Platelet Function Testing as Part of a Perioperative Treatment Algorithm in Patients Undergoing Surgery during Dual Antiplatelet Therapy

Mahla E¹, Tantry US², Gurbel PA²* and Prüller F³

¹Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Austria

²Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, USA

³Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria

*Corresponding author: Gurbel PA, Director, Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, USA

Received: September 04, 2018; Accepted: October 24, 2018; Published: October 31, 2018

Abstract

Up to 11% of patients presenting with acute coronary syndrome undergo coronary artery bypass grafting and up to 20% of patients need non-cardiac surgery During Dual Antiplatelet Therapy (DAPT). Guidelines largely recommend a “one size fits all” preoperative discontinuation period for P2Y12 receptor blockers to avoid bleeding. These recommendations do not account for highly variable pharmacodynamic responsiveness and for variable recovery of platelet reactivity following discontinuation of P2Y12 receptor blockers. Several observational studies demonstrated both an association between ontreatment platelet reactivity and surgery-related bleeding and that an objective measurement of preoperative platelet inhibition among these patients may reduce the waiting period while mitigating the risk of bleeding. Based on these findings recent guidelines included a Class IIa or IIb recommendation for preoperative platelet function testing to individualize preoperative waiting and intraoperative coagulation management in bleeding patients undergoing surgery during DAPT. However larger scale well controlled prospective studies employing standardized bleeding endpoints are needed to establish and validate bleeding cutoffs. The following review article describes the rationale for discontinuation of DAPT before surgery; The risks associated with this approach and provides a concept for preoperative platelet function testing to individualize preoperative waiting and anticoagulation management in these patients.

Keywords: Antiplatelet therapy; Surgery; Bleeding; Coagulation management; P2Y12 inhibitors

Introduction

In patients with Acute Coronary Syndrome (ACS) treated with coronary artery stent implantation or managed medically, Dual Antiplatelet Therapy (DAPT) with a P2Y12 receptor inhibitor on top of aspirin is recommended for 12 months unless there is excessive high risk of bleeding (Class I Level A) [1]. Up to 11% of patients presenting with ACS undergo Coronary Artery Bypass Grafting (CABG) and up to 20% of patients need non-cardiac surgery during DAPT [2-5]. While preoperative discontinuation of DAPT has been associated with an increased risk of ischemic events particularly when non-cardiac surgery is performed with in the first month after stenting, recent exposure to DAPT carries an increased risk of major bleeding, particularly associated with major non-cardiac and cardiac surgery [6-11]. Abundant evidence supports a graded association between major bleeding and the occurrence of 30 day thrombotic events, infectious complications and mortality after cardiac and noncardiac surgery [12-18].

Recent guidelines recommend a “one size fits all” concept of withholding ticagrelor for at least 3-5 days, clopidogrel for at least 5 days and prasugrel for at least 7 days before non-emergent surgery (Class II a Level B), to continue aspirin perioperatively if bleeding risk allows, and to resume the recommended antiplatelet therapy as soon as possible after cardiac and non-cardiac surgery [1,19,20]. The latter recommendations aim to decrease the risk of surgery related bleeding in patients on DAPT. However, this “one size fits all” concept does neither account for the highly variable pharmacodynamic responsiveness nor for the variable platelet function recovery time after discontinuation of clopidogrel therapy, specifics which appear to be attenuated with prasugrel and ticagrelor [21-24]. Moreover, urgency of surgery, surgical preferences and economic constraints may shorten the recommended P2Y12 receptor inhibitor specific preoperative waiting period [25,26].

Antiplatelet therapy and bleeding in cardiac and noncardiac surgery

In a recent Randomized Controlled Trial (RCT) enrolling 2,100 low risk patients undergoing CABG, preoperative aspirin therapy did neither reduce the composite of death and thrombotic complications (19.3% vs 20.4%) nor increase major hemorrhage (1.8% vs 2.1%) as compared to placebo [27]. This lack of a difference in major bleeding may be attributed to the intraoperative administration of tranexamic acid in 50% of the patients in each group. Tranexamic acid is an antifibrinolytic agent and has been proposed to preserve platelet function by mitigating the effect of plasmin on the glycoprotein Ib receptor [28]. Likewise, compared to placebo perioperative aspirin did not reduce the composite of death or non-fatal myocardial infarction in a RCT enrolling 10,010 patients at risk for vascular complications undergoing non-cardiac surgery (7.1% vs 7.0%). However, major bleeding was more common in the aspirin group than in the placebo group (4.6% vs 3.8%; p=0.04) [12].

There is accumulating evidence of increased surgery-related bleeding with enhanced P2Y12 receptor inhibition, albeit encumbered by different bleeding definitions (Table 1) [29-31].

Table 1: Commonly used definitions for major surgery-related bleeding.




  
     
    Definition
     
    References
  
  
    Chest tube output
     
    Reflects bleeding from chest but not    from graft harvesting sites
      Amount depends on sampling period,    which varies in the literature
    [23,41-50,52,53] 
  
  
    Transfusion requirements
    Units of transfused packed red blood    cells and other blood components
    Does not account for preoperative    anemia occurring in up to 20% of patients undergoing cardiac surgery and for    different transfusion triggers
    [23,41-50,52,53] 
  
  
    Perioperative    red blood cell loss  
    =    (blood volume*preoperative hematocrit*0.91) - (blood volume*hematocrit*0.91 on    postoperative 
       day 5) + (ml of transfused red blood    cells*0.59). 
    Accounts for preoperative anemia and    hidden blood loss
    [30,42]
  
  
    BARC-4 bleeding
    One or more of the following:
      
        Perioperative intracranial bleeding within 48    hours 
        Re-operation after closure of sternotomy for    the purpose of controlling bleeding 
        Transfusion of = 5 units of packed red blood cells within a 48-hour period 
        Chest tube output = 2L within a 24-hour    period. 
      
       
     
    [31] 
  
  
    TIMI Major Bleeding 
       
       
       
       
       
      TIMI Minor Bleeding
       
       
      TIMI Bleeding Requiring Medical    Attention
    One or more of the following:
      
        Any    intracranial bleeding
        Clinically    overt signs of hemorrhage associated with a drop in hemoglobin = 5 g/dL
        Fatal    bleeding (within 7 days)
      
       
     
    [31] 
  
  
    
      Clinically    overt bleeding (including imaging), resulting in hemoglobin drop of 3 to    <5 g/dL 
    
       
  
  
    
      Any overt sign of hemorrhage that meets one of    the following criteria and does not meet criteria for a major or minor    bleeding:
      
        Requiring re-operation.
        Requiring platelet transfusion.
      
    
      – Prompting diagnostic evaluation.
  
  
    UDPB severe or massive bleeding
    One or more of the following:
      
        Delayed    sternal closure for bleeding 
        Postoperative    blood loss > 1000 ml within 12 hours 
        =    5 units of red blood cells 
        =    5 units of fresh frozen plasma
        Use    of recombinant factor VII a
        Re-operation    due to excess bleeding
      
     
    [29] 
  
  
    Abbreviations: RBC: Red Blood Cell;    BARC: Bleeding Academic Research Consortium; TIMI: Thrombolysis In Myocardial    Infarction; UDPB: Universal Definition Of Perioperative Bleeding In Adult    Cardiac Surgery.



Table 1: Commonly used definitions for major surgery-related bleeding.

Five recent meta-analyses including up to 50,048 patients undergoing mainly cardiac surgery evaluated risks and benefits of preoperative P2Y12 receptor inhibitors. Compared to P2Y12 receptor inhibitor naïve patients and patients with early preoperative drug discontinuation (= 5 days) those with late preoperative drug discontinuation (< 5 days) demonstrated a consistent 2-fold increased relative risk of re-operation for bleeding and a 50% increased relative mortality risk [10,32-35]. However, the results of these meta-analyses are encumbered by the inclusion of mainly non-randomized and, in part, retrospective studies, variable P2Y12 receptor inhibitor washout periods, the inherent limitations in the diagnosis of postoperative MI in patients with ACS, and substantial heterogeneity among studies [36].

In a nationwide registry including 2,244 ACS patients undergoing CABG, Hansson et al recently evaluated the incidence of BARC-4 bleeding, depending on preoperative discontinuation period and on whether patients were on clopidogrel or ticagrelor. Overall, there was a lower incidence of major bleeding in the ticagrelor group as compared to the clopidogrel group (12.9 vs 17.6%, p=0.012). The incidence of BARC-4 bleeding was similarly high when surgery was performed within 24 hours after last drug intake (38% vs 31%). However, there was a continuous decrease in BARC-4 bleeding with increasing days off clopidogrel, but there was no difference in BARC- 4 bleeding beyond a three days discontinuation period in ticagrelortreated patients. The sharp decline in BARC bleeding after a 72 hours discontinuation period of ticagrelor is attributed to the inherent reversibility of ticagrelor [9].

A recent systemic review including five randomized controlled trials of patients on single or dual antiplatelet therapy undergoing elective non-cardiac surgery (including abdominal, urologic, orthopedic and gynecological) compared the effects of continuation versus at least 5 days discontinuation of antiplatelet drugs on bleeding and mortalityin 666 patients. Specifically, either continuation or discontinuation of antiplatelet therapy made little or no difference to 30-day mortality (RR: 1.21; 95% CI: 0.34-4.27), re-operation due to bleeding (RR: 1.54; 95% CI: 0.31-7.58) or ischemic event occurrence (RR: 0.67; 95% CI: 0.25-1.77), albeit with low certainty evidence. The authors concluded that three ongoing studies might change the results of this review and acknowledge that the limited number of patients precludes subgroup analysis in order to explore whether single or dual antiplatelet therapy would influence the results [37].

Rationale for platelet function testing and association between on-treatment platelet reactivity to ADP and bleeding in cardiac and non-cardiac surgery

Evidence from translational research studies suggests a therapeutic window concept for ADP-induced platelet reactivity in patients on DAPT after Percutaneous Coronary Intervention (PCI) [38-40].

A recent collaborative observational analysis sought to evaluate the prognostic value of low (LPR)-, optimal- and High (HPR) Platelet Reactivity by applying uniform cut-off values for standardized devices in 20,839 patients on DAPT after PCI [38,39]. Compared to optimal platelet reactivity, HPR, as was associated with a significant 2.73 fold increased relative risk of stent thrombosis and a significant 16% relative reduced of bleeding. In contrast, LPR was significantly associated with 1.74 fold increased relative risk for bleeding without a protective association with stent thrombosis. Although the causes of bleeding differ between PCI and surgical patients, the high variability in on-treatment reactivity to ADP and also in platelet function recovery that these data amply provide, serve as the rationale for evaluating the association between preoperative on-treatment platelet reactivity and surgery-related bleeding [21-24]. Several small observational studies including altogether 1,600 patients undergoing cardiac surgery during DAPT demonstrated a graded association between on platelet reactivity, as assessed by various platelet function assays and surgery-related bleeding. However, reported bleeding cutoffs/tertile ranges and their predictive accuracy for different bleeding endpoints vary among these studies [23,41-50].

Although hemodilution and coagulation disorders associated with the use of cardiopulmonary bypass limit comparability between cardiac and non-cardiac surgery, the recent BIANCA study (Platelet Inhibition and Bleeding in Patients undergoing non-cardiac Surgery) demonstrated a similarly graded association between tertiles of preoperative on-treatment platelet reactivity, as assessed by light transmittance aggregometry, and TIMI bleeding in 197 patients undergoing heterogeneous non-cardiac surgery during antiplatelet therapy with aspirin and clopidogrel or clopidogrel immunotherapy [26,51]. TIMI, mostly minor bleeding occurred in 25% of the patients. Textiles of platelet reactivity, age and urgency of surgery were independent predictors of bleeding. Importantly, timing of surgery was at the discretion of the attending surgeons and 72% and 12% of the patients underwent surgery within 24 and 48 hours, respectively. The findings of the BIANCA study extend the results of a recent retrospective multicenter study in patients with coronary stents undergoing cardiac and predominantly various non-cardiac surgeries [8]. Perioperative antiplatelet discontinuation was the strongest independent predictor of 30-day MACE (OR: 25.8, 95% CI: 3.37-198, p=0.002). Perioperative aspirin (adjusted OR: 0.27, 95 % CI: 0.11-0.71, p=0.008) was significantly associated with a lower risk of MACE. Intermediate / high risk surgery but not discontinuation of aspirin and or clopidogrel independently predicted BARC > 2 bleeding, which occurred in 20% of the patients [8]. Hence, Rossini et al suggested to tailor perioperative antiplatelet drug therapy and discontinue based on the individual thrombotic and surgery-specific bleeding risks [11].

An individualized strategy for preoperative clopidogrel discontinuation based on preoperative platelet function testing has been demonstrated to reduce both preoperative waiting and surgeryrelated bleeding after on-pump and off-pump CABG [52,53]. The TARGET CABG study, a non-randomized prospective investigation, demonstrated that stratifying 180 patients on clopidogrel and aspirin therapy into time-based platelet function recovery groups, as assessed by preoperative Thrombelastography (TEG) platelet mapping assay, resulted in similar bleeding as compared to clopidogrel naïve patients undergoing first time elective on-pump CABG. Surgery was scheduled within one day in those with an MAADP > 50mm (high platelet reactivity), within 3 to 5 days in those with an MAADP 35-50mm (intermediate platelet reactivity), and after five 5 days in those with an MAADP < 35mm (low platelet reactivity). Lacking a validated bleeding cutoff, we hypothesized that a cutoff associated with short and long-term occurrence of ischemic events in a previous study of patients treated with coronary stents would serve as a surrogate measure for adequate surgical hemostasis [54,55]. Mean 24-hour chest tube drainage in clopidogrel-treated patients was 93% (95% CI: 81-107%) of the amount observed in clopidogrel naive patients and the total amount of red blood cells transfused did not differ between groups (1.80 units vs 2.08 units, respectively, p=.540). Importantly, using covariate analysis to correct for potential confounders, there was no difference in chest tube drainage and transfusion requirements between the two groups. Individualized waiting resulted in a 50% shorter preoperative waiting period than would have been recommended by current guidelines [1,19].

The results of TARGET CABG were recently supported by Mannacio et al in patients undergoing off-pump CABG [53]. The investigators evaluated the role of platelet function monitoring to assess the optimal preoperative waiting time by comparing 100 patients undergoing individualized waiting with two propensity score matched groups comprising 100 patients undergoing CABG after discontinuing clopidogrel for 5 days and 100 clopidogrel naïve patients. In the individualized group, patients underwent CABG after complete recovery of platelet function as reflected by Innovance PFA2Y assessed closure time = 106seconds. Compared to standardized waiting, individualized waiting significantly reduced chest tube drainage, units of transfused red blood cells and length of hospital stay (14.7 ± 2.2 vs11.9 ± 2.5 days; p<0.001).

Preoperative platelet function monitoring to guide transfusion and coagulation management in cardiac surgery

Based on the known graded association between platelet inhibition and surgery-related bleeding and several studies showing that an objective measurement of platelet function may reduce the preoperative waiting period while mitigating the risk of bleeding, current guidelines included a Class IIa or IIb recommendation to time surgery based on preoperative platelet function testing [1,19,20]. The Guidelines of the Society of Thoracic Surgeons specifically state that because of their high negative predictive value, preoperative Point of Care (POC) testing may be useful in identifying patients with high platelet reactivity after usual doses of antiplatelet drugs and who can undergo operation without elevated bleeding risk. However, validated absolute levels of platelet inhibition/reactivity have not been established and the ideal assay to assess platelet inhibition remains elusive [20].

Fibrinogen is a plasma protein critical to hemostasis. Fibrinogen enhances platelet aggregation by acting as a ligand for activated platelet glycoprotein IIb/IIIa receptors. Subsequent cleavage of fibrinogen to fibrin results in formation of a stable platelet-fibrin clot and hemostasis [56]. Although low fibrinogen concentrations have been associated with increased surgery-related bleeding, there is currently no consensus on the optimal fibrinogen concentration in patients undergoing surgery [57,58]. A recent meta-analysis of 8 RCTs including 597 patients undergoing cardiac surgery, evaluated efficacy of fibrinogen either administered prophylactically or as treatment of bleeding. In these 8 RCTs, patients administered P2Y12 receptor inhibitors within 48 hours preoperatively were excluded. Although, fibrinogen significantly reduced the proportion of patients receiving allergenic red blood cell transfusion as compared to placebo (RR: 0.64; 95% CI, 0.49–0.83, p= 0.001), supplemental fibrinogen did not affect all-cause mortality (RR: 0.41; 95% CI, 0.12-1.38, p=0.15) which was the primary endpoint of interest [59].

The 2017 ESC guidelines on patient blood management for adult cardiac surgery recommend to transfuse platelet concentrates in bleeding patients with a platelet count below 50×109/L or in bleeding patients on antiplatelet therapy (Class IIa Level C) and the implementation of perioperative treatment algorithms based on POC testing to reduce bleeding (Class IIa Level B) [19].Thrombelastometry (ROTEM) / TEG lack long turnaround times associated with assessment of standard coagulation tests and can more rapidly detect changes in coagulation, differentiate between a predominant plasmatic or platelet bleeding cause and therefore provide goal directed, individualized therapy [60-64]. However, cutoffs for ROTEM/TEG to trigger specific therapeutic interventions are not provided by these guidelines. Moreover, the cutoffs both for clotting time, clot strength and FIBTEM/functional fibrinogen vary in the studies that are included in two meta-analyses and the multicenter trial supporting these guidelines [65-67]. While both meta-analyses, including around 8,000 patients demonstrated efficacy of POC guided transfusion management with respect to a reduction of red blood cell transfusions, they reported equivocal results on the effect of reexploration rate due to bleeding and no benefit on mortality [65,66].

In the largest multicenter study thus far, Karkouti et al recently demonstrated the benefits of a POC based transfusion algorithm sequentially implemented in a randomized fashion in 12 hospitals [67]. Overall red blood cell transfusionsand platelet transfusionswere 45% and 25% respectively, with considerable variation between different hospitals. Major bleeding as defined by the Universal Definition of Bleeding occurred in 24.1% of the patients undergoing cardiac surgery with cardiopulmonary bypass. As compared to 3,555 patients who underwent surgery during the control phase, implementation of the algorithm in 3,847 patients during the intervention phase was associated with significant 9%, 23% and 17% relative reduced risk of red blood cell transfusions, platelet transfusions and major hemorrhage, respectively after adjusting for hospital, time of algorithm implementation, and pre-specified patient-specific risk factors such as demographic variables, type and urgency of surgery, cardiopulmonary bypass time, use of cell salvage and tranexamic acid. However, the intervention had no impact on major complications. The algorithm was based on ROTEM and Platelet works assays and a simple stepwise treatment approach targeting thet hree most common causes of cardiac surgery-associated coagulopathy after protamine reversal, i.e. thrombocytopenia/platelet dysfunction, hypofibrinogenemia and impaired thrombin generation. The authors acknowledge that they did not collect information on baseline anticoagulant therapy and that these medications could have impacted bleeding rates [67].

In a RCT including 76 patients on aspirin immunotherapy and 173 patients on a P2Y12 receptor inhibitor on top of aspirin within 5 days before CABG, Agarwal et al investigated the benefits of preoperative platelet function testing as part of a transfusion algorithm on surgery-related bleeding [68]. Patients were randomized to preoperative platelet function monitoring performed with either Multiplate (Group A) or TEG platelet mapping (Group B) immediately preoperatively, or no preoperative testing (Group C). A standardized protocol including transfusion triggers, routine use of tranexamic acid and post-cardiopulmonary TEG assessment using kaolin and heparinase to assess time to clot formation, platelet-fibrin clot strengthand residual heparin, were used. If, after protamine reversal, microvascular bleeding occurred, treating physicians were informed about preoperatively-assessed platelet inhibition which, based on two arbitrarily defined cutoffs, triggered transfusion of 1 or 2 platelet poolsin group A and B patients. TEG (kaolin, hepariase and functional fibrinogen) was then rechecked. Group C patients underwent routine clinical management based solely on a post-pump TEG measurement employing kaolin and heparinase. In patients on DAPT, but not in aspirin only treated patients, platelet function monitoring guided management and extended TEG evaluations were associated with significantly reduced units of any transfusion and reexploration for bleeding as compared to control. Notably, Group A and B patients received less units of red blood cells and coagulation proteins but more platelet pools than control patients. This beneficial effect was accompanied by cost savings of almost 50% [68].

Despite accumulating evidence of an association between the extent of platelet inhibition and surgery-related bleeding, covariates like comorbidity, urgency of surgery, type of surgery, experience of the treating physicians, preoperative anemia, transfusion triggers and transfusion practice, use of cardiopulmonary bypass and cardiopulmonary bypass time, use of anti-fibrinolytics and potentially decompressing, may additionally affect surgery-related bleeding [8,11,26,30,35,42,69-71].

As long as well controlled large scale studies establishing and validating assay specific bleeding cutoffs are lacking, institutional algorithms incorporating validated cutoffs for increased risk of bleeding and stent thrombosis in patients after coronary artery stenting may guide preoperative discontinuation of P2Y12 receptor inhibitors and add to targeted intraoperative coagulation management in the bleeding patient (Figure 1) [1,19,20,38,39,65-67]. Institutional specifics, the risk of stent thrombosis, the consequences of delaying surgery and the individual surgery specific risk need additional consideration [1,11].

Conclusion

Current guidelines issue Class IIa or IIb recommendations for preoperative platelet function assaying patients undergoing surgery during DAPT. These patients may particularly benefit from preoperative platelet function monitoring to both target individualized preoperative waiting based on an objective measure of platelet inhibition, and as part of a transfusion algorithm aiming at targeted hemostasis management in bleeding patients. However larger scale, well controlled prospective studies, employing standardized bleeding endpoints, are needed to establish and validate bleeding cutoffs.

References

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Citation: Mahla E, Tantry US, Gurbel PA and Prüller F. Platelet Function Testing as Part of a Perioperative Treatment Algorithm in Patients Undergoing Surgery during Dual Antiplatelet Therapy. Thromb Haemost Res. 2018; 2(2): 1015.

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