Prasugrel versus adjusted high-dose clopidogrel in patients with high-on- clopidogrel platelet reactivity: the PECS-HPR randomised, multicentre study

Aims: Repeated loading doses (LD) of clopidogrel were shown to effectively overcome high-on-clopidogrel platelet reactivity (HPR); however, comparison to potent P2Y12-inhibitors is lacking. We sought to compare the antiplatelet effect of high-dose clopidogrel versus prasugrel at both short- and long-term in acute coronary syndrome patients (ACS) with HPR (NCT01493999). Methods and results: ACS patients receiving 600 mg clopidogrel pre-treatment were randomised to prasugrel or high-dose clopidogrel in a multicentre, controlled trial if platelet function testing revealed HPR (>46 U) after PCI. In the prasugrel group, patients received an immediate 60 mg LD followed by 10 mg for three days. After day 3, patients were randomised to either standard (10 mg) or reduced (5 mg) maintenance doses (MD-s) up to 30 days. Patients randomised to high dose clopidogrel received repeated LDs of 600 mg clopidogrel based on controlled platelet function testing for three days, and then were randomised to 75 mg or 150 mg MDs for 30 days. ADP-induced platelet reactivity was measured with the Multiplate assay at day 0 (randomisation), 1, 2, 3 and 25. Between May 2011 and March 2013, 147 patients were randomised. Although baseline platelet reactivity did not differ between groups (p=0.22), prasugrel provided significantly more rapid and more potent platelet inhibition compared to repeated LDs of clopidogrel through all three days after randomisation (p<0.0001). During the maintenance phase, there was a dose-dependent increase in platelet reactivity from prasugrel 10 mg to clopidogrel 75 mg (p for trend <0.0001), demonstrating the superiority of both doses of prasugrel over 75 and 150 mg clopidogrel. No difference was observed between clopidogrel groups at day 25 (p=0.35), leading to a rebound in HPR and returning to the level of baseline platelet reactivity with both 75 and 150 mg clopidogrel (p=0.66 vs. day 0). Conclusions: Prasugrel provides significantly more rapid and more potent platelet reactivity inhibition compared to repeated loading doses of clopidogrel. The observed differences persisted with maintenance dosing, leading to rebound in HPR with both standard and high-dose clopidogrel

Therapeutic window for P2Y12-Receptor inhibition: a collaborative analysis of the relation between platelet reactivity, stent thrombosis and bleeding

background: Although residual platelet reactivity during treatment with P2Y12-inhibitors is associated with stent thrombosis (ST) and bleeding, clinically validated, standardized cut-offs for platelet function testing are lacking. We sought to determine the prognostic impact of low (LPR), optimal (OPR), or high platelet reactivity (HPR) by applying standardized cut-off criteria in patients undergoing PCI treated with clopidogrel or prasugrel. methods: Authors of studies published before January 2014, reporting the association between platelet reactivity, ST and major bleeding were contacted for a collaborative analysis using a priori defined, uniform cut-off values for standardized platelet function assays. Based on the best available evidence (exploratory studies), LPR-OPR-HPR categories were defined as 208 PRU for VerifyNow, 46U for the Multiplate analyzer and 50% for VASP assay. Results: Fifteen studies including 18,169 patients were used for the analysis. Patients with HPR had a 2.6-fold higher risk of ST (p<0.00001) but a similar risk for bleeding (p=0.053) compared to those with OPR. In contrast, patients with LPR had a 1.8-fold higher risk for bleeding (p<0.0001), but identical risk for ST (p=0.81) as those with OPR. Mortality was 1.6-fold higher in patients with HPR compared to others (p<0.001). Validation cohorts confirmed the clinical relevance of cut-off values suggested by exploratory studies. conclusion: During thienopyridine treatment, mortality and ST is significantly higher in HPR, while LPR is a predictor of bleeding. Potential benefits of targeting OPR as a therapeutic window for P2Y12-inhibition need to be confirmed in randomized trials

Bleeding and stent thrombosis on P2Y12-inhibitors: collaborative analysis on the role of platelet reactivity for risk stratification after percutaneous coronary intervention

Although platelet reactivity during P2Y12-inhibitors is associated with stent thrombosis (ST) and bleeding, standardized and clinically validated thresholds for accurate risk stratification after percutaneous coronary intervention (PCI) are lacking. We sought to determine the prognostic value of low platelet reactivity (LPR), optimal platelet reactivity (OPR), or high platelet reactivity (HPR) by applying uniform cut-off values for standardized devices. ..................................................................................................................................................................................... Methods and results Authors of studies published before January 2015, reporting associations between platelet reactivity, ST, and major bleed- ing were contacted for a collaborative analysis using consensus-defined, uniform cut-offs for standardized platelet func- tion assays. Based on best available evidence for each device (exploratory studies), LPR–OPR–HPR categories were defined as ,95, 95–208, and .208 PRU for VerifyNow, ,19, 19–46, and .46 U for the Multiplate analyser and ,16, 16–50, and .50% for VASP assay. Seventeen studies including 20 839 patients were used for the analysis; 97% were treated with clopidogrel and 3% with prasugrel. Patients with HPR had significantly higher risk for ST [risk ratio (RR) and 95% CI: 2.73 (2.03 – 3.69), P , 0.00001], yet a slight reduction in bleeding [RR: 0.84 (0.71 – 0.99), P 1⁄4 0.04] com- pared with those with OPR. In contrast, patients with LPR had a higher risk for bleeding [RR: 1.74 (1.47–2.06), P , 0.00001], without any further benefit in ST [RR: 1.06 (0.68 – 1.65), P 1⁄4 0.78] in contrast to OPR. Mortality was sig- nificantly higher in patients with HPR compared with other categories (P , 0.05). Validation cohorts (n 1⁄4 14) confirmed all results of exploratory studies (n 1⁄4 3). Platelet reactivity assessment during thienopyridine-type P2Y12-inhibitors identifies PCI-treated patients at higher risk for mortality and ST (HPR) or at an elevated risk for bleeding (LPR)

PrasugRel versus adjusted high-dose clopidogrel in patients with high on- clopidogrel platelet reactivity: the PECS-HPR randomized, multicenter study

background: Repeated loading doses (LD) of clopidogrel were shown to effectively overcome high on-clopidogrel platelet reactivity (HPR); however, comparison to potent P2Y12-inhibitors is lacking. We sought to compare the antiplatelet effect of high-dose clopidogrel versus prasugrel at both short- and long-term in acute coronary syndrome patients (ACS) with HPR. methods: ACS patients receiving 600 mg clopidogrel pretreatment were randomized to prasugrel or high-dose clopidogrel in a multicenter, controlled trial if platelet function testing revealed HPR (>46U) after PCI. In the prasugrel group, patients received an immediate 60-mg LD followed by 10 mg for three days. After day 3, patients were randomized to either standard (10 mg) or reduced (5 mg) maintenance doses up to 30 days. Patients randomized to high-dose clopidogrel received repeated loading doses of 600 mg clopidogrel based on controlled platelet function testing for three days, then were randomized to 75 mg or 150 mg maintenance doses for 30 days. ADP-induced platelet reactivity was measured with the Multiplate assay at day 0 (randomization), 1, 2, 3 and 25. Results: Between May 2011 and March 2013, 147 patients were randomized. Although baseline platelet reactivity did not differ between groups (p=0.22), prasugrel provided significantly more rapid and more potent platelet inhibition compared to repeated LD-s of clopidogrel through all three days after randomization (p<0.0001). During the maintenance phase, there was a dose-dependent increase in platelet reactivity from prasugrel 10 mg to clopidogrel 75 mg (p for trend <0.0001), demonstrating the superiority of both doses of prasugrel over 75 and 150 mg clopidogrel. No difference was observed between clopidogrel groups at day 25 (p=0.35), leading to a rebound in HPR and returning to the level of baseline platelet reactivity with both 75 and 150 mg clopidogrel (p=0.66 vs. day 0). conclusion: Prasugrel provides significantly more rapid and more potent platelet reactivity inhibition compared to repeated loading doses of clopidogrel. The observed differences persisted with maintenance dosing, leading to rebound in HPR with both standard and high-dose clopidogrel

Apixaban and risk of myocardial infarction: meta-analysis of randomized controlled trials

The coagulation system contributes greatly to the evolution of myocardial infarction (MI). Anticoagulation may reduce the occurrence of MI as monotherapy or with con- comitant use of aspirin. Activated factor X antagonists (anti- Xa) and direct thrombin inhibitors have promising results in various indications in non-inferiority trials. However, results regarding their cardiovascular safety are heterogeneous. We systematically evaluated the risk of MI and mortality in patients receiving the new-generation oral anti-Xa agent apixaban. Electronic databases were searched to find pro- spective, randomized, controlled clinical trials (RCT) that evaluated the clinical impact of apixaban. Efficacy measures included frequency of MI, cardiovascular and overall mor- tality. Outcome parameters of RCTs were pooled with a ran- dom-effects model. Between January 2000 and December 2013, 12 RCTs comprising 54,054 patients were identified. Based on the pooled results, there was no increase in the risk of MI in patients treated with apixaban [odds ratio (OR) 0.90;95 % confidence interval (CI) 0.77–1.05; p = 0.17] com- pared to different controls. Cardiovascular and overall mor- tality with apixaban was comparable to the control groups (OR 0.88; 95 % CI 0.72–1.06; p = 0.18, OR 0.89; 95 % CI 0.77–1.03; p = 0.11, respectively). The pooled risk of major bleeding was lower in the apixaban treated groups (OR 0.84; 95 % CI 0.62–1.12; p = 0.23) however this reached signifi- cant level only in subgroup analysis of trials with anticoagu- lant regimes in the control (OR 0.66; 95 % CI 0.51–0.87; p = 0.003). In a broad spectrum of patients and compared to different controls apixaban treatment was not associated with an increase in MI or mortality

Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data.

Prior studies have shown an association between high on-clopidogrel platelet reactivity (PR) and the risk of major adverse cardiovascular events (MACE). However, large intervention trials on PR-tailored treatments have been neutral. The role and usefulness of PR with regard to levels of cardiovascular risk are unclear. We undertook a systematic review and meta-analysis of individual patient data on MACE outcomes (acute coronary syndromes (ACS), ischaemic strokes, and vascular deaths) in relation to PR and its interaction with cardiovascular risk levels. PR was determined using ADP-induced light transmission aggregometry with a primary concentration of 20 µM ADP. Thirteen prospective studies totaled 6,478 clopidogrel-treated patients who experienced 421 MACE (6.5 %) during a median follow-up of 12 months. The strength of the association between the risk of MACE and PR increased significantly (p=0.04) with the number of risk factors present (age> 75 years, ACS at inclusion, diabetes, and hypertension). No association was detected in patients with no risk factor (p=0.48). In patients presenting one risk factor, only high-PR was associated with an increased risk of MACE (HR 3.2, p=0.001). In patients presenting ≥ 2 risk factors, the increase of risk started from medium-PR (medium-PR: HR=2.9, p=0.0004; high-PR: HR=3.7, p=0.0003). PR allowed the reclassification of 44 % of the total population to a different risk level for the outcome of MACE, mostly in intermediate or high risk patients. In conclusion, the magnitude of the association between PR and MACE risk is strongly dependent on the level of cardiovascular risk faced by patients on clopidogrel