Switching Between DAPT Agents
The Right Strategy
Harinder K. Bali, MD, DMa ; Hiteshi K.C. Chauhan, MDb
aDirector Cardiology, Fortis Hospital, Mohali, Punjab.
bDept. of Cardiology, Fortis Hospital, Mohali, Punjab.
Running Head: Switching Between DAPT Agents
Financial or grant support for this manuscript: None.
Corresponding author:
Harinder K. Bali, MD, DM
Director Cardiology
Fortis Hospital – Super-specialty in Heart
Sector 62, Phase VIII
Mohali, Punjab, India – 160062.
Phone: +91-987273580. E-Mail: hkbalipgi@gmail.com.
Introduction: DAPT and the Clinical Conundrums
Dual antiplatelet therapy [DAPT] – the amalgamation of aspirin and an oral inhibitor of the platelet P2Y12 receptor for adenosine 5’ – diphosphate [ADP] – is the linchpin of therapy with the aim of preventing atherothrombotic events in patients with acute coronary syndromes [ACS] and in those undergoing percutaneous coronary intervention [PCI] [1 – 5].
With a research-timeline spanning 22 years [6] and over 35 randomized clinical trials, DAPT may be classified as one of the most meticulously and extensively researched treatment strategies in the annals of cardiovascular medicine [Figure 1] [2]. The last two decades are testimony to DAPT’s rapid evolution: from a mere “local” stent-related treatment strategy to a wider “systemic” one capable of forestalling thrombotic arterial occlusion [2].
Despite intense clinical research leading to updated guidelines and focused updates [1-5] on DAPT; practicing clinicians in our Country have found it difficult to incorporate these into real-life clinical practice; especially considering specific patient subsets, varied clinical setting, cost constraints and geographic drug availability issues.
Questions regarding the optimal type and duration of DAPT in patients with coronary artery disease [CAD] persist in the mind of the practicing physician [7], as the trade-off between ischaemic versus bleeding risks for each individual patient is to be carefully and consistently evaluated; at initiation, during follow-up and at completion.
The availability of different oral P2Y12 inhibitors [clopidogrel, prasugrel and ticlopidine] and an intravenous P2Y12 inhibitor [cangrelor] has given physicians the seemingly attractive option of switching antiplatelet therapy to address a multitude of factors; including adherence, adverse effects, cost, drug interactions, and patient-specific characteristics [8].
However, one must be well versed with the pharmacology of P2Y12 inhibitors, different modalities and available literature [1-8] and latest consensus recommendations [9] to decide upon the right timing and strategy of switching antiplatelet therapies. Failing to do so might be the tipping point for patients at risk for bleeding or thrombosis.
P2Y12 Receptor Antagonists: Pharmacological Profile, Potential For Drug-drug Interactions while switching and Clinical Indications
P2Y12 receptor antagonists have unique pharmacological properties including drug half-life, site and mechanism of P2Y12 receptor binding and speeds of onset and offset of drug effect [Table 1] [8-9]. These differences in their pharmacological profile may enhance the potential for DDIs when switching P2Y12 inhibitors, due to varied [inadequate or excessive] platelet reactivity leading to adverse clinical outcomes [thrombotic or bleeding complications] [10, 11].
a. Ticlopidine: The first available platelet P2Y12 inhibitor – Ticlopidine – has been largely withdrawn due to its safety concerns [12].
b. Clopidogrel: The ‘staple’ quintessential P2Y12 inhibitor – retains its position of being the most prescribed P2Y12 inhibitor [1,13]. This second-generation thienopyridine is a prodrug, which is ~ 85% hydrolysed by human carboxylesterase-1 into an inactive metabolite after intestinal absorption [14]. Therefore, only 15% of the prodrug undergoes a two-step oxidation by cytochrome P-450 isoenzymes to generate the active thiol metabolite, which irreversibly blocks the ADP-binding site. This lessens the drug’s stability and potency. There is also a wide variability in the pharmacodynamic response to this drug due to several factors, including genetic polymorphisms, which further compromises its predictability [15]. Clopidogrel is the only oral P2Y12 inhibitor indicated for the treatment of patients with stable coronary artery disease [1,2]. In patients with STEMI after thrombolysis, clopidogrel may be safer to use than its newer counterparts [16,17].
c. Prasugrel: Although prasugrel is also a prodrug like clopidogrel; its active metabolite is generated faster via a single-step hepatic CYP oxidation and in higher plasma concentrations. Therefore, this third-generation thienopyridine achieves faster, greater and more consistent platelet inhibitory effects as compared with clopidogrel [14]. Due to irreversible binding of active metabolites plus the enhanced platelet inhibition achieved by prasugrel, platelet recovery time after treatment discontinuation is longer at 7 – 10 days, as compared with clopidogrel [5-7 days] [18,19].
The newer kids on the P2Y12-inhibitor block – prasugrel and ticagrelor – being more potent – are recommended as first-line agents in ACS as they cause a greater reduction in ischemic events in patients and lower risk of stent thrombosis [ST] in those undergoing percutaneous coronary intervention [PCI] [20, 21].
a. Ticagrelor: This oral, direct-acting cyclopentyl-triazolopyrimidine reversibly binds the P2Y12 inhibitor at a distinct site through a noncompetitive, allosteric mechanism [22]. Although, it doesn’t require hepatic metabolism, approximately one-third of its effect is due to an active metabolite generated via CYP3A4/5 enzymes [22]. Therefore, this drug is more potent and predictable, as compared to clopidogrel. However, due to its reversible binding and relatively short half-life of 6-12 hours; ticagrelor has a quicker offset of antiplatelet effect [23]. The short half-life of ticagrelor necessitates a twice – daily dosing [22].
b. Cangrelor: This is the only intravenous P2Y12 receptor inhibitor available currently. It is an ATP analogue, which directly and reversibly binds to the P2Y12 receptor at an undetermined site. Its effect is dose-dependent and is characterized by a high level of receptor occupancy [24,25]. Due to its rapid inactivation by ectonucleotidase via dephosphorylation, platelet function is recovered within ~60 minutes after stopping its infusion [24,25].
Optimal Aspirin Dosing with P2Y12-receptor inhibitors:
The optimal aspirin dose in patients on DAPT, which seems to provide maximal protection from ischemic events and minimize bleeding risk, is 75–100 mg [26 – 32]. The efficacy of ticagrelor may be decreased in patients treated with higher aspirin doses, therefore lower aspirin doses are recommended for patients on ticagrelor [33].
Switching Modalities: Practical Aspects
Although switching is not recommended, there are a few real-life clinical scenarios, where it may be mandated [Table 2]. As registry data indicate that switching is not infrequent in practice, switching algorithms based on pharmacodynamic studies are provided (Figure 2) [2].
Similarly, all other switching possibilities, including between prasugrel and ticagrelor or from ticagrelor/prasugrel to clopidogrel, have not been investigated with outcome data.92–94
There are various switching modalities, which would be discussed in detail:
a. Switching between oral P2Y12 inhibitors.
b. Switching between oral and intravenous P2Y12 inhibitors.
c. Switching between different classes of P2Y12 inhibitors, which may cause DDIs.
a. Switching between oral P2Y12 inhibitors [Table 3; Figure 2]: In concordance with the Academic Research Consortium definition for stent thrombosis [34], time is defined based on the index event, which led to the initiation of the P2Y12 inhibitor [34]. Switching between oral agents may, therefore, be categorized according to relationship from the index event into acute [less than 24 hours], early [1 – less than 30 days], late [more than 30 days – 1 year] and very late [beyond one year] [9]. This modality of switching [Table 3] may be further sub-divided into:
1. Escalation: Variation from a less potent to more potent oral P2Y12 inhibitors is termed escalation, for example, moving from clopidogrel to prasugrel or ticagrelor.
Escalation during early, especially acute, phase of treatment: Inadequate platelet inhibition may lead to stent thrombosis given the high thrombotic milieu of coronary vasculature in the first few weeks after an ACS or PCI [10,11]. Escalation from clopidogrel to prasugrel or ticagrelor in the early, particularly acute phase of treatment, should occur with the use of a 60- or 180-mg loading dose (LD), respectively. Administration of an LD regimen may occur regardless of the timing of the last dose of clopidogrel. One may then transit to standard maintenance dose (MD) regimens (prasugrel 10 mg daily or ticagrelor 90 mg twice daily) [2,9].
The transition from clopidogrel to ticagrelor is the only switch between P2Y12 inhibitors that has been investigated in a trial powered for clinical endpoint, even if the study was not specifically designed to assess the safety and efficacy of the transition from clopidogrel to ticagrelor. In PLATO, nearly 50% of patients randomly allocated to receive ticagrelor had been pre-treated with clopidogrel, mostly given as a 300–600 mg loading dose [2, 20, 33]. The efficacy and safety of ticagrelor were not affected by previous clopidogrel exposure [2,39].
Au contraire, the TRITON-TIMI 38 trial mandated that previous exposure of patients to a P2Y12 receptor inhibitor should be an exclusion criterion for study entry [21]. While registry data provide reassuring information with respect to the safety profile of switching from clopidogrel to prasugrel [40 – 42], no randomized data exist in the setting of studies powered for clinical endpoint.
Escalation during chronic / late phase of treatment: Beyond the early phase, it is reasonable to escalate with a 10-mg daily or 90-mg twice-daily MD regimen of prasugrel or ticagrelor, respectively, without an LD. The patient may start the new MD regimen at the time of the next scheduled dose of P2Y12-inhibiting therapy (e.g., approximately 24 hours from last dose of clopidogrel) [2,8,9].
2. De-escalation: Moving from either prasugrel or ticagrelor to clopidogrel is defined as de-escalation. There was a lack of group consensus [9] on the appropriate approach to de-escalate from prasugrel to clopidogrel in the acute/early phase (i.e., with an MD or an LD) given the limited data on therapy de-escalation. In the early and, in particular, the acute phases of de-escalation, it also may be reasonable to administer a 600-mg LD of clopidogrel.
As ticagrelor has a relatively fast offset of action, the use of a clopidogrel 600-mg LD should be considered when de-escalating from ticagrelor confers a short-term 48 hours pharmacodynamic advantage and avoids any significant gap in platelet inhibition, regardless of the timing of switching (i.e., acute, early, or late). However, de-escalation to clopidogrel with an MD is a reasonable option, particularly in patients in whom switching occurs as a result of bleeding.
Beyond the early phase or in more stabilized patients, the use of a 75-mg MD of clopidogrel (without an LD) at the time of the next scheduled dose (e.g., approximately 24 hours from last dose of prasugrel) should be considered [2,8,9].
In the TOPIC study [35], switching from ticagrelor directly to clopidogrel 75 mg daily one month following ACS was found to decrease bleeding without an increase in ischemic events, with the caveat that the study was not powered for ischemic outcomes.
The optimal time for the initiation of clopidogrel has not been studied extensively. In the CAPITAL OPTI-CROSS study [36], the switch was made at the next scheduled ticagrelor dose. However, extending the switch to the following morning (i.e. 24h post last ticagrelor dose) may also be reasonable based on pharmacodynamics data from the RESPOND study [37].
The SWAP – 4 study [38] results underlined that de-escalation from ticagrelor to clopidogrel therapy is associated with an increase in platelet reactivity suggestive of a drug-drug interaction. Administration of a LD prior to initiating a MD regimen of clopidogrel mitigates these observations by delaying and hampering the increase in platelet reactivity. Larger studies are definitely warranted to assess the safety and efficacy of de-escalation strategies.
3. Changes: Switches between prasugrel and ticagrelor are called changes. On the basis of pharmacodynamic data suggesting a potential drug-drug interaction (DDI), a 60-mg LD of prasugrel should always be used when changing from ticagrelor to prasugrel, regardless of timing (early or late), and switching with a 10-mg MD should be avoided [2,8,9]. Pharmacodynamic studies do not suggest DDI when changing from prasugrel to ticagrelor therapy. Therefore, this change can be performed with a standard 90-mg twice-daily MD dose regimen, without the need for an LD.
b. Switching between oral and intravenous P2Y12 inhibitors [Table 4].
1. Bridging: For switches involving cangrelor, going from oral to IV P2Y12 inhibitors is termed bridging. Bridging from oral P2Y12 inhibitors to cangrelor occurs mostly in patients needing to undergo procedures, which require discontinuation of oral P2Y12 inhibitor therapy.
Because the effects of the oral agents persist with meaningful levels of P2Y12 inhibition after drug discontinuation, it is reasonable to wait to start cangrelor bridging (0.75 μg·kg−1·min−1 infusion without a bolus) for up to 3-4 days after prasugrel discontinuation and 2-3 days of clopidogrel and ticagrelor discontinuation to minimize the duration of infusion. In the transition from cangrelor to a thienopyridine, the thienopyridine should be administered immediately after discontinuation of cangrelor with an LD (clopidogrel 600 mg or prasugrel 60 mg) to avoid a potential DDI.
2. Transition: When one transits from IV cangrelor to oral P2Y12 inhibitors, mostly after PCI, it is termed transition. After noncardiac surgery, regardless of bridging strategy, clopidogrel should be resumed with an LD as soon as oral administration is possible and the risk of severe bleeding is acceptable. Prasugrel and ticagrelor administration should be discouraged in the early period after major noncardiac surgery when there is an ongoing risk of serious bleeding.
The timing of administration of P2Y12 inhibitors in patients receiving cangrelor infusion at the time of percutaneous coronary intervention [PCI] should be drug-specific [8]. While ticagrelor can be given any time before, during or at the end of cangrelor infusion, it is recommended that clopidogrel or prasugrel is given at the time of cangrelor infusion discontinuation (or within 30 minutes before the end of infusion in the case of prasugrel administration) [8,9].
c.Switching between different classes of P2Y12 inhibitors: Of all those modifications, only the switch from ticagrelor to prasugrel and from ticagrelor to clopidogrel have the potential for a drug-drug interaction, which may cause thrombotic or safety concerns. Drug-drug interactions involving cangrelor may occur with transition to clopidogrel or prasugrel.
Platelet function testing, genetic testing, and switching of P2Y12 inhibitors:
High and low platelet reactivity on P2Y12 antagonist treatment predicts ischaemic and bleeding risks, respectively [2, 43]. These data advocate individualized antiplatelet therapy based on platelet function monitoring to identify the patients out of the expected range of platelet inhibition [44]. All randomized trials have failed to demonstrate any benefit of platelet function monitoring to adjust therapy [45 – 47]. The low-risk level of the study populations, the exclusive use of clopidogrel, and the P2Y12 reaction unit thresholds to define the optimal window of P2Y12 inhibition have been recognized as the main limitations of these trials [2, 48 – 50].
The Way Forward:
Switching between DAPT agents remains a clinical conundrum. Current recommendations are derived largely from pharmacodynamic and registry data, integrated with an understanding of the pharmacological principles of the agents involved. Dedicated prospective studies are needed to provide important insights into this topic.
Until new clinical or pharmacokinetic/pharmacodynamics data become available, we must adhere to the current evidence and tailor switching of DAPT in every patient, if required, in an individualised manner.
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