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

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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 ...

Section: Precise-dapt Versus Daptmentioning

confidence: 70%

Section: Editorialmentioning

confidence: 99%

Section: Precise-dapt Versus Daptmentioning

confidence: 99%

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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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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...

Closing Patent Foramen Ovale (PFO) for Cryptogenic Stroke - Deeper Thoughts

Wong¹

2018

EditorialIn the fetal heart, the foramen ovale (open channel between the septum primum and the septum secundum) allows oxygenated blood returning from the umbilical vein to pass into the left heart and be pumped into the systemic circulation. The Eustachian valve between the inferior vena cava and the right atrium directs blood flow through the foramen ovale into the left atrium.The foramen ovale remains patent in up to a quarter of adults thus traditionally considered a normal variation. However, patent foramen ovale (PFO) is found to be more prevalent among patients having cryptogenic stroke in whom the mechanism for the ischemic stroke is not found despite an extensive evaluation of head and neck vessels and the heart. Paradoxical embolism across the PFO likely explains the stroke. The PFO Closure Trials for Cryptogenic StrokeTo support this theory of paradoxical embolism closing PFO should reduce recurrence of ischemic stroke. The development of closure devices delivered through a trans-catheter route (without open-heart surgery) allows PFO closure to be performed safely with low morbidities. However, three randomized trials reported early in this decade (CLOSURE I [1], PC trial [2], and RESPECT [3]) individually failed to show a clear benefit of trans-catheter PFO device closure for secondary stroke prevention. In retrospect, this is partly due to the individually small-size cohorts and partly the short follow-up durations. More recently, a meta-analysis of patient-level data from CLOSURE I, PC, and RESPECT (with longer follow-up duration) found that PFO closure prevented recurrent ischemic stroke (adjusted hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.34-0.99) [4]. Further, the Amplatzer PFO occluder device out-performed its counterparts, and received Food and Drug Administration (FDA) approval for patients aged 18-60 years with PFO and cryptogenic stroke.Last year, two randomized controlled PFO closure trials (CLOSE [5] and REDUCE [6]) with stricter enrolment criteria were published. CLOSE included patients aged 16-60 years with a cryptogenic stroke supported by imaging findings within the prior 6 months and a PFO with large inter-atrial shunt or atrial septal aneurysm. CLOSE also used stringent criteria to exclude patients with vascular disease which may be potentially causal (intra-cerebral small vessel disease or ≥ 30% stenosis of an artery supplying the brain). Over 5.3 years of mean follow-up, the closure group had a lower risk of recurrent stroke than the non-closure group (0% vs. 6%; HR, 0.03; 95% CI, 0-0.26) [5].REDUCE included patients aged 18-59 years with cryptogenic stroke (symptoms ≥ 24 hours or positive imaging) in the prior 6 months and a PFO; but without any stenosis of ≥ 50% of a major vessel supplying the brain, lacunar lesions on imaging, or uncontrolled stroke risk factors. After a median follow-up of 3.2 years, there was a lower risk of recurrent stroke in patients with than in patients without PFO closure (1.4% vs. 5.4%; HR, 0.23; 95% CI, 0.09-0.62) [6].