Unmet Needs in Antithrombotic Therapy for STEMI Management
Acute STEMI is a major cause of morbidity, mortality and disability worldwide. At present, STEMI comprises approximately 25% to 40% of MI presentations. Over the years, the approach to patients with STEMI has significantly changed in terms of antithrombotic therapy, reperfusion strategies — with the introduction of primary PCI — and development of coordination systems of care, which have resulted in impressive reductions in clinical event rates. Although in-hospital (approximately 5% to 6%) and 1-year (approximately 7% to 18%) mortality rates from STEMI have decreased significantly, there is still room for improvement in CV outcomes. Defining the optimal antithrombotic treatment regimen is indeed critical in achieving this goal.
The Standard Strategy
In patients with STEMI undergoing primary PCI, dual oral antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor should be initiated as soon as possible in order to allow time for these agents to exert their effects, and treatment should be maintained for 1 year. The use of bivalirudin (Angiomax, The Medicines Company) in patients undergoing primary PCI has been shown to be particularly advantageous given that it is associated with markedly less bleeding without any trade-off in efficacy compared with treatment with heparin plus glycoprotein IIb/IIIa inhibitors (GPIs). This better net clinical benefit profile ultimately translates into reduced mortality at long-term follow-up. However, the main concern with bivalirudin is the higher risk of acute thrombotic complications, as shown in the HORIZONS-AMI trial, in which there was a more than fourfold increase in acute (<24 hours) stent thrombosis (1.3% vs. 0.3%; P<.001). This is likely attributed to the delay for the P2Y12 receptor inhibitor clopidogrel to exert its antiplatelet effects.
Clopidogrel, in fact, requires several hours to achieve maximal antiplatelet effects, and pharmacodynamic (PD) studies have shown that patients with STEMI are more likely to have high levels of platelet reactivity. These findings can be in part attributed not only to the hyperreactive platelet phenotype that characterizes STEMI patients, but also to the lower circulating levels of clopidogrel’s active metabolite, as shown in pharmacokinetic (PK) studies that indicated impaired intestinal absorption or hepatic metabolism in this setting. Therefore, STEMI patients may not have adequate antithrombotic protection following discontinuation of bivalirudin infusion immediately after PCI, exposing patients at an increased risk for thrombotic complications.
Newer Agents: Prasugrel and Ticagrelor
The introduction into clinical practice of the newer P2Y12 receptor inhibitors — prasugrel (Effient, Daiichi Sankyo/Eli Lilly) and ticagrelor (Brilinta, AstraZeneca) — characterized by prompt and potent antiplatelet effects, has represented an important advancement in our armamentarium of pharmacological agents to overcome the limitations of clopidogrel. Indeed, these pharmacological properties and the clinical benefit of these agents in patients with ACS, including STEMI, have led to their more rapid uptake in this setting. In the TRITON-TIMI 38 trial, prasugrel reduced the primary composite endpoint (death from CV causes, nonfatal MI or non-fatal stroke) compared with standard-dose clopidogrel over 6 to 15 months. Importantly, the benefit of prasugrel was consistent in the subgroup of patients who underwent PCI for STEMI (10% vs. 12.4%; HR=0.79; 95% CI, 0.65-0.97; P for interaction=.77). In the PLATO trial, ticagrelor significantly reduced the rate of the composite of death from vascular causes, MI or stroke at 12 months compared with clopidogrel. Again, the reduction in the primary endpoint achieved with ticagrelor was consistent in patients with STEMI (9.4% vs. 10.8%; HR=0.87; 95% CI, 0.75-1.01; P for interaction=.41).
To date, most studies assessing the PK and PD effects of prasugrel and ticagrelor have been conducted in low-risk settings. However, recently, these agents have been studied in patients with STEMI undergoing primary PCI. In particular, studies have consistently shown both agents to have a delayed onset of action, requiring at least 2 hours to exert their full antiplatelet effects and thus exposing these high-risk patients to an increased risk for early thrombotic complications (Figure 1, see page 16). Increasing the loading dose regimen of these oral agents has been advocated, although this has so far not yielded greater antiplatelet effects. Inability to achieve adequate platelet inhibition with oral P2Y12 receptor inhibitors is also a concern in other clinical settings commonly associated with STEMI, such as patients unable to swallow (patients sedated, intubated, in shock, or those with nausea or vomiting). Moreover, in STEMI patients, therapeutic hypothermia or morphine administration may also lead to impaired intestinal absorption and hepatic metabolism.
The use of prasugrel and ticagrelor has also been advocated as a strategy to reduce the incidence of early thrombotic events in patients treated with prolonged infusion of bivalirudin during primary PCI. However, the EUROMAX trial showed that, despite an improvement in outcomes compared with heparin plus optional GPIs, driven by a significant reduction of major bleeding, the use of bivalirudin continued to be associated with a sixfold increase in acute stent thrombosis. Stent thrombosis rates, however, were markedly reduced when the post-PCI bivalirudin infusion occurred at the PCI dose rather than the reduced dose.
Further, the HEAT-PPCI trial recently questioned the effectiveness of bivalirudin when compared with heparin monotherapy, with only bailout GPI use. In this phase 4, single-center, randomized, open-label trial that enrolled 1,917 STEMI patients undergoing primary PCI, the use of heparin was associated with a significant reduction of major ischemic adverse events at 28 days as compared with bivalirudin (5.7% vs. 8.7%; P=.01), with a threefold decrease in acute stent thrombosis and similar rates of major bleeding. Notably, radial access was used in about 80% of cases and roughly 90% of patients received prasugrel and ticagrelor, in line with current recommendations. However, trial limitations should also be acknowledged, such as the single-center design, the short duration of bivalirudin therapy without post-PCI infusion, and the lack of heparin bolus in the bivalirudin arm. Overall, these findings underscore the need for an IV agent with prompt and potent antiplatelet properties.
Source: Parodi G. Copyright © Elsevier. 2013.
GPIs: Intravenous and Intracoronary Delivery
Currently, GPIs are the only antiplatelet agents clinically available for IV use and indeed have shown to be useful in patients requiring immediate and potent platelet inhibition. Recently, the FABOLUS PRO trial evaluated the degree and rapidity of platelet inhibition in STEMI patients undergoing primary PCI comparing prasugrel 60 mg alone (administered immediately before PCI) with the administration of tiroﬁban (Aggrastat) bolus with or without a 2-hour post-bolus infusion of tiroﬁban with concomitant or post-infusion administration of either 60 mg prasugrel or 600 mg clopidogrel. The study showed that prasugrel alone had a suboptimal platelet inhibition for at least 2 hours; instead, prasugrel given in association with a bolus only of tirofiban obviated the need of post-bolus infusion and almost completely abolished residual variability of platelet inhibition after treatment. However, the use of GPIs, particularly with prolonged infusions, has markedly reduced over the past years given its high risk for bleeding complications and the introduction of alternative antithrombotic treatment regimens, such as bivalirudin, which have been shown to have a more favorable safety profile, without any trade off in overall efficacy.
Nevertheless, periprocedural thrombotic complications still remain a concern, highlighting the need for effective platelet inhibiting strategies. This has also led to the consideration of an intracoronary bolus only strategy. Intracoronary bolus administration of eptifibatide during PCI has been associated with early and potent platelet inhibition in patients with ACS, with a PD effect comparable to IV bolus administration. In the INFUSE-AMI trial, patients (n=452) with anterior STEMI undergoing primary PCI were administered anticoagulation with bivalirudin and were randomly assigned 2:2 to intracoronary bolus of abciximab at the infarct lesion site vs. no abciximab and to manual aspiration thrombectomy vs. no thrombectomy. At 30 days, infarct size assessed by cardiac MRI was reduced in the abciximab group, although efficacy and safety outcomes were similar with the two strategies.
Direct-, Fast-Acting Cangrelor
Cangrelor (The Medicines Company) is a potent IV direct-acting (no metabolism required) P2Y12 receptor inhibitor with immediate onset of action. Moreover, cangrelor has an ultra-short half-life of 3 to 6 minutes, leading to a very rapid off-set of action with return to baseline platelet function within 30 to 60 minutes. These pharmacological properties may represent an attractive treatment option in patients undergoing surgery who cannot discontinue P2Y12 inhibiting therapy. In the BRIDGE trial, a dosing regimen of cangrelor that achieved a “thienopyridine-like” PD effect was identified and administered for up to 7 days in patients awaiting CABG with the ability to stop the infusion up to 1 hour prior to surgical incision without any increase in major bleeding complications. Further, cangrelor may represent an attractive treatment option for patients in whom immediate and potent P2Y12 receptor blockade is required.
Although two phase 3 clinical trials — CHAMPION PCI and CHAMPION PLATFORM — were interrupted prematurely for futility and the primary efficacy endpoint was not met, likely attributed to the definition of the study endpoints, the primary efficacy endpoint was met in the CHAMPION PHOENIX trial. In this trial, conducted in 11,145 clopidogrel-naive patients undergoing PCI, cangrelor significantly reduced the rate of ischemic events at 48 hours (4.7% vs. 5.9%; P=.005), including stent thrombosis (0.8% vs. 1.4%; P=.01), with no significant increase in severe GUSTO bleeding (0.16% vs. 0.11%; P=.44). The benefit achieved with cangrelor, in addition to standard-of-care therapy, was irrespective of clinical presentation (stable angina, unstable angina/non-STEMI and STEMI) and was persistent at 30 days.
In patients with STEMI, cangrelor achieved a 25% reduction in the primary endpoint, with a treatment effect consistent with the overall population (2.8% vs. 3.7%; HR=0.75; 95% CI, 0.46-1.25; P for interaction=.98). This trial confirmed that cangrelor is an attractive strategy in patients requiring PCI who have not been pretreated with an oral P2Y12 inhibitor. The benefit of cangrelor in patients undergoing PCI was later confirmed in a patient-level meta-analysis of approximately 25,000 patients.
However, one cannot discuss the positives of cangrelor without also acknowledging that this agent is currently not approved for clinical use. In February, an FDA advisory panel advised against approval of cangrelor, citing concerns about trial design and risk/benefit profile, which was then followed 3 months later by the FDA’s response letter. The FDA requested a series of clinical data analyses of CHAMPION PHOENIX, a review of certain processes regarding data management, and bioequivalence information on the clopidogrel clinical supplies for the CHAMPION trials. For the “bridging” indication, FDA has required a prospective, adequate and well-controlled study specifically evaluating bleeding. Hence, despite its potential, the question still remains as to if and when cangrelor will find a spot in our clinical armamentarium.
Antithrombotic therapy in patients with STEMI has been a continuing evolution over the past years, in which we have been able to define which strategy is associated with the best safety/efficacy balance. The next challenge is to extrapolate from these trials agents that may represent the optimal antithrombotic treatment regimen. To this extent, the recently announced HORIZONS AMI II trial will include nearly 10,000 patients with STEMI undergoing primary PCI in which all patients will be treated with bivalirudin, cangrelor and the novel-generation P2Y12 receptor inhibitor ticagrelor.