From Arctic to Antarctic: Is There any Remaining Role for Platelet Function Testing to Tailor Therapy after Coronary Stent Implantation?

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EditorialTicagrelor and prasugrel are newer and stronger platelet P2Y12 receptor antagonists than their predecessor clopidogrel. Clopidogrel is a pro-drug requiring a 2-step hepatic activation processes. Speed of activation varies according to the cytochrome P-450 2C19 allele [1,2]. Ticagrelor is a direct non-thienopyridine P2Y12 antagonist producing equal or stronger inhibition of the P2Y12 receptor even when compared to the newer thienopyridine prasugrel [3]. The PLATO TrialIn the PLATO trial of 18624 patients with acute coronary syndrome on background aspirin therapy, ticagrelor 90 mg twice daily significantly reduced all-cause and cardiovascular mortality as compared to clopidogrel 75 mg daily (4.5% vs. 5.9% and 4.0% vs. 5.1% respectively over 1-year) [4]. In PLATO, the Kaplan-Meier curves showing the adjudicated primary end point (a composite of death from vascular causes, myocardial infarction, or stroke) separated in the first month and kept diverging throughout the year. These positive findings held true in the very large subgroup of patients with coronary stent implanted, and ticagrelor reduced stent thrombosis more as compared to clopidogrel [5]. Ticagrelor treated patients had higher nonprocedural but not CABG-related or fatal bleeding compared to clopidogrel treated patient [4], perhaps an expected finding given that ticagrelor is a stronger but reversible P2Y12 antagonist (with faster offset of action) while clopidogrel is a weaker but non-reversible P2Y12 antagonist.In PLATO a geographical regional interaction was noted (with interaction P value of 0.05) where outcome trended in opposite direction between patients randomized in North America (n=1814) and patients randomized elsewhere. In these 1814 patients, outcome tended to be worse with ticagrelor than with clopidogrel (HR 1.25, 95% CI 0.93-1.67). Exploratory analysis revealed only one factor-aspirin dose (higher in North America than elsewhere) that might explain the observed regional interaction [6]. Currently, the advantage from ticagrelor as compared with clopidogrel is believed to be associated only with the use of low-dose (<100 mg) aspirin, and guidelines specify this point. Dual antiplatelet therapy post coronary stentingPrevious editorials in the Journal have reviewed the basis for dual antiplatelet therapy post coronary stenting [1,2]. In a very recent patient level meta-analysis of 11,473 patients with coronary stenting (58.5% with stable coronary disease) from 6 randomized trials, patients with ≤6 month dual antiplatelet therapy tended to have higher 1-year event rates of myocardial infarction or stent thrombosis than patients with 1-year dual antiplatelet therapy (HR 1.48; 95% CI, 0.98-2.22) if they were stented for unstable disease; while rates were similar if they were stented for stable disease (HR 0.93; 95% CI, interaction P value=0.09). By network meta-analysis, 3-month but not 6-month dual antiplatelet therapy was associated with higher event rates in the former patients whereas no significant differences were apparent in the...

Section: Editorialmentioning

confidence: 99%

Section: Dual Antiplatelet Therapy Post Coronary Stentingmentioning

confidence: 99%

Section: Dual Antiplatelet Therapy Post Coronary Stentingmentioning

confidence: 99%

Section: The Future Of Ticagrelor For Atherosclerotic Cardiovascular mentioning

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Trials Evaluating Ticagrelor in Cardiovascular Disease: Will It Reign Supreme in the Anti-Platelet World?

Wong¹

2017

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“…The benefit-torisk assessment for longer versus shorter duration of DAPT depends on the coronary ischemic risks, the nature of antiplatelet medications and the general bleeding risks. Previous editorials in the journal have addressed in part the former 2 issues [1][2][3] and the current editorial will focus on the last and integrate them in clinical application.The PRECISE-DAPT score: predicting out-of hospital bleeding post-coronary stenting This score was derived using patient-level data among 14963 clinical trial patients treated with DAPT post-coronary stenting (patients requiring oral anticoagulation excluded) from 8 multicentre randomised trials [4]. All relevant TIMI major or minor bleeding events were independently adjudicated.…”

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Tailoring Dual Antiplatelet Therapy after Coronary Stenting: The PRECISE-DAPT Score versus the DAPT Score

Wong¹

2017

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EditorialBoth aspirin mono-therapy and dual aspirin-P 2 Y 12 receptor antagonist therapy (DAPT) are commonly used for coronary disease. The use of DAPT post-coronary stenting is standard. The benefit-torisk assessment for longer versus shorter duration of DAPT depends on the coronary ischemic risks, the nature of antiplatelet medications and the general bleeding risks. Previous editorials in the journal have addressed in part the former 2 issues [1][2][3] and the current editorial will focus on the last and integrate them in clinical application.The PRECISE-DAPT score: predicting out-of hospital bleeding post-coronary stenting This score was derived using patient-level data among 14963 clinical trial patients treated with DAPT post-coronary stenting (patients requiring oral anticoagulation excluded) from 8 multicentre randomised trials [4]. All relevant TIMI major or minor bleeding events were independently adjudicated. Using Cox proportional hazards regression, multivariable predictors for out-of-hospital bleeding occurring ≥7 days after the initial stenting procedure were obtained on which the numerical PRECISE-DAPT bleeding risk score was developed. PRECISE-DAPT consists of 4 continuous parameters scored on a linear or near linear scale (listed from zero to maximum value in score calculation: age ranging from 50 to 90 years, creatinine clearance ranging from 100 to 0 ml/min, haemoglobin ranging from 12 to 10 g/dL, white-blood-cell count ranging from 5 to 20 × 10 3 cells per μl), and the dichotomous parameter previous spontaneous bleeding.The predictive performance of the PRECISE-DAPT score was examined in patients treated with percutaneous coronary intervention (PCI) from the PLATO trial involving 8595 patients and from the BernPCI registry involving 6172 patients. In the derivation cohort PRECISE-DAPT had a C-index of 0.73 (95% CI 0.61-0.85) predicting out-of-hospital TIMI major or minor bleeding. The corresponding Cindex was 0.70 (0.65-0.74) in the PLATO trial validation cohort and 0.66 (0.61-0.71) in the BernPCI registry validation cohort. The score also performed well in predicting TIMI major bleeding, albeit with a lower C-index in all the examined cohorts.DAPT duration was randomly allocated in 5 of the 8 studies included in the derivation cohort involving 10,081 of the 14,963 patients. A longer DAPT duration (i.e., 12-24 months versus 3-6 months) was found to significantly increase bleeding in patients with higher PRECISE-DAPT score (≥25), but not in those with lower (<25) score; (Interaction P value 0.007), an expected finding as PRECISE-DAPT score reflected bleeding risks. Of interest, the anti-ischemic benefit of a longer DAPT duration was observed only in the latter (lower bleeding risks) patients. Patients with a PRECISE-DAPT score ≥25 represented the upper quarter of the cohort.To provide an idea in PRECISE-DAPT score calculation, a history of previous spontaneous bleeding alone will give 25 points; an age of 75 and having creatinine clearance of 30 ml/min and haemoglobin level of 11.1 g/dl will ...

Can PCI Ever Replace Optimal Medical Therapy in Treating“ Stable” Epicardial Coronary Stenosis?

Wong¹

2017

EditorialIn 2007, the COURAGE trial was published showing that in the 2287 randomized patients with stable coronary disease PCI was no better than medical therapy in altering outcome over a median followup period of 4.6 years [1]. The same mortality rate observed among the 2 randomized groups held true at late median follow-up of 6.2 years amongst the 1211 patients with available survival data [2]. One major criticism of COURAGE is that PCI (including the nature of the deployed stents and adjunctive pharmacological therapy) has evolved so rapidly in the last 10 years that the COURAGE findings are no longer applicable today. Modern drug eluting stents plus appropriately potent antiplatelet regimes have ensured almost 100% procedural successes with <1% stent thrombosis and low restenosis rates. Prior editorials in the Journal have discussed some of these aspects [3][4][5][6]. It is tempting for one to think that PCI with stenting will fix any stable epicardial coronary stenosis relieving myocardial ischemia with measurable clinical benefit. However, 2 recent trials have reported somewhat unexpected results.In the ORBITA trial [7], a double-blinded, multicentre randomised trial of real PCI versus "sham PCI" for angina relief at 5 UK study sites, symptomatic patients with severe (≥ 70% diameter narrowing) singlevessel stenosis were enrolled. They first received 6 weeks of medical therapy optimisation followed by cardiopulmonary exercise testing, symptom questionnaires, and dobutamine stress echocardiography. Then, they were randomised 1:1 to undergo PCI or a placebo procedure. In both groups fractional flow reserve (FFR) and instantaneous flow reserve (iFR) were measured. These FFR and iFR measurements required introducing special coronary wires across the coronary lesion so all patients actually needed the cath lab procedures. Patients were sufficiently sedated together with "auditory isolation" that they were unaware as to whether they received real or sham PCI. Six weeks after the procedure the aforementioned non-invasive assessments were repeated. The primary endpoint was difference in exercise time increment between groups.Of 230 patients enrolled, 200 were finally randomised in the period from January 2014 to August 2017 after completing the medication optimisation phase. The coronary lesions had mean area stenosis of 84·4%, FFR of 0·69 (FFR <0.75-0.8 generally considered significant indicating myocardial ischemia in the subtended territory), and iFR of 0·76 (iFR <~0.9 generally considered significant). All PCI procedures were successful but the primary endpoint, exercise time increment between groups (PCI minus placebo), was only non-significantly higher by 16·6 seconds (P=0.20).Intervention trials with "clinical procedures" are almost always confounded because of the absence of patient blinding unless sham procedures are performed in the control group with all their implications. In the hypertension field, there had been high hopes for renal denervation until it was refuted by the sham-procedure controlled S...