Author + information
- †Houston Methodist DeBakey Heart and Vascular Center, Houston, Texas
- ‡Weill Cornell Medical College, New York, New York
- §Brigham and Women’s Hospital, Boston, Massachusetts
- ‖Harvard Medical School, Boston, Massachusetts
- ¶Massachusetts Institute of Technology, Cambridge, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Neal S. Kleiman, Houston Methodist DeBakey Heart and Vascular Center, 6565 Fannin Street, MS F-1035, Houston, Texas 77030.
It is an axiom of Major League Baseball that “all prospects are suspect.” Many newly identified players seem promising initially but do not ultimately develop into stars. However, all big-league stars were prospects at one time, and new players are needed to supplement teams and replace aging athletes.
The situation is similar when it comes to cardiovascular drugs, particularly antithrombotic agents. Some have succeeded, many have failed, and others have not been widely adopted. Although mortality related to atherosclerosis has fallen impressively, clinicians must now choose from a bewildering number of therapeutic choices for nearly every clinical situation they face. When antithrombotic drugs alone are considered in the setting of ST-segment elevation myocardial infarction (MI), 96 potential combinations of antithrombotic drugs are currently available, even before dose and duration are considered. If cangrelor and low-dose rivaroxaban receive federal approval, the number may reach 384. An episode of atrial fibrillation captured on a telemetry monitor will push this figure well beyond 800.
When a new drug is proposed, one cannot help but wonder whether it is needed, how it will be evaluated, how it will fit into the current pharmacopeia, and, most critically, how clinicians will determine that prescribing it is worthwhile. Nonetheless, new “prospects” are needed in both hospital and outpatient settings. For example, although rapid reperfusion is widely practiced and door-to-balloon time has fallen considerably, 30-day mortality for patients with ST-segment elevation MI is still nearly 10% (1). Among patients who were discharged alive after acute coronary syndromes (ACS) and enrolled in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), nearly 15% experienced MI, nearly 5% had strokes, and more than 15% had died by the end of 7 years despite aggressive lipid lowering (mean low-density lipoprotein cholesterol 53 mg/dl) (2).
Virtually all clinicians recognize the central role of thrombosis in the acute manifestations of atherosclerotic vascular disease. However, clinicians are often reluctant to adopt new antithrombotic drugs, particularly when administered on top of existing regimens. The new P2Y12 antagonists prasugrel and ticagrelor offer more potent antiaggregation than clopidogrel and are superior in preventing numerous serious cardiovascular events after ACS presentation. Prasugrel was approved in 2009, ticagrelor in 2011. Estimates of their adoption vary, but are disappointing. In the recent TOTAL (A Trial of Routine Aspiration Thrombectomy With Percutaneous Coronary Intervention [PCI] Versus PCI Alone in Patients With ST-Segment Elevation Myocardial Infarction [STEMI] Undergoing Primary PCI) trial of thrombectomy in patients with STEMI, slightly fewer than one-third of patients were discharged on either prasugrel or ticagrelor (3). The recent demonstration that ticagrelor used with aspirin was superior to aspirin alone for secondary prevention after MI raises the likelihood that more patients will be treated with aggressive dual-antiplatelet therapy (4).
Vorapaxar, a platelet protease–activated receptor (the principal thrombin receptor) antagonist, was approved in late 2014 for secondary prevention in peripheral artery disease or after MI. When added to a background of aspirin (97% of patients) and clopidogrel (71%), vorapaxar reduced the composite risk for death, MI, or stroke in this population from 9.5% to 7.9%, while moderate or severe bleeding (according to the GUSTO [Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries] criteria) was increased from 2.4% to 3.7% (5). How often vorapaxar will be used as a third antithrombotic drug remains to be seen.
Given the reluctance to compound medications, it makes sense to search for new antithrombotic targets with the intent of perhaps replacing some older ones. In this issue of the Journal, Jamasbi et al. (6) report significant progress in assessing glycoprotein (GP) VI antagonists as antithrombotic candidates. The seminal role of platelet adhesion and activation in arterial thrombosis on a disrupted endothelial surface has been reviewed previously (7). GPVI, the primary platelet receptor for collagen (8), recognizes a glycine-proline-hydroxyproline motif on collagen and facilitates platelet adhesion and activation, particularly under low-shear conditions. On quiescent platelets, GPVI exists as a monomer. After platelet activation, GPVI complexes cluster on the platelet surface, and the cytoplasmic tails of adjacent GPVI molecules become linked, causing GPVI to assume a dimeric configuration that binds collagen with greater affinity than does the monomeric form (9) (Figure 1).
GPVI is regarded as an attractive prospect for several reasons. It is expressed only on megakaryocytes and platelets, thus reducing the risk that its inhibitors will have off-target effects. Increased GPVI expression has been shown in patients with ACS (10) and with ischemic stroke (11). GPVI also shares some signaling pathways with GP Ib/IX/V. Thus, GPVI blockade should theoretically allow von Willebrand Factor–GP Ib/IX/V–mediated hemostasis to continue (12). GPVI deficiency, whether acquired or congenital, is often said to be associated with mild bleeding, although of the 11 cases amassed by Arthur et al. (13), 3 required transfusion, particularly in relation to surgery (13).
Jamasbi et al. (6) chose 2 approaches to assess GPVI blockade: blocking the collagen target for GPVI binding and blocking the active site on GPVI itself. For the former, they used a human Fc fusion protein, GPVI-Fc (Revacept, AdvanceCOR GmbH, Munich, Germany), which mimics the collagen-binding domain of GPVI. GPVI-Fc attaches to the gly-pro-hyp motif of collagen that is recognized by GPVI, masking it from recognition by the platelet. Previously, in a rabbit model of balloon injury, GPVI-Fc reduced mural thrombus formation and preserved endothelial function (14). In a study of healthy volunteers, it was well tolerated and produced dose-dependent inhibition of collagen-induced platelet aggregation that lasted 2 to 7 days, depending on the dose administered (15). It is now in an exploratory trial of carotid stenosis (NCT01645306).
Jamasbi et al. (6) compared this effect with direct blockade of GPVI on the platelet surface using antibodies directed at the monomeric and dimeric forms of GPVI. They observed that in static blood, the anti-GPVI antibodies inhibited platelet aggregation induced by human carotid artery plaque homogenate much more completely than did GPVI-Fc, even when the latter was used at high doses (35- to 50-fold) with extended periods of plaque pre-incubation (3 to 30 min).
However, under flow conditions, the differences narrowed at high shear rates. GPVI-Fc adhered incompletely to a surface consisting of plaque homogenate, leaving small areas uncovered despite high dosing. Under low shear, its effect on plaque-induced platelet deposition was modest, but at higher shear, it became considerably more effective. The investigators inferred that at low shear, the uncovered areas allowed collagen-induced platelet adhesion and activation, but under high shear, platelets were washed off the collagen surface. Conversely, the antibodies were effective at all shear rates tested. The clinical implication is that cloaking the collagen sites recognized by GPVI might offer a safety advantage compared with that of complete blockade of platelet GPVI, in that this process might permit hemostasis to occur outside of stenotic arteries.
These tantalizing observations offer the hope that thrombosis and hemostasis may at last be uncoupled. Features of dimeric GPVI-Fc such as inhibitory effect saturation without full inhibition of the GPVI-collagen axis and inhibition that is localized to sites of collagen exposure, in contrast to systemic platelet inhibition, are certainly favorable in many regards. How do we determine whether the GPVI “prospect” is ready for prime time? Obviously, more extensive characterization of GPVI blockade is needed before such compounds are fully ready to enter the pharmacologic armamentarium. The appropriate degree and duration of blockade need to be explored.
Background therapy must also be defined. Indeed, when the GPVI-Fc experiment was repeated with the fusion protein in the presence of aspirin and a P2Y12 antagonist, platelet aggregation was almost completely eliminated, even at low shear (6). Will GPVI blockade be clinically effective in the absence of either of these drugs—or hazardous if used in their presence? Omitting drugs from established therapeutic regimens is not an easy task, yet few will likely use a GPVI antagonist if it is to be given as a third or even fourth ingredient in a cocktail of antithrombotic drugs.
It is clear that at some point, new antithrombotic agents will need to be tested as substitutes for accepted drugs rather than simply additions to existing regimens. Although aspirin has long been a mainstay of pharmacotherapy for atherosclerotic disease, at least 3 studies are under way to test the safety of eliminating it from ACS or post–percutaneous coronary intervention regimens (NCT02270242, NCT01776424, and NCT02293395).
Simplification and substitution: both of these steps appear to be necessary parts of renewing our therapeutic roster.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- ↵Cannon C. IMPROVE-IT trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Presented at: Annual Scientific Sessions of the American Heart Association; November 17, 2014; Chicago, IL.
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