A COMPASS to REACH the right patients with thrombocardiology: benefits, risks, and future of the new concept

This editorial refers to ‘External applicability of the COMPASS trial: an analysis of the reduction of atherothrombosis for continued health (REACH) registry’†, by A. Darmon et al., on page 750. Cardiology, platelets, and plasmatic coagulation have always been in an intense and productive dialogue. From the substantial portion of patients with stable coronary artery disease (CAD) with PCI or after an acute coronary syndrome (ACS) combined with atrial fibrillation (AF), we have just recently learned again what has been shown before,1 namely that triple anticoagulant therapy is too much of a good thing and will result in a high incidence of bleeding problems.2–4 The period of triple anticoagulation should be discussed in a conservative risk assessment and kept as short as possible.5 Dual platelet inhibition after ACS is bound to be reduced to single antiplatelet therapy in most patients after 1 year.5 Guidelines encourage clinicians to stop platelet inhibitors [anti-platelet agents (APAs)] in stable CAD after 1 year if patients are on oral anti-coagulants [vitamin K antagonist (VKA) or NOACs] due to AF or venous thrombo-embolism (VTE),5 again with the aim to reduce bleeding while keeping an adequate protection for ACS, embolic stroke, and VTE. So why did the COMPASS investigators decide to go the opposite way6 and chose again to combine aspirin with a very low dose NOAC (rivaroxaban)? It has long been known that aspirin as a platelet inhibitor may partially reduce the incidence of VTE as well, and this is reflected in the VTE guidelines.7 Plasmatic coagulation on the platelet membrane phospholipid surface (i.e. the tenase and prothrombokinase complex) is greatly enhanced up to 105-fold compared with kinetics in the fluid phase (Take home figure). Conversely, a reduced tissue factor activity has been observed as a pleiotropic effect in addition to the anti-platelet activity with new anti-platelet agents such as ticagrelor.8 , 9 Platelets adhere effectively to coagulation proteins and extracellular matrix including fibrinogen, fibrin, and von Willebrand factor (vWF) (Take home figure). VKAs with or without aspirin have long been known to be more effective than aspirin alone in stable CAD;10 however, with unacceptable bleeding risk. Interestingly, already 5 years ago, the effectiveness of NOACs in ACS was demonstrated in the ATLAS trial, where very low dose rivaroxaban (2 × 2.5 mg) was superior in combination with two APAS.11 The cross-talk between inflammation, platelets, coagulation, endothelial cells, and the vascular wall in the time course of atherosclerosis. Serial magnifications depict (i) the early inflammatory response, (ii) platelet rolling, adhesion, activation, aggregation, (iv) the coagulation cascade with the X-ase–tissue factor complex and the prothrombinase complex on the membrane surface, and (iv) the intrinsic pathway which, besides phospholipids, interacts in particular with polyphosphates and is activated on artificial surfaces of devices. They illustrate the basis for targeted and individualized interventions. The above-mentioned pioneers paved the way for COMPASS for patients with stable CAD/peripheral artery disease (PAD),11 again combining aspirin with a very low dose of the anti-Xa inhibitor rivaroxaban (2 × 2.5 mg) as used in ATLAS (where the combination of aspirin and clopidogrel with very low dose rivaroxaban was used in patients with recent ACS). COMPASS clearly demonstrated that this combination was superior to aspirin alone (and, interestingly, also to the higher dose of rivaroxaban of 2 × 5 mg alone) in patients with stable CAD/PAD; a significant reduction of the combined endpoint (stroke, myocardial infarction, and cardiovascular death) of 1.3% (from 5.4% to 4.1%) and of deaths (from 4.1% to 3.4% or from 313 to 378 patients) compared with aspirin alone was achieved. Remarkably, there were considerably fewer ischaemic strokes (1.4% vs. 0.7%). The benefits came at the expense of an increase in major bleeds (defined as bleedings that led to presentation to an acute care facility or hospitalization) of 3.1% vs. 1.9%, partially driven by bleeding of gastrointestinal origin (1.5% vs 0.7%), which is not surprising with two medications with a gastrointestinal bleeding signal. The ISTH-defined bleeding rate was also significantly higher. Fatal or intracranial bleedings, however, were low in number (fatal 15 vs. 10 cases, intracranial bleeds 28% vs. 24% or 0.3%), and not significantly different. Rivaroxaban at the higher dose (2 × 5 mg) was not more effective than aspirin alone but caused more severe bleeds. There is also good and solid news for angiologists from the large subgroup of 7470 PAD patients who profited significantly from the new regime.12 Further subgroup data and additional studies with this intervention are coming up in the near future. Of particular interest is also the ischaemic stroke reduction (from 1.4% to 0.7%), particularly in the light of the recent results with the higher rivaroxaban dose (15 mg vs. aspirin) in embolic cryptogenic stroke (NAVIGATE ESUS study), which was stopped early due to comparable results in the two treatment arms.13 Darmon et al. in this issue of the journal14 rightly deserve the merits of evaluating the external applicability of the COMPASS results and correctly conclude that a substantial fraction of stable CAD patients encountered in routine clinical practice as in the large REACH registry15 are likely candidates for the new regime. The authors were also right to be cautious to identify carefully important differences and caveats between the two cohorts: whereas COMPASS was a recent randomized controlled trial, REACH was an observational registry conducted >10 years ago. Cardiovascular diagnostics, therapy, and the different endpoints have fortunately been subject to significant change, and mortality has been reduced substantially over time.16 , 17 Baseline characteristics differed importantly in terms of age, in a higher proportions of patients with stroke/transient ischaemic attack (15.8% vs. 6.1%), in the proportion of women, in kidney function, hypertension, hypercholesterolaemia, obviously dual antiplatelet therapy, smoking, unstable angina, myocardial infarction, heart failure, etc., LDL levels were not recorded in COMPASS, but overall a higher risk can be anticipated in REACH. The consequences of these differences will probably result in a higher rate of events avoided and potentially in a higher rate of bleeds observed (particularly in gastrointestinal bleeds). The authors of COMPASS anticipated this as well, and also randomized for the prophylaxis with pantoprazole. The severe bleeding will hopefully still be lower in the future with the application of the new combination due to a better risk–benefit profile of the direct oral anti-coagulants. All these questions will probably be answered soon by analyses of the mentioned subpopulation at risk. One of the authors of both articles, John Eikelboom, assumed at this year’s ESC that 300 million patients with stable CAD/PAD worldwide are prevalent and he went on to hypothesize that if just 10% of them would be eligible and treated with the new regimen, then this could result in ∼100 000 fewer deaths and several 100 000 fewer combined endpoints. We all hope he is right. Future prospective registries are likely to confirm these data, but are urgently awaited. The REACH and COMPASS data are the basis for and just the beginning of fascinating future study questions, some of which are already underway and will consolidate our knowledge; they will probably further reduce mortality, morbidity, and side effects as proposed by the net clinical benefit.6 The following questions may be derived in logical order from the study results (Take home figure) and deserve to be studied. Is aspirin (without clopidogrel) + very low dose anti-FXa also superior to a dual platelet inhibition in CAD? How about other platelet inhibitors in combination with rivaroxaban or with other low dose anti-Xa agents compared with different dual anti-platelet therapy or even vs. a monotherapy with new platelet inhibitors that have exhibited pleiotropic effects.8 Is very low dose anti-IIa as effective as anti-Xa? At which dose exactly? Could patients with a history of ACS (dual APA was an exclusion criterion in COMPASS, but some patients with an ACS history were included) or those with heart failure (exclusion criterion in COMPASS) also profit from such combinations? A strong reduction in stroke incidence was observed. Is the combination also effective in neurology in the secondary prevention of ischaemic (but not embolic) stroke (recent stroke was an exclusion criterion in COMPASS)? ‘How low can we go’ with very low dose anti-Xa in stable CAD over time? Just recently, a lower dose of anti-Xa has been shown to be effective in VTE after 6 months of treatment with rivaroxaban (1 × 10 mg) and apixaban (2 × 2.5mg).18 , 19 How about dosing intervals? Should a single, very low dose of anti-Xa be reconsidered in CAD patients? Similarly, APAs, especially those which are reversibly binding, have the potential of lower dosing in stable CAD which may reduce the bleeding risk of dual therapy. More and more patients will present with artificial surfaces, including valves, devices, patches, and prostheses, where inhibitors of the contact activation and the intrinsic coagulation system, particularly inhibitors of factor XI, have shown very promising results at low bleeding risk (Take home figure). Last, but not least, how will we handle future combination therapies that will address coagulation (choice of three low dose anti-Xa and possibly anti-IIa), platelets (choice of > 4 APAs), inflammation (see CANTOS trial20), and LDL lowering [proprotein convertase subtilisin/kexin type 9 (PCSK9)] in our polymorbid patient population? Probably with prevention first and then with the polypill or with a ‘polyinjector’. ‘Thrombocardiology’ is a fast moving field and fortunately offers us many individualized approaches. They remind us of the differential use of antibiotics (even the jargon is similar, e.g. in ‘aspirin resistance’!) and their developments in infectious disease as well as in other fields (oncology). However, these developments should let us carefully consider individual indications (CAD, ACS, AF, VTE, stroke, and PAD), critical patient characteristics (age, kidney function, co-morbidities, bleeding and thrombotic risk, peri-operative procedures, etc), timing, selection of the NOACs (according to their individual risk–benefit profile for a given patient, nicely summarized in Diener et al.3), selection of the dose and the dosing interval (e.g. in the case of rivaroxaban: 2 × 15 mg 1 × 20 mg, 1 × 15 mg, 1 × 10 mg, 2 × 2.5 mg!), the selection of the APA, their combinations, and, most importantly, to set a stop order over time to protect our patients from bleeding complications. We are getting all these questions daily in large numbers, and this calls for detailed, individualized, and smart decision-making involving patients, their treating physicians, and, in special situations, particularly experienced, specialized physicians from internal medicine, cardiology, haematology, neurology, angiology, anaesthesiology, and surgery: the thrombocardiologists. We thank Professors Jan Steffel and Thomas Lüscher, Zürich, for constructive discussions. Conflict of interest: J.H.B. has received grant support from the Swiss National Foundation of Science, the Swiss Heart Foundation, and the CARDIO foundation. He has received grant support and/or lecture fees from Daichii Sankyo, Böhringer, Bayer, BMS, Pfizer, and Astra-Zeneca. N.B. has no conflicts of interests to declare.