PART III - PERI-PROCEDURAL AND POST-PROCEDURAL ANTITHROMBOTIC PHARMACOTHERAPY
TABLE OF CONTENTS
BOOKSHOP
Updated on May 18, 2018
PART III

Peri-procedural and post-procedural antithrombotic pharmacotherapy

Kurt Huber

Summary

Peri- and post-procedural antithrombotic therapeutic strategies after coronary angiography (CAG) and percutaneous coronary intervention (PCI) with or without stent implantation is characterized by permanent changes over the past few years based on increasing knowledge from updated guidelines, observational cohorts and prospective randomized trials. This is particularly true for patients presenting with acute coronary syndromes (ACS). Interestingly, bivalirudin has lost its high recommendation for use during PCI in non-ST-elevation ACS (NSTE-ACS) only short time after a downgraded recommendation in patients presenting with ST-elevation myocardial infarction (STEMI) referred for primary PCI. Prasugrel and ticagrelor, two stronger and faster acting antiplatelet agents (P2Y12- receptor inhibitors), have increasingly replaced clopidogrel in patients presenting with ACS and the use of the IV agent cangrelor has become of interest in P2Y12-inhibitor naive ACS patients due to its fast on- and off-effects. Moreover and similar to bivalirudin, GP IIb/IIIa-inhibitors (GPIs) have become less important for clinical routine and are only recommended as down stream use in bail-out situations or in the presence of massive thrombus load and also their pre-hospital use has retained only a weak recommendation in patients presenting with STEMI in certain specifically trained systems of care.

The optimal duration of dual antiplatelet therapy (DAPT) after coronary interventions in ACS patients is now recommended according to an individual risk stratification including ischemic and bleeding risks. It may be prolonged up to several years in patients with high ischemic and low-to-normal bleeding risk and shortened down to 1 month in patients with increased bleeding but normal ischemic risk. Such shortening of triple therapy has also been offered to ACS patients with high bleeding risk and is also supported by use of last generation metallic DES with fast re-endothelialisation and low stent thrombosis rates.

Special knowledge has been gained recently in patients who need antithrombotic combination therapy consisting of oral anticoagulants and antiplatelet agents and there is a trend in clinical routine from triple antithrombotic therapy (usually a vitamin K antagonist, aspirin and clopidogrel) to dual antithrombotic therapy (DAT; consisting of a non-vitamin K oral anticoagulant, NOAC, and P2Y12-inhibitor, mainly clopidogrel) by skipping aspirin. Whether aspirin could also be neglected in stable coronary artery disease (SCAD) or ACS patients after 1 to 3 months of initial dual antiplatelet therapy (DAPT) by proceeding with ticagrelor monotherapy is currently under investigation.

The present chapter on peri- and post-procedural antithrombotic strategies summarizes current facts and updates and should help optimizing treatment strategies in daily routine.

Background

Choice, initiation and duration of antithrombotic strategies associated with percutaneous coronary intervention (PCI) are based on the presentation of either a SCAD or an ACS patient [1]. To optimise therapeutic efficacy without increasing potential bleeding hazards, both ischaemic and bleeding risks have to be evaluated on an individual basis. Important data from recently published randomised controlled trials (RCTs) had already an impact on the update of pre-existing guidelines [2, 3, 4, 5, 6, 7], will undoubtly influence future guidelines, and are basis of this updated version of this chapter.

FOCUS BOX 1Background
To optimise efficacy of therapy and reduce the potential bleeding hazard both, ischaemic and bleeding risks, have to be evaluated on an individual basis

Basic understanding of the action of antithrombotic agents

For a better understanding of the action of anticoagulants and antiplatelet agents Figure 1 depicts a schematic overview about the coagulation cascade and about platelet activation and aggregation as well as the current strategies for inhibition of thrombin formation and platelet activation and/or aggregation [3].

Periprocedural antithrombotic therapy

ANTITHROMBOTIC THERAPY IN STABLE/ELECTIVE PATIENTS

Anticoagulation

Unfractionated heparin (UFH) is the gold standard and a bolus of 70-100 IU/kg IV should be administered [2]. As an alternative, enoxaparin (0.5 mg/kg IV bolus) can be used as the best-tested low molecular weight heparin (LMWH) in patients undergoing elective PCI as enoxaparin was associated with reduced bleeding complications when compared with UFH [8].

Antiplatelet therapy

In non-pre-treated patients, the irreversible cyclo-oxygenase inhibitor acetylsalicylic acid (ASA) should be initiated with a 250 mg IV bolus followed by 75 to 100 mg per os daily in all patients [2]. Alternatively, ASA can also be initiated orally by use of 300 mg tablets preferably chewed for quick buccal absorption.

In previous recommendations clopidogrel, a prodrug and irreversible P2Y12-inhibitor, was initiated more than 6 hours before the planned intervention with a loading dose of 300 (to 600) mg and followed by 75 mg daily for all patients [2]. Recent guidelines for SCAD recommend clopidogrel only after the diagnostic angiogram, when PCI±stenting is the strategy of choice [5] because the bleeding risk of routine DAPT, administered before catheterization in patients who do not require stenting (no significant CAD or CAD requiring CABG surgery), is not balanced by a detectable benefit in terms of ischemic events in those undergoing PCI.

In patients already on clopidogrel maintenance therapy, a re-loading with 300 (or 600) mg clopidogrel might be advantageous but is not strongly recommended by international guidelines. A higher maintenance dose (MD: 150 mg daily) following the higher loading dose of clopidogrel in patients with a reduced response to clopidogrel, as measured by the Verify Now platelet function assay, was tested against the usual dosage (300/75 mg LD/MD) in the GRAVITAS trial. Although a more consistent platelet inhibition in the therapeutic range over time could be reached by increasing the dosage of clopidogrel, this had no impact on clinical outcome and should therefore not become general practice in stable patients [9]. The new P2Y12-inhibitors prasugrel and ticagrelor do not carry a strong recommendation in these patients at present due to missing data [5], although they might be useful in patients that are non-responders to clopidogrel [10]. An off label use of these drugs is common practice in some high-risk patients e.g. patients with left main interventions, with diabetes, but a logical consequence in patients with a history of stent thrombosis under clopidogrel.

Based on the fact that recent trials could not demonstrate any additional benefit of GPIs after a clopidogrel loading dose of 600 mg [11, 12], GPIs should only be used in “bail-out”- situations e.g. in no-reflow situations, or intermediate vessel closure during PCI [2].

A pre-treatment with P2Y12-receptor inhibitors is not recommended in SCAD patients [2, 5].

FOCUS BOX 2Stable/elective patients
  • Unfractionated heparin and ASA plus clopidogrel are the antithrombotic therapies of choice
  • GPIs should only be used in bailout situations elective PCI

ANTITHROMBOTIC THERAPY IN PATIENTS WITH NON-ST ELEVATION ACUTE CORONARY SYNDROME (NSTE-ACS)

Anticoagulation

The choice of anticoagulants is based on the acuity of the individual situation and the consecutive risk of the patients to develop thrombotic complications. Special care in the selection of anticoagulants has to be taken in patients with renal impairment [3].

In low-risk patients in whom a primarily conservative strategy is planned, fondaparinux (2.5 mg SC once daily) or enoxaparin (1 mg/kg SC twice daily; 0.75 mg/kg SC twice daily in patients with reduced kidney function) have received the highest recommendation in the recently published myocardial revascularisation and non-ST-elevation myocardial infarction guidelines [2, 3]. Also, the use of UFH (60 IU/kg IV bolus followed by an aPTT-controlled infusion until PCI) is an option.

In patients with an intermediate (-to-high) risk (e.g., troponin-positive, recurrent angina, dynamic ST changes, diabetes, renal dysfunction, early post-MI angina, prior PCI < 6 months, prior CABG, intermediate or high GRACE score) an early invasive strategy is preferred over a primarily conservative approach and should be performed within 24 (-48) hours [2, 3]. Most patients are already pre-treated with a parenteral anticoagulant when they undergo CAG and PCI. It is recommended that the initial anticoagulant be continued (except after initial therapy with fondaparinux) [13]:

  • In case treatment was started with enoxaparin and the intervention is performed < 8h after the last SC application, no additional bolus is necessary; if enoxaparin was initiated 8-12h before the planned intervention (1 mg/kg SC; 0.75 mg/kg in patients >75 years) then 0.30 mg/kg IV bolus should be added; >12h after the last SC application of enoxaparin a 0.5 mg/kg IV bolus must be administered. A switch to UFH in the cath lab is not recommended.
  • If UFH (bolus plus infusion) was started before the cath lab, continue infusion.
  • Repeated ACT measurements might be useful in which the target range should be 200-250 sec with GPIs and 250-350 sec when GPIs have not been used.
  • If under bivalirudin treatment (0.1 mg/kg IV bolus followed by an infusion of 0.25 mg/kg/h for the diagnostic angiogram) an additional IV bolus of 0.5 mg/kg and an increase of the consecutive infusion to 1.75 mg/kg/hour before PCI is recommended in case PCI is performed.
  • If fondaparinux was used before the cathlab, 80 IU/kg UFH should be given as soon as angiography and PCI is performed due to increased catheter-related thrombus formation in patients with fondaparinux alone [2, 13].

Patients with very high risk NSTE-ACS (e.g., persistent angina and/or ST-deviations, haemodynamic instability, refractory arrhythmias) should be immediately transferred to the cathlab and treated like a STEMI. Therapeutic options, besides DAPT with ASA and a P2Y12-inhibitor, consist of either monotherapy with bivalirudin (dosage as above); or UFH 60 IU/kg IV bolus followed by infusion until PCI; or enoxaparin 0.5 mg/kg IV, respectively.

UFH and enoxaparin should be stopped immediately after PCI, except in specific individual situations (e.g., thrombotic complication, atrial fibrillation) while an infusion with bivalirudin should be maintained for up to 4 hours after PCI in order to reduce the risk of early stent thrombosis [2, 14].

Antiplatelet therapy

ASA 250 mg bolus (or 300 mg per orally) followed by 75 to 100 mg daily is usually given to all patients.

Ticagrelor (oral intake, 180 mg LD followed by 2x90 mg/day MD), a reversible and fast-acting (>80% platelet inhibition in 60-90 minutes) ADP-receptor blocker [15], has been investigated in the PLATO trial and has been shown to be superior to clopidogrel with respect to a combined primary endpoint (cardiovascular mortality, re-infarction and stroke) in primarily conservative, as well as primarily invasive, treated patients with NSTE-ACS [16]. Ticagrelor has demonstrated a significant reduction of all-cause and cardiovascular mortality, which was also shown in a pre-specified subgroup analyses for diabetics [17] and patients referred for coronary bypass surgery [18]. Potential side effects, beside an increase in spontaneous major bleeding events (an absolute increase of 0.6%), include dyspnoea and bradycardia, both of which have been associated with the adenosine-like properties of the agent.

FOCUS BOX 3Patients with NSTE-ACS
  • Ticagrelor (in all NSTE-ACS patients) and prasugrel (in high-risk patients referred for PCI after the coronary anatomy is known) are recommended over clopidogrel
  • Pre-treatment of patients with suspected NSTE-ACS is no longer recommended by the updated guidelines

Prasugrel (oral intake, 60 mg LD followed by 10mg/day MD, dose reduction to 5mg/day in patients >75 years), an irreversible, but fast-acting blocker of the P2Y12 receptor [19], has been tested in patients with known coronary anatomy who were clopidogrel-naïve when they entered the trial, and was also superior to clopidogrel with respect to the same combined primary endpoint as in the PLATO trial [20]. A statistical mortality benefit could not be shown for this agent in NSTE-ACS patients. Prasugrel seems to be especially effective in diabetic patients [21], high-risk patients with recurrent thromboembolic events [22] and in reducing stent thrombosis but should be avoided in patients with prior stroke or TIA [20]. In patients older than 75 years and in underweight patients (< 60 kg) the effect is neutral vs. clopidogrel. The main side effect is an increase in spontaneous major bleeding events (an absolute increase of 0.6%) compared to clopidogrel.

A recent trial (ACCOAST) investigating prasugrel pre-treatment in patients with NSTE-ACS undergoing PCI showed no benefit in preventing ischaemic events but exhibited a statistically greater bleeding rate [23]. Also, pre-treatment with clopidogrel was less effective as expected in NSTE-ACS patients [24] and data with ticagrelor are still missing to date. The most obvious explanation for these findings is that NSTE-ACS patients represent an inhomogeneous group of patients with different underlying pathomechanisms that frequently would not benefit from early DAPT or even be harmed from it. Accordingly, it is now recommended to avoid pre-treatment with prasugrel and initiate also other P2Y12-inhibitors after the diagnostic CAG if PCI and stent implantation is mandatory [3].

Clopidogrel (oral intake, 600 mg loading dose followed by 75 mg daily) was for many years the P2Y12-receptor inhibitor of choice, is still widely used, but has been increasingly replaced by the more efficacious agents ticagrelor or prasugrel [3]. Despite partially beneficial effects of a higher clopidogrel loading and maintenance dose (600 mg LD, 150 mf MD for 1 week) as investigated in the CURRENT OASIS 7 trial (in terms of a reduced stent thrombosis and combined clinical endpoint rate) [25] the more effective P2Y12 inhibitors should be preferred, because up to 25% of individuals are non- or low-responders to Clopidogrel. This is partially based on genetic polymorphisms [26, 27] and other non-genetic reasons [28] when a consistent optimal inhibition of platelet function cannot be guaranteed. Homocygote carriers of the most important loss-of-function polymorphism (CYP2C19*2 ; 2-3% of all patients) are non-responders to therapy, while heterozygotes might react to increasing doses of clopidogrel (ELEVATE-TIMI 56 trial) [29].

Prasugrel, as well as ticagrelor, do not depend on these loss-of-function genetic variants [30, 31]. While neither genetic profiling nor regular platelet function testing in order to detect non-responders to clopidogrel and to tailor therapy have been effective so far and their increased use for clinical routine was controversially discussed and not recommended by guidelines [2, 3, 4, 32, 33], a recent publication exhibited that platelet function guided de-escalation of antiplatelet treatment (stented NSTE-ACS patients were switched from prasugrel after one week to clopidogrel, which was maintained in responders to therapy; non-responders were switched back to prasugrel) was non-inferior to standard treatment with prasugrel in terms of net clinical benefit [34].

Three GPIs have been tested in patients with NSTE-ACS, but impressive data with respect to efficacy go back to a time when P2Y12-receptor inhibitors were not part of the usual clinical practice. The recent guidelines recommend GPIs in angiographically confirmed increased thrombus load and in bailout situations [2, 3]. Since the ACUITY Timing and EARLY-ACS trials [35, 36] “upstream” therapy with eptifibatide or tirofiban in the organisation phase to the catheter laboratory is no longer recommended. Accordingly, the recently published ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation recommend eptifibatide and tirofiban with a similar level of recommendation mainly for “downstream” use [3].

ST ELEVATION MYOCARDIAL INFARCTION (STEMI)

FOCUS BOX 4Patients with STEMI
  • In primary PCI, unfractionated heparin (UFH) is the first choice as anticoagulant
  • Fondaparinux is contraindicated in patients referred for primary PCI (but can be used in patients treated with fibrinolytic therapy or conservatively)
  • Prasugrel and ticagrelor have replaced clopidogrel as the first choice therapy

Anticoagulation

Best option for anticoagulation in primary PCI of acute STEMI is good old UFH, which should be started with 60 IU/kg IV bolus when a GPI is used or with up to 100 IU/kg IV bolus without the planned use of a GPI. Similar to NSTE-ACS, UFH should be stopped immediately after successful PCI unless there are specific indications requiring its continued use (e.g., left ventricular aneurysm and/or thrombus, atrial fibrillation, prolonged bed rest, deferred sheath removal after femoral access). As long as patients need bed rest, the use of low molecular weight heparin in a prophylactic dose to minimise the risk of venous thrombosis is recommended [2].

Bivalirudin monotherapy was originally reported as a better alternative as UFH+ a GPI antagonist in patients with acute STEMI undergoing primary PCI [HORIZONS-AMI study; 37]. Ischaemic events were similar between both study arms, but severe bleeding complications were significantly reduced under bivalirudin monotherapy and as a consequence, short- and long-term mortality was statistically reduced [38]. These data could not be confirmed in the single centre prospective, randomized HEAT PPCI trial, which showed a reduced effect of bivalirudin on ischemic outcomes and a tendency for increased bleeding rates vs. UFH [39]. More recent publications have also questioned the role of bivalirudin in ACS patients [40, 41, 42]. Accordingly, the ESC guidelines on revascularization [2] as well as the recent ESC guidelines on ST-elevation myocardial infarction [4] have downgraded the recommendation for bivalirudin in STEMI patients referred for primary PCI. If bivalirudin is used during primary PCI, the dosage during intervention of acute STEMI is 0.75 mg/kg as IV bolus followed by an infusion of 1.75 mg/kg/hour up to 4 hours.

Also enoxaparin (0.5 mg/kg IV bolus) has been tested vs. UFH in STEMI patients undergoing primary PCI (ATOLL study), failed to reach a statistical benefit with respect to the combined primary endpoint (cardiovascular death, re-MI, re-intervention and severe bleeding after 30 days), but was superior to UFH with respect to the different secondary endpoints of the trial [43].. A possible explanation for not demonstrating superiority over UFH was the fact that more than 70% of patients were treated via radial access, which led unexpectedly to comparable severe bleeding rates in both treatment arms [43].

AS discussed above, fondaparinux is not recommended for primary PCI due to an increased thrombus formation in the catheter material [2, 4, 44].

Antiplatelet therapy

ASA is given in an initial dose of 250 mg bolus IV (alternatively 300 mg per os) followed by 75 to 100 mg daily.

A very effective P2Y12-receptor inhibitor in combination with ASA is prasugrel (60 mg LD followed by 10 mg MD), which showed statistical benefit over clopidogrel with respect to the combined primary endpoint and to cardiovascular mortality [45]. In the clinical setting of STEMI prasugrel should be administrated as soon as possible pre-cath lab, which has been incorporated in the recently updated ACC/AHA STEMI guidelines as well in the new ESC myocardial revascularisation guidelines [2, 4, 46] and has become real-world practice in several STEMI networks.

Ticagrelor was also superior to clopidogrel and showed similar severe bleeding hazards but failed to demonstrate significant superiority over the comparator with respect to the combined clinical endpoint [47]. In the prospective randomized ATLANTIC trial, pre-hospital initiation of full-dose ticagrelor vs. in-cath lab use was investigated [48]. Primary efficacy endpoints were the surrogates ST segment elevation resolution and TIMI-3 flow at diagnostic angiography and safety endpoints included different bleeding classifications. Ticagrelor pre-treatment was not superior with respect to the clinical endpoints, which in part might be explained by the relatively short time-delay between pre- and in-hospital use of ticagrelor of only 31 minutes [48], while bleeding complications were similar between groups. However, the secondary single endpoint of early stent thrombosis was significantly reduced in pre-treated patients [48]. A recent analysis of STEMI patients from the SWEDEHEART registry failed also to show a benefit of ticagrelor pre-treatment [49]. Again, bleeding complications were comparable between groups. Moreover, no benefit with respect to stent thrombosis at 30 days could be demonstrated [49]. Again, a majority of patients received pre-cath lab ticagrelor within 60 minutes before the intervention.

Despite such findings recent guidelines still recommend P2Y12-inhibtors as early as possible (e.g. at the first medical contact) [4] and it cannot be excluded that specific patient subgroups (e.g. high ischemic risk, short onset of pain) may benefit from such strategy [50].

Prospective randomized studies comparing prasugrel and ticagrelor in primary PCI are rare and it seems that prasugrel and ticagrelor are comparable in pPCI of STEMI patients [51, 52].

The use of GPIs in acute STEMI patients referred for primary PCI has decreased in the last few years and is almost exclusively indicated in bailout situations or in case of high thrombus load [2, 4]. Data exists for the use of abciximab (0.25 mg/kg IV bolus followed by infusion of 0.125 μg/kg/min up to a maximum of 10 μg/min for 12 h) as well as for other GPIs in combination with UFH [2, 4]. The “upstream” use of GPIs is in general no more recommended [2, 4]. However, based upon a meta-analysis [53], some registries [54, 55], large post hoc analysis [56], and the OnTIME II trial [57], GPIs might be used in specifically trained STEMI systems of care in patients with recent onset infarctions (diagnosed and treated < 3 hours of onset of pain) [56]. Controversial data of intracoronary administration of abciximab compared with its intravenous administration have shown either a beneficial effect by use of a specific delivery catheterl [58] or no effect at all (AIDA-STEMI trial) [59].

It has been discussed that due to the use of the fast-acting and highly effective antiplatelet drugs prasugrel or ticagrelor a strategy of early use of GPIs seems less promising. However, the guideline-recommended early use of prasugrel or ticagrelor does not sufficiently inhibit platelet activity at the time when primary PCI is actually performed [60]. This finding might be explained by the frequent use of morphine or morphine derivatives in STEMI patients that hinder fast reabsorption of the oral P2Y12-receptor inhibitors [61] and/or by hemodynamic compromise of some STEMI patients. Interestingly, recent data have not demonstrated an impact on clinical outcome of morphine use in STEMI patients pre-treated with P2Y12-inhibitors [62].

Clinical outcome after primary PCI might be improved by use of the recently investigated IV P2Y12-inhibtor cangrelor. Cangrelor is an intravenous, potent, rapidly acting and reversible P2Y12 receptor inhibitor (30 μg/kg IV bolus; 4 μg/kg/min infusion). In the CHAMPION-PHOENIX trial, which included stable patients as well as NSTEMI and STEMI patients, cangrelor reduced the rate of ischaemic events, including stent thrombosis, without a significant increase in severe bleeding [63, 64]. Cangrelor, with its fast on/off effect, seems superior to clopidogrel, is recommended in P2Y12-inhibitor-naive patients when pre-loading was not performed [3, 4]., but has so far not been compared against prasugrel, ticagrelor, or GPIs, respectively.

Post-procedural antithrombotic therapy

DURATION OF DUAL ANTIPLATELET THERAPY

Duration of DAPT after bare metal stent (BMS) implantation in stable/elective patients is one month and after drug eluting stent (DES) implantation 6 months based on the recently updated guidelines [6]. This is mainly based on the EXCELLENT [65] and PRODIGY [66] trials, which demonstrated no evidence of benefit with a up to 2 years of DAPT duration compared with a shorter course of therapy (6 months), also including patients with ACS.

After an ACS a 1-year DAPT is still recommended (ASA + ticagrelor or prasugrel; clopidogrel only when the stronger P2Y12-inhibtors are not available or contraindicated), irrespective of the treatment strategy or stent type used [2, 3, 4, 6].

A FDA-initiated trial has investigated a 12 month vs. a prolonged (30 months) duration of DAPT after an ACS [67]. Patients underwent PCI either with BMS or DES. Those who tolerated 12 months of a P2Y12-receptor inhibitor (mainly clopidogrel) without bleeding, were randomized to DAPT for additional 18 months or placebo. This, however, did not result in a statistically significant difference in stent thrombosis, MACCE, or moderate or severe bleeding [67]. The PEGASUS trial compared a re-initation and prolongation of DAPT (ticagrelor plus aspirin) vs. aspirin alone for up to 3 years. DAPT was restarted 1 month to 2 yeas after the initial DAPT was stopped. There was a statistical benefit with respect to a combined clinical ischemic endpoint, which was paralleld by a statistical increase in bleeding complications. FDA and EMA have approved this prolonged DAPT strategy (60 mg of ticagrelor BID plus 80-100 mg aspirin OD), for patients with high ischemic but low bleeding risk [68]. The results of PEGASUS suggest that the decision to prolong DAPT should be drawn early, if possible without interruption of DAPT [69].

COMBINATIONS OF ANTITHROMBOTIC THERAPY

In patients with atrial fibrillation on oral anticoagulation (OAC) who need PCI and coronary stenting in stable CAD or in ACS a combination of OAC plus DAPT (triple therapy) is recommended for different time duration (1-6 months) depending on the individual ischemic and bleeding risks [2, 5, 6]. Triple therapy consists usually of ASA, clopidogrel and a vitamin K antagonist (VKA) or a non-vitamin K oral anticoagulant (NOAC) and is followed by dual antithrombotic therapy (DAT) up to 12 months and OAC monotherapy thereafter [5, 6, 70].,Because severe bleeding complications increase with antithrombotic combination therapy [71], such strategy should only be performed for the shortest necessary time. When VKAs are used frequent INR checks to guarantee an INR goal between 2 and 2.5 (3.0 as maximum) are mandatory [72].

In contrast to prior recommendations [73] two prospective randomized trials (PIONEER AF and RE-DUAL PCI) have meanwhile demonstrated that DAT consisting of a NOAC (rivaroxaban or dabigatran) and a thienopyridine (mainly clopidogrel) can be started already at hospital discharge [74, 75]. This strategy reduced bleeding hazards while exhibiting a neutral effect on combined ischemic outcomes compared with triple therapy in patients with an increased bleeding risk [74, 75]. It is expected that this new strategy will influence clinical routine very soon. Two further trials with the other available NOACs, apixaban (AUGUSTUS; NCT02415400) and edoxaban (ENTRUST-AF; NCT02866175; 76) are still under investigation.

The improved designs of newer generation DES with absorbable polymer or without polymer, has led to very low late and very late stent thrombosis rates compared to BMS as shown by the prospective randomized LEADERS FREE and SENIOR trials [77, 78]. Accordingly, new generation DES have gained a leading role in patients on antithrombotic combination therapy as they have been shown to be superior to BMS also in patients under short duration of DAPT or triple therapy due to increased bleeding risk [77, 78, 79].

In case of mandatory PCI under triple or dual antithrombotic therapy, radial access should be preferred over femoral access to lower bleeding complications [2, 4, 5]. In case of DAPT or trlple therapy the use of proton pump inhibitors for gastric protection is recommended [2, 4, 6, 80].

OTHER COMBINATION THERAPIES IN SECONDARY PREVENTION

Triple therapy (DAPT plus a NOAC)

Very low-dose rivaroxaban (2,5 mg BID, known as “vascular dose”) plus conventional DAPT (aspirin plus clopidogrel), was effective in terms of reducing ischaemic endpoints including all-cause and cardiovascular mortality and but increased bleeding in the ATLAS-2 trial [81]. This strategy showed similar efficacy as DAPT with aspirin plus ticgrelor or prasugrel, has been approved by the EMA, and might be useful if prasugrel or ticagrelor are either unavailable, produced side effects, or are contraindicated.

Triple therapy with three antiplatelet agents

Vorapaxar is an oral protease-activated-receptor 1 (PAR-1) antagonist and inhibits thrombin-induced platelet activation. Vorapaxar was recently investigated in patients with ACS, who were either treated with conventional DAPT (aspirin and clopidogrel) alone or who received the combination of vorapaxar and DAPT, in the TRACER study [82]. This study demonstrated no reduction in ischaemic events, but major bleeding was increased. Furthermore, in the secondary prevention TRA 2P-TIMI 50 trial [83] no change in all-cause mortality was detected, but cardiovascular death was decreased while the risk of major bleeding was increased. Based on subsequent analyses this strategy might be effective and safe in the subgroup patients with an age of <75 years, body weight of >60 kg, and no history of stroke/TIA, but further investigation is mandatory for approval of this strategy.

Dual antithrombotic therapy

The recently published COMPASS trial in patients with stable cardiovascular diseases including patients with peripheral artery disease (PAD) revealed a net clinical benefit for patients treated with aspirin (75-100 mg OD) plus rivaroxban (2,5 mg BID) vs. aspirin or rivaroxaban (5mg BID) monotherapy [84]. Most importantly there was an even more pronounced antiischemic effect in the subgroup of PAD patients [85].

In the GEMINI-ACS-1 trial the safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (2,5 mg BID; in place of aspirin) with a P2Y12 inhibitor (clopidogrel or ticagrelor) vs. aspirin plus a P2Y12 inhibitor was investigated in ACS patients [86]. This new approach combining low-dose rivaroxaban with a P2Y12 inhibitor had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor, but a larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach.

Can we avoid the use of aspirin?

It is currently investigated in two prospective randomized trials whether monotherapy with ticagrelor initiated 1 (GLOBAL LEADERS trial) to 3 months (TWILIGHT trial) after an index PCI in stable CAD or ACS by skipping aspirin as compared with long-term DAPT is safe and effective [87, 88].

BLEEDING PREVENTION

To reduce the burden of bleeding complications in the post-procedural phase several strategies should be followed: 1) The individual patient should be stratified for his/her bleeding risk; 2) Overdosing of antithrombotic agents should be avoided; 3) Use a low ASA maintenance dose in all patients (75-100 mg per day); 4) Reduce the prasugrel maintenance dose to 5 mg per day in elderly (> 75 years) and underweight (< 60 kg) patients; 5) Reduce the enoxaparin dose to 75% of the full dose in the elderly; 6) Anticoagulants should be immediately stopped after angiography and PCI, unless bivalirudin is used or if thrombosis prophylaxis is essential (e.g., when bed rest is mandatory); 7) Multiple combinations between anticoagulants and antiplatelet agents should be avoided, or at least reduced to a minimum duration; 8) Radial access should be the preferred option when repeat angiography and/or PCI is necessary, especially in high bleeding risk; 9) Consider use of proton pump inhibitors in patients receiving dual antiplatelet therapy or double or triple antithrombotic therapy; and 10) the use of newer generation DES is equal as or even beneficial over BMS.

BRIDGING TO CARDIAC AND NON-CARDIAC SURGERY

If possible, surgical procedures should be postponed until dual antiplatelet therapy is no longer recommended [2]. In the case surgical procedures having to be performed during DAPT, there is, in general, an increased perioperative bleeding risk. Accordingly, decisions should be based upon discussion on a case-by-case basis with the responsible surgeon and anaesthesiologist whether the specific type of surgery can be performed under DAPT, ASA alone or affords complete cessation of both antiplatelet agents. When it is only the P2Y

12-receptor-inhibitor that has to be stopped before surgery; this has to be done 5 days in advance for clopidogrel or ticagrelor, and 7 days for prasugrel, respectively [3]. As a general rule, the substitution of combined antiplatelet therapy with LMWH is ineffective and of no benefit. Following surgery ADP receptor blockers should be restarted as soon as possible with the respective loading dose.

In very high-risk patients for stent thrombosis, in whom cessation of antiplatelet therapy before surgery is deemed to be dangerous, it has been suggested to switch from clopidogrel five days before surgery to a short half-life antiplatelet agent, e.g., the GPIs tirofiban or eptifibatide, and stop infusion of these agents four hours before surgery [89, 90].

Personal perspective - Kurt Huber

Antithrombotic strategies before, during and after CAG and PCI with or without stent implantation have been repeatedly updated in the past few years and will also face changes in the near future.

Some new developments have the potential to change clinical routine in specific patient cohorts as e.g. dual antithrombotic therapy (DAT) consisting of a non-vitaminK oral anticoagulant (NOAC) plus a P2Y12-inhibitor in patients with atrial fibrillation who undergo coronary stenting; or the use of low- dose rivaroxaban in combination with two antiplatelet agents after ACS or with one antiplatelet agent in stable coronary artery disease, both in secondary prevention.

Other strategies as skipping aspirin in secondary prevention 1-3 months after the index event and proceeding with ticagrlor montherapy are currently under investigation and might influence future guidelines in case of beneficial outcome.

A challenge for the future is to investigate currently available antithrombotic strategies with respect to efficacy and safety in patient cohorts that have not been investigated sufficiently in prospective randomized trials, e.g. in the elderly or in patients with co-morbidities (e.g. renal dysfunction or cancer).

An absolute must is an individualized strategy i.e. stratifying the risk of a patient for ischemic or bleeding events in order to choose between best investigated treatment options.

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