Dual antiplatelet therapy — the combination of aspirin and a P2Y12-receptor inhibitor — is the cornerstone of treatment of patients with acute coronary syndromes (ACS) and of those undergoing percutaneous coronary intervention (PCI)1–4. Clopidogrel is the most frequently used oral P2Y12-receptor inhibitor5,6. Prasugrel and tica-grelor are new-generation oral P2Y12-receptor inhibitors that have more potent antiplatelet effects than those of clopidogrel, and are associated with a greater reduction in ischaemic recurrences in patients with ACS, as well as the risk of stent thrombosis among those undergoing PCI7,8. Therefore, the latest guideline recommendations support the preferential use of these novel agents when dual antiplatelet therapy is clinically indicated3,4.
An important obstacle to the widespread use of the new-generation P2Y12-receptor inhibitors has been that many patients have already received previous treatment with clopidogrel9. Despite the controversies surrounding the benefit of early initiation of P2Y12-inhibiting ther-apy, particularly before the coronary anatomy of patients undergoing an invasive procedure is known, pretreat-ment with clopidogrel has been part of standard-of-care algorithms in many centres for the past decade5,6,10–12. Although the prevalence of pretreatment with P2Y12-receptor inhibitors varies, and with this approach being more common in Europe than in the USA, how to switch
to a new-generation P2Y12-receptor inhibitor has been a conundrum for many clinicians12,13. Other challenges that clinicians currently face include how to switch from a novel P2Y12-receptor inhibitor to clopidogrel, as well as how to switch between different novel P2Y12-receptor inhibitors. How to transition from an intravenous (that is, cangrelor) to an oral P2Y12-receptor inhibitor is also an emerging dilemma. In this Review, we provide an overview of the literature on switching antiplatelet treat-ment strategies involving P2Y12-receptor inhibitors, and discuss practical considerations for switching therapies in the acute and chronic phases of disease presentation in patients requiring dual antiplatelet therapy.
PharmacologyDifferences in the pharmacology of P2Y12-receptor inhibitors with regard to their binding site, half-life, and speed of onset and offset of action are important factors that might lead to drug interactions when switching from one agent to another14,15. ADP contributes to platelet acti-vation during protective haemostasis and in pathological thrombosis16,17. ADP, which is released from dense gran-ules of platelets or from injured cells, binds to P2Y1 and P2Y12 receptors on the platelet membrane16. Activation of the P2Y1 receptor induces a series of signalling events that initiate a weak and transient phase of platelet
University of Florida College of Medicine–Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA.
Correspondence to D.J.A. dominick.angiolillo @jax.ufl.edu
doi:10.1038/nrcardio.2015.113Published online 18 Aug 2015
Switching P2Y12-receptor inhibitors in patients with coronary artery diseaseFabiana Rollini, Francesco Franchi and Dominick J. Angiolillo
Abstract | Dual antiplatelet therapy — the combination of aspirin and a P2Y12
-receptor inhibitor — is the cornerstone of treatment of patients with acute coronary syndromes (ACS) and of those undergoing percutaneous coronary intervention. Prasugrel and ticagrelor have more prompt, potent, and predictable antiplatelet effects than those of clopidogrel, and result in reduced ischaemic outcomes in patients with ACS, albeit at the expense of an increased risk of bleeding. However, clopidogrel is still very commonly used. Switching between oral P2Y
12-inhibiting
therapies occurs very frequently in clinical practice for a variety of reasons, which raises the question of which switching approaches are preferable. In 2015, cangrelor (an intravenous P2Y
12-receptor inhibitor) was approved for clinical use, which adds to the conundrum of how to
switch between intravenous and oral therapies. Differences in the pharmacology of P2Y
12-receptor inhibitors, such as their binding sites (competitive or noncompetitive), half-life,
and speed of onset and offset of action, are important factors that might lead to drug interactions when switching between agents. In this Review, we provide an overview of the literature on switching antiplatelet treatment strategies with P2Y
12-receptor inhibitors, and discuss practical
considerations for switching therapies in the acute and chronic phases of disease presentation.
aggregation. Binding of ADP to the P2Y12 receptor results in signalling cascades that amplify and sustain platelet aggregation, as well as strongly increasing granule release from platelets and procoagulant activity, which culmi-nates in thrombus growth and stabilization18. The cen-tral role of the P2Y12 receptor in amplification of platelet activation and stable thrombus formation has made this receptor an important target in the management and prevention of arterial thrombosis14–19. The intercellu-lar signalling pathways triggered by P2Y1-receptor and P2Y12-receptor activation and their physiological effects are illustrated in FIG. 1 (REFS 16,18,20).
Two principal types of inhibitors of the P2Y12 recep-tor exist: irreversibly and reversibly binding agents (TABLE 1)14,15. Thienopyridines (clopidogrel, prasugrel, and ticlopidine) are irreversibly binding inhibitors21. These agents are inactive prodrugs and need to undergo hepatic metabolism to generate an active metabolite that binds covalently to the ADP-binding site on the P2Y12 receptor15,21. Ticlopidine is a first-generation thienopyridine; its use has been mostly abandoned owing to the more favourable safety profiles of other thienopyridines15,21. Clopidogrel is a second-generation thienopyridine that requires a two-step oxidation pro-cess by the cytochrome P450 (CYP) system to produce its active metabolite; however, ~85% of the prodrug is hydrolysed by esterases in the blood into an inactive carboxylic acid derivative, leaving only ~15% of the prodrug to be metabolized by the CYP system15,21. Prasugrel is a third-generation thienopyridine with a more favourable pharma cokinetic profile than that of clopidogrel, because the prodrug is not hydrolysed to the same extent by esterases, and requires only a single step of hepatic oxidation. Therefore, more active metab-olite is generated, which leads to more prompt, potent, and predictable platelet inhibitory effects15,21. The active metabolites of thienopyridines are very unstable, because they have a very short half-life and, therefore, are rapidly eliminated if they do not bind to the P2Y12 receptor. As the binding of these drugs is irreversible and more P2Y12 receptors are inhibited after prasugrel administration than after clopidogrel administration, the recovery time after treatment discontinuation is longer with prasugrel than with clopidogrel. Most (≥75%) patients return to baseline platelet reactivity 7 days after prasugrel discontinuation, compared with 5 days after clopidogrel discontinuation22.
Reversibly binding inhibitors include cangrelor, elinogrel, and ticagrelor19,23–25. The clinical development of elinogrel has been stopped, and this drug will not be discussed25–27. Ticagrelor is an oral agent that belongs to the cyclopentyltriazolopyrimidine class23. Ticagrelor is rapidly absorbed and has a half-life of 7–12 h; ther-apy with ticagrelor consequently requires twice-daily dosing. In contrast to thienopyridines, which require hepatic metabolism, ticagrelor is directly active after oral administration. However, ticagrelor also under-goes CYP metabolism to generate an active metabolite, AR-C124910XX. This metabolite is rapidly formed, is present in blood at about one-third of its parent con-centration, and has a pharmacokinetic profile similar
P2Y12
Cangrelor
Direct-acting Prodrugs
P2Y1
P2X1
Shape change
Ca2+ flux
Ca2+ mobilizationGranule secretion
βY
PKAVASP
Platelet activation Stabilization of platelet aggregation
cAMP
GqGs
Platelet activation Platelet activation
Initiation ofplatelet aggregation
Gi
Inactive metabolite
Intestinalabsorption
Intestinalabsorption
Esterases
Prasugrel ClopidogrelTicagrelor
Intestinalabsorption
Active metabolite
Hepatic CYP metabolism
PGR
αi
Adenylatecyclase
Adenylatecyclase
VASP-P
Nature Reviews | CardiologyFigure 1 | Metabolism and mechanism of action of P2Y12‑receptor inhibitors. P2Y receptors are a family of purinergic G-protein-coupled receptors and are activated by extracellular nucleotides, such as ADP. Platelets express at least two ADP receptors, P2Y
• Dual antiplatelet therapy with aspirin and a P2Y12
-receptor inhibitor is the cornerstone of treatment of patients with acute coronary syndromes and of those undergoing percutaneous coronary intervention
• Although the novel P2Y12
-receptor inhibitors prasugrel and ticagrelor have been associated with better net clinical outcomes than clopidogrel in patients with acute coronary syndromes, clopidogrel is still frequently used
• Switching between P2Y12
inhibitors is common in clinical practice, which has been attributed to multiple factors, including individual risk of bleeding and ischaemic events, socioeconomic factors, and pharmacodynamics and/or genetics
• Drug interactions have been described when switching between P2Y12
-receptor inhibitors (oral and intravenous) with different receptor-binding properties, which raises concerns about the optimal switching strategies
• Guideline recommendations on how to switch from clopidogrel to prasugrel or ticagrelor and vice versa, as well as between prasugrel and ticagrelor, and between intravenous and oral therapies, are lacking
• Understanding the pharmacological properties of P2Y12
-inhibiting therapies (competitive or noncompetitive) and the timing of disease presentation (acute or chronic) are important factors to define switching strategies
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to that of the parent compound23. Unlike the active metabolites of thienopyridines, ticagrelor does not directly block the ADP-binding site; instead, the drug reversibly binds to a distinct site on the P2Y12 recep-tor and prevents ADP from activating the P2Y12 path-way, in a noncompetitive fashion (FIG. 2)23. Owing to its rapid absorption and direct activity, ticagrelor is characterized by more prompt, potent, and predictable pharmaco dynamic effects than those achieved with clopidogrel15,21. Owing to its reversible binding and fairly short half-life, the speed of recovery of platelet function is faster after discontinuation of ticagrelor than after discontinuation of clopidogrel28.
Cangrelor is an analogue of ATP and is the first reversible intravenous P2Y12 inhibitor19,24. Cangrelor does not undergo metabolic biotransformation and binds to the P2Y12 receptor in a dose-dependent man-ner, achieving potent (>90%) platelet inhibition very rapidly15,19,24,29. Although the binding site of cangrelor at the P2Y12-receptor level is not clearly defined, cangrelor is associated with high levels of receptor occupancy, pre-venting ADP signalling30. Moreover, because cangrelor is promptly inactivated through dephosphorylation and has a very short plasma half-life (3–6 min), recovery of platelet function is very rapid (30–60 min) after discon-tinuation of intravenous infusion19,24. In June 2015, the European Medicines Agency approved the use of cangr-elor for reducing the risk of thrombotic cardiovascular events in patients with coronary artery disease (CAD) undergoing PCI who did not receive an oral P2Y12 inhibitor before the PCI procedure, and in whom oral therapy with P2Y12 inhibitors is not feasible or desira-ble31. Also, the FDA approved cangrelor as an adjunct to PCI for reducing the risk of periprocedural myocar-dial infarction, repeat coronary revascularization, and stent thrombosis in patients who have not been treated with a P2Y12-receptor inhibitor and are not being given a g lycoprotein IIb/IIIa inhibitor32.
Effects of switching strategiesFrom clopidogrel to novel inhibitorsResults from randomized clinical trials. Important dif-ferences in the design of trials leading to the approval of the novel P2Y12-receptor inhibitors prasugrel and ticagrelor have clinical implications for switching ther-apies in daily practice. In the TRITON–TIMI 38 trial8, prasugrel (60 mg loading dose followed by a 10 mg daily maintenance dose) was compared with clopidogrel (300 mg loading dose followed by a 75 mg daily mainte-nance dose) selectively in patients with ACS undergoing PCI (n = 13,608). At 15 months, prasugrel was associated with a significant reduction in the primary composite end point (death from cardiovascular causes, myocar-dial infarction, or stroke), which was mainly driven by a reduction in the frequency of myocardial infarction, at the expense of an increased risk of bleeding, including fatal bleeding8. The TRITON–TIMI 38 trial8 mandated that patients be enrolled only after their coronary anat-omy was defined (with the exception of patients with ST-segment elevation myocardial infarction [STEMI] undergoing primary PCI). Importantly, previous expo-sure to a P2Y12-receptor inhibitor was an exclusion c riterion for study entry8.
By contrast, the PLATO trial7, in which ticagrelor (180 mg loading dose followed by a 90 mg twice-daily maintenance dose) was compared with clopidogrel (300–600 mg loading dose followed by a 75 mg daily maintenance dose), had broader study entry crite-ria, and investigators enrolled patients with ACS (n = 18,624) irrespective of whether they were managed by an invasive or a noninvasive approach7. Moreover, patients were randomly assigned within 24 h of clinical presentation, and typically before coronary anatomy was defined. Finally, the trial allowed for patients who had been pretreated with clopidogrel to be enrolled. At 12 months, ticagrelor reduced the primary end point (death from cardiovascular causes, myocardial
Table 1 | Pharmacological properties of P2Y12‑receptor inhibitors
infarction, or stroke), which was mainly driven by a reduction in cardiovascular-related mortality and fre-quency of myocardial infarction7. No overall signif-icant differences in the frequency of major bleeding events, as defined by the study protocol, were observed, although differences in the frequency of adverse events not related to CABG surgery, including more instances of fatal intracranial bleeding and fewer of fatal bleed-ing of other types, were reported. Importantly, nearly 50% of patients randomly allocated to receive ticagre-lor had been pretreated with clopidogrel, mostly given as a 300–600 mg loading dose. The efficacy (P = 0.43) and safety (P = 0.94) of ticagrelor were not affected by previous clopidogrel exposure. Although based on a subgroup analysis, these efficacy and safety data are very informative for clinical practice. The suitability of using ticagrelor in patients with ACS regardless of pre-vious treatment with clopidogrel is reflected in the ESC guidelines on myocardial revascularization4, but is not specified in the AHA/ACC guidelines3. Of note, none of the guidelines makes any recommendations about switching from clopidogrel to prasugrel therapy1–4.
In the TRILOGY–ACS trial33, the clinical effect of long-term use of prasugrel was compared with that of clopidogrel in patients with non-ST-segment elevation ACS selected for medical management without revascu-larization (n = 9,326). Patients who were not randomly assigned within 72 h of the index event, who comprised ~95% of the trial population, were treated with a 300 mg loading dose of clopidogrel before the beginning of
the trial, and were later randomly allocated to receive a daily maintenance dose of either prasugrel or clopi-dogrel (without a loading dose). Therefore, most patients (~70%) randomly assigned to receive prasugrel had been treated with clopidogrel. The primary efficacy end point (a composite of death from cardiovascular causes, non-fatal myocardial infarction, or nonfatal stroke among patients aged <75 years) was not met in this trial33. Although no significant differences in the primary safety end point (major bleeding complications, including fatal bleeding and intracranial haemorrhage) were observed between the two treatment groups, these results need to be interpreted with caution — both within the context of a trial that did not reach its primary end point, and because prasugrel does not have an indication for clinical use in this setting.
Findings from registries. The introduction of novel P2Y12-receptor inhibitors into clinical practice has prompted the development of registries to help us to understand how these agents are used, and to define the prevalence and reasons for switching therapies in real-world settings (TABLE 2). As prasugrel has been clini cally available for longer than ticagrelor, more registry data have been recorded on the switch from clopidogrel to prasugrel than on the switch from clopidogrel to ticagrelor. Prospective registries specifically designed for collecting data on switching strategies include GRAPE34, European MULTIPRAC35, TRANSLATE–ACS36, and EYESHOT37. Several other post-hoc obser-vational analyses on switching therapies have also been reported38–41.
Overall, the prevalence of switching from clopidogrel to a new-generation P2Y12-receptor inhibitor reported in registries ranges from 5% to 50% (TABLE 2)37–41. Although not powered to assess clinical outcomes, data from these registries have not raised any major safety concerns (that is, differences in the risk of bleeding) associated with switching between therapies. Several of these registries have recorded factors commonly associated with switch-ing, which include clinical and socioeconomic factors such as high-risk angiographic characteristics (throm-botic, long, and bifurcating lesions), STEMI presentation, in-hospital reinfarction, young age, high body mass, male sex, being employed, and having private health-insurance coverage. In most patients registered, the switch occurred in the catheterization laboratory at the time of, or imme-diately after, PCI. Administration of a loading dose was more common with ticagrelor than with prasugrel.
Results from pharmacodynamic investigations. A large number of pharmacodynamic studies have been conducted to understand the profiles of platelet reactivity when switching from clopidogrel to a novel P2Y12-receptor inhibitor (TABLES 3,4)42–60. All studies have consistently shown enhanced platelet inhibitory effects of prasugrel and ticagrelor over clopidogrel, irre-spective of the population analysed (healthy volunteers, patients with stable CAD, patients with ACS). Moreover, rates of high on-treatment platelet reactivity (HPR), a pharmacodynamic marker associated with the risk of
Nature Reviews | Cardiology
P2Y12 receptor
ADP
G protein
a b
c d
Activemetabolite of
thienopyridines Ticagrelor
Figure 2 | Binding properties of P2Y12‑receptor inhibitors23. a | ADP binds to the P2Y
12 receptor, which b | leads to a conformational change of the receptor and to
G-protein activation. c | Competitive binding of the active metabolite of thienopyridines to the P2Y
12 receptor. Binding is irreversible, which renders the receptor nonfunctional
for the life of the platelet. d | Ticagrelor binds reversibly to the P2Y12
receptor at a site that is distinct from the ADP‑binding site (noncompetitive binding). Ticagrelor inhibits ADP signalling and conformational change of the receptor by ‘locking’ the receptor in an inactive state; the receptor is functional after dissociation of the ticagrelor molecule. ADP can still bind at its binding site, and the degree of receptor inhibition is dependent on the concentration of ticagrelor. Modified with permission from Husted, S. & van Giezen, J. J. Ticagrelor: the first reversibly binding oral P2Y
12 receptor antagonist.
Cardiovasc. Ther. 27 (4), 259–274 (2009), with permission from Wiley.
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ischaemic recurrences (including stent thrombosis), are also markedly reduced with prasugrel and ticagrelor61–63. Most pharmacodynamic studies to date have evaluated switching from clopidogrel to prasugrel, whereas limited pharmacodynamic data exist on switching from clopi-dogrel to ticagrelor. This lack of information is probably
attributable to the availability of robust clinical data from the PLATO trial7, which reduced the need to conduct investigations on surrogate pharmacodynamic markers of the effects of ticagrelor.
The exclusion of patients with previous exposure to a P2Y12-receptor inhibitor from the TRITON–TIMI 38 trial8
Table 2 | Switching between oral P2Y12‑receptor inhibitors: registry findings
Study Study population (n)
Prevalence of switch from clopidogrel to novel inhibitors (%)
Prevalence of switch from novel inhibitors to clopidogrel (%)
Prevalence of switch between novel inhibitors (%)
Clinical outcomes (exploratory)
Alexopoulos et al. (GRAPE)34
ACS undergoing PCI (1,794)
C to P: 40.1
C to T: 50.3
P to C: 1.0
T to C: 4.3
Between P and T: 4.3* At 1 month: higher risk of bleeding and fewer MACE in patients who switched from C to P or T than in those treated with C only; no differences in MACE and bleeding in patients initially treated with C compared with those initially treated with either P or T
Clemmensen et al. (MULTIPRAC)35
STEMI (2,053) C to P: 48.7
C to T: 11.6
P to C: 8.3
T to C: NA
P to T: 2.8
T to P: NA
In-hospital: no differences in MACE and bleeding not related to CABG surgery between patients who switched from C to P and those receiving P only
Bagai et al. (TRANSLATE–ACS)36
NSTEMI and STEMI (11,999)
C to P: 10.4
C to T: 1.0
P to C: 11.5
T to C: 2.1
P to T: 0.3
T to P: 3.4
At 6 months: no significant differences in MACE and bleeding between patients who switched therapy (any switching) and those who did not
De Luca et al. (EYESHOT)37
NSTE-ACS and STEMI (2,585)
In the cath lab, C to P or T: 3.0
At discharge, C to P or T: 9.6
In medically managed patients, C to P or T: 2
In the cath lab, P or T to C: 0.3
At discharge, P or T to C: 3.2
In medically managed patients, P or T to C: 3.4
In the cath lab, between P and T: 0.3
At discharge, between P and T: 1.3
In medically managed patients, between P and T: 0.3
NA
Bagai et al. (ACTION Registry–GWTG and CathPCI)38
NSTEMI and STEMI undergoing PCI (47,040)
C to P: 5.2
C to T: NA
P to C: 11.5
T to C: NA
NA NA
De Luca et al.39 NSTEMI, STEMI, and UA undergoing PCI (450)
150 patients who switched from C to P matched with 300 patients treated with C only
NA NA At 30 days: no differences in MACE, NACE, and bleeding between groups
Loh et al.40 ACS undergoing PCI (606)
C to P: 14.8
C to T: NA
NA NA In-hospital: no differences in bleeding between patients who switched to P and those receiving P only; MACE were more frequent in patients who switched to P than in those receiving P only
Almendro-Delia et al.41
ACS (468) C to P: 25.0
C to T: NA
NA P to T: 0.3
T to P: NA
In-hospital: no difference in bleeding and MACCE between patients who switched to P and those receiving C only
IPA 45.4% when receiving 150 mg C to 60.8% after 15 days of 10 mg PPRI 39.7% when receiving 150 mg C to 25.1% after 15 days of 10 mg PVNP2Y
12: consistent findings (data not
reported in the original article)
At 29 days: bleeding occurred in four patients who switched from C to P
Montalescot et al. (ACAPULCO)44
Double-blind, randomized, crossover
UA and NSTEMI (56)
LTA, VNP2Y
12,
VASP
MPA 38.6% after 900 mg C to 28.9% after 15 days of 10 mg PMPA 38.6% after 900 mg C to 38.2% after 15 days of 150 mg C to 25% after 15 days of 10 mg PPRU 96.3 ± 67.6 when receiving 150 mg C to 47.1 ± 32.4 after 15 days of 10 mg PPRI 40.6 ± 22.5% when receiving 150 mg C to 22.8 ± 15.7% after 15 days of 10 mg P
At 60 days: no differences in any non‑CABG‑related major (according to TIMI criteria) or severe and/or life-threatening (according to GUSTO criteria) bleeding events; five patients (three treated with P and two with C) experienced bleeding during MD treatment
MPA 60.2% when receiving 75 mg C to 41.1% after 7 days of 10 mg MD PMPA 55.5% when receiving 75 mg C to 41% after 60 mg LD P plus 7 days of 10 mg MD PMPA 53.8% when receiving 75 mg C to 55% after 7 days of 75 mg MD CVNP2Y
12 and VASP: consistent findings
(data not reported in the original article)
At 15 days: bleeding according to TIMI criteria was reported in 8.5% of the 10 mg MD P group, 13.6% of the 60 mg LD plus 10 mg MD P group and 12.5% of the 75 mg MD C group
Trenk et al. (TRIGGER–PCI)46
Randomized, parallel assignment, double-blind
Stable CAD with HPR undergoing PCI (212)
VNP2Y12
Substantial decrease in PRU in the P group compared with the C group176 (94.1%) patients of the P group reached a PRU ≤208
At 6 months: major non-CABG-related bleeding (according to TIMI criteria) occurred in three and one patients receiving P and C, respectively
PRU 57.9 at 6 h after placebo plus 60 mg P administrationPRU 35.6 at 6 h after 600 mg C plus 60 mg P administrationPRU 53.9 at 6 h after 600 mg C plus 30 mg P administration
At 72 h: three treatment‑related adverse events in the placebo plus 60 mg P group, four in the 600 mg C plus 60 mg P group, and seven in the 600 mg C plus 30 mg P group; two deaths occurred in the placebo plus 60 mg P group
Sardella et al. (RESET GENE)48
Open-label, crossover, randomized
Stable CAD with HPR undergoing PCI (32)
MEA HPR defined as AUC >450AUC 576 when receiving C to 180.5 after 15 days of 10 mg PAUC 380.5 when receiving 150 mg C to 256 after 15 days of 10 mg P
At 3 months: three minor bleeding events in patients initially treated with P and one minor bleeding event in patients receiving C
Lhermusier et al.49
Prospective, open- label, randomized
ACS (48) VNP2Y12
, VASP
PRU 143 after 600 mg C to 111 at 4 h after 10 mg P to 97 at 24 h after the initial P dosePRU 122 after 600 mg C to 7 at 4 h after 30 mg P to 27 at 24 h after the initial P dosePRI 44% after 600 mg C to 35% at 4 h after 10 mg P to 21% at 24 h after the initial P dosePRI 59% after 600 mg C to 15% at 4 h after 30 mg P to 10% at 24 h after the initial P dose
NA
Alexopoulos et al.50
Randomized, single‑ centre, single-blind, crossover
ACS with HPR (44)
VNP2Y12
PRU 280.3 when receiving C to 90.8 after 15 days of 10 mg P to 32.1 after 15 days of 90 mg twice‑daily T
At 30 days: no patient experienced a major adverse cardiovascular event or a major bleeding event; four patients (two treated with P and two with T) reported minor bleeding events; allergic reactions (n = 2), dyspepsia (n = 2), and dyspnoea (n = 4) occurred with T therapy
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translates into a need to define the optimal approach to switching from clopidogrel to prasugrel therapy on the basis of surrogate pharmacodynamic measures. In the early phases of clinical investigation of prasu-grel and before the TRITON–TIMI 38 trial was con-ducted, several studies with the aim of defining the pharmacodynamic effects of prasugrel compared with those of clopidogrel, in which switching between thera-pies was part of the study design, were performed in healthy volunteers and in patients with stable CAD undergoing PCI42,43. These studies were followed by
pharmacodynamic investigations specifically designed to assess switching from clopidogrel to prasugrel therapy in patients with ACS or undergoing PCI44–50; other retro-spective analyses in which the pharmacodynamic effects of switching from clopidogrel to prasugrel therapy were assessed have also been reported51–57. These studies are summarized in TABLE 3. Overall, the results of these investigations have consistently shown decreased lev-els of platelet reactivity and reduced rates of HPR when switching from clopidogrel to prasugrel. However, prac-tice guidelines do not provide any recommendations on
Table 3 (cont.) | Switching from clopidogrel to prasugrel: pharmacodynamic studies
Study Study design Study population (n)
Pharmaco‑dynamic test
Main pharmacodynamic findings about switching
Clinical outcomes (exploratory)
Koul et al.51 Prospective, observational, registry
STEMI undergoing PCI (223)
VASP PRI 79% after 600 mg C (pre‑PCI) to 74% after 60 mg P (after PCI) to 17% 1 day after PCI
In‑hospital: 1.1% of patients experienced major bleeding events
Cuisset et al.52 Prospective, observational, registry
NSTE-ACS with diabetes mellitus undergoing PCI (107)
VASP PRI 47 ± 21% after 600 mg C to 31 ± 13% after 1 month of 10 mg PWhen receiving C: HPR 50%, LPR 13%When receiving P: HPR 8%, LPR 22%
At 30 days: one stent thrombosis and 10 bleeding complications (according to BARC criteria) were reported
Nührenberg et al.53
Nonrandomized, observational
STEMI undergoing PCI (47)
VNP2Y12
, LTA, MEA
PRU 10 after 600 mg C plus 60 mg PMPA 1% after 600 mg C plus 60 mg PAU*min 214 after 600 mg C plus 60 mg P
NA
Parodi et al.54 Nonrandomized, observational
CAD undergoing PCI (454)
LTA HPR group: MPA 72 ± 11% when receiving C to 43 ± 16% when receiving P
In‑hospital and at 6 months: no differences in major or minor bleeding rates (according to TIMI criteria) or in bleeding rates or ischaemic events (according to BARC criteria) between patients who switched therapy and therapy-naive patients
Aradi et al.55 Prospective, observational, registry
ACS undergoing PCI (741)
MEA 60 mg LD plus 10 mg MD P provided significantly more potent platelet inhibition than a repeated LD of 600 mg C86% of the patients treated with MD P remained below the cut-off point for HPR
At 1 year: the rates of thrombotic complications in the HPR group were similar to those in the non-HPR group without significant differences in all-cause death, myocardial infarction, stent thrombosis, or stroke; the incidence of major bleeding did not increase after switching to P therapy in the HPR group compared with the non-HPR group
Mayer et al. (ISAR–HPR)56
Prospective, observational, registry
ACS with HPR undergoing PCI (428)
MEA AU*min 651 after 600 mg C to 156 after 60 mg P
At 30 days: two events (1.7%) of combined death and stent thrombosis, and 10 events (8.7%) of major bleeding (according to TIMI criteria)
PRU 234 after 600 mg C to 23 at 4 h after 60 mg P to 9 at discharge when receiving 10 mg PPRI 68.4% after 600 mg C to 8.6% at 4 h after 60 mg P to 8.0% at discharge when receiving 10 mg P
At discharge: no significant differences in bleeding between groups (three events in the C‑to‑P group and three in the P‑only group)
Abbreviations: ACS, acute coronary syndromes; AU*min, arbitrary aggregation units over time; BARC, Bleeding Academic Research Consortium; C, clopidogrel; GUSTO, Global Use of Strategies to Open Occluded Arteries; HPR, high on‑treatment platelet reactivity; IPA, inhibition of platelet aggregation; LD, loading dose; LPR, low on‑treatment platelet reactivity; LTA, light‑transmission aggregometry; MD, maintenance dose; MEA, multiple electrode platelet aggregometry; MPA, maximal platelet aggregation; NA, not available; NSTE, non‑ST‑segment elevation; NSTEMI, non‑ST‑segment elevation myocardial infarction; P, prasugrel; PCI, percutaneous coronary intervention; PRI, platelet reactivity index; PRU, P2Y
switching from clopidogrel to prasugrel, leaving clini-cians uninformed on how to manage these patients, who are frequently encountered in daily practice. Data from specifically designed pharmacodynamic investigations have been used by drug-regulatory agencies to update the package insert of prasugrel to provide c linicians with available information on therapy switching.
The SWAP study45 was designed to assess the effects of switching from clopidogrel to prasugrel, and to eval-uate how these effects were influenced by the adminis-tration of a loading dose of prasugrel. Patients who had experienced an ACS (n = 139) and were stable for at least 1 month while receiving dual antiplatelet therapy with aspirin and clopidogrel were enrolled in this open-label study. After a 10–14-day run-in period during which
a 75 mg daily dose of clopidogrel was administered in combination with aspirin therapy, patients were ran-domly assigned to one of the following three treatments: a loading dose of placebo followed by a 75 mg mainte-nance dose of clopidogrel; a loading dose of placebo followed by a 10 mg maintenance dose of prasugrel; or a 60 mg loading dose followed by a 10 mg maintenance dose of prasugrel. Platelet function was evaluated at 2 h, 24 h, 7 days, and 14 days after switching therapies, using multiple pharmacodynamic assays. The findings of this study reinforced the concept that switching from clopidogrel to prasugrel is associated with increased lev-els of platelet inhibition and reduced rates of HPR45,64. These effects can be achieved more rapidly (within 2 h) if a 60 mg loading dose of prasugrel is given than if no
Table 4 | Switching from clopidogrel to ticagrelor: pharmacodynamic studies
Study Study design Study population (n)
Pharmaco‑ dynamic test
Main pharmacodynamic findings about switching
Clinical outcomes (exploratory)
Gurbel et al. (RESPOND)58
Randomized, double-blind, double-dummy, crossover
Stable CAD (98)
LTA, VNP2Y12
, VASP
Nonresponder cohort: MPA 59 ± 9% when receiving C to 35 ± 11% at 4 h after 180 mg TResponder cohort: MPA 47 ± 15% when receiving C to 32 ± 8% at 4 h after 180 mg TVNP2Y
12 and VASP: consistent findings
(data not reported in the original article)
At 30 days: four patients (two nonresponders and two responders) experienced five serious adverse events, and all events occurred during or after T therapy; one major and three minor bleeding events occurred during T treatment, and no bleeding events occurred during C treatment; dyspnoea was reported in 13 and four patients receiving T and C, respectively; two nonresponders had dyspnoea during switching
Caiazzo et al. (SHIFT- OVER)59
Randomized, single-blind
ACS (50) MEA, LTA AU 34.4 ± 1.3 when receiving C to 17.6 ± 7.2 at 2 h after 90 mg TAU 41.7 ± 2.0 when receiving C to 18.1 ± 6 at 2 h after 180 mg TMPA 24 ± 17% when receiving C to 9 ± 4% at 2 h after 90 mg TMPA 25 ± 14% when receiving C to 9 ± 3% at 2 h after 180 mg T
At 30 days: no deaths nor strokes were reported after switching; two patients underwent a new hospitalization during the shift to T
Lhermusier et al.49
Prospective, open-label, randomized
ACS (48) VNP2Y12
, VASP
PRU 146 after 600 mg C to 12 at 4 h after 90 mg T to 9 at 24 h after the initial T dosePRU 92 after 600 mg C to 4 at 4 h after 180 mg T to 4 at 24 h after the initial T dosePRI 57% after 600 mg C to 3% at 4 h after 90 mg T to 4% at 24 h after the initial T dosePRI 47% after 600 mg C to 2% at 4 h after 180 mg T to 3% at 24 h after the initial T dose
At 24 h: one bleeding event after the switch to 90 mg T
Alexopoulos et al.50
Prospective, randomized, single-blind, crossover
ACS with HPR (44)
VNP2Y12
PRU 277.4 when receiving C to 34.1 after 15 days of 90 mg twice‑daily T to 111.4 after 15 days of 10 mg P
At 30 days: no major adverse cardiovascular or a major bleeding events; four patients (two treated with P and two with T) reported minor bleeding events; allergic reactions (n = 2), dyspepsia (n = 2), and dyspnoea (n = 4) occurred with T therapy
Koul et al.51 Prospective, registry
STEMI undergoing PCI (223)
VASP PRI 64% after 600 mg C (pre‑PCI) to 53% after 60 mg P (after PCI) to 29% 1 day after PCI
In‑hospital: the rate of major in‑hospital bleeding events was 3.3%
Hibbert et al. (CAPITAL RELOAD)60
Prospective, observational
STEMI (52) VNP2Y12
PRU 252 in therapy-naive patients to 220 at 2 h after 180 mg TPRU 255 after 600 mg C to 90 at 2 h after 180 mg T
loading dose is used, whereas similar levels of platelet inhibition are reached after 1 week of a 10 mg mainte-nance dose of prasugrel regardless of whether a loading dose is used (FIG. 3). The main limitation of the SWAP study is that it was performed in patients with ACS whose disease was already stabilized with maintenance clopidogrel therapy, whereas in clinical practice the need to switch to a more potent agent occurs in the acute set-ting. This reality was the basis for the TRIPLET trial47, in which a strategy of adding a loading dose of prasugrel after a loading dose of clopidogrel was tested in patients with ACS undergoing PCI (n = 282). Patients were ran-domly assigned to undergo three different strategies: pla-cebo plus a 60 mg loading dose of prasugrel; a 600 mg loading dose of clopidogrel plus a 60 mg loading dose of prasugrel; or a 600 mg loading dose of clopidogrel plus a 30 mg loading dose of prasugrel. The effect of adding a loading dose of 60 mg of prasugrel within 24 h after a 600 mg loading dose of clopidogrel had been administered was not significantly different to that of administering a 60 mg loading dose of prasugrel alone, which demon-strates that clopidogrel pretreatment has no additive pharmacodynamic benefit (FIG. 4).
Overall, these findings do not show any form of drug interaction or overdosing when prasugrel is given to patients previously exposed to clopidogrel. Indeed, after administration of a loading dose of clopidogrel, a considerable number of P2Y12 receptors remain unin-hibited, which enables further blockade of the receptors when a loading dose of prasugrel is subsequently given. After blockade of all of the P2Y12 receptors available
on the platelet surface, further platelet inhibition can-not occur and, given the unstable nature of the active metabolite of prasugrel, this metabolite is eliminated from the systemic circulation. Therefore, the degree of P2Y12-receptor blockade after prasugrel adminis-tration is similar ir respective of previous exposure to clopidogrel (FIG. 5).
The largest pharmacodynamic investigation to explore the switch from clopidogrel to ticagrelor was the RESPOND trial58. In this study, patients with stable CAD were stratified into two groups according to HPR status (responders or nonresponders) after a 300 mg loading dose of clopidogrel. All patients were randomly allocated to receive either clopidogrel (600 mg loading dose followed by a 75 mg daily maintenance dose) or ticagrelor (180 mg loading dose followed by a 90 mg twice-daily maintenance dose) for 14 days, and were then crossed over to the alternative treatment. The study, which involved multiple pharmacodynamic assays, showed that ticagrelor therapy could overcome HPR in patients who had already been treated with clopidogrel, and that the antiplatelet effect of ticagrelor was similar irrespective of clopidogrel responsiveness. Furthermore, all patients who switched therapy to ticagrelor showed levels of platelet reactivity below the HPR cut-off that is associated with increased ischaemic risk (FIG. 6). The main limitation of the study is that it was performed in patients with stable CAD, which is not the clinical setting in which switching commonly occurs. This and other studies in which the effects of switching from clopidogrel to ticagrelor therapy were analysed are summarized in TABLE 4 (REFS 49–51,58–60).
The consistent finding that prasugrel and ticagre-lor markedly reduce the rates of HPR have prompted an interest in defining whether switching to a novel antiplatelet agent in patients who have HPR when receiving clopidogrel can ameliorate clinical outcomes. In an analysis of the TRANSLATE–ACS registry con-ducted in a subgroup of patients (n = 1,505) undergoing platelet-function testing, HPR was observed in 24% of patients (most of whom were receiving an early-genera-tion antiplatelet drug: clopidogrel or ticlopidine)65. After platelet-function testing, switching to a new-generation P2Y12-receptor inhibitor occurred in 37% of patients with HPR and in only 10% of patients with therapeutic levels of platelet reactivity (defined by the investigators as platelet reactivity units <235)65. However, and impor-tantly, despite the fact that registry data on switching patients with HPR to therapy with a more-potent agent are encouraging55,56,66–68, none of the randomized clin-ical trials performed to date has shown a benefit of a switching strategy on the basis of pharmacodynamic testing46,69,70. Although a detailed description of these trials is beyond the scope of this manuscript, several drawbacks that are likely to have made a large contribu-tion to the reported findings should be highlighted, most importantly the low clinical risk profile of the patient populations enrolled in these trials71. Ongoing rand-omized studies to assess the use of novel P2Y12-receptor therapies on the basis of results of pharma codynamic testing, such as the TROPICAL–ACS trial72, and genetic
0 24 4 6
Max
imum
pla
tele
t agg
rega
tion
(%)
10 12 140
80
60
40
20
100Placebo LD plus clopidogrel 75 mg MD (n = 33)
Placebo LD plus prasugrel 10 mg MD (n = 36)Prasugrel 60 mg LD plus 10 mg MD (n = 31)
testing, such as the POPular Genetics trial73, in patients with ACS undergoing PCI, will provide more insights into this topic.
Given the lack of robust clinical outcome data to support switching from clopidogrel to a novel P2Y12-inhibiting therapy on the basis of pharmacodynamic or genetic testing results, current guidelines recommend against the routine use of these approaches to guide clinical decisions in this area (class III recommenda-tion)1,3,4. Platelet-function or genetic testing, however, might be considered (class IIb recommendation, level of evidence C) for patients at high risk of poor clinical outcomes. In this scenario, alternative agents, such as prasugrel or ticagrelor, might be used1,3,4.
From novel inhibitors to clopidogrelSwitching from a novel P2Y12-receptor inhibitor to clopi-dogrel occurs very commonly in clinical practice, but very few data support this approach13. Reduced costs associated with a generic formulation of clopidogrel as well as concerns about bleeding caused by the new- generation P2Y12-receptor inhibitors remain important
reasons for switching to clopidogrel. To date, no rand-omized trials have assessed the clinical outcomes of such a switching strategy, and most information on this issue derives from registries (TABLE 2)34–38. Overall, the prev-alence of in-hospital switching from a new-generation P2Y12-receptor inhibitor to clopidogrel that is reported in registries ranges from 5.0% to 13.6% (TABLE 2). Patients who underwent this transition were less likely to be privately insured and had risk factors associated with increased risk of bleeding, such as old age, low body mass, previous transient ischaemic attack or stroke, in-hospital treatment with CABG surgery, atrial fibril-lation or flutter, and use of oral anticoagulants32–36. In most patients, the switch occurred after PCI or at the time of hospital discharge and very rarely was a loading dose of clopidogrel used. Although rates of switching after hospital discharge are not reported in the literature, this switch is likely to occur in a considerable number of patients who realize the financial burden associated with the use of the novel P2Y12-receptor inhibitors only after discharge. Indeed, these drugs are often used for only the first month after the start of antiplatelet therapy in patients with economic restraints, who might use a voucher or temporary financial assistance provided by the pharmaceutical companies that make these agents.
The effect of switching from a novel P2Y12-receptor inhibitor (most often prasugrel) to clopidogrel on phar-macodynamic measures has been assessed in several crossover studies in various clinical settings, as well as in other small cohort studies (TABLE 5)43,44,48,58,74–76. These studies have consistently shown that this switching strat-egy is associated with a reduction in platelet-inhibitory effects and an increase in rates of HPR. Although some of these studies have reported a lower potential risk of bleeding complications when switching to clopidogrel, these safety considerations need to be interpreted with caution, because they were made in the context of small pharmacodynamic studies. Moreover, the increased rate of HPR can also potentially enhance long-term ath-erothrombotic risk in these patients68,77. Although the safety and efficacy of switching from a more expensive therapy to a generic clopidogrel formulation are of great interest to many clin icians and patients because of the cost-saving potential of such a strategy, an overall lack of robust data exists in this field. The ongoing SWAP-4 study78 is specifically designed to analyse the optimal strategy (dosing and timing) of switching from tica-grelor to clopidogrel on the basis of pharmacodynamic measures. The TROPICAL–ACS trial72 will provide information on the safety and efficacy of switching from prasugrel to clopidogrel if patients have levels of platelet reactivity that are below the t hresholds associated with ischaemic risk.
Between novel inhibitorsLimited data exist on the effects of switching between the novel P2Y12-receptor inhibitors prasugrel and tica-grelor. Registry data indicate that this type of drug switching is rare, ranging from 2% to ~4% (TABLE 2)34–37,41. Therefore, the information on factors associated with switching is also limited. Theoretically, given
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*
*
* * *
** *
a
b
Figure 4 | Pharmacodynamic profile of switching from clopidogrel to prasugrel therapy: the TRIPLET study47. Time course of platelet inhibition measured as a | P2Y
12
reaction units, and b | percent of inhibition, in patients with an acute coronary syndrome whose therapy was switched from clopidogrel to prasugrel. Eligible patients undergoing a percutaneous coronary intervention were randomly assigned to receive one of three therapeutic strategies. The results at time 0 are the baseline values obtained after intake of the first clopidogrel or placebo LDs, immediately before the second LD (with prasugrel) was administered. *No significant difference. **P <0.05. Data are presented as the least squares mean ± SE. Abbreviations: LD, loading dose; MD, maintenance dose. Reprinted from Diodati, J. G. et al. Effect on platelet reactivity from a prasugrel loading dose after a clopidogrel loading dose compared with a prasugrel loading dose alone: Transferring From Clopidogrel Loading Dose to Prasugrel Loading Dose in Acute Coronary Syndrome Patients (TRIPLET): a randomized controlled trial. Circ. Cardiovasc. Interv. 6 (5), 567–574 (2013), with permission from Wolters Kluwer Health and the American Heart Association.
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that ticagrelor can be administered before knowing the coronary anatomy, switching to prasugrel later on might improve compliance, because prasugrel is administered only once daily. Another reason to con-sider switching from ticagrelor to prasugrel is to over-come dyspnoea, which occurs more frequently with ticagrelor and which was also shown to affect drug compliance79,80. Conversely, potential reasons to con-sider switching from prasugrel to ticagrelor include the reduction in body mass to <60 kg during maintenance antiplatelet treatment, and the occurrence of a cerebro-vascular event, after which prasugrel is contraindicated. Of note, registry data have shown that the use of prasu-grel in patients with a previous cerebrovascular event is not uncommon in clinical practice, despite being contraindicated35,36,38. The proven benefit of ticagrelor in decreasing mortality, as well as the potential for using this agent in the long term (>1 year) have been supported by the findings of the PEGASUS trial81. Ultimately, insurance coverage might have an important influence on which drugs will be used.
The SWAP-2 study82 showed the pharmacodynamic effects of switching from ticagrelor to prasugrel. Patients switched to prasugrel therapy (with or without a 60 mg loading dose) 12 h after the last maintenance dose of tica-grelor. Platelet reactivity was higher in prasugrel-treated patients than in ticagrelor-treated patients at 7 days, and, therefore, the trial did not meet the noninferiority pri-mary end point. Moreover, at 24 h and even more so at 48 h, platelet reactivity increased in patients switched to prasugrel therapy compared with levels before the switch, with a greater increase in patients who did not receive the prasugrel loading dose (FIG. 7). These data suggest a potential pharmacodynamic interaction between prasu-grel and ticagrelor, which might be mitigated by admin-istration of a loading dose of prasugrel82. The binding of ticagrelor to the P2Y12 receptors on platelets could still be present after 12 h, not allowing the active metabolite of prasugrel to occupy the receptor and create a covalent bond; given the short half-life of prasugrel, a mainte-nance dose of this agent would be degraded before the metabolite could bind to the receptor. The possibility that ticagrelor (or its major metabolite) also induces a change in receptor conformation that precludes binding of the active metabolite of prasugrel cannot be excluded23,82.
Pharmacodynamic investigations of the switch between novel P2Y12-receptor inhibitors are limited to two small studies, both showing that levels of plate-let reactivity and HPR rates are lower when switching from prasugrel to ticagrelor50,83. A more comprehen-sive understanding of the pharmacodynamic effects of switching from prasugrel to ticagrelor will be provided by the ongoing SWAP-3 study84, whereas the effect of switching therapy in patients with HPR receiving pra-sugrel to ticagrelor is being specifically investigated in the HEIGHTEN study85.
From cangrelor to oral inhibitorsCangrelor is an intravenous direct-acting P2Y12-receptor inhibitor with immediate onset and offset of action15,19,24. Given the different pharmacological properties of can-grelor and oral P2Y12-receptor inhibitors, concerns have emerged about the potential for drug interactions when these different drug formulations are concomitantly administered24. A pharmacodynamic investigation con-ducted in healthy volunteers showed that concomitant administration of clopidogrel and a cangrelor infusion leads to inadequate clopidogrel-induced antiplatelet effects, because clopidogrel does not bind to the P2Y12 receptor while the receptor is occupied by cangrelor86. However, clopidogrel-induced antiplatelet effects were not affected when clopidogrel was administered after a cangrelor infusion, given the very rapid offset of action of cangrelor making it possible for the active metabo-lite of clopidogrel to bind the P2Y12 receptor86. Similar findings were observed in blood incubated with can-grelor before the addition of the active metabolites of clopidogrel or prasugrel, in which the capacity of these thienopyridines to inhibit platelet aggregation was reduced87. Conversely, addition of cangrelor to whole blood preincubated with the active metabolites of clopi-dogrel or prasugrel, as well as blood from patients treated
Figure 5 | Biological hypothesis for P2Y12‑receptor occupancy after administration of a LD of prasugrel, with or without previous exposure to clopidogrel. After administration of a LD of clopidogrel, P2Y
12 receptors are only
partially occupied by the active metabolite of the drug. Therefore, the administration of a LD of prasugrel to a patient already treated with clopidogrel would lead to blockade of the remaining uninhibited P2Y
12 receptors by the active metabolite of prasugrel. When all
the receptors have been occupied, the remaining molecules of the active metabolite of prasugrel do not bind to any receptor and are immediately hydrolysed. The extent of P2Y
12-receptor occupancy when prasugrel is added to clopidogrel would be similar to
that resulting from therapy with prasugrel alone. Abbreviation: LD, loading dose.
with these agents, led to sustained platelet inhibition87,88. The absence of drug interaction and the capacity of can-grelor to enhance platelet inhibition in patients already exposed to thienopyridine therapy has also been shown in the BRIDGE trial83. This trial was a phase II, ex vivo pharmacodynamic study conducted in 210 patients (of whom approximately 50% had experienced an ACS) treated with a thienopyridine and requiring CABG sur-gery. A 0.75 μg/kg/min dose of cangrelor was associated with ‘thienopyridine-like’ levels of platelet inhibition. Cangrelor was associated with high and stable levels of platelet inhibition up to 7 days of infusion (median duration ~3 days), with an extremely rapid offset of action after discontinuation before surgery and without an increased risk of major bleeding or adverse effects before or during CABG surgery83.
These pharmacodynamic investigations were piv-otal for the design of phase III clinical trials in which clopidogrel was administered immediately after dis-continuation of cangrelor infusion to avoid drug inter-action90–92. The primary end point was not met in two of these phase III clinical trials90,91, probably because of how the study end points (that is, myocardial infarction) were defined93. However, in the CHAMPION PHOENIX trial92, cangrelor was shown to reduce the rate of ischae-mic events, including stent thrombosis, at 48 h, with no significant increase in the incidence of severe bleeding across the spectrum of patients with CAD undergoing PCI who were enrolled in the trial. Although no clini-cal studies have been performed with the aim of under-standing the effects of cangrelor when the drug is used concomitantly with the novel P2Y12-receptor inhibitors, pharmacodynamic studies have been conducted in patients with stable CAD (not in the setting of PCI) to define the optimal transition strategy from cangrelor to prasugrel or ticagrelor therapy94,95. The results showed that treatment with prasugrel, either during cangrelor
infusion or before treatment with cangrelor, does not alter the antiplatelet effects of cangrelor. Conversely, the transi-tion from cangrelor to prasugrel was associated with tran-sient recovery of platelet reactivity, in particular within 1 h after cangrelor discontinuation. However, the recov-ery of platelet function was attenuated when prasugrel was administered 30 min before stopping cangrelor infu-sion94. By contrast, a pharmacodynamic study to evaluate the transition from cangrelor to ticagrelor and vice versa showed that the pharmacodynamic effects of ticagrelor and cangrelor are consistently preserved independently from the sequence in which the drugs are adminis-tered95. These results indicate that ticagrelor can be administered before, during, or after cangrelor i nfusion without pharmacodynamic interaction occurring95.
The existence of an interaction between thienopyri-dines and cangrelor, but not between ticagrelor and cangrelor, is probably owing to the different sites and types of binding of these drugs86,94,95. The active m etabo-lites of thienopyridines bind to the ADP-binding site of the P2Y12 receptor (competitive antagonism). Although the binding site of cangrelor at the P2Y12-receptor level is not clearly defined, cangrelor is associated with high levels of receptor occupancy, which prevents thieno-pyridine access and ADP signalling86,94. Cangrelor binds reversibly to the P2Y12 receptor and has a very short half-life, whereas the active metabolites of clopidogrel and prasugrel bind irreversibly to the receptor, rendering it nonfunctional for the entire life of the platelet86,94,95. Therefore, if prasugrel and clopidogrel are administered during cangrelor infusion, transient blockade of the P2Y12 receptor by cangrelor prevents thienopyridine binding, as the drugs compete for the same binding site. As the active metabolites of prasugrel and clopidogrel have a very short half-life in blood, they are immediately hydrolysed and no longer available when cangrelor dissociates from the receptor. By contrast, ticagrelor reversibly binds the P2Y12 receptor at a site distinct from the ADP-binding site (noncompetitive antagonism), leading to an inac-tive state of the receptor, which will become functional again immediately after ticagrelor dis sociation86,94,95. No interactions between ticagrelor and cangrelor have been shown95,96. Moreover, ticagrelor is a direct agent with a longer half-life in blood than that of thienopirydines, which allows it to be available at its binding site when cangrelor dissociates from the P2Y12 receptor86,94,95.
Practical considerationsIn the absence of trials specifically designed for to assess the safety and efficacy of switching strategies, we rely on the analysis of existing clinical trials and registries, as well as pharmacodynamic studies, to provide guidance on the best modalities of switching between clinically available P2Y12-receptor inhibitors (FIG. 8).
Switching from clopidogrel to ticagrelorSuch a switching strategy occurred in nearly half of the patients enrolled in the pivotal phase III clinical trial leading to approval of ticagrelor (PLATO7), which showed consistently that ticagrelor is safe and efficacious irrespective of previous clopidogrel exposure. In the trial,
*
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** * *
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‡‡
‡
* ** *
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Day 1 Day 15Day 14 Day 286 6 6 6
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Figure 6 | Pharmacodynamic profile of switching between clopidogrel and ticagrelor therapy: results from the RESPOND study58. P2Y
12 reaction units in clopi-
dogrel-nonresponsive patients before and after crossover. Patients treated with ticagrelor in period 1 received a 600 mg clopidogrel loading dose followed by 75 mg daily maintenance therapy in period 2; patients treated with clopidogrel in period 1 received a 180 mg ticagrelor loading dose followed by 90 mg twice-daily maintenance therapy in period 2. *P <0.0001. ‡P <0.05. Reprinted from Gurbel, P. A. et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation 121 (10), 1188–1199 (2010), with permission from Wolters Kluwer Health and the American Heart Association.
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patients randomly assigned to receive ticagrelor therapy were treated with a 180 mg loading dose of the drug irre-spective of timing of their last dose of clopidogrel, which was followed by a 90 mg maintenance dose of ticagre-lor administered 12 h after the loading dose. A similar dosing regimen was used in a pharmacodynamic study
conducted in patients with stable CAD58. Accordingly, in the acute phase of disease presentation, a similar approach should be applied whenever switching from clopidogrel to ticagrelor. As large-scale clinical investi-gations of ticagrelor in patients with more-stable clinical presentations consider initiation of treatment directly
Table 5 | Switching from novel P2Y12‑receptor inhibitors to clopidogrel: pharmacodynamic studies
Study Study design Study population (n)
Pharmaco‑ dynamic test
Main pharmacodynamic findings about switching
Clinical outcomes (exploratory)
Gurbel et al. (RESPOND)58
Randomized, double-blind, double-dummy, crossover
Stable CAD (98)
LTA, VNP2Y
12,
VASP
Nonresponder cohort: MPA 36 ± 14% when receiving T to 56 ± 9% at 4 h after 600 mg CResponder cohort: MPA 25 ± 11% when receiving T to 45 ± 8% at 4 h after 600 mg CVNP2Y
12 and VASP: consistent
findings (data not reported in the original article)
At 30 days: four patients (two nonresponders and two responders) experienced five serious adverse events, and all events occurred during or after T therapy; one major and three minor bleeding events occurred during T treatment, and no bleeding events occurred during C treatment; dyspnoea was reported in 13 and four patients receiving T and C, respectively; two nonresponder patients had dyspnoea during drug switching
IPA 61.9% when receiving 10 mg P to 46.8% after 15 days of 150 mg CPRI 21.7% when receiving 10 mg P to 48% after 15 days of 150 mg CVNP2Y
12: consistent findings (data
not reported in the original article)
At 29 days: no bleeding events in patients switching from P to C
Montalescot et al. (ACAPULCO)44
Double-blind, randomized, crossover
UA and NSTEMI (56)
LTA, VNP2Y
12,
VASP
MPA 28.9% when receiving 10 mg P to 42.5% after 15 days of 150 mg CPRU 41.3 ± 43.8 when receiving 10 mg P to 101.3 ± 60.8 after 15 days of 150 mg CPRI 21.5 ± 13.4% when receiving 10 mg P to 38.1 ± 19.8% after 15 days of 150 mg C
At 60 days: no differences in any non‑CABG‑related major (according to TIMI criteria) or severe or life-threatening (according to GUSTO criteria) bleeding events; five patients (three receiving P and two C) experienced bleeding during MD treatment
Sardella et al. (RESET GENE)48
Open-label, crossover, randomized
Stable CAD with HPR undergoing PCI (32)
MEA HPR defined as AUC >450AUC 180.5 after 15 days of 10 mg P to 330 after 15 days of 150 mg C
At 3 months: three minor bleeding events in patients initially treated with P and one minor bleeding event in those taking C
Pourdjabbar et al. (CAPITAL OPTI-CROSS)74
Prospective, randomized, open-label
ACS (60) VNP2Y12
PRU ~40 when receiving T* to 114 ± 73.1 at 48 h after 600 mg CPRU ~40 when receiving T* to 165.1 ± 70.5 at 48 h after 75 mg CPRU ~40 when receiving T* to 165.8 ± 71 at 72 h after 600 mg CPRU ~40 when receiving T* to 184.1 ± 68 at 72 h after 75 mg CHPR rate after 600 mg C: 27%HPR rate after 75 mg C: 57%
At 30 days: no differences in MACE, major bleeding events (according to TIMI criteria) or stent thrombosis between groups
Kerneis et al.75 Prospective, observational, registry
ACS (31) LTA, VNP2Y
12,
VASP
MPA 21.0 ± 10.4% when receiving 10 mg P to 43.8 ± 15.1% after 15 days of 75 mg CPRU 14.2 ± 27.9 when receiving 10 mg P to 155 ± 87.2 after 15 days of 75 mg CPRI 12.5 ± 11.9% when receiving 10 mg P to 43.6 ± 21.8% after 15 days of 75 mg C
At 30 days: no major bleeding events
Deharo et al. (POBA)76
Prospective, observational
ACS with LPR (20)
VASP PRI 7 ± 2% when receiving P to 37.8 ± 15.6% when receiving C
At 30 days: no bleeding events after switching to C
*Value estimated from a Figure in the original article. Abbreviations: ACS, acute coronary syndromes; AUC: area under the curve; BARC, Bleeding Academic Research Consortium; C, clopidogrel; CAD, coronary artery disease; GUSTO, Global Use of Strategies to Open Occluded Arteries; HPR, high on‑treatment platelet reactivity; IPA, inhibition of platelet aggregation; LPR, low platelet reactivity; LTA, light‑transmission aggregometry; MD, maintenance dose; MPA, maximal platelet aggregation; NSTEMI, non‑ST‑segment elevation myocardial infarction; P, prasugrel; PCI, percutaneous coronary intervention; PRI, platelet reactivity index; PRU, P2Y
with the maintenance dose regimen (without a load-ing dose)76,97,98, a 90 mg twice-daily maintenance dose seems reasonable when switching therapy in patients who are clinically stabilized (after their acute presenta-tion). Treatment should be initiated at the timing of the next scheduled maintenance dose of antiplatelet therapy, which is ~24 h from the last dose of clopidogrel.
Switching from clopidogrel to prasugrelMost of the insights into the optimal strategy of switch-ing from clopidogrel to prasugrel come from specific pharmacodynamic studies, given that the study leading to approval of prasugrel (the TRITON–TIMI 38 trial8) did not allow for patients pretreated with a P2Y12 inhib-itor to be enrolled43–48,52–55. Results of these studies indi-cate that administering a 60 mg loading dose of prasugrel has potent and immediate platelet inhibitory effects, irrespective of whether the treated patient was receiv-ing maintenance therapy with a 75 mg daily dose or had been exposed to a 600 mg loading dose of clopidogrel in the previous 24 h43–48,52–55. Similar levels of platelet inhibition to those achieved within hours of adminis-tration of a loading dose of prasugrel are observed after 1 week when switching to a 10 mg maintenance dose of prasugrel45. Therefore, clinicians can choose either strategy depending on how much immediate potent platelet inhibition is needed. Given that switching from clopidogrel to prasugrel is more likely to occur in the acute phase of clinical presentation, such as at the time of PCI when immediate and potent platelet inhibition is desired, the use of a 60 mg loading dose should be con-sidered in this setting irrespective of the timing of the
last dose of clopidogrel. The use of a 10 mg maintenance dose of prasugrel should be considered when switching is remote from an acute setting, after a patient has been stabilized, and should be initiated at the timing of the next scheduled maintenance dose of antiplatelet therapy, which is ~24 h from the last dose of clopidogrel.
Switching from ticagrelor to clopidogrelData on the best strategy of switching from ticagrelor to clopidogrel therapy are very limited74. Pharmacodynamic data indicate that ticagrelor has a rapid offset of action (3–5 days)28. This time frame does not allow clopidogrel to achieve its full antiplatelet effects if administered at a 75 mg daily maintenance dose regimen. Moreover, clopidogrel has an unpredictable and variable pharmaco dynamic profile even if given at a 600 mg loading dose12. On the basis of these considerations, a 600 mg loading dose of clopidogrel should always be given when switching from ticagrelor therapy. Although the optimal timing of switch-ing after the last dose of ticagrelor is unknown, a phar-macodynamic study showed evidence of drug interaction in patients whose therapeutic regimen was switched to prasugrel therapy 12 h after the last maintenance dose of ticagrelor, which suggests the presence of a residual effect of ticagrelor (or its metabolite) on the P2Y12 receptor72. Therefore, waiting 24 h after the last maintenance dose of ticagrelor was given to patients to administer the 600 mg loading dose of clopidogrel should be considered, because this strategy would allow enough time for ticagrelor and its metabolite to be eliminated (half-life ~8–12 h), as well as for new platelets to be released into circulation and be exposed to the active metabolite of clopidogrel.
Figure 7 | Pharmacodynamics profile of switching therapy from ticagrelor to prasugrel: results from the SWAP‑2 study82. Time course of platelet inhibition as measured with P2Y
12 reaction units in patients with stable coronary
Switching from prasugrel to clopidogrelData on the best strategy of switching from pra-sugrel to clopidogrel therapy are also very limited. Pharmacodynamic data indicate that prasugrel has a long offset of action (7–10 days)22. This time frame enables clopidogrel to achieve its full antiplatelet effects even if administered at a 75 mg daily maintenance dose regimen. However, given the unpredictable pharmaco-dynamic profile of clopidogrel, a 600 mg loading dose should be given, particularly in the early phase of ACS and/or PCI treatment, when thrombotic risk is high. If the switch to clopidogrel therapy is not occurring in an acute setting (ACS or PCI), a 75 mg daily maintenance dose (without a loading dose) might be a reasonable approach. Waiting 24 h after the last maintenance dose of prasugrel was given to patients before administering clopidogrel should be considered, as this strategy would allow enough time for new platelets to be released into the circulation and be exposed to the active metabolite of clopidogrel.
Switching between novel oral inhibitorsAvailable pharmacodynamic data suggest a potential drug interaction when switching from ticagrelor to pra-sugrel therapy82. This interaction can be mitigated with the use of a 60 mg loading dose of prasugrel, whereas switching to a 10 mg maintenance dose should be avoided because of the very high rates of HPR in the first 24–48 h after the switch82. Waiting 24 h after the last
maintenance dose of ticagrelor was given to patients before administering the 60 mg loading dose of prasugrel should be considered, because this strategy would allow enough time for ticagrelor and its metabolite to be elim-inated (half-life ~8–12 h). No clinical data are currently available on switching from prasugrel to ticagrelor ther-apy, but this approach is currently under investigation in the SWAP-3 trial84, in which the administration of a 180 mg loading dose of ticagrelor given 24 h after the last maintenance dose of prasugrel is hypothesized to be the optimal strategy.
Using cangrelor before or after oral agentsIn the acute setting, the bolus and infusion of cangrelor should be initiated before PCI and continued for ≥2 h or for the duration of the procedure, whichever is longer; the infusion can be continued for a total duration of 4 h, at the discretion of the physician. Patients should tran-sition to oral P2Y12-inhibiting therapy for chronic treat-ment using a loading dose of the drug. When switching therapy from cangrelor to thienopyridines (clopidogrel or prasugrel), these drugs should be administered imme-diately after discontinuation of cangrelor to avoid a phar-macodynamic interaction31,32. However, the recovery of platelet function is attenuated when prasugrel is admin-istered 30 min before stopping cangrelor infusion31,86,87,94. By contrast, ticagrelor can be administered before, during, or after cangrelor infusion without pharmaco-dynamic interaction95. When transitioning from therapy
Prasugrel Clopidogrel
Nature Reviews | Cardiology
Clopidogrel
Acute phaseP 60 mg LD
(24 h after last T dose)Chronic phase
P 60 mg LD(24 h after last T dose) Acute phase
T 180 mg LD(24 h after last P dose)
Chronic phaseT 180 mg LD
(24 h after last P dose)
Acute phaseT 180 mg LD* (irrespective of timing and dosing of C)
Chronic phaseT 90 mg twice daily (24 h after last C dose)
Acute phaseC 600 mg LD (24 h after last P dose)
Chronic phaseC 75 mg MD (24 h after last P dose)
CangrelorClopidogrel
PrasugrelC or P should be administered immediately after
discontinuation of cangrelor infusion
Cangrelor TicagrelorT can be administeredbefore, during, or after
cangrelor infusion
Ticagrelor
Acute phaseP 60 mg LD
(irrespectiveof timing and
dosing of C)Chronic phase
P 10 mg MD(24 h after last
C dose)
Acute phaseC 600 mg LD(24 h after lastT dose)Chronic phaseC 600 mg LD(24 h after lastT dose)
Oral
Intravenous
Figure 8 | Practical recommendations for switching between oral and intravenous antiplatelet agents. Switching from an oral agent (upper panel), and switching from an intravenous agent (lower panel). *Followed by ticagrelor 90 mg twice daily with first MD administered 12 h after the LD. Abbreviations: LD, loading dose; MD, maintenance dose.
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with any oral P2Y12-receptor inhibitor (clopidogrel, pra-sugrel, or ticagrelor) to cangrelor, the cangrelor infusion can be started at any time86,87,95.
ConclusionsSwitching between P2Y12-inhibiting therapies occurs very commonly in clinical practice. Differences in the pharmacology of P2Y12-receptor inhibitors, par-ticularly with regard to their binding sites (competi-tive and noncompetitive to ADP), drug half-life, and speeds of onset and offset of action, are all factors that could have an important role in drug interactions when switching from one agent to another. However, the clinical effect of most switching strategies is not fully determined, given the lack of trials adequately pow-ered or designed to test for safety and efficacy of these
strategies. The PLATO trial, the only large-scale study in which patients who were already receiving treat-ment with clopidogrel (nearly half of the overall trial population) were allowed to be randomly allocated to receive ticagrelor, showed consistent safety and efficacy profiles and no evidence of drug interaction when the switching approach was used. All other available data on the effects of switching between currently approved therapies derive from registries and pharmacodynamic studies. In particular, results from specifically designed pharmacodynamic studies have been useful in opti-mizing switching approaches through the use of surro-gate markers of platelet reactivity. A series of ongoing investigations will provide further insights to define the best strategies when a switch between P2Y12-inhibiting therapies is required.
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Author contributionsAll the authors researched data for the article, substantially contributed to discussion of content, and reviewed and edited the manuscript before submission. F.R. and D.J.A. wrote the manuscript.
Competing interests statementD.J.A. has received payment as an individual for consulting fees or honoraria from Abbott Vascular, AstraZeneca, Daiichi-Sankyo, Eli Lilly, Merck, PLx Pharma, Sanofi, and The Medicines Company; and for participation in review activities from CeloNova, Johnson & Johnson, and St. Jude Medical. Institutional payments for grants have been received from AstraZeneca, CSL Behring, Daiichi-Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, Osprey Medical, and The Medicines Company. The other authors declare no competing interests.
