Currently, there is no evidence to suggest that a combination of aspirin and clopidogrel, even in high-risk patients, such as those with diabetes, has any therapeutic advantage in the secondary prevention of cardio-vascular events after ischemic stroke/TIA. The MATCH trial considered patients with stroke or TIA and one other risk factor. Individuals already taking clopidogrel were randomized to receive either aspirin or placebo, in addition to clopidogrel. The trial failed to show a reduction in its composite cardiovascular end point (which included stroke) but did demonstrate increased rates of bleeding when using a combination of the two drugs [29
]. Further, the CHARISMA study, which compared over 15000 people with cardiovascular disease in primary or secondary prevention, did not show any benefit of clopidogrel and aspirin combined, when compared with aspirin alone, in their chosen end point, a composite of myocardial infarction, stroke, or cardiovascular death [22
CHANCE showed that in 5170 Chinese patients with TIA/ischemic stroke, treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of haemorrhage [30
]. The potential explanation of the benefit of DAPT in the CHANCE study is probably the short course of the combination aspirin plus clopidogrel treatment, in contrast with the long duration of DAPT in the MATCH study.
Newer antiplatelet agents
To overcome the sub optimal pharmacodynamic and pharmacokinetic profile of clopidogrel, new P2Y12
inhibitors were developed that are more predictable, more potent and have a faster onset of action, characteristics that make them particularly attractive for PCI. Prasugrel and ticagrelor are two agents that are now approved for the treatment of NSTE-ACS and STEMI predominantly treated with PCI based on evidence that has demonstrated a reduction in mortality and recurrent cardiovascular events when compared with clopidogrel [31
Prasugrel is a third generation thienopyridine that has a similar mechanism of action to clopidogrel in that its active form binds covalently to the P2Y12
receptor, via a disulfide bond causing irreversible blockade for ADP binding. It has however much more rapid, potent and consistent inhibitory effects on platelet aggregation than clopidogrel due to more efficient in vivo generation of its active metabolite [35
]. The esterase-mediated step for prasugrel occurs mainly in the intestine, as does the CYP-mediated oxidative step leading to the active metabolite formation [36
]. The polymorphisms in CYP2C9, CYP2C19, 17 and ABCB1 that have an effect on clopidogrel, do not significantly alter prasugrel clinical efficacy, pharmacokinetics or pharmacodynamics [37
]. The peak concentration of the active metabolite of prasugrel is achieved rapidly at 30 minutes and a maximum of 60-70% inhibition is usually achieved within 2-4 hours [38
The ACAPULCO trial specifically evaluated the pharmacodynamic effects of a 10 mg maintenance dose prasugrel in 56 patients with UA/NSTEMI, compared with high maintenance dose clopidogrel (150 mg daily) after high loading dose (900 mg). Greater platelet inhibition with prasugrel 10 mg daily was observed over 14 days compared with clopidogrel 150 mg daily [39
The superior antiplatelet effect of prasugrel was demonstrated in the phase II PRINCIPLE-TIMI (prasugrel in Comparison to clopidogrel for Inhibition of Platelet Activation and Aggregation-TIMI) 44 trial (overall population: n=201) which compared a 60 mg prasugrel dose with a 600 mg loading dose of clopidogrel. Among patients planned for PCI, loading with 60 mg prasugrel resulted in greater platelet inhibition than a 600 mg clopidogrel loading dose. Daily maintenance therapy with prasugrel 10 mg resulted in a greater antiplatelet effect than 150 mg daily clopidogrel. As often in this type of population, the diabetic subgroup represented around 30% of the overall cohort [40
The pharmacodynamic benefit of prasugrel in diabetic patients with CAD (n=35) was assessed in the OPTIMUS-3 study, in which prasugrel was compared with high-dose clopidogrel. Compared with clopidogrel 600 mg LD, a prasugrel 60 mg LD demonstrated significantly higher levels of IPA as measured by VN-P2Y12 as early as 1 hour following the LD and this effect was maintained over the subsequent 24 hours (greater platelet inhibition with prasugrel at 4 hours post-LD than clopidogrel: least squares mean, 89.3% vs. 27.7%, p<0.0001). Prasugrel 10 mg MD maintained a higher IPA than clopidogrel 150 mg MD after 1 week of therapy (61.8% vs. 44.2%, p<0.0001) [41
The superior pharmacodynamic and pharmacokinetic profile of prasugrel has been translated into clinical benefit when compared with clopidogrel. The TRITON TIMI-38 trial evaluated 13,608 patients with moderate to high-risk ACS including 10,074 patients with unstable angina (UA) or non-ST segment elevation myocardial infarction and 3,534 patients with STEMI33. Patients were randomized to receive prasugrel 60-mg loading dose, followed by 10mg/day, or clopidogrel 300 mg, followed by 75 mg/day. Patients continued therapy for 6-15 months after enrollment. Prasugrel was associated with a significant 18% relative risk reduction of the primary endpoint (CV death, non-fatal MI or nonfatal stroke) compared with clopidogrel (p<0.001), and a number needed to treat (NNT) of 46. In the total population, prasugrel's ischemic benefit was partly counterbalanced by a 0.6% absolute risk increase of TIMI major non-CABG related bleeding with a number needed to harm of 167. Regarding the bleeding risk, the study showed that three specific subgroups were at high risk for bleeding: patients ≥75 years old, <60 kg, with previous TIA or stroke. When the rates of certain efficacy and bleeding end points (death from any cause, nonfatal myocardial infarction, nonfatal stroke, and TIMI major hemorrhage) were included in a prespecified analysis of net clinical benefit, the findings favored prasugrel (13.9% of patients in the clopidogrel group vs. 12.2% in the prasugrel group; hazard ratio, 0.87; 95% CI, 0.79 to 0.95; P=0.004).
For the pre-specified analysis of the diabetic subgroup of the TRITON study, Prasugrel significantly reduced the incidence of the primary endpoint compared with clopidogrel among nondiabetics (9.2 and 10.6%, respectively; HR 0.86; P=0.02) and DM patients (12.2 and 17.0%, respectively; HR 0.70; P<0.001, P interaction=0.09) [42
]. DM subjects taking insulin also had greater benefit with reduced the incidence of the primary endpoint when treated with prasugrel compared to clopidogrel (DM patients with insulin: 14.3 and 22.2%, respectively; HR 0.63; P=0.009; DM patients without insulin: 11.5 and 15.3%, respectively; HR 0.74; P=0.009). Nondiabetics taking prasugrel were more likely than those receiving clopidogrel to develop major hemorrhage (2.4% vs. 1.6%, HR 1.43; P=0.02). Rates of major hemorrhage with clopidogrel and prasugrel were similar in DM patients (2.6 and 2.5%, respectively; HR 1.06, P=0.81, Pinteraction=0.29) [42
]. Therefore, prasugrel produced a greater (14.6%) net clinical benefit (composite of all-cause mortality, nonfatal MI, nonfatal stroke or nonfatal TIMI major bleeding not related to CABG) than clopidogrel in DM patients (19.2%, HR 0.74; P=0.001) and this was greater than in those without DM (11.5 and 12.3%, respectively; HR 0.92; P=0.16, Pinteraction=0.05), as stated in the ESC Guidelines regarding diabetic ACS PCI patients [10
Prasugrel was approved by the FDA (US) in July 2009 and by the EMEA (Europe) in February 2009. In the field of NSTE-ACS patients, pretreatment with aspirin and a P2Y12 antagonist is a class I recommendation and common practice. However, no trial has ever randomized patients presenting with NSTE-ACS, invasively managed, to pre-treatment with clopidogrel, prasugrel or ticagrelor versus no pre-treatment. Therefore the debate about the usefulness of preloading has remained opened until the ACCOAST trial. This study was designed to randomize 4100 patients to an early administration of prasugrel vs. an administration in the catheterization laboratory. In November 2012, Daiichi Sankyo and Eli Lilly and Company discontinued enrollment in the ACCOAST trial at 4033 patients, following a recommendation by an independent Data and Safety Monitoring Board (DSMB), which found that pre-treatment in NSTEMI patients resulted in no reduction of cardiovascular events, but was associated with an increased risk of early TIMI major (including life-threatening) bleeding, without difference in mortality. However, the power of the trial was not affected, since at the time the trial was stopped, 398 patients had had a primary efficacy end-point event, and this event driven study was due to stop when 400 patients had an end-point event. Among patients with NSTE myocardial infarction, no heterogeneity was found in diabetic patients (20% of the study population). These results, consistent among patients undergoing PCI, support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy [43
]. Whether the use of a fast acting and potent platelet inhibitor may play an upstream role in STEMI patients is investigated in the on-going ATLANTIC study.
For medically-treated patients with unstable angina or myocardial infarction without ST-segment elevation, the results of the TRILOGY study, including almost 40% of diabetic patients, showed that prasugrel did not significantly reduce the frequency of major cardiovascular events, as compared with clopidogrel [44
Tigagrelor is the first of a new class of antiplatelet family called cyclopentyl-trazolo-pyrimidines (CPTP) and is also the first oral, reversible selective P2Y12
receptor antagonist. Like the thienopyridines, ticagrelor binds the platelet P2Y12
receptor to inhibit ADP's prothrombotic effects. However, unlike the thienopyridines this effect is non-competitive and reversible. Ticagrelor appears to act through an allosteric modulation site and exhibits a conformational change in the receptor by binding independently of ADP. It therefore does not prevent ADP binding but seems to have an effect on ADP-receptor induced signaling and platelet aggregation [45
]. It is a direct acting compound and does not require metabolic activation thus obviating any influence of the CYP450 pathway on the antiplatelet response. It is, however, also metabolized into an active metabolite (approximately 30-40%) by CYP3A4 [32
]. The plasma half-life of ticagrelor may be prolonged by co-administration of cytochrome P450 (CYP)3A4 inhibitors, such as diltizem, since hepatic metabolism via CYP3A is the principal mode of excretion of ticagrelor [47
]. Ticagrelor demonstrates linear pharmacokinetics, and exposure to ticagrelor active metabolite (AR-C124910XX) is approximately dose proportional up to 1260 mg, with a median Tmax of approximately 2.5 hours [31
]. It achieves greater antiplatelet effect than clopidogrel and also has a relatively short half-life and an offset of action more rapid than clopidogrel [48
]. However, this pharmacodynamic profile also could put patients at risk of acute events like stent thrombosis especially after DES implantation if they are not strictly compliant with therapy.
Ticagrelor has shown clinical benefit in head to head phase II and III studies with clopidogrel in ACS showing decreased incidence of adverse cardiac events with a higher rate of non-CABG related bleeding [34
The PLATO study is the largest randomized study to compare ticagrelor with clopidogrel. In total 18,624 patients with ACS were included and randomized to either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-600 mg loading dose, 75 mg daily thereafter). All patients took aspirin and treatment began within 24 hours of symptom onset.
The design of PLATO differs from TRITON-TIMI 38 in several ways. Firstly, the proportion of patients with NSTE-ACS was 59.5 and 59.3% in the ticagrelor and clopidogrel arms respectively compared with 74% in the TRITON trial. Secondly, in TRITON 99% of the patients were treated with PCI, while this was only 64% in PLATO. Thirdly, the PLATO protocol allowed clopidogrel treatment before randomization, while TRITON patients were naive patients (no use of any thienopyridine within 5 days before enrolment). The median duration of the follow up in PLATO was 9 months vs. 14.5 in TRITON.
At 12 month follow-up there was a lower rate of the primary composite endpoint of cardiovascular mortality, MI or stroke in patients receiving ticagrelor (9.8% vs. 11.7%; P<0.001), which translates to a NNT of 53. This ischemic benefit was balanced by an increased bleeding for major non-CABG related bleeding with the PLATO definition (4.5 vs. 3.8%, respectively; p=0.03) and with the TIMI definition (an absolute 0.6% increased bleeding risk: 2.8 vs. 2.2%; p=0.025, with a NNH of 167). No increase of overall bleeding (PLATO definition) was observed.
The analysis of the diabetic subgroup showed the following results for the primary endpoint: 14.1% with ticagrelor vs. 16.2% with clopidogrel, HR 0.88 (0.76-1.03) (in non- diabetics 8.4% vs. 10.2% (HR 0.83 (0.73-0.93)). P-value for interaction was not significant (Pinteraction=0.49) [50
]. Thus, this benefit was consistent with the overall trial results but did not reach nominal statistical significant. No diabetes status-by-treatment interaction was found.
Apart from the increased bleeding risk, ticagrelor has the propensity to elevate uric acid and creatinine concentrations, increase ventricular pauses and cause dyspnea, side-effects which represent potential barriers to optimal compliance. Ticagrelor received regulatory approval in Europe in December 2010 and in the US in July 2011.
Cangrelor (AR-C69931MX) belongs to a family of ATP analogs that are relatively resistant to the breakdown of endonucleotidases. It does not require metabolic activation and acts as a reversible, competitive antagonist on the P2Y12
receptor. Administered parentally rather than orally, it has a short half-life of <5 minutes with a rapid onset of effect, inhibiting platelets to a high degree, and a quick offset of effect with resolution of normal platelet function within an hour of cessation of treatment [51
]. While the pivotal trials to date have shown a satisfactory rate of major bleeding side effects, the highly potent cangrelor has not impacted significantly the occurrence of adverse cardiac events. The phase III CHAMPION-PCI and CHAMPION-PLATFORM trials compared cangrelor with clopidogrel 600 mg in ACS patients scheduled for PCI and were discontinued prematurely due to insufficient evidence of the clinical effectiveness of cangrelor, including that in diabetic patients [53
]. The lack of overall demonstrable clinical benefit of cangrelor may be related to the definition of myocardial infarction used that made it difficult to adjudicate early ischemic events. This hypothesis is supported by a pooled analysis of the two trials using the universal definition of MI that showed cangrelor to be associated with a significant reduction in early ischemic events when compared with clopidogrel in patients with non-ST elevation ACS undergoing PCI [54
The definition of MI was carefully chosen in a subsequent trial to assess cangrelor, the CHAMPION PHOENIX study [56
]. This was a randomized double-blind, double-dummy trial that compared cangrelor with clopidogrel standard of care in 11,145 patients who had not previously received a P2Y12
antagonist and who required PCI, including patients with stable angina and with acute coronary syndromes (with or without ST-segment elevation), the diabetic patients representing 28% of the study population. The primary efficacy end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization) was lower in the cangrelor group versus the clopidogrel group (4.7% versus 5.9%; OR 0.78, p=0.005), driven by the reduction of the rate of acute periprocedural MI and by a reduced rate of stent thrombosis (0.8% versus 1.4% p=0.01). The benefit from cangrelor was consistent across several prespecified subgroups, with no significant interaction, including the diabetic subgroup (pinteraction=0.26). The rate of the primary safety end point was 0.16% versus 0.11% in the cangrelor and clopidogrel groups, respectively (p=0.44). Future studies are needed, however, to determine the optimal way to transition patients from cangrelor to prasugrel or ticagrelor, in patients with ACS and PCI, who represented only 43% of patients recruited in the CHAMPION-PHOENIX.
Due to its rapid on/off effect cangrelor has also the potential as a bridging agent in patients requiring surgery by adequately preventing ischemic events while allowing rapid restoration of platelet function on therapy discontinuation in the event of bleeding. The BRIDGE study evaluated this strategy for patients taking thienopyridine antiplatelet agents such as clopidogrel who are scheduled for surgery. Study drug was discontinued one to six hours before CABG surgery. Patients randomized to cangrelor had lower levels of platelet reactivity throughout the treatment period compared with placebo. There was no significant difference in major bleeding prior to CABG surgery. With the use of a surrogate endpoint, platelet reactivity as the primary endpoint, the findings of this trial must be interpreted with caution. However, it does demonstrate the potential role of cangrelor in this not uncommon setting.
Numerous trials have shown clinical benefits for the GPIIb/IIIa antagonists (abciximab, eptifibatide and agrastat). These agents significantly reduce mortality after PCI, including that in diabetic patients. Thus, there is support for the use of GPIIb/IIIa receptor antagonists in high risk ACS patients [10
]. These potent intravenous antiplatelet agents can restore a TIMI III flow in emergency cases of no-reflow procedure during PCI. For NSTEMI PCI patients, their use is mainly based on angiographic results (e.g. presence of thrombus and extent of disease), with a level of recommendation Ib [10
For STEMI primary PCI patients, their use is recommended both in bail-out (massive thrombus, no-reflow) and planned in-lab situations, with a level of evidence of IIbA for abciximab, IIbB for eptifibatide and IIbB for agrastat. Furthermore, upstream use might be considered in high risk patients (IIbB recommendation) [11
]. Having said that, the reduction of MACE with anti GPIIbIIIa might be linked to various factors, such as the ischemic level of risk of the included ACS population, the time of initiation of anti GPIIbIIIa, the P2Y12 inhibitors used (clopidogrel, prasugrel or ticagrelor) for the dual antiplatelet therapy with aspirin or the choice of anti-thrombotic drugs (UFH or LMWH or bivalirudin). Furthermore, the delay of action observed even with the new P2Y12 antagonists may be longer than expected especially in STEMI population, and recent studies have shown that optimal inhibition of platelet aggregation is reached between 2 to 6 hours after the LD administration and rarely before one hour [58
]. Thus, GPIIb/IIIa antagonists may be useful in the early phase of ACS. However, their place will probably be challenged by Cangrelor in IV administration, because its antiplatelet effect stops quickly after cessation of the infusion.
Clinical implications of novel agents in diabetic patients
The above mentioned trials have clearly changed experts' recommendations with ESC guidelines recommending the use of either prasugrel or ticagrelor over clopidogrel for both STE-ACS and NSTE-ACS [10
]. Prasugrel was approved by the FDA (US) in July 2009 and by the EMA (Europe) in February 2009. Ticagrelor received regulatory approval in Europe in December 2010 and in the US in July 2011.
Although there has been no trial with outcome endpoint, but exclusively pharmacodynamics studies comparing prasugrel with ticagrelor, additional analysis of the pivotal trials may help identify preferential targets for these agents [59
Is there still a place for clopidogrel in diabetic patients with ACS ?
With the advent of newer P2Y12 antagonists, the question as to the future role if any for clopidogrel in the acute and long-term treatment of ACS in diabetes must be addressed. Indeed, the newer agents are now recommended as first line for moderate to high-risk presenting patients. However, there are several clinical situations where clopidogrel may be preferable to these agents in the non-diabetic population. Firstly, for low risk, biomarker negative patients, clopidogrel remains the preferable agent. Secondly, for patients with high bleeding risk or for STEMI patients treated with lytics, or on concomitant oral anticoagulant therapy, the current guidelines advocate short duration of triple therapy and that the P2Y12 agent is clopidogrel [10
]. Thirdly, generic clopidogrel is considerably cheaper and so may temper the enthusiasm for these newer agents in real-life practice. However, in a cost analysis comparing clopidogrel with prasugrel, prasugrel remained an economically dominant strategy: if a hypothetic generic cost for clopidogrel of $1 per day is used, the incremental net cost with prasugrel is $996 per patient, yielding an incremental cost-effectiveness ratio of $9727 per life-year gained [60
]. Furthermore, putting in perspective the clinical outcome of diabetic patients, switching from prasugrel to clopidogrel will expose some patients to a higher risk of ischemic events, by reducing the level of platelet inhibition, and is probably not a wise strategy for this group [61
]. Furthermore, based on clinical and health-economic evidence from the PLATO study, the treatment with ticagrelor was associated with increased health-care costs of 362 and a QALY gain of 0.13 compared with generic clopidogrel, yielding a cost per QALY gained with ticagrelor of €2753. Thefore, treating ACS patients with ticagrelor for 12 months is associated with a cost per QALY below generally accepted thresholds for cost-effectiveness [62