Since the last newsflash from ESC 2009 some interesting studies on antiplatelet and anticoagulant have been published.
The first clinical study (POPULAR) came from the Netherland and addressed the value of 6 platelet function tests (light transmission aggregometry (LTA), VerfyNow, PlateletWorks, PFA-100, IMPACT-R, and INNOVANCE-PFA) in the prediction of clinical events, stent thrombosis and major bleeding in 1,069 clopidogrel treated patients on aspirin undergoing stent implantation.1 Follow-up was 1 year and the primary endpoint was death, non-fatal reinfarction, definite stent thrombosis and stroke.. Surprisingly, good old LTA, but also the newer tests VerifyNow and PlateletWorks predicted clinical events, where the others failed. LTA predicted events occurring after 6 months, whereas the other 2 predicted early events as well. Yet, the positive and negative predictive value of the 3 tests largely depend on the cut-off values calculated from the ROC curves and are still rather low. Major bleeding could not be predicted by either test.
POPULAR is the first large prospective study on the clinically predictive value of platelet function tests after stent implantation. The head-to-head comparison identified at least 2 easy bed-side tests that carry a promise for future tailoring of antiplatelet therapy in patients undergoing stent implantation. Whether tailoring will work or not, depends on the results of the large running trials GRAVITAS, ARCTIC and others. Another study drawing large attention was the ONSET/OFFSET trial comparing ticagrelor, clopidogrel and placebo in 123 stable coronary patients.2 Platelet aggregation by ADP was measured at baseline, after loading (180 mg for ticagrelor and 600 mg for clopidogrel), during maintenance and after stopping either treatment. As expected, ticagrelor reached its maintenance level of platelet inhibition within 1 hour, whereas clopidogrel did so only at 8 hours, and that only at about half compared to that of ticagrelor. After stopping treatment platelet reactivity on ticagrelor equaled that of clopidogrel 24 hours after last drug intake. At 72 to 120 hours after stopping treatment platelet reactivity was significantly greater on ticagrelor than on clopidogrel. Thereafter, no differences were seen anymore. This important mechanistic study highlights the fast onset-fast offset mode of antiplatelet action of ticagrelor, which may have been responsible for the favorable safety results in PLATO. Furthermore, it suggests that 3 days after ticagrelor discontinuation platelet reactivity has recovered more than after clopidogrel discontinuation, enough for hemostasis after bleeding, or for major surgery to be performed safely. Interruption of antiplatelet therapy for bleeding or surgery is a daily hassle for many cardiologists. Some registries have shown deleterious results from stopping aspirin, but randomized trials were lacking until recently. A small, but well performed study was carried out in Hong-Kong in 156 elderly vascular patients with gastric bleeding on aspirin.3 They were all treated subsequently with a proton pump inhibitor and randomized to 80 mg aspirin daily or placebo. After 4 weeks bleeding was shown to continue more on aspirin (10%) than on placebo (5%, p = 0.25), but death occurred in 1 patient on aspirin continuation and in 10 patients on placebo (p = 0.005).
This study confirms the risk of stopping aspirin for gastric bleeding in vascular patients. Aspirin plus a proton pump inhibitor will not stop bleeding adequately, but is al least better than clopidogrel alone without a proton pump blocker.4 Furthermore, stopping aspirin seems to increase early mortality in high-risk patients. This small, but elegant study also suggests that aspirin in vascular disease should not only be continued in elective surgery, but also after gastric bleeding. Proton pump inhibitors (PPIs) are common drugs in patients with coronary disease. Clopidogrel metabolism is influenced by PPIs. The COGENT trial was presented late September 2009, in which 3,627 patients who had undergone stent implantation were randomized to a new combination compound (clopidogrel plus omeprazole) or to clopidogrel alone.5 Primary endpoints were gastrointestinal and cardiovascular events. The study was terminated because of bankruptcy of the sponsor at a median follow-up of 4.4 months. As expected GI events were reduced by 45% by PPIs, but death, MI, stroke and revascularisation were low and similar: about 8% in either group
This is the only randomized study of a PPI versus placebo in clopidogrel treated patients and makes a clinically relevant interaction between the agents unlikely. Yet, the trial was prematurely halted, the follow-up was short and the events were low. On the other hand, the outcome corroborates with observational data from the huge TRITON and PLATO studies An interaction between vitamin K antagonists and clopidogrel has not been described until recently. In the German Heart Center Munich 124 patients on warfarin were tested against 1,099 patients without warfarin.6 All patients were on dual antiplatelet therapy and the ADP induced platelet aggregation was significantly less inhibited in patients on warfarin compared to the controls, even after correction for patients’ characteristics.
The mechanism involved is probably the same hepatic CYP pathways, by which both clopidogrel and vitamin K antagonists are metabolized. Whether this interaction has clinical significance, remains to be established. From the well-known PLATO trial the CABG substudy was presented at ACC 2010.7 About 10% of the PLATO population underwent CABG during the trial, of whom 1,261 underwent surgery 7 days or less after study medication was stopped. About 64% of patients restarted study therapy after surgery. Clinical outcome like stroke, bleeding and MI were similar, but total mortality as well as cardiovascular mortality were strikingly reduced in the patients randomized to ticagrelor compared to those randomized to clopidogrel.
The mechanism of reduced mortality is unclear, like in the main trial. Bleeding is unlikely cause, since this was similar. Possibly, long-term clopidogrel may be harmful and ticagrelor not. This may be also the reason for the increased mortality seen in the primary prevention arm of CHARISMA, and in the trial described below. A long awaited first randomized study on optimal clopidogrel duration after stent implantation was presented at ACC 2010 and published simultaneously.8 In South-Korea 2,701 patient on clopidogrel and aspirin with drug-eluting stents were randomized 12 months after implantation to continuation of double antiplatelet therapy, or stopping clopidogrel and continuing aspirin alone in the REAL-LATE/ZEST-LATE trials. At the end of follow-up of 19 months after randomization there was not even a hint of benefit of continuing double therapy compared to aspirin alone. On the contrary, there was significant increase of death, MI and stroke on double antiplatelet therapy (p < 0.05). Stent thrombosis was infrequent and not different, as was TIMI major bleeding.
Continuation of dual antiplatelet therapy beyond 1 year after DES implantation does not seem to be useful. Further results from the much larger ISAR-SAFE and DAPT trial have to be awaited.
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