary syndrome (ACS) and ischemic heart disease [29-32] as described previously. In the large CURE trial, compared to Aspirin alone, the addition of Clopidogrel reduced the development of post ACS thrombotic events by 20%, [26,29]. However, in roughly 10% of ACS patients subsequently undergoing cardiac surgery, the effect of DAPT on perioperative bleeding is problematic [31-33]. Several studies have addressed the clinical outcomes of administering clopidogrel prior to CABG surgery [29,31]. Although flawed by the lack of baseline platelet function, the significant increase in bleeding in the clopidogrel exposure groups in every study examining the issue is impressive [29,34,35].

a) In the Acute Catheterization and Urgent Intervention Triage study (ACUITY), the CABG sub-study [32], randomized 1,520 patients to receive either clopidogrel or Aspirin prior to surgery vs ASA alone. The 30-day results demonstrated significantly lower mortality (12.7% vs 17.3%, p=0.01) and lower incidence of MI (8.8% vs 14.5%, p=0.0006) in patients who received dual antiplatelet therapy, remarkably without an increase in post-CABG major bleeding, re-exploration for bleeding, blood transfusion, or chest tube output. Although an improvement in mortality and ischemic events was seen at 30 days, at one year, this advantage no longer held true. Further analysis of those patients undergoing surgery split them into three groups, those never receiving Clopidogrel (749), those receiving Clopidogrel within 5 days of surgery (524), and those whose Clopidogrel was stopped ≥ 5 days prior to surgery(249). By multivariable analysis, any exposure to Clopidogrel prior to surgery improved composite ischemic events at 30 days (OR 0.67, p =0.001) with an almost significant improvement in 1-yr ischemic events (OR 0.77, p= 0.07). The effect, though, was entirely attributed to those who had an early withdrawal of Clopidogrel (≥5 days) before surgery, as their lower 30-day (8.8% vs 17.3%, p=0.001) and 1-year (14.9% vs 21.4%, p=0.02) mortality drove the results. These findings support a washout period of at least 5 days for Clopidogrel prior to CABG, as it is associated with lower rates of net adverse clinical events as well as blood transfusions.

b) Despite the results of the ACUITY study, there appears to be an increase in post op bleeding with the use of preop thienopyridines. In a prospective observational study of 150 patients, of whom 89 were treated with aspirin and 61 treated with DAPT (Aspirin and Clopidogrel) [30], preoperative platelet activity was measured to identify Clopidogrel good/poor-responders and to allow an analysis of the effect of platelet inhibition on outcomes. First, the study showed that only 54% of those receiving clopidogrel were good responders.Second, the median chest tube output at 24 hours, which was the primary outcome of the study, was 22% higher in the DAPT group than in the aspirin group (680ml vs 558ml, p<0.01), and the postoperative RBC transfusion was significantly higher in the DAPT group compared to the aspirin group (p=0.01). As expected, postoperative bleeding in the DAPT group correlated with the degree of Clopidogrel-mediated platelet inhibition. The study concluded that variable response to clopidogrel should be considered when developing guidelines regarding its use, independent of the need for surgery [30].

Prasugrel

The ACCOAST trial randomized 4033 patients with an NSTEMI undergoing angiography within 2-48 hours to Prasugrel in anticipation of catheterization vs administration of Prasugrel after catheterization, given only if PCI was indicated [38]. There was no difference between the two groups regarding the primary endpoint (MI, stroke, and death from cardiovascular causes). However, in the pre-angiography group treated with Prasugrel, there was more major bleeding, by a factor of 3. The study concluded that in patients who are undergoing catheterization in the setting of an NSTEMI, so as to avoid unnecessary bleeding, pre-angiography treatment with prasugrel does not reduce ischemic events and should wait until the post-catheterization films can be interpreted. In the 7.8% (314 patients) who subsequently underwent CABG within 30 days, those who received prasugrel preoperatively (no attempt was made to determine timing prior to surgery) experienced significantly more major bleeding (OR of 1.77 (p=0.07)).

Ticagrelor

Ticagrelor Effect on Cardiac Surgery

In an attempt to study the clinical outcomes of Ticagrelor vs. Clopidogrel in post-MI ACS patients, 45,073 patients were enrolled in the SWEDEHEART registry study, of which 33,119 patients were discharged on Clopidogrel with the remaining 11,954 receiving Ticagrelor [42]. Results showed that the primary outcome of death occurred less frequently with Ticagrelor (5.8%, 95% CI 5.3-6.3) compared to Clopidogrel (12.9%, 95% CI 12.5-13.3). The incidence of MI was also significantly lower in patients who received Ticagrelor (6.1%, 95% CI 5.2-7.0) vs. 10.8%, 95% CI 10.4-11.1). However, the risk of bleeding requiring readmission, roughly 5%, was 20% higher in the Ticagrelor group [42]. Although the Platelet Inhibition and Patient Outcomes study (PLATO), a prospective randomized controlled trial in close to 18,600 patients, also showed Ticagrelor to be superior to Clopidogrel in reducing mortality, the risk of MI and in-stent thrombosis, there was no significant increase in bleeding complications. Approximately 10% of those patients underwent subsequent coronary artery surgery, with 2/3 of that group forming the basis for a comparison of post-surgical outcomes, clopidogrel vs ticagrelor [40]. In the 1,261 patients randomly assigned to each treatment, when the study drugs were discontinued more than 4 days prior to surgery, or within 24 hours of surgery, at one year, there was no significant difference in mortality between the two groups.However, when the study drugs were discontinued within the window 2 to 4 days prior to surgery, the rate of CV death did differ, 4.1% vs 7.9%. p <0.01, in favor of Ticagrelor [40].

In 2016, a prospective multicenter European study that included 786 patients presenting with an ACS undergoing CABG examined severe bleeding (UDPB definition) and blood product requirements associated with preoperative Ticagrelor with or without Aspirin [43]. Results showed that the preoperative administration of Ticagrelor was associated with a similar risk of bleeding complications defined by the UDPB compared to Aspirin alone. However, if Ticagrelor was discontinued less than 2 days prior to surgery, in some instances continuing it until the time of surgery, a significantly higher risk of severe bleeding (UDPG grades 3 and 4) was seen (23% vs 10%, p = 0.06) as well as more platelet transfusions (13.5% vs 6%, p < 0.01)) [43]. The two-day window that is associated with increased bleeding seen in Ticagrelor, vs the 5-day window seen with Clopidogrel, is consistent with Ticagrelor’s shorter half-life which allows it to be discontinued closer to the time of surgery while still avoiding the complication of increased bleeding. Consistent with this, a retrospective study done to test this hypothesis found that there was no increased risk of perioperative bleeding comparing cessation of Ticagrelor 3-5 days prior to surgery vs >5 days prior to surgery [44].

Cangrelor

Cangrelor and CABG

The risk of a coronary event or death upon discontinuation of DAPT in patients with ACS has been evaluated in several studies [50-53]. A retrospective cohort study of 3137 ACS patients assessed the rate of death and MI after the discontinuation of Clopidogrel in patients who were treated medically (n=1568) vs those who underwent PCI with stenting [50]. The primary outcome of death and MI occurred in 17.1% of those treated medically and in 7.9% of patients who had PCI, with the majority of the cases (60.8% and 58.9% respectively) occurring within 90-days after treatment discontinuation. A more recent prospective study of 1656 ACS patients showed similar results and demonstrated that the early clustering of adverse events could be attributed to Clopidogrel discontinuation, which may induce a hyper-thrombotic state [53]. This increase in early ischemic events (10-20%) in ACS patients in whom DAPT therapy is withdrawn the majority occurring in the first 90 days from the time of discontinuation, provides the impetus for bridging with Cangrelor in preparation for surgery, allowing the antiplatelet effect of the oral thienopyridenes to wash out. In 2012, a prospective randomized trial examined this issue in 210 patients with an ACS or PCI who subsequently required CABG surgery. Thienopyridines were discontinued and Cangrelor or placebo was administered 48 hours before CABG and then discontinued 1-6 hours before CABG. Patients treated with cangrelor had less platelet reactivity during the treatment period, and, reassuringly, had similar significant bleeding rates. (11.8 % in the cangrelor group vs 10.4% in the placebo group, NS) [46].

DAPT Post-CABG

The American College of Cardiology (ACC) recommends resuming P2Y12inhibitor after surgery to complete a 12-month duration in patients with a recent Acute Coronary Syndrome (Class I recommendation). In patients with stable ischemic heart disease (SIHD), but without an ACS event, the continuation of clopidogrel may be reasonable up to 12 months after surgery (Class IIb) [54]. However, whether DAPT should be continued after CABG remains controversial as it is uncertain that it improves graft patency, and yet it may put the patient at bleeding risk. In 2010, Kulik et al. reported the results of the CASCADE trial (Clopidogrel after Surgery for Coronary Artery Disease Randomized trial) [55] which randomly assigned close to 100 patients to either DAPT or ASA alone. With 80% one-year angiography compliance, there was no difference in overall graft patency, approximately 93-95% respectively. Bleeding events, early or late, were no different, as well. A subsequent sub-cohort analysis of these patients examining the progression of the disease, not in bypass grafts but in the native circulation, showed that DAPT afforded no benefit regarding protection from recurrent ischemic events, nor, however, did it contribute to harm. It did, apparently, slow the progression of native coronary disease and diminished new native coronary occlusions at one year [56]. This may explain the 8 years follow up data [57] which showed a trend toward freedom from death and major cardiac or cerebrovascular events, with no difference in saphenous vein graft patency.

In 2010, Sun et al. [57] also performed a prospective, randomized study of 100 patients assigned immediately postop to either Aspirin monotherapy or Aspirin with clopidogrel. This study showed that a) by CT angiogram at 30 days, approximately 20% of patients had ≥ 1 graft occlusion (P = NS), b) it appeared that radial artery grafts might be better protected (p = 0.05), and c) there were no differences in bleeding or ischemic events. In ameta-analysis of11 trials and 25,728 patients, in contrast to the 2 randomized trials noted above, Deo et al. [58] found that DAPT significantly decreased early saphenous vein graft occlusions (RR=0.59,p= 0.02), improved postop mortality, (0.8 vs 1.9%, p < .0001), but with a trend towards higher major bleeding. It was even more effective in off-pump surgery. Perhaps the most up to date meta-analysis performed by Cardoso et al [59] of both observational as well as randomized clinical trials (RCTs) analyzed 22 studies of over 22,000 patients 37% of whom received DAPT. In the entire cohort, they found that DAPT was associated with lower cardiovascular mortality (OR 0.67, p=0.02), and a trend towards lower all-cause mortality. However, RCTs failed to corroborate this finding of improved mortality with DAPT. However, the extended duration DAPT was significantly associated with fewer strokes (OR (0.47) and saphenous vein graft occlusions (OR 0.64). Bleeding was significantly higher, though (OR1.3). These two analyses suggest that DAPT during the early postop phase improves graft patency, survival and decreases ischemic events, but at the expense of an increase in with significant bleeding events.In summary, and in keeping with the evidence above, the American College of Cardiology (ACC) current guidelines assign a Class IIb recommendation for the initiation of postoperative DAPT. It indicates that DAPT (Clopidogrel + Aspirin) may be used up to until 12 months post-op [54].

The current treatment for patients experiencing an ACS or undergoing PCI involves the administration of Aspirin and P2Y12 inhibitors. The ACC/AHA 2016 Guidelines recommend DAPTtherapy for at least 6-12 months. In patients treated with DAPT undergoing CABG, the P2Y12 inhibitor should be restarted postoperatively for the recommended duration of 12 months [54]. European and American Guidelines recommend the discontinuation of clopidogrel and ticagrelor 5 days and prasugrel 7 days prior to surgical procedures due to the risk of bleeding [59,60]. Although discontinuing platelet inhibition minimizes the risk of bleeding after surgery, it may predispose to interval thrombotic events. As a result, when considering the timing of surgery, one must consider the risk of such an event while waiting for “drug washout” to occur [61,62]. As DAPT, as opposed to ASA monotherapy, is the cornerstone treatment for preventing thrombotic complications in ACS and PCI stented patients, perioperative bleeding complications associated with cardiac surgery will continue to remain a challenge. Establishing a baseline coagulation profile and platelet function for patients undergoing cardiac surgery is an essential measure that helps physicians decide on the type and dosage of antiplatelet and anticoagulation medications to be administered. In addition, knowledge of the literature, particularly the value of the reversible platelet inhibitor, Cangrelor, should better inform decision making in these patients.

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