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Understanding the pathology of acute coronary syndromes has led to significant improvements in patient outcome. Platelet adhesion to the arterial wall, especially under high shear forces, such as are present in stenotic arteries, is facilitated through multiple high-affinity interactions between platelet membrane receptors and ligands within the exposed subendothelium, most notably collagen and von Willebrand factor. Platelet activation, initiated by the collagen exposed by plaque disruption and locally-generated soluble platelet agonists (primarily thrombin, ADP, and thromboxane A2), results in release of growth factors and adhesion molecules and most importantly the activation of the coagulation pathway. Activation of adjacent platelets occurs, with conformational changes in the platelet GP IIb IIIa receptor. Platelet aggregation, mediated primarily by interaction between the activated platelet GP IIb IIIa receptor and its ligands, fibrinogen and vWF, results in the formation of the platelet-rich thrombus. It is the formation of this platelet-rich clot and its extent at sites of coronary stenosis, plaque erosion, or a recent plaque rupture that determine the clinical consequences in acute coronary syndromes by altering vessel patency.
Antiplatelet therapy has therefore become central to the management of non-ST elevation MI, although the complex nature of the clot and the presence of multiple constituents suggest potential additional benefit from direct antithrombins such as bivalirudin1 and low molecular weight heparin,2 but interestingly, and despite the presence of “red thrombus”, not from thrombolytic therapy. The impact of any treatment on outcome will also be influenced by other factors such as the amount of myocardial territory at risk, amount of myocardium already jeopardised, the balance between presenting ischaemia versus previous infarction, heterogeneity amongst the population in terms of risk factors (diabetes, age), as well as the confounder of having three antiplatelet agents with different, specific and potentially interactive efficacies being used against a background of antithrombotic heparin/LMWH administration. Aspirin was tested against heparin3 and the combination was found to be better than either alone; clopidogrel was tested against aspirin (with the majority of patients also receiving unfractionated or low molecular weight heparin)4; the upstream low molecular synthetic GP IIb IIIa inhibitors were trialled with aspirin, but in the pre-clopidogrel era. It was this clopidogrel-free data that led to the National Institute for Clinical Excellence publishing positive guidance on GP IIb IIIa inhibitors.
The perennial questions then are: just how good is the data for upstream Glycoprotein IIb IIIa receptor inhibitors in NSTEMI; which outcome of the MACE test is benefited, if any; in which patients are they most efficacious; what is their associated risk:benefit ratio; are they additive to clopidogrel (which has now become part of standard therapy) or are they less relevant now; importantly, how are they perceived by cardiovascular physicians; are they being used “appropriately” (ie according to Guidance) and if not is this par-for-the-course for proven therapies or does it especially relate to these particular GP IIb IIIa inhibitors? These questions are pertinent when considering the article in this issue of Heart, in which the GRACE investigators have evaluated GP IIb IIIa inhibitor use in a real-world scenario and according to whether or not the population examined would have been eligible for inclusion in the clinical trials see article on page 159.5 Only by fully understanding the value or otherwise of upstream Gp IIb IIIa inhibitors, however, can we address the authors’ conclusion that “GpIIb IIIa inhibitors were markedly underused in the real-world population…” One might argue that, with rapid ACS diagnosis, routine administration of clopidogrel, aspirin, and low molecular weight heparin, rapid transfer for PCI6 and possibly peri-procedure Abciximab, there is indeed less need for upstream small molecule IIb IIIa inhibitors, and then the GRACE Investigators’ conclusion might not hold.
The data supporting the use of Gp IIb IIIa inhibitors upstream in ACS derives from trials that seem strangely dated now. The Boersma meta-analysis supporting their use7 included studies such as PRISM, PRISM-PLUS, PARAGON-A, PURSUIT, PARAGON-B and GUSTO-IV ACS. All were undertaken at the very start of the era of aggressive identification and management of NSTEMIs, and none was performed in the presence of routinely administered clopidogrel. Looking in detail at the meta-analysis shows that benefit for their use is clearly driven by “enzyme defined myocardial infarction” (or non-fatal MI) in combination with mortality but not by mortality alone. This combined end point at 30 days ranged in studies included in the meta-analysis from 5.8% in Gp IIb IIIa patients vs 7.1% in controls, to 13.4% in Gp IIb IIIa patients vs 15.7% in controls. Overall for all studies the incidence of death occurred in 3.4% of treated and 3.7% of controls (absolute difference 0.4%, NS): for non-fatal MI the difference was 7.4% versus 8.1% (absolute difference 0.7%, p = 0.063) and the combined end point of death or MI 10.8% of treated versus 11.8% controls (1% absolute (9% relative) difference, p = 0.015). As such these differences, especially in the relative absence of thienopyridine therapy in “control” patients (the trials making up the meta-analysis were published in 1998; CURE, the clopidogrel trial, was published in 2001), do not seem particularly persuasive. Even less convincing for their routine use even in a clopidogrel-free control era, was that benefit held only for those undergoing coronary intervention within the 30 days. Furthermore, those who would be likely to benefit could be further stratified, benefit being seen in those who were Troponin positive only and/or with ST segment depression on admission ECG. Presence of diabetes, but interestingly not increased age, also determined who might benefit most.
The CURE trial produced very similar results and was tested in the absence of up-stream GP IIb IIIa inhibitors – the primary end point (this time of death, non-fatal MI and stroke and at 12 months) occurred in 9.3% of clopidogrel/aspirin-treated patients compared with 11.4% in those treated with aspirin alone (20% relative difference, p<0.001). Indirect comparisons can be made if stroke (rates = 1.2/1.4% respectively for treated/controls) is taken out of the CURE combined end point and then death and non-fatal MI are compared. Outcomes appear better with clopidogrel (end point now 8.1% for clopidogrel/aspirin versus 10.0% for aspirin alone) compared with 10.8% versus 11.8% reported in the Gp IIb IIIa Boersma meta-analysis.7 However, there have been no randomised controlled trials in patients with ACS comparing upstream small molecule GpIIbIIIa administration against clopidogrel or the additive effects of both versus either alone. What about ISAR-REACT-2? This trial8 compared the additional benefit of adding the modified-IgG Abciximab to 600 mg of front-loaded clopidogrel in the setting of ACS-PCI and showed a 5% reduction in MACE with Abciximab in patients with a raised admission Troponin. This is not the same as the administration of small molecule GP IIb IIIa described in the meta-analysis7 and the focus of the GRACE article. Interestingly, the recently-published NRMi-4 registry of 38 000 patients,9 while clearly not a randomised controlled trial, demonstrated that the composite end point of death, re-AMI and major bleeding in non-PCI ACS patients was lower in the 18% of patients receiving a combination of clopidogrel and Gp IIb IIIa inhibitors than in the 65% receiving GPI alone, but higher than in the 16% receiving clopidogrel alone; that is, clopidogrel alone may be sufficient and safer in these patients. Whether clopidogrel and glycoprotein IIb IIIa inhibitors given upstream, even in those undergoing PCI, are complementary or whether clopidogrel use negates the need for intravenous antiplatelet agents remains undetermined, although the ACS subgroup of CREDO showed similar clopidogrel-induced reductions in MACE in the presence or absence of Gp IIb IIIa inhibitors in patients undergoing PCI.10 There have been only two small studies comparing dual and triple antiplatelet therapy – the ELISA trial,11 which showed a non-significant reduction in enzyme-defined infarct size and improved TIMI flow but only a trend towards event-free survival, and the CLOTIDA study, which showed no benefit of upstream tirofiban in reducing markers of myocardial necrosis compared with aspirin, heparin and clopidogrel with selective use of Abciximab.12
What, then, can we conclude? The data suggests that patients with high-risk ACS (Troponin +ve, St segment change, diabetes,13 and probably also those with haemodynamic instability, major arrhythmias, previous MI, recurrent chest pain or recurrent ischaemia) should, in the absence of clopidogrel use, receive small molecule Gp IIb IIIa upstream, but only as part of a strategy of subsequent early coronary intervention.6 Doubts remain regarding those of lower risk, those not undergoing intervention for whatever reason (generally mostly their risk) and whether in any patient (high-risk or low-risk, PCI or not) the current standard use of clopidogrel (NICE guideline TA80, July 2004) attenuates the benefits of any upstream Gp IIb IIIa administration. Cost efficacy data for combining clopidogrel and Gp IIb IIIa inhibitors is certainly needed at the very least. Despite these caveats and the issues related to the therapeutic window between efficacy and bleeding, NICE provided guidance for the use of these agents (“NICE has recommended that patients should be given a small-molecule GP IIb IIIa inhibitor as soon as it appears that they are at high risk”). The use of GP IIb IIIa inhibitors upstream has also received the endorsement of the AHA/ACC and European Guidelines. Should we then believe there is still a place for such agents in contemporary ACS management even in the absence of a trial of their adjunctive use with clopidogrel? As it is unlikely that a comparison or combined trial of these agents will be undertaken, what are we to make of their use in the real world?
Translating guidance into practice is a complex process that involves the physician’s perception of the validity of the evidence base (which may be an issue in particular with the use of Gp IIb IIIa now that clopidogrel is standard therapy), establishment of regional, hub-and-spoke policy documents, resource allocation, prioritisation within the NHS and presence or absence of any regular audit suggesting underutilisation in real time (as opposed to quarterly or more likely “never any audit of use”). Certainly, if a therapy is thought to offer patients benefit at reasonable cost to the healthcare system, then its appropriate use is mandatory and adherence to guidelines has, in a number of publications, been shown to improve outcomes.14 Equal in importance to underutilisation are the issues related to inappropriate use, which may mean two things: (1) truly inappropriate use where patients may be at excess risk from the treatment (as in the GRACE paper case which examined actual contra-indication because of bleeding risk) or (2) their use in the lower-risk patient where lesser benefit is outweighed by the risk of bleeding in those not normally at excess risk of bleeding. So, underuse in eligible patients, completely inappropriate use (safety), and the lower risk – lesser benefit/relatively higher safety risk patients who exist in the real world, all need to be considered.
The paper by the GRACE group in this edition of Heart again raises awareness of the issues related to compliance with guidelines. The GRACE investigators have developed a reputation for providing important information about how acute coronary syndromes are managed in the real world, and their ability to shine a torch into the dark recesses of everyday, supposedly evidence-based practice has improved awareness of the gulf that sometimes exists between what we think should be done in terms of patient care, what we think is being done and what is actually being done. Clearly from their data there is a good deal of unusual prescribing in the real world. It is important first to examine and understand their definitions, however. The GRACE definitions of eligibility are based on the previous trials to try and determine which patients benefit most. If the Gp IIb IIIa inhibitors are worthwhile in the high-risk population, even in the presence of clopidogrel administration, then it is truly shocking that they are prescribed in only 20% of trial-eligible patients. We should have even more trouble with the “trial-ineligible” group. These appear to be not the lower-risk patient cohort in whom there is less benefit (not going to PCI for example) but those with true contra-indications to treatment (see paper Appendix). That 15% of patients with such “ineligibility criteria” received these agents is thus again truly worrying. Perhaps, then, it is not surprising that “ineligible” patients (for which read patients normally excluded for safety reasons from trials) suffered significantly higher death and greater bleeding (the former previously having been shown in a number of studies, eg REPLACE-2, to influence the former). It is comforting that those who were eligible in the real GRACE world and who actually received Gp IIb IIIa inhibitors did as well as the previous trial patients (mortality ∼3%).
So, if a treatment has robust data to support its use, appears to be cost-effective15 and is recommended by Guideline committees, it would appear important that we now read that it is not being delivered to sufficient patients in the real world. That it is being given to patients who should not get it on trial exclusion grounds is very worrying. What we still do not know is how many patients who are less eligible (lower/moderate risk, perhaps not going for PCI) are receiving Gp IIb IIIa in the real world and what their outcome is. It would be useful to know why patients are not getting what appears to be a Guideline-recommended treatment and whether in this case it is because physicians are less convinced about its true value in the presence of standard clopidogrel administration. I suspect there may be added advantage from these agents in very high-risk subsets in contemporary management, but a trial including cost efficacy would be the only way of being sure. If, however, they are now of no additional value, then maybe in a cost-constrained healthcare system they should not be routinely given, and the GRACE data merely reflects such physicians’ genuine and appropriate understanding, since the previous trials in their minds do not support widespread contemporary use of Gp IIb IIIa inhibitors.
It is likely that such agents will be used only in the highest risk (continuing symptoms/ECG changes despite clopidogrel) and that physician perception of benefit/risk has moved with the published data. Routine use for lower risk in the era of thienopyridines cannot be supported by the evidence.
Competing interests: None declared.